Slide 1

Pathophysiology of DM
Topics:
•Aetiology
•Pathophys of hyperglycaemia complications


I talk more on the pathophys of hyperglycaemic complications than the pathogenesis of DM
itself (because it’s boring and not much is known, read Kumar if you really want to know)



Slide 2

Causes/Types of DM
Type 1 (IDDM):
•5-10% of diabetics
•Characterised by pancreatic β-cell destruction and absolute deficiency of insulin
•Caused by combo of genetic, immunological and environmental stimuli causing
auto-immune destruction of β-cells
•Auto-antigens responsible aren’t necessarily always β-cell specific?
Type 2 (NIDDM):
•90-95% of diabetics
•Combination of peripheral resistance to insulin and inadequate insulin secretion
•Caused by insulin resistance which is initially compensated by increased insulin
secretion, but eventually becomes uncompensated
•Has a stronger genetic component, but is polygenic/multifactorial
Gestational
Others


Type 1 DM is an autoimmune disease characterized by pancreatic β-cell destruction and an
absolute deficiency of insulin. It accounts for approximately 5% to 10% of all cases, and is the
most common subtype diagnosed in patients younger than 20 years of age. Polymorphisms in
the HLA complex account for 40–50% of the genetic risk of developing type 1 DM and primarily
involve the DR3/4 and some of the DQ phenotypes.

Type 2 DM is caused by a combination of peripheral resistance to insulin action and an
inadequate secretory response by the pancreatic β cells (“relative insulin deficiency”).
Approximately 90% to 95% of diabetic patients have type 2 diabetes, and the vast majority of
such individuals are overweight/obese. Although classically considered “adult-onset,” the
prevalence of type 2 diabetes in children and adolescents is increasing at an alarming pace.

A more in-depth pathophys analysis of NIDDM aetiology: Type 2 DM is characterized by
impaired insulin secretion, insulin resistance, excessive hepatic glucose production, and
abnormal fat metabolism. Obesity, particularly visceral or central (as evidenced by the hip-waist
ratio), is very common in type 2 DM (80% or more are obese). In the early stages of the
disorder, glucose tolerance remains near-normal, despite insulin resistance, because the
pancreatic beta cells compensate by increasing insulin output. As insulin resistance and
compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable
to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose,
then develops. A further decline in insulin secretion and an increase in hepatic glucose
production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure
ensues.




Slide 3

Causes/Types of DM
American Diabetes Association:
Position statement from the American
Diabetes Association on the diagnosis
and classification of diabetes mellitus.


A variety of monogenic and secondary causes are responsible for the non-Type I/II cases. It
should be stressed that while the major types of diabetes have different pathogenic
mechanisms, the long-term complications affecting the kidneys, eyes, nerves, and blood vessels
are the same, as are the principal causes of morbidity and death. The pathogenesis of the two
major types is discussed separately, but first we briefly review normal insulin secretion and the
mechanism of insulin signaling, since these aspects are critical to understanding the
pathogenesis of diabetes.

Note MODY – mentioned in lecture



Slide 4

Pathophys of Hyperglycaemia
Complications
Chronic:
•Advanced Glycation End-Products
•Activation of PKC
•Polyol Pathway Disturbance
•Hexosamine Pathway
Acute:
•Diabetic Ketoacidosis
•Hyperglycaemic Hyperosmolar State
Crash Course!


The morbidity associated with long-standing diabetes of either type results from several serious
complications, caused mainly by lesions involving both large- and medium-sized muscular
arteries (macrovascular disease) and capillary dysfunction in target organs (microvascular
disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting
in increased risk of myocardial infarction, stroke, and lower extremity gangrene. The effects of
microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting
in diabetic retinopathy, nephropathy, and neuropathy, respectively.

At least three distinct metabolic pathways have been implicated in the deleterious effects of
persistent hyperglycemia on peripheral tissues, although the primacy of any one over the others
is unclear. The pathways are discussed below.



Slide 5

Diabetic Ketoacidosis (DKA)


Someone else



Slide 6

Hyperglycaemic Hyperosmolar State
Typical HHS:
•elderly individual with type 2 DM
•Several-week history of polyuria, weight loss, and diminished oral
intake
•Culminates in mental confusion, lethargy, or coma.
•Ex: profound dehydration and hyperosmolality and reveals
hypotension, tachycardia, and altered mental status.
High BGL Glycosuria
High Blood
Osmolarity
Dehydration
of Cells
CNS Failure


Coma in diabetes can be due to acidosis and dehydration. However, the plasma glucose can be
elevated to such a degree that independent of plasma pH, the hyperosmolarity of the plasma
causes unconsciousness (hyperosmolar coma). Accumulation of lactate in the blood (lactic
acidosis) may also complicate diabetic ketoacidosis if the tissues become hypoxic, and lactic
acidosis may itself cause coma. --- CNS sensitive to osmolarity

Cause:
When a person with a very high (usually considered to be above 300 mg/dl (16 mmol/L)) BGL,
water is osmotically drawn out of cells into the blood and there is glycosuria. This results in loss
of water and an increase in blood osmolarity. If fluid is not replaced, the osmotic effect of high
glucose levels, combined with the loss of water, will eventually lead to dehydration. The body's
cells become progressively dehydrated as water is taken from them and excreted and
electrolyte imbalances are also common.



Slide 7

Advanced Glycosylation End-Products
Elevated intracellular levels of glucose cause a non-enzymatic covalent
bonding with proteins, which alters their structure and inhibits their function.
AGE cause:
•Bind to AGE receptors (RAGE) on leukocytes, endothelium and
vascular smooth muscle
•Cross-link proteins (esp ECM)
Effects:
•Cytokines from intimal macrophages
•ROS in endothelium
•Procoagulant activity
•Proliferation of SM and ECM synthesis
•Decreased vessel elasticity
•Proteolytic resistance and protein
deposition enhancement
•Reduce NO synthesis
•Endothelial Dysfunction
•Glomerular dysfunction
Contribution to microangiopathy
and hence neuropathy


Increased intracellular glucose leads to the formation of advanced glycosylation end products
(AGEs), which bind to a cell surface receptor, via the nonenzymatic glycosylation of intra- and
extracellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with
amino groups on proteins.



Slide 8

Activation of PKC
Hyperglycaemia stimulates synthesis of DAG from glycolytic
intermediates (DAG required for PKC activation)
Abnormal PKC activity causes:
•Production of proangiogenic vascular endothelial growth factor (VEGF),
implicated in the neovascularization characterizing diabetic retinopathy

•Elevated levels of endothelin-1 and decreased levels of NO, due to
decreased expression of endothelial nitric oxide synthase

•Production of profibrogenic factors like TGF-β, leading to increased
deposition of extracellular matrix and basement membrane material

•Production of PAI-1, leading to reduced fibrinolysis and possible
vascular occlusion

•Production of pro-inflammatory cytokines by the vascular endothelium


Activation of intracellular protein kinase C (PKC) by Ca
*2+
+ ions and the second messenger diacyl
glycerol (DAG) is an important signal transduction pathway in many cellular systems.
Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic
intermediates, and hence causes activation of PKC. The downstream effects of PKC activation
are numerous.

It should be evident that some effects of AGEs and activated PKC are overlapping, and both
contribute to the long-term complications of diabetic microangiopathy.




Slide 9

Polyol Pathway Disturbance
Some tissues don’t require insulin for glucose
transport – nerves, lenses, kidneys, blood vessels
ICF Glucose
Glycolysis etc
Sorbitol
Aldose Reductase
Effects:
•Redox potential -> ROS generation
•Inc cellular osmolality
NADPH NAD
NADPH required for reduced
glutathione regeneration (antioxidant)


In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys,
blood vessels), persistent hyperglycemia in the extracellular milieu leads to an increase in
intracellular glucose. Hyperglycemia increases glucose metabolism via the sorbitol pathway.
Intracellular glucose is predominantly metabolized by phosphorylation and subsequent
glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose
reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality,
generates reactive oxygen species. Minimal effect though?



Slide 10

Hexosamine Pathway
ICF hyperglycaemia increases flux through the hexosamine
pathway via F6P synthesis (glycolysis intermediate).
-> O-linked glycosylation and proteoglycan production
Effects:
•Glycosylation of endothelial NO synthase
•Changes in gene expression of TGF and PAI-1


A fourth theory proposes that hyperglycemia increases the flux through the hexosamine
pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and
proteoglycan production that alters signalling pathways and TF inductino. The hexosamine
pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase
or by changes in gene expression of transforming growth factor (TGF-) or plasminogen activator
inhibitor-1 (PAI-1).



Slide 11

Synthesis of Everything
= everything goes wrong


I was going to go through an example (e.g. Diabetic retinopathy) that went through it all, but it
would have taken all day. Wikipedia is actually quite accurate on each topic



Slide 12

• Lecture material, 2012
•Harrison's Online
•Boron: Medical Physiology, Updated Edition, 2nd ed.
•Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional
Edition, 8th ed.
•Hall: Guyton and Hall Textbook of Medical Physiology, 12th ed.
•Something else I forgot to write down
References




Endocr i ne Phy si ol og y, 3e > Chapt er 7. Endocrine Pancreas >
OBJECTI VES
I dent ify t he principal hormones secret ed from t he endocrine pancreas, t heir cells of or igin, and t heir chemical nat ure.
Underst and t he nut rient , neural, and hormonal mechanisms t hat r egulat e pancreat ic hormone r elease.
List t he pr inci pal t arget organs for insulin and glucagon act ion and t hei r maj or physiologic effect s.
I dent ify t he t ime course for t he onset and durat ion of t he biologic act ions of insulin and glucagon.
I dent i f y t he disease st at es caused by oversecret i on, undersecret i on, or decreased sensi t i vit y t o i nsul in, and descr ibe t he
pri ncipal manif est at i ons of each.
ENDOCRI NE PANCREAS: I NTRODUCTI ON
The pancreas is a mixed exocrine and endocr ine gland t hat plays a cent r al rol e in digest ion and in t he met abol ism, ut ili zat ion,
and st or age of energy subst rat es. Normal pancreat ic funct ion involving t he product ion and release of t he hormones insulin and
glucagon is essent ial for t he physiol ogic cont rol of glucose homeost asis. This chapt er focuses on t he endocrine funct ion of t he
pancr eas t hrough t he r elease of insulin and glucagon and t he mechanisms by which t hese hormones regulat e event s cent ral t o
mai nt aining glucose homeost asi s. Mai nt enance of gl ucose homeost asi s is similar t o t he mai nt enance of calcium balance
discussed in Chapt er 6, in which several t issues and hor mones int er act in t he r egulat ory process. I n t he case of glucose, t he
process i nvolves a regulat ed bal ance among hepat i c gl ucose rel ease ( f rom glycogen breakdown and gl uconeogenesi s) , diet ary
glucose absorpt ion, and glucose upt ake and disposal from skel et al muscl e and adi pose t issue. The pancreat ic hormones insulin
and glucagon play cent r al roles i n r egulat ing each of t hese processes and t hei r overall effect s are in part modified by ot her
hormones such as growt h hormone, cort isol, and epinephr ine. I n addit ion t o secret ing insulin and glucagon, t he endocr ine
pancr eas also secr et es somat ost at in, amyli n, and pancr eat i c pol ypept ide.
FUNCTI ONAL ANATOMY
The pancreas is a ret roperit oneal gland divided i nt o a head, body, and t ail and is l ocat ed near t he duodenum. Most of t he
pancr eat i c mass i s composed of exocr ine cel ls t hat are cl ust er ed i n lobul es ( aci ni) divided by connect ive t i ssue and connect ed
t o a duct t hat drains i nt o t he pancreat ic duct and int o t he duodenum. The product of t he pancreat ic exocrine cells is an
al kaline fluid rich wit h digest ive enzymes, which is secret ed int o t he small int est ine t o aid in t he digest ive process. Embedded
wit hi n t he acini ar e ri chly vasculari zed, small clust ers of endocri ne cell s cal led t he i sl et s of Langer hans, in which 2 endocrine
cell t ypes ( and ) predominat e. The - cells const it ut e about 73–75% of t he t ot al mass of endocrine cells, and t heir principal
secr et or y pr oduct is i n sul i n . The - cells account for about 18–20% of t he endocrine cells and ar e responsible for gl ucagon
secret ion. A small number of - cells ( 4–6%) secret e somat ost at i n, and an even smaller number of cells ( 1%) secret e
pancr eat i c pol ypept i de. The localizat ion of t hese cell t ypes wit hin t he islet s has a part icular pat t er n, wit h t he - cell s locat ed
cent rally, surrounded by - and - cel ls. This arrangement plays a r ole in t he cell- t o- cel l paracr ine r egulat ion of hor mone
r el ease.
The ar t er ial blood suppl y t o t he pancr eas i s deri ved f rom t he spleni c art ery and t he super ior and i nf eri or pancreat icoduodenal
art eri es. Al t hough i sl et s r epresent only 1–2% of t he mass of t he pancr eas, t hey receive about 10–15% of t he pancreat ic blood
flow. The rich vascularizat ion by fenest rat ed capillaries al lows ready access t o t he cir culat ion for t he hormones secret ed by t he
isl et cells. The direct ion of blood flow is prefer ent iall y from t he cent er of t he isl et t o t he periphery. Therefor e, - and - cells
are exposed t o high concent rat ions of hormones produced by t he - cel ls ( ie, i nsulin) , cont r ibut ing t o t he inhibit i on of glucagon
r elease by hi gh local insulin concent rat ions. Venous blood from t he pancreas drains int o t he hepat ic port al vein. Ther efore, t he
liver , a principal t arget organ for t he physiologic effect s of pancreat ic hormones, is exposed t o t he hi ghest concent rat ions of
pancr eat i c hor mones. Fol lowing fi rst - pass hepat ic met abolism, t he pancreat ic endocrine hormones are dist r ibut ed t o t he
syst emi c ci rculat i on.
Parasympat het ic, sympat het i c, and sensory nerves ri chly innervat e t he pancr eat i c i slet s, and t he respect i ve neurot ransmi t t ers
and neuropept ides released from t heir nerve t erminals exert import ant r egulat ory effect s on pancreat ic endocrine hor mone
r el ease. Acet ylchol ine, vasoact i ve i nt est i nal polypept i de, pi t uit ar y adenylat e cyclase–act ivat i ng pol ypept ide, and gast ri n-
r el easi ng pept i de ar e rel eased f rom t he parasympat het ic ner ve t er mi nals. Norepi nephri ne, galanin, and neuropept i de Y are
r el eased f rom sympat het i c nerve t erminals. Vagal ner ve act ivat ion st i mulat es t he secr et i on of i nsulin, glucagon, somat ost at in,
and pancreat ic polypept i de. Sympat het ic nerve st imul at ion inhibit s basal and gl ucose- st imulat ed insuli n secret ion and
somat ost at i n rel ease and st imulat es glucagon and pancreat i c pol ypept ide secr et i on.
PANCREATI C HORMONES
I nsul i n
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I NSULI N SYNTHESI S
The process involved in t he synt hesis and release of insul in, a polypept ide hormone, by t he - cell s of t he pancreas is similar t o
t hat of ot her pept ide hormones, as discussed in Chapt er 1 ( Figure 1–5) . Preproi nsuli n undergoes cl eavage of it s signal pept i de
dur ing i nser t ion int o t he endoplasmi c ret i culum, generat ing proinsul in ( Figur e 7–1) . Proinsul in consist s of an amino- t erminal -
chain, a carboxy- t er minal - chain, and a connect ing pept ide in t he middle known as t he C- pept i de. C- pept i de l i nks t he - and
- chains, allowing proper folding of t he molecule and t he format ion of disulfide bonds bet ween t he 2 chains. I n t he
endopl asmi c ret icul um, pr oinsuli n i s processed by specif i c endopept i dases known as prohormone conver t ases, which cleave
t he C- pept ide t o generat e t he mat ure form of insul in. Removal of t he C- pept ide exposes t he end of t he insulin chai n t hat
int er act s wit h t he insulin recept or . I nsulin and t he fr ee C- pept ide are packaged int o secret ory granules in t he Golgi apparat us
and are released t oget her. These secret or y gr anules accumulat e in t he cyt oplasm. About 5% of t he granules ar e st or ed in a
r eadily releasable pool. Most of t he granul es ( more t han 95%) belong t o a reserve pool and need t o be chemicall y modified, or
even physi call y t r ansl ocat ed, t o become i mmedi at el y avail able f or release. Thi s rel ease of i nsul in granules f rom dif ferent pools
leads t o a biphasic pat t ern of insul in release in r esponse t o st imulat ion of t he - cell by glucose. Only a small pr oport ion of t he
cel lular st ores of insuli n are released even under maximal st i mulat ory condit ions.
St imulat ion of t he pancreat i c - cell leads t o exocyt osis of t he cont ent s of t he secret or y gr anules, wit h t he result ing release of
equal amount s of insulin and C- pept ide int o t he port al circulat ion. I nsuli n circulat es in it s fr ee form and has a half - life of 3–8
minut es. I nsuli n l evel s i n t he cir culat i on average 43–186 pmol/ L ( 6–26 U/ mL) i n t he f ast i ng st at e. I nsul i n i s degr aded
Fi gu r e 7–1.
A. I nsulin synt hesis st art s wit h t he t ranslat ion of insulin mRNA int o an inact ive prot ein called preproinsulin. Preproinsulin under goes
post - t ranslat ional modificat ion in t he endoplasmic ret iculum ( ER) t o for m proinsulin. The act ive for m of insulin is produced by
modificat ion of proinsulin by cleavage of t he C- pept ide st ruct ur e linking t he and chains. I nsulin is composed of 2 chains; an chain
of 21 amino acids and a chain of 30 amino acids. The chains are held t oget her by 2 disulfi de ( S- S) bonds. A t hird disulfide bond is
pr esent wit hin t he chain. Bot h insulin and t he cleaved C- pept ide ar e packaged in secret ory granules, which accumulat e in t he - cell
cyt osol and are coreleased in response t o glucose st imulat ion. B. I nsulin release occurs in a biphasic mode and is derived from secret ory
gr anules t hat ar e immediat ely available for release ( < 5%) , from granules t hat must undergo a series of preparat ory react ions including
mobilizat ion t o t he plasma membrane ( > 95%) . These gr anule pr eparat ory or mat urat ion processes are modulat ed by int racellular levels
of ATP, ADP and, Ca
+ +
. C. I nsulin release in response t o a meal is charact erized by increased frequency and amplit ude of pulsat ile
release. Shown are port al insulin concent rat ions dur ing basal st at e (left ) and aft er ingest ion of a mixed meal ( right ) in normal pat ient s.
( Reproduced, wit h permission, from: Porksen N, Groft e T, Gr eisen J, Mengel A, Juhl C, Veldhuis JD, Schmit z O, Rossle M, Vilst rup H.
Human insuli n release pr ocesses measured by int raport al sampling. Am J Physiol Endocrinol Met ab. 2002; 282( 3) : E695–E702. Figur e 4
of art icle.)
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predominant ly by t he liver dur ing it s first pass, which ext ract s about 40–80% of insulin delivered. Addit ional degradat ion of
insulin occurs in t he kidneys as well as at t arget t issues by insul in prot eases following endocyt osis of t he recept or - bound
hormone. C- pept ide, which was pr eviously t hought t o be biologically inert , appears t o have some biol ogical act ion as recent
evidence indicat es t hat replacement of C- pept ide improves renal funct ion and nerve dysfunct ion in pat ient s wit h t ype 1
diabet es. The recept or and signal ing mechani sms invol ved i n medi at ing t hese responses ar e st il l under invest i gat i on. The
impor t ance of C- pept i de is t hat unli ke insuli n, it is not readi ly degraded i n t he li ver. Thus, t he relat i vely l ong hal f- li f e of t he
pept ide ( 35 minut es) al lows it s release t o be used as an index of t he secret ory capacit y of t he endocrine pancreas.
The amino acid sequence of i nsulin i s highl y conserved among species. I n t he past , porcine and bovine insulin wer e used t o
t reat pat ient s wi t h di abet es. Curr ent l y, human r ecombi nant insul in is avai labl e and has replaced animal - der ived insulin,
avoiding pr oblems such as t he development of ant ibodies t o nonhuman i nsulin.
REGULATI ON OF I NSULI N RELEASE
The rel ease of i nsulin t hroughout t he day is pulsat ile and rhyt hmic in nat ur e; 2 i dent ifiable rhyt hms occur wit h per iods
of 5–10 and 60–120 minut es ( Figur e 7–1) . The pulsat ile release of insulin is impor t ant for achieving maximal physiologic
effect s. I n part icul ar , it appear s t o be crit ical in t he suppr ession of li ver glucose product ion and in insulin- mediat ed gl ucose
disposal by adipose t issue. I nsul in release rises aft er a meal in response t o t he increases in plasma levels of glucose and
amino acids. Secret ion is t he result of a combinat ion of an i ncrease in t he t ot al amount of insulin released in each secret ory
bur st ( by about 50%) and an i ncreased pulse fr equency of a similar magnit ude Figure 7–1) . The synchronized increase in
insulin r elease is t hought t o be t he r esult of recruit ment of - cells t o release insuli n. Alt hough it is not clear how t he - cell s
communicat e wit h each ot her t o synchronize t he r elease of insuli n, some of t he proposed mechanisms incl ude gap j unct ions
bet ween t he pancreat ic - cel ls, all owi ng t he passage of ions and smal l mol ecules; membrane depolari zat ion, aiding t he
pr opagat ion of t he synchronizat ion bet ween t he cells; and glucose- induced changes in t he ext r acellular pot assium
concent rat ion and in nit ric oxide. I n addit ion, int rapancreat ic neural, hor monal , and subst rat e fact ors have been shown t o play
an import ant role in t he pulsat ile pat t er n of i nsul in release.
The pancreat ic - cell funct ions as a fuel sensor t hat r esponds t o changes in plasma levels of energy subst r at es
r el easi ng insuli n in response t o int egrat ed si gnals f r om nut r ient s ( gl ucose and ami no aci ds) , hor mones ( i nsul in, glucagon- l ike
pept ide- 1 ( GLP- 1) , somat ost at in, and epinephrine) , and neurot r ansmit t er s ( norepinephr ine and acet ylcholine) ( Figur e 7–2) .
Gl ucose is t he pri ncipal st i mulus f or i nsuli n r el ease fr om t he pancr eat i c - cell s, and in addit ion exert s a permissive effect for
t he ot her modulat ors of i nsul i n secret i on.
Fi gu r e 7–2.
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The gl ucose- induced st imulat ion of insulin release is t he result of glucose met abolism by t he - cell , t he gener at ion of
met abolic int ermediat es, an i ncrease in t he ATP/ ADP rat io i n t he cyt osol, and a ri se in int racellular Ca
2+
( Figure 7–3) . Glucose
ent er s t he - cell t hrough a membrane- bound glucose t ransport er ( GLUT- 2) . Once inside t he - cel l, t he enzyme gl ucokinase
phosphorylat es glucose in t he init ial st ep of glycolysis, leading event ually t o t he generat i on of acet yl- coenzyme A ( CoA) and
adenosine t ri phosphat e ( ATP) by t he Krebs cycle. The r esul t i ng increase i n i nt racell ul ar ATP l evel s inhibit s ( cl oses) t he ATP-
sensi t ive K
+
channels ( K
ATP
) i n t he - cell, reduci ng t he efflux of K
+
. This process r esult s in membrane depolari zat i on,
act ivat ion ( openi ng) of volt age- dependent Ca
2+
channels, and increased Ca
2+
influx. The ri se in int racellular Ca
2+
concent rat ions t riggers t he exocyt osis of insul in secret ory granules and t he release of insulin int o t he ext racellul ar space and
int o t he circulat ion. I t is i mport ant t o not e t hat t he regulat ion of K
+
channels by ATP is mediat ed by t he sulfonylurea recept or.
This is t he basis for t he t herapeut ic use of sulfonylur ea dr ugs in t he t reat ment of diabet es.
Regulat ion of insulin release. Glucose is t he principal st imulus for insulin release from t he pancreat ic - cell. Glucose ent er s t he - cell by
a specific glucose- t ransport er pr ot ein ( GLUT- 2) and is immediat ely phosphorylat ed by glucokinase. Format ion of glucose- 6- phosphat e in
t he first st ep of glycolysis init iat es t he glycolyt ic met abolism of glucose f ollowed by t he Krebs cycle leading t o generat ion of adenosine
t riphosphat e ( ATP) . The increased concent r at ions of ATP and result ing gr eat er ATP/ adenosine diphosphat e ( ADP) rat io leads t o inhibit ion
and closure of t he ATP- sensit ive K
+
channels ( t he t arget of sulfonylurea drugs), result ing in depolar izat ion of t he plasma membrane and
opening of t he vol t age- dependent Ca
2+
channels. As a result , t her e is an increased influx of ext racellular Ca
2+
as well as mobilizat ion of
Ca
2+
f rom int racellular st ores leading t o t he fusion of insulin- cont aining secr et ory granules wit h t he plasma membrane and t he r elease
of insulin ( and C- pept ide) int o t he circulat ion. Addit ion fact ors can also st imulat e insulin release from t he - cell, including hormones
( glucagon- like pept ide- 1) and neur ot ransmit t er s ( acet ylcholine) . Glucose syner gizes wit h t hese mediat ors and enhances t he secret ory
response of t he - cell t o t hese fact ors. AC, adenylat e cyclase; CCK, cholecyst okinin; GLP- 1, glucagon- like pept ide- 1; PLC, phospholipase
C. ( Modified, wit h permission, from Faj ans SS et al. Mechanisms of disease: Molecular mechanisms and clinical pat hophysiology of
mat urit y- onset diabet es of t he young. NEJM. 2001; 345: 971. Copyright © Massachuset t s Medical Societ y. All right s reserved.)
Fi gu r e 7–3.
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The - cel l Ca
2+
concent rat ions can also be elevat ed by amino acids t hrough t heir met abol ism and ATP generat ion, or by direct
I nsulin- recept or signaling. I nsulin binding t o t he recept or act ivat es t he int rinsic kinase act ivit y of t he int racellular domain of t he
recept or. This result s in downst ream act ivat ion of cellular event s mediat ed t hrough t he phosphorylat ion of insulin recept or subst r at es.
Signaling pat hways including t he phosphat idyli nosit ol- 3- kinase ( PI
3
- K) and t he mit ogen- act ivat ed prot ein kinase ( MAPK) cascades
cont ribut e t o t he over all effect s of insulin. As shown in t he insert , one of t he immediat e effect s of insulin is t he act ive recruit ment of
GLUT- 4, st ored in int racellular vesicles t o t he cell sur face. I nsulin binds t o it s recept or in t he plasma membrane, result ing in
phosphorylat ion of t he recept or and insulin- recept or subst rat es such as t he I RS molecules. These subst r at es form complexes wit h
docking prot eins such as phosphoinosit ide- 3- kinase at it s 85-kDa subunit ( p85) by means of SH2 ( Scr homology region 2) domains.
Then p85 is const it ut ively bound t o t he cat alyt ic subunit ( p110) . Act ivat ion of phosphoinosit ide- 3- kinase is a maj or pat hway in t he
mediat ion of insulin- st imulat ed glucose t ranspor t and met abolism. Exercise can also st imulat e glucose t r ansport by pat hways t hat are
independent of phosphoinosi t ide- 3- kinase and t hought t o involve 5' - AMP- act ivat ed kinase. ( Reproduced, wit h permission, from
Shepherd PR, Kahn BB. Glucose t r ansport ers and insulin act ion: I mplicat ions for insulin r esist ance and diabet es mellit us. NEJM.
1999; 341( 4) : 248–257. Copyright © Massachuset t s Medical Societ y. All right s reserved.)
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depolarizat ion of t he plasma membrane. Ot her fact ors ( shown in Figur e 7–2) t hat amplify t he glucose- i nduced rel ease of
insulin f rom t he - cell incl ude acet yl choli ne, chol ecyst okinin, gast roi nt est inal pept ide, and GLP- 1. These subst ances all bind t o
cell surface recept ors and act ivat e adenylat e cycl ase and phospholipase C. Acet ylcholine and cholecyst okinin promot e
phosphoinosit ide breakdown, wit h a consequent mobilizat ion of Ca
2+
from int racellular st or es, Ca
2+
influx acr oss t he cel l
membrane, and act ivat ion of prot ein kinase C. GLP- 1 raises l evels of cycli c adenosi ne monophosphat e ( cAMP) and act ivat es
cAMP- dependent prot ein kinase A. The subsequent generat ion of cAMP, inosit ol 1, 4, 5- t r isphosphat e, diacylglycer ol, and
arachidonic acid and t he act ivat ion of prot ein kinase C amplify t he Ca
2+
signal by decreasing Ca
2+
upt ake by cel lul ar st ores
and pr omot ing bot h t he phosphor ylat ion and act ivat ion of prot eins t hat t rigger t he exocyt osis of insulin. Cat echolamines and
somat ost at in inhibit insulin secr et ion t hrough G prot ein–coupl ed recept or ( GPCR) mechanisms, i nhi bi t ion of adenylat e cycl ase,
and modificat ion of Ca
2+
and K
+
channel gat ing.
The short - t erm regulat ion of insulin release is mediat ed t hrough modificat ion of proi nsulin mRNA t ranslat ion. Over longer
per iods, glucose also increases pr oinsulin mRNA cont ent by bot h st imulat ing pr oinsulin gene t r anscript ion and st abilizing t he
mRNA. As ment ioned above, t he release of i nsul in in response t o glucose is biphasi c, wit h an init i al rapid r elease of prefor med
insulin followed by a more sust ained release of newly synt hesized insulin. An elevat ion in plasma glucose concent rat ions is
fol lowed by a t ransi ent st imulat ion of i nsulin secr et ion known as " f i r st - phase secr et i on, " which consist s of a rapid burst of
r elease t o a high peak and t hen a st eep decline t o a low secret ion rat e. This is fol lowed by " secon d- phase secr et i on," which
consi st s of a gradual ly increasing rat e of secret ion t o a plat eau level. Thi s biphasic response t o glucose is a maj or
charact eri st i c of gl ucose- st imulat ed insulin secret ion. The first phase occurs over a period of minut es, t he second over an hour
or more. Several hypot heses have been proposed t o explain t he biphasic nat ure of insul in secret ion. The mechanism may
involve insuli n r elease fr om 2 separ at e pool s of granules, wit h t he first phase repr esent ing t he readily r eleasable pool of -
granul es al ready docked at t he - cell pl asma membrane t hat does not require addi t i onal movement al ong micr ot ubules. The
second phase would require mobil izat ion of - granules from a st or age pool t o repleni sh t he readily r eleasable pool of -
granul es bef ore - granule docking and exocyt osis.
PHYSI OLOGI C EFFECTS OF I NSULI N
I nsul in produces a wide variet y of effect s t hat range from immediat e ( wit hin seconds) , such as t he modulat ion of ion ( K
+
) and
glucose t ranspor t int o t he cell; early ( wit hin minut es) , such as t he regulat ion of met abolic enzyme act ivit y; moderat e ( wit hin
minut es t o hours) , such as t he modul at ion of enzyme synt hesis; t o delayed ( wit hin hours t o days) , such as t he effect s on
growt h and cellular differ ent iat ion. Overall , t he act ions of insulin at t ar get organs ar e anabolic and promot e t he synt hesis of
car bohydr at e, fat , and prot ein, and t hese effect s ar e mediat ed t hrough binding t o t he insulin recept or ( Table 7–1) .
I NSULI N RECEPTOR
The insulin recept or is part of t he insulin- r ecept or f amil y, which i ncludes t he i nsul i n recept or , t he i nsul i n- l ike growt h- fact or
r ecept or , and t he i nsulin- r el at ed r ecept or, all of which are invol ved i n cel l di vi si on, met aboli sm, and devel opment ( Figure 7–3) .
The insuli n recept or is a het er ot et ramer ic glycoprot ei n membrane recept or composed of 2 - and 2 - subunit s, linked by
disulfide bonds. The - chain i s t he ext r acellular port ion and is t he sit e for insulin binding. The - chai n consist s of a short
ext racel lul ar region, a t ransmembr ane segment , and an int r acel lular segment t hat has int ri nsic t yrosine kinase act ivit y
cont r oll ed by i nsul i n bindi ng t o t he ext racel lul ar - subuni t .
I nsul in bi nding t o t he recept or t riggers recept or aut ophosphorylat i on on t yrosi ne residues in t he cyt opl asmic domain ( - chain) .
The act ivat ed recept or phosphorylat es t yrosine residues of several prot eins known as i nsul i n- r ecept or su st r at es ( I RS- 1, -
2, - 3, - 4) . These I RS prot eins facilit at e t he int er act ion of t he insulin recept or wit h int racellular subst rat es by serving as a
Ta l e 7 –1. I nsul i n Ef f ect s on Car ohy dr at e, Fat , and Pr ot ei n Met a ol i sm
Met a ol i c ef f ect s I nsu l i n st i mul at es I nsu l i n i n hi i t s
Carbohydr at e
met abol ism
Gl ucose t r anspor t in adipose t issue and muscl e
Rat e of gl ycol ysi s i n muscle and adi pose t i ssue
Glycogen synt hesis in adipose t issue, muscle, and
li ver
Gl ycogen breakdown i n muscle and li ver
Rat e of gl ycogenolysis gluconeogenesis in t he
li ver
Li pi d met abol ism Fat t y aci d and t ri acyl gl ycerol synt hesis i n t issues
Upt ake of t ri gl yceri des f rom t he bl ood int o adi pose
t issue and muscl e
Rat e of cholest erol synt hesi s i n t he li ver
Li pol ysi s in adi pose t issue, l oweri ng t he plasma
fat t y acid l evel
Fat t y aci d oxi dat i on i n muscle and li ver
Ket ogenesi s
Prot ein met abol ism Ami no aci d t ransport i nt o t issues
Prot ein synt hesis in muscl e, adipose t i ssue, li ver,
and ot her t i ssues
Prot ein degradat i on i n muscl e
Ur ea for mat ion
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scaffol d for recr uit ment of prot eins involved in si gnal t ransduct ion t o downst ream pat hways. The result is coupling of insulin
r ecept or act ivat ion t o si gnali ng pat hways, mainly t he phosphat idyli nosit ol - 3- kinase ( PI
3
- ki nase) and t he mi t ogen- act i vat ed
prot ein kinase ( MAPK) pat hways ( Figur e 7–3) .
The PI
3
- ki nase pat hway i nvolves phosphoryl at ion of inosi t ol phospholi pids and t he gener at ion of phosphat idyl inosit ol -
3,4, 5- t r isphosphat e and phosphat idylinosit ol - 3,4- bisphosphat e. These product s, i n t urn, at t ract serine kinases t o t he plasma
membr ane, including t he phosphoinosit ide- dependent kinase and different isoforms of prot ein kinase B, which, when
act ivat ed, cat alyze some of t he cellular effect s of insulin. The Pl
3
- kinase pat hway is invol ved pr edominant ly in mediat i ng t he
met abolic effect s of t he hormone, i ncluding glucose t ransport , glycolysis, and glycogen synt hesis, and plays a crucial role in
t he regulat ion of prot ein synt hesis by insulin. Mor eover, t his pat hway is involved in cell gr owt h and t ransmit s a st rong
ant i apopt ot i c si gnal, promot i ng cell survi val . The ot her main si gnal i ng pat hway t hat i s act ivat ed by i nsuli n bindi ng t o i t s
r ecept or is t he MAPK pat hway. Alt hough si gnali ng cascades in t his pat hway do not appear t o play a significant role in t he
met abolic effect s of insul in, t hey are involved in mediat ing t he pr oliferat ive and different iat ion effect s elicit ed by insul in.
Signal t ransduct ion by t he insulin recept or is not limit ed t o i t s act ivat ion at t he cell sur face. The act ivat ed ligand- recept or
complex is int er nal ized int o endosomes. Endocyt osis of act ivat ed recept ors is t hought t o enhance t he insuli n r ecept or t yr osine
kinase act ivit y on subst rat es t hat are dist ant fr om t hose readily accessible at t he plasma membrane. Following acidificat ion of
t he endosomal lumen, insul in di ssoci at es f r om it s recept or, endi ng t he i nsul in recept or–medi at ed phosphorylat i on event s and
promot ing t he degradat ion of insul in by prot eases such as t he acidic i nsulinase. The insulin recept or can t hen be recycled i nt o
t he cell sur f ace, where it becomes avai l able f or insuli n bi nding agai n.
The number of avai lable insuli n recept ors is modulat ed by exercise, diet , insulin, and ot her hormones. Chroni c exposure t o
hi gh insulin levels, obesit y, and excess gr owt h hor mone all lead t o a downregul at ion of i nsuli n recept ors. I n cont rast , exercise
and st ar vat ion upregulat e t he number of recept ors. The affinit y of t he r ecept or for insul in is increased fol lowing a peri od of
decr eased i nsul in l evel s and during adr enal i nsuf fi ci ency.
I NSULI N EFFECTS AT TARGET ORGANS
Ear l y ef f ect s Alt hough t he expression of insulin recept ors is widespread, t he specific effect s of insulin on skelet al
muscle glucose ut ilizat ion dominat e insulin act ion. I nsulin mediat es about 40% of glucose disposal by t he body, t he great
maj ori t y ( 80–90%) of whi ch occur s in skelet al muscle. The movement of glucose int o t he cell is mediat ed by a family of carr ier
pr ot eins, or glucose t r anspor t ers, wit h t heir own unique t issue dist ribut ion. The main t ranspor t er s and t heir pr edominant
t issue di st ri but i ons ar e summar ized i n Table 7–2.
I nsulin- st imulat ed glucose t ransport is mediat ed t hrough GLUT- . Appr oxmat ely 90% of GLUT- 4 is sequest er ed int racell ularl y
in t he absence of i nsul in or ot her st imuli such as exercise. I nsulin binding t o it s recept or result s in recrui t ment of GLUT- 4 from
Ta l e 7 –2. Mai n Feat ur es of Gl ucose Tr anspor t er s
Tr anspor t er E pr essi on Funct i on
GLUT- 1 Ubi quit ous, wi t h part i cularl y high l evel s i n human eryt hr ocyt es
and in t he endot hel ial cel ls li ning t he blood vessel s of t he brain.
Expr essed in skelet al muscle and fat .
Glucose upt ake by skelet al muscle and fat
under basal condit ions
GLUT- 2 Low- affinit y glucose t r ansport er present in pancreat ic - cel ls,
l iver, int est i ne, and ki dney
Funct ions in t he glucose sensor syst em
and ensures t hat glucose upt ake by
pancreat ic - cells and hepat ocyt es occurs
only when cir culat i ng gl ucose l evel s are
high
GLUT- 3 Pri maril y i n neur ons Toget her , GLUT- 1 and GLUT- 3 are cruci al
in allowing glucose t o cr oss t he blood- brai n
barri er and ent er neurons
GLUT- 4 Predominant ly in st riat ed muscle and adipose t issue. I n cont rast
t o t he ot her GLUT isoforms, which are pr imaril y localized on t he
cell membr ane, GLUT- 4 t r anspor t er prot ei ns are sequest er ed in
speci ali zed st or age vesi cl es t hat remain wit hi n t he cel l ' s i nt eri or
under basal condit ions.
The maj or i nsul in- responsi ve t ransport er
GLUT- 5 Spermat ozoa and small i nt est ine Predomi nant ly a fr uct ose t ransport er
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cyt osolic vesicular compart ment s t o t he plasma membrane. Accumul at ion of GLUT- 4 at t he membrane is t he net resul t of
increased t ranslocat ion t hrough t arget ed exocyt osis and decreased rat e of GLUT- 4 endocyt osis. This i s t he underl yi ng
mechani sm by whi ch insulin st imulat es glucose t ransport i nt o fat and muscl e cells.
I nt er medi at e ef f ect s The int ermediat e effect s of insulin are mediat ed by modulat ion of prot ein phosphorylat ion of
enzymes involved in met abolic processes in muscle, fat , and li ver ( Figur e 7–4) . I n fat , insul in inhibit s li polysi s and ket ogenesi s
by t riggering t he dephosphorylat ion of hormone- sensi t ive l ipase and st i mulat es l ipogenesis by act i vat i ng acet yl - CoA
car boxylase. I n t he adipocyt es, dephosphorylat ion of hormone- sensi t ive li pase inhibit s t he breakdown of t r iglycer ides t o fat t y
acids and glycerol , t he rat e- limit ing st ep in t he release of fr ee fat t y acids mediat ed by li polysis. This process t hereby r educes
t he amount of subst rat e t hat is available for ket ogenesis. I nsulin ant agonizes cat echolamine- i nduced l ipolysis t hrough t he
phosphoryl at ion and act ivat ion of phosphodi est erase, l eadi ng t o a decrease i n i nt racel lul ar cAMP l evel s and a concomi t ant
decrease in pr ot ei n kinase A act ivit y.
Fi gu r e 7– .
Glucagon and insulin effect s on hepat ic glucose met abolism. Binding of glucagon and insulin t o t heir respect ive recept ors st imulat es a
cascade of pr ot ein phosphorylat ion st eps t hat act ivat e ( or inhibit ) key enzymes i nvolved in t he regulat ion of glycogenolysis,
gluconeogenesis, and glycolysi s. The principal t arget enzymes for insulin- and glucagon- mediat ed effect s are present ed. The overall
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I n t he li ver, i nsul in st i mul at es t he gene expressi on of enzymes i nvolved in gl ucose ut i li zat i on ( eg, glucokinase, pyr uvat e
kinase, and l i pogeni c enzymes) and i nhibit s t he gene expressi on of enzymes invol ved i n glucose product ion ( eg,
phosphoenolpyruvat e carboxykinase and glucose- 6- phosphat ase) ( Figure 7–5) . I nsul in st i mulat es glycogen synt hesi s by
increasing phosphat ase act ivit y, leading t o t he dephosphorylat ion of glycogen phosphorylase and glycogen synt hase. I n
addit ion, i nsul in- medi at ed dephosphoryl at i on of inhibit or y si t es on hepat ic acet yl- CoA carboxylase increases t he product ion of
mal onyl- CoA and simult aneousl y reduces t he rat e at which fat t y acids can ent er hepat ic mit ochondr ia for oxidat ion and ket one
body pr oduct ion.
result is an increase in hepat ic glucose out put . ADP, adenosine diphosphat e; ATP, adenosine t riphosphat e; G, glucagon; I , insulin; PEP,
phosphoenolpyruvat e.
Fi gu r e 7– .
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Process of ket ogenesis in insulin deficiency. I nsulin def iciency and high levels of count erregulat or y hormones glucagon, epinephrine, and
cort isol combine t o increase t he act ivit y of hormone- sensit ive lipase, incr ease t he release of fr ee fat t y acids, and decrease t he act ivit y of
acet yl- coenzyme A ( CoA) carboxylase, t hereby impairing t he r eest erificat ion of free fat t y acids and promot ing fat t y acid conversion int o
ket one bodies. The excess supply of fat t y acet yl- CoA and t he deficiency in oxaloacet at e increase t he oxidat ion t o ket one bodies, wit h t he
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I n muscle, insul in st imulat es glucose upt ake and favors prot ein synt hesi s t hough phosphor ylat ion of a serine/ t hreonine prot ein
kinase known as mammalian t arget of rapamyci n. I n addit ion, i nsul in favors lipid st orage in muscle as well as in adipose
t issue. As discussed lat er, i nsuli n def i ci ency l eads t o gl ucose accumul at i on in bl ood, a decrease i n l ipid st orage, and pr ot ei n
l oss, r esul t i ng in negat i ve nit r ogen bal ance and muscle wast ing.
Long- t er m ef f ect s Sust ai ned insuli n st imulat ion enhances t he synt hesis of lipogenic enzymes and t he repression of
gluconeogenic enzymes. The growt h- promot ing and mit ogenic effect s of insuli n are long- t erm responses mediat ed t hrough t he
MAP pat h ay. Bot h MAPK and part icularly t he chronic act ivat ion of ext r acellular r ecept or kinase by insulin recept or binding
lead t o excessive cell growt h. Alt hough t his pat hway of insulin act ion is not as well elucidat ed as t he effect s t hat are mediat ed
t hr ough t he act ivat ion of I RS, evidence is now sur facing on t he pat hophysiol ogic effect s of chronic el evat ions of insulin on
specif i c cell popul at ions.
I nsul in levels ar e high dur ing t he development and earl y st ages of t ype 2 diabet es. Chronic hyper insuli nemi a has been linked
t o increased risk of cancers i ncluding endomet rium, post - menopausal breast , colon, and kidney. Condit ions t hat cause
elevat ed i nsul in l evel s incl ude hi gh waist ci rcumf erence, excess visceral fat , hi gh wai st - t o- hip rat io, high body mass index,
sedent ary lifest yle, and high energy i nt ake. I n addit ion, t he prolifer at ive effect s of chr onic hyperi nsulinemia influence vascular
smoot h muscle cells, which are r esponsible for t he maint enance of vascular t one. These cells play an impor t ant role in t he
pat hogenesis of several diseases, incl udi ng hypert ension, at her osclerosi s, car diovascular di sease, and dysl ipidemi a, all of
which are closely associat ed wit h insulin resist ance and hyperi nsuli nemi a. The mol ecul ar basis of insuli n' s effect on vascular
smoot h muscle cell growt h and it s associat ion wit h hypert ension are current ly unclear.
Gl ucagon
GLUCAGON SYNTHESI S
Glucagon, is a 29–amino acid polypept ide hor mone secret ed by t he - cells of t he islet s of Langerhans, which plays an
impor t ant role in t he r egulat ion of glucose homeost asis by produci ng ant agoni st ic effect s on insul in act ion. The primary
sequence of glucagon is almost perfect ly conserved among vert ebrat es, and it is st ruct urall y relat ed t o t he secret in family of
pept ide hormones. Glucagon is synt hesi zed as proglucagon and t hen prot eolyt ically processed t o yield glucagon. The
prohormone progl ucagon i s expressed i n t he pancreas, and al so i n ot her t i ssues, such as ent er oendocr ine cel ls i n t he int est i nal
t ract and in t he brain. However , t he processing of t he pr ohormone differs among t issues. The 2 main product s of proglucagon
processi ng ar e glucagon in t he - cells of t he pancr eas and GLP- 1 in t he i nt est i nal cel ls. GLP- 1 is produced i n t he int est i ne i n
r esponse t o a high concent rat ion of glucose in t he int est inal lumen. GLP- 1 is known as an incr et i n, a mediat or t hat ampli fies
i nsulin r el ease fr om t he - cell i n response t o a glucose load. Glucagon has a short half- li fe ( 5–10 minut es) and is degraded
most ly in t he liver. Plasma glucagon concent rat ions aver age 50–100 ng/ L ( 50–100 pg/ mL) .
REGULATI ON OF GLUCAGON RELEASE
The mechanisms i nvolved i n t he regulat i on and st imul us- secret ion coupling of glucagon r elease are not as well under st ood as
t hose f or i nsul in. Gl ucagon r el ease is i nhi bi t ed by hypergl ycemi a ( hi gh bl ood gl ucose l evel s) and st imul at ed by hypoglycemia
( low blood glucose levels) . A meal rich in carbohydrat es suppresses glucagon release and st imulat es insuli n rel ease fr om t he
- cel ls t hrough i nt est inal release of GLP- 1. Somat ost at in al so inhibit s glucagon release. High amino acid levels fol lowing an
amino acid–ri ch meal st i mulat e gl ucagon release. Epinephri ne st i mulat es release of gl ucagon t hr ough a
2
- adr ener gi c
mechani sm ( whil e i t suppresses insuli n rel ease f rom - cells t hrough an
2
- adrenergi c mechani sm) . Vagal ( par asympat het i c)
st imulat ion incr eases gl ucagon r el ease.
PHYSI OLOGI C EFFECTS OF GLUCAGON
The principal t arget t issues for glucagon are t he liver and adipose t issue. The rol e of glucagon recept ors in t he rest of t he
t issues i s st ill unclear. Glucagon' s main physiologic effect is t o increase plasma glucose concent rat ions by st imulat ing de novo
hepat ic glucose product ion t hr ough gluconeogenesis and glycogen br eakdown; overall, t hese act ions count eract t he effect s of
i nsuli n ( Fi gure 7–5) . Glucagon mediat es it s effect s by binding t o t he glucagon G
s
prot ein–coupl ed recept or.
GLUCAGON RECEPTOR
The gl ucagon and GLP- 1 pept ide recept ors belong t o a family of GPCRs t hat include t hose for secret in, calcit onin, vasoact ive
int est inal polypept ide, parat hyroid hormone, and growt h hormone–rel easi ng f act or. The gl ucagon r ecept or is expressed in
l iver , pancreat ic - cells, kidney, adipose t issue, heart , and vascular t issues, as well as in some regions of t he br ain, st omach,
and adrenal glands. Glucagon binding act ivat es adenylat e cyclase and result s in int racel lular accumul at ion of cAMP,
mobil i zat ion of int racell ular Ca
2+
, prot ein kinase A act ivat ion, and phosphorylat ion of effect or prot eins. The glucagon- r ecept or
compl ex undergoes endocyt osis i nt o int r acel lular vesi cl es, wher e glucagon is degraded.
result ing release of ket one bodies int o t he blood. The plus sign ( + ) denot es st eps t hat are favor ed by insulin defici ency. FA, fat t y acid;
HMG, 3- hydroxy- 3- met hylglut aryl; HSL, hormone- sensit ive lipase.
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GLUCAGON EFFECTS AT TARGET ORGANS
The princi pal physiologic effect s of glucagon are mediat ed i n t he liver. Glucagon st imulat es hepat ic glucose out put by
st imul at ing glycogen breakdown and gl uconeogenesi s and decreasi ng gl ycol ysis Fi gure 7–6) . The key enzymat ic st eps
r egulat ed by glucagon t hat mediat e t he st imulat ion of hepat ic glucose out put ar e summarized in Table 7–3. The effect s of
glucagon on adi pose t i ssue are relevant pri mari ly duri ng periods of st ress or f ood depri vat i on, par t i cul arl y when i nsul in release
i s suppressed.
Fi gu r e 7– .
Glucagon recept or–mediat ed cellular effect s. Glucagon binds t o G prot ein–coupled recept or ( GPCR) on t arget cells. The principal eff ect s
of glucagon are mediat ed in hepat ocyt es wher e glucagon t hrough act ivat ion of adenylat e cyclase, elevat ion in cAMP leads t o incr eased
pr ot ein kinase A act ivit y leading t o phosphor ylat ion of enzymes responsible for cont rol of glucose met abolism. The ult imat e result is an
incr ease in hepat ic glucose product ion t hrough increased gluconeogenesis and glycogenolysis. G- 6- Pase, glucose- 6- phosphat ase; PEPCK,
phosphoenolpyruvat e carboxykinase; PGC- 1, per oxisome prolifer at or–act ivat ed recept or- coact ivat or- 1; PI P2, phosphat idylinosit ol 4,5-
biphosphat e. ( Repr oduced, wit h permission, from Guoqiang Jiang, Bei B. Zhang. Glucagon and regulat ion of glucose met abolism. Am J
Physiol Endocrinol Met ab. 2003; 284: E671–E678. Figure 1 of art icle.)
Ta l e 7 –3 . Ef f ect s of Gl u cagon on Hepat i c Gl u cose Met a ol i sm
Ef f ect on t ar get en yme Met a ol i c r espon se
I ncreased expressi on of glucose- 6- phosphat ase Frees gl ucose t o ent er
t he cir culat i on
Suppressi on of gl ucoki nase Decreases glucose ent r y
i nt o t he gl ycol yt ic
cascade
Phosphor ylat ion ( act ivat ion) of glycogen phosphor ylase St imulat es glycogenolysis
I nhibit ion of glycogen synt hase I nhibit s glycogen
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I n t he adipocyt e, glucagon st imulat es prot ein kinase A–mediat ed phosphor ylat ion ( act ivat ion) of hor mone- sensit ive l ipase, t he
enzyme t hat br eaks down t ri gl yceri des ( st or ed f at ) int o di acyl gl ycerol and f ree fat t y acids, r el easi ng t hem i nt o t he ci rcul at ion.
Gl ycerol released int o t he circul at ion can be ut i li zed i n t he li ver f or gl uconeogenesi s or f or reest erif i cat i on. Fr ee f at t y aci ds are
used as fuel by most t issues, pr edominant ly skelet al muscle and liver . I n t he liver, free fat t y acids are used for reest erificat ion
or t hey can undergo - oxidat ion and conver sion int o ket one bodies. Thus, ket ogenesis is regulat ed by t he balance bet ween
t he effect s of glucagon and insulin at t heir t ar get organs. The import ance of t his balance is evident during insulin deficiency
and gl ucagon excess, as seen in uncont r oll ed diabet es ( discussed lat er) .
Somat ost at i n
Somat ost at in is a 14–amino acid pept ide hor mone pr oduced by t he - cells of t he pancr eas. I t s release is st imulat ed by high-
fat , high- carbohydrat e, and part i cularl y prot ein- ri ch meal s, and is inhibi t ed by insul in. Somat ost at in has a gener alized
i nhi bi t ory ef fect on vir t ual ly all gast roi nt est inal and pancreat ic exocr ine and endocri ne f unct ions. The regulat i on of i t s release i s
not well st udied because of t he difficult y in analyzing t he small number of isl et cells t hat produce t his hormone. Furt her, t he
impor t ance of endogenous paracrine inhibit ion of insulin and glucagon release is not well est ablished. Because - cell s are
l ocat ed in t he per iphery of t he - cells and because blood flows from t he cent er of t he islet s of Langerhans t oward t he
per iphery, pancreat ic somat ost at in may have a limit ed cont r ibut ion t oward physiologic cont r ol of insulin and glucagon release.
However, exogenous admini st rat ion of somat ost at in does suppress t he r elease of bot h insulin and glucose and is used in t he
cli ni cal set t ing f or t he management of i nsuli n- or glucagon- produci ng t umors.
Pancr eat i c Pol ypept i de
Pancreat ic pol ypept i de i s a 36–amino acid pept ide hormone t hat bel ongs t o a pept ide family including neur opept ide Y and
pept ide YY. I t is pr oduced in t he endocrine t ype F cells locat ed in t he per iphery of pancr eat ic islet s and is released int o t he
circulat ion aft er ingest ion of food, exercise, and vagal st imulat ion. The effect s of pancreat ic polypept ide incl ude inhibit i on of
pancr eat i c exocri ne secret i on, gal l bladder cont ract i on, modulat i on of gast ri c acid secr et ion, and gast r oi nt est i nal mot il it y.
Pancreat ic pol ypept ide crosses t he blood- brai n bar rier and has been post ul at ed t o play a r ol e i n r egul at ing f eeding behavi or.
Amyl i n
Amyl in, or i sl et amyloi d polypept i de, is a 37–ami no aci d pept ide hormone t hat bel ongs t o t he cal ci t onin famil y, which i ncl udes
calcit onin, calcit onin gene- r el at ed pept i de, and adrenomedul li n. Amyli n i s synt hesi zed as a small precursor, undergoes post -
t ranslat ional modificat i on ( ami dat ion) , is st ored in - gr anules, and i s released al ong wi t h i nsuli n and C- pept ide. Pl asma amyli n
concent rat ions increase aft er a meal or glucose infusion. Amylin appears t o work wit h insuli n t o r egulat e plasma glucose
concent rat ions in t he bloodst ream, suppr essing t he post prandial secret ion of glucagon and slowing gast ric empt ying. I n
muscle, amyl i n opposes gl ycogen synt hesis and act i vat es gl ycogenol ysi s and gl ycol ysi s, t hereby i ncreasi ng l act at e product i on.
Ci rculat i ng amyl in i s increased in obesi t y, hypert ension, and gest at i onal diabet es; i t is l ow or absent i n t ype 1 di abet es
mellit us. I n t ype 2 diabet es, t he secret ion of amylin is impaired before t hat of i nsul in. Amylin is t he main component of
pancr eat ic islet amyloid, found in t he vast maj orit y of pat ient s wit h noni nsulin- dependent ( t ype 2) diabet es mell it us, and i s
t hought t o cont r ibut e t o dest ruct ion of t he pancreat ic - cell. Amylin binds t o a var iant of t he cal cit oni n GPCR. The modified
calci t onin recept or has hi gher affinit y for amylin, an effect mediat ed by t r ansmembrane prot eins known as recept or act ivit y–
modifying prot eins ( RAMPs) .
synt hesi s
St imul at ion of phosphoenolpyruvat e carboxykinase expressi on St imulat es
gluconeogenesi s
I nact ivat ion of phosphofruct okinase- 2 ( PFK- 2) and act ivat ion of fr uct ose- 6- phosphat ase. PFK- 2 is
t he kinase act ivit y and fruct ose- 2,6- bisphosphat ase ( F- 2,6- BPase) is t he phosphat ase act ivit y of
t he bifunct ional regulat ory enzyme, phosphofruct okinase- 2/ fr uct ose- 2, 6- bisphosphat ase ( PFK- 2/ F-
2,6- BPase) .
I nhibit s glycol ysi s
St imulat es
gluconeogenesi s
Suppression of act ivit y of t he pyr uvat e kinase Decreases glycolysi s
DI SEASES ASSOCI ATED I TH PANCREATI C HORMONES
Hor mone- Pr oduci n g Tumor s
Excess pancreat ic hormone pr oduct ion and release are usually due t o hormone- producing t umor s, wit h insulinoma being t he
most frequent . I nsulinomas pr oduce excessive amount s of insulin, and pat ient s present wit h episodes of hypoglycemia,
confusi on, aggressi veness, palpit at i ons, sweat i ng, convul sions, and even unconsciousness. These sympt oms are most l y
obser ved before breakfast and foll owing physical exercise. The compensat ory or count erregulat ory r esponse of t he body
i ncludes t he rel ease of cat echol amines, gl ucagon, cort i sol , and growt h hormone.
Glucagonomas ar e unusual t umor s t hat may produce sympt oms of diabet es. Excessive glucagon pr oduct ion by t he t umor may
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al so result i n an over all cat abolic effect on fat and muscle, l eading t o severe weight l oss and anorexia. Somat ost at inoma is a
r ar e t umor t hat may cause moderat e di abet es.
Di a et es Mel l i t us
The most common disease result i ng from impaired pancreat ic hormone r elease is diabet es mellit us. The 2 forms of diabet es,
t ype 1 and t ype 2, are charact erized by impair ed insulin release. Type 1 diabet es, also known as i nsulin- dependent di abet es
mellit us, is t he r esul t of - cell dest ruct ion. I t account s for 2–5% of cases and it occurs mor e frequent ly in younger people,
hence i t s ot her name, j uveni le- onset diabet es. Type 1 diabet es i s char act er ized by t he development of ket oacidosis in t he
absence of insulin t herapy. Type 2 diabet es result s from a loss of nor mal regulat ion of insulin secret ion and account s for more
t han 90% of diabet es cases. I t is usually associat ed wit h obesit y in adult s and is charact erized by mild hyperglycemia. I t rarely
leads t o ket oacidosis. Type 2 diabet es is oft en part of "syndrome X" or " insul in resist ance syndrome, " a met abolic syndrome
charact eri zed by hypert ension, at her oscl erosi s, and cent ral obesi t y.
The diagnosis of diabet es is based on plasma glucose levels obt ai ned i n t he fast ing st at e ( great er t han 126 mg/ dL) . Diabet es
can also present as random plasma glucose levels higher t han 200 mg/ dL in associat ion wit h sympt oms of diabet es ( polyuria,
polydipsia, and polyphagia) or as persist ent elevat ions i n plasma glucose levels fol lowing an or al glucose load ( gr eat er t han
200 mg/ dL, 2 hours aft er glucose ingest ion) . The pat hophysiology of t he disease involves impaired ent r y of glucose int o t he
cells and accumulat ion of glucose in t he blood. This process result s in increased plasma osmolarit y and urinary loss of glucose,
accompanied by excess loss of wat er and sodium ( pol yur i a) . The result ing dehydrat ion t r igger s compensat ory mechanisms
such as t hir st ( pol ydi psi a) . The i nabi l it y of t he cell s t o ut i li ze glucose resembl es a st at e of cel l ul ar st arvat ion, st i mulat i ng
hunger ( pol y phagi a) and t riggeri ng t he act ivat ion of compensat ory responses t o increase t he release and availabilit y of fuel
subst rat es t hough act ivat ion of lipol ysis and prot eolysi s. Lack of insulin result s in increased circul at ing levels of free fat t y acids
and gluconeogenic amino aci ds. These exceed t he liver' s capacit y for t heir met abolic ut ilizat ion, leading t o t he buildup of
ket one bodi es in t he blood ( diabet i c ket oacidosi s) and t hei r ur inary excret ion.
Di a et i c et oaci dosi s
Diabet i c ket oacidosi s is an acut e pat hol ogic event charact erized by elevat ed blood glucose levels and ket one bodi es
and met abol ic aci dosi s, r esul t ing dir ect ly from decreased insuli n availabil it y and simult aneous el evat ions of t he
count erregulat or y hor mones glucagon, cat echolami nes, cor t i sol, and growt h hormone. Diabet i c ket oacidosis is precipit at ed by
inf ect ions, discont inuat ion of or inadequat e insulin use, new- onset ( unt r eat ed) diabet es, and ot her event s such as t he st ress
associat ed wi t h surgery.
The insulin defici ency causes glucose t o accumulat e in t he blood. As ment ioned earlier, insuli n mediat es t he maj orit y of t he
body' s gl ucose disposal t hrough i t s ef fect s on skel et al muscl e. I n diabet i c ket oacidosi s, gl uconeogenesi s in t he li ver pr oceeds
unopposed by t he physi ologic presence of i nsuli n. The excess bl ood glucose increases osmolari t y, which, if severe, can r esul t
in diabet ic coma. The lack of insuli n and t he high levels of count er regulat ory hormones glucagon, epinephrine, and cort isol
combine t o increase t he act ivit y of hormone- sensi t i ve l i pase, increase t he release of f ree f at t y acids, and decrease t he act ivit y
of acet yl - CoA carboxylase, t hereby impairi ng t he reest erificat i on of free fat t y acids and promot ing fat t y acid conversion int o
ket one bodi es ( Figur e 7–6) . Fat t y acids r eleased int o t he circulat ion undergo - oxi dat i on t o acet yl - CoA in t he li ver. Act el y- CoA
condenses wit h oxaloacet at e t o form cit rat e in t he ent ry st ep t o t he Krebs cycle ( cit ric acid cycle or t ricarboxylic cycle) . Dur ing
i nsuli n def i ciency and excess gl ucagon, oxaloacet at e i s pr ef erent iall y used f or gluconeogenesi s, t hus decr easi ng it s avai l abil it y
for condensat ion wit h acet yl- CoA. As a result , acet yl- CoA is divert ed fr om ent eri ng t he Krebs cycl e and is used pref erent iall y
for ket one body format ion or ket ogenesis, t he process by which fat t y acids ar e t ransfor med int o acet oacet at e and 3-
hydroxybut yrat e i n hepat ocyt e mit ochondr ia. The st eps i nvolved i n ket ogenesi s ar e - oxidat ion of fat t y acids t o acet yl- CoA,
format ion of acet oacet yl - CoA, and conversion of acet oacet yl- CoA t o 3- hydroxy- 3- met hylglut aryl- CoA and t hen t o
acet oacet at e, which i s t hen reduced t o 3- hydr oxybut yrat e. The enzymes invol ved in ket ogenesis are summari zed i n Tabl e 7–4.
Acet oacet at e can be spont aneousl y decarboxylat ed t o acet one, a highl y fat - soluble compound t hat is excret ed slowly by t he
lungs and is r esponsible for t he fruit y odor of t he breat h of i ndividual s wit h diabet ic ket oacidosis.
Ta l e 7 – . Thr ee Pr i nci p al En y mes I n ol ed i n et ogenesi s
En yme Ti ssue Funct i on
Hor mone- sensit ive
l ipase
Adi pocyt es Breaks down t ri gl yceri des, releasing f at t y acids i nt o t he ci rculat i on
Acet yl- CoA
carboxylase
Liver Cat al yzes t he conver sion of acet yl- CoA t o malonyl - CoA, t he primar y subst rat e of fat t y
acid bi osynt hesi s
HMG- CoA synt hase Liver I nvolved in t he conversion of acet yl- CoA t o acet oacet at e
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During diabet ic ket oacidosis, high amount s of ket one bodies are released int o t he blood, and a high r at io ( 3: 1 or higher) of 3-
hydroxybut yrat e t o acet oacet at e i s generat ed because of t he hi ghl y reduced st at e of hepat i c mi t ochondri a. These ket one
bodies can freely diffuse across cell membranes and serve as an energy source for ext rahepat ic t issues i ncluding t he brain,
skelet al muscl e, and kidneys. Ket one bodi es are f il t ered and reabsorbed i n t he ki dney. At physi ologi c pH, ket one bodi es, wi t h
t he except i on of acet one, dissociat e compl et el y. The result i ng li berat i on of H
+
from ket one body met abolism exceeds t he
blood' s buffer ing capacit y, leading t o met abolic acidosis wit h an increased anion gap. I f severe, t hi s condit ion can lead t o
coma.
Type 2 Di a et es
Type 2 diabet es i s t he r esul t of i nadequat e responsi veness of t he - cells t o glucose, which is lat er followed by a net reduct ion
in - cel l mass and a decreased responsiveness of peri pheral t issues t o insuli n act i on. Pat ient s wi t h t ype 2 di abet es secr et e
normal amount s of insulin during fast ing, but in response t o a glucose load ( or a meal ) , t hey secret e considerably less insulin
( 70%) t han nondiabet ic pat ient s. I n addit ion t o a r educt ion in i nsulin release, t he pat t ern of insul in release is also alt ered
fol lowing a meal, wit h pulses t hat are si gnificant ly smaller, sluggish, and errat ic, part icularly aft er dinner. Thi s abnormalit y
r esul t s in signi ficant ly higher level s of fast ing glucose in t hese pat ient s.
Regardl ess of t he et iol ogy ( eg, abnor mali t i es i n glucose t ranspor t ; abnormal i nsul i n synt hesi s, processi ng, st or age, or
secr et i on) , t he earli est physiol ogic indi cat i on of - cel l dysfunct i on i s a delay i n t he acut e i nsul in response t o gl ucose. The
defect in t he ini t ial response t o a glucose load leads t o an excessive r ise in plasma glucose, which i n t urn produces a
compensat or y and exaggerat ed second- phase hyperinsuli nemic r esponse. Thi s ini t ial period of sust ai ned hyperinsul inemia
downregulat es t he insulin r ecept or s, decreasing t he sensit ivit y of t issues t o insulin act ion and pr oducing a st at e of insulin
r esi st ance. The mai n pat hol ogi c def ect s in di abet es ar e excessi ve hepat i c gl ucose product i on, def ect ive - cell secret ory
f unct i on, and per ipheral i nsul in resi st ance.
I nsul i n Resi st ance
I nsul in resist ance is t he i nabi li t y of per ipheral t ar get t issues t o r espond proper ly t o normal ci rculat i ng concent r at ions of insuli n.
To maint ain euglycemia, t he pancr eas compensat es by secret ing increased amount s of insulin. I n pat ient s wit h t ype 2
diabet es, insulin resi st ance precedes t he onset of t he disease by several years. Compensat ing for insuli n resist ance by an
i ncrease i n i nsul in release i s ef fect ive only t emporari ly. As i nsul i n resi st ance i ncreases, impai red glucose t olerance devel ops.
Ul t imat el y, f ai lure or exhaust i on of t he pancr eat i c - cell resul t s i n decreased i nsuli n secr et i on. The combinat i on of insul in
r esi st ance and i mpai red - cel l f unct i on charact eri zes cl inical t ype 2 di abet es. Exerci se has been demonst r at ed t o i ncrease
glucose t ranspor t in skel et al muscl e and t o decrease i nsul in resi st ance i n pat ient s wi t h t ype 2 diabet es. The i ncrease i n glucose
t ransport r esul t ing f r om exer cise i s not mediat ed t hrough t he i nsuli n r ecept or . The si gnali ng pat hways invol ve increased
cyt osol ic Ca
2+
and t he enzyme AMP- act i vat ed pr ot ei n kinase. AMP- act i vat ed prot ein ki nase is act ivat ed during exerci se and
has been t ermed a mast er met abol ic swit ch because it phosphorylat es key t arget prot eins t hat cont rol flux t hrough met abolic
pat hways.
Cl i ni cal E al uat i on of Di a et es
According t o t he American Diabet es Associat ion, hyperglycemia ( fast ing glucose at least 126 mg/ dL or random glucose at least
200 mg/ dL) is t he diagnost ic crit eri on and a main pr ognost ic paramet er in diabet es. The sl ow post - t ransl at ional and
nonenzymat ic glycat ion of hemoglobin provides a measur e of chronic glycemia. Values of glycosylat ed hemoglobin are st r ongly
cor relat ed wi t h t he average bl ood gl ucose l evel over t he preceding 1–3 mont hs and can be obt ained in t he nonfast ed st at e.
The measurement of glycosylat ed hemoglobin is used t o moni t or gl ycemi c cont r ol in pat i ent s wi t h known di abet es.
Tr eat ment of t h e Di a et i c Pat i ent
The goal of t herapy is t ight glycemic cont rol , which has been shown t o delay t he development of microvascul ar complicat ions
associat ed wi t h di abet es. Glucose homeost asis r esul t s f rom t he regulat ed bal ance among hepat i c gl ucose r el ease, di et ar y
glucose absorpt ion, and skelet al muscle and adipose t issue glucose upt ake and disposal. All 3 of t hese component s have been
t ar get ed for pharmacologic t reat ment of diabet ic pat ient s. Some of t he approaches used, in addit ion t o convent ional insulin,
warrant ment ion because t hey affect t he physiologic mechanisms of pancr eat ic hor mone release and t arget or gan effect s on
t he cont rol of glucose.
Su l f onyl ur eas Sulfonyl ur eas incr ease insuli n r el ease by closi ng K
+
ATP channels i n t he pancreat ic - cell membr ane. This
act ion is mediat ed by binding of t he drug t o t he sulfonylurea recept or subunit of t he channel. Because t ype 1 diabet es i s
charact eri zed by - cell dest ruct ion, t his approach is ineffect ive in t hose pat ient s.
Bi gu an i des Biguanides such as met f ormi n reduce hepat ic glucose out put ( primar il y t hrough inhibit ion of gluconeogenesis
and, t o a l esser ext ent , glycogenol ysis) and i ncrease insuli n- st i mulat ed glucose upt ake in skel et al muscle and adipocyt es. I n
CoA, coenzyme A, HMG, 3- hydroxy- 3- met hyl gl ut aryl.
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insulin- sensi t ive t issues ( such as skelet al muscle) , met for min facilit at es glucose t ranspor t by increasing t yrosi ne kinase act i vit y
in insulin r ecept ors and enhanci ng glucose t ransport er t r afficking t o t he cell membrane.
Al pha- gl ucosi dase i nhi i t or s Alpha- glucosidase inhibit ors delay t he int est inal absor pt ion of carbohydrat es t hrough
inhibit ion of t he br ush- border enzymes t hat hydrol yze pol ysacchari des t o gl ucose.
Th i a ol i di nedi on es Thiazol idinediones reduce i nsul i n resi st ance i n skelet al muscle by act ivat i on of t he - isoform of t he
per oxisome proli fer at or –act ivat ed recept or in t he nucl eus, t hereby affect ing t he t ranscript ion of several genes involved in
glucose and lipid met abolism and energy bal ance. Among t he genes t hat are affect ed are t hose t hat code for lipoprot ein
lipase, fat t y acid t ranspor t er prot ei n, adipocyt e fat t y acid–binding prot ein, fat t y acet yl- CoA synt hase, malic enzyme,
glucokinase, and t he GLUT- 4 glucose t ransport er.
Gl ucagon- l i e pept i de GLP- 1 ampl ifi es glucose- i nduced insuli n r el ease. I n addi t i on, GLP- 1 increases insulin biosynt hesi s
and insulin gene expression and has t ropic and ant iapopt ot ic effect s on t he pancreat ic - cells.
EY CONCEPTS
I nsulin release is under nut r ient , neur al, and hor monal regulat ion.
The pancr eat i c - cell funct ions as a glucose sensor in t he process of insulin release.
The PI
3
- kinase pat hway mediat es most of insuli n' s met abolic effect s, and t he MAPK pat hway is most ly involved in
mediat i ng t he proli fer at ive responses.
The pri ncipal met aboli c eff ect s of i nsuli n are t o incr ease glucose ut il i zat ion in skel et al muscl e, suppress hepat i c
gl ucose pr oduct i on, and i nhi bi t li pol ysi s.
Gl ucagon ant agonizes i nsulin' s ef fect s by st imul at ing hepat ic glucose release.
A disr upt ion in t he balance of insuli n and glucagon leads t o ket ogenesis and hyperosmol ar coma.
SUGGESTED READI NGS
Bergst en P. Pat hophysi ol ogy of i mpai red pul sat il e i nsuli n r el ease. iabet es Met ab es ev. 2000; 16: 179. [ PMI D: 10867718]
Cefalu WT. Evaluat ion of alt ernat ive st rat egies for opt imizing glycemia: progress t o dat e. Am J Med. 2002; 113( suppl 6A) : 23S.
Ger ich JE. Mat ching t reat ment t o pat hophysiology in t ype 2 diabet es. l in her . 2001; 23: 646. [ PMI D: 11394726]
Hauner H. The mode of act ion of t hiazolidinediones. iabet es Met ab es ev. 2002; 18( suppl 2) : S10.
Kirpichnikov D, McFarlane SI , Sowers JR. Met formin: an updat e. Ann I nt er n Med. 2002; 137: 25. [ PMI D: 12093242]
Laffel L. Ket one bodies: A review of physiology, pat hophysiology and applicat ion of monit oring t o diabet es. iabet es Met ab es
ev. 1999; 15: 412. [ PMI D: 10634967]
Lang J. Molecular mechanisms and regulat ion of i nsulin exocyt osis as a paradigm of endocrine secret i on. Eur J iochem.
1999; 259: 3. [ PMI D: 9914469]
LeRoi t h D. Bet a- cell dysf unct i on and i nsul in resi st ance i n t ype 2 di abet es: r ole of met abol i c and genet ic abnormal i t ies. Am J
Med. 2002; 113( suppl 6A) : 3S.
Por ksen N et al. Human insuli n rel ease pr ocesses measured by int rapor t al sampli ng. Am J Physiol Endocrinol Met ab.
2002; 282: E695.
Ri cht er EA, Derave W, Woj t aszewski JFP. Glucose, exerci se and i nsul in: emergi ng concept s. J Physiol . 2001; 535( Pt 2) : 313.
Ryder JW, Chibal in AV, Zi erat h JR. I nt racell ular mechani sms underl yi ng increases i n gl ucose upt ake i n r esponse t o i nsul in or
exer cise i n skel et al muscl e. Act a Physi ol cand. 2001; 171: 249. [ PMI D: 11412137]
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Salt iel AR, Pessin JE. I nsulin signaling pat hways in t ime and space. rends ell iol . 2002; 12: 65. [ PMI D: 11849969]
St r aub SG, Sharp GWG. Glucose- st imulat ed signaling pat hways in biphasic insulin secr et ion. iabet es Met ab es ev.
2002; 18: 451. [ PMI D: 12469359]
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Slide 2

Causes/Types of DM
Type 1 (IDDM): •5-10% of diabetics •Characterised by pancreatic β-cell destruction and absolute deficiency of insulin •Caused by combo of genetic, immunological and environmental stimuli causing auto-immune destruction of β-cells •Auto-antigens responsible aren’t necessarily always β-cell specific?

Type 2 (NIDDM): •90-95% of diabetics •Combination of peripheral resistance to insulin and inadequate insulin secretion •Caused by insulin resistance which is initially compensated by increased insulin secretion, but eventually becomes uncompensated •Has a stronger genetic component, but is polygenic/multifactorial Gestational Others

Type 1 DM is an autoimmune disease characterized by pancreatic β-cell destruction and an absolute deficiency of insulin. It accounts for approximately 5% to 10% of all cases, and is the most common subtype diagnosed in patients younger than 20 years of age. Polymorphisms in the HLA complex account for 40–50% of the genetic risk of developing type 1 DM and primarily involve the DR3/4 and some of the DQ phenotypes. Type 2 DM is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β cells (“relative insulin deficiency”). Approximately 90% to 95% of diabetic patients have type 2 diabetes, and the vast majority of such individuals are overweight/obese. Although classically considered “adult-onset,” the prevalence of type 2 diabetes in children and adolescents is increasing at an alarming pace. A more in-depth pathophys analysis of NIDDM aetiology: Type 2 DM is characterized by impaired insulin secretion, insulin resistance, excessive hepatic glucose production, and abnormal fat metabolism. Obesity, particularly visceral or central (as evidenced by the hip-waist ratio), is very common in type 2 DM (80% or more are obese). In the early stages of the disorder, glucose tolerance remains near-normal, despite insulin resistance, because the pancreatic beta cells compensate by increasing insulin output. As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose

production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure ensues.

The pathogenesis of the two major types is discussed separately. A variety of monogenic and secondary causes are responsible for the non-Type I/II cases. and blood vessels are the same. It should be stressed that while the major types of diabetes have different pathogenic mechanisms.Slide 3 Causes/Types of DM American Diabetes Association: Position statement from the American Diabetes Association on the diagnosis and classification of diabetes mellitus. but first we briefly review normal insulin secretion and the mechanism of insulin signaling. since these aspects are critical to understanding the pathogenesis of diabetes. the long-term complications affecting the kidneys. eyes. as are the principal causes of morbidity and death. Note MODY – mentioned in lecture . nerves.

kidneys. and peripheral nerves. respectively. At least three distinct metabolic pathways have been implicated in the deleterious effects of persistent hyperglycemia on peripheral tissues. stroke. . resulting in increased risk of myocardial infarction. caused mainly by lesions involving both large. The effects of microvascular disease are most profound in the retina. and lower extremity gangrene.and medium-sized muscular arteries (macrovascular disease) and capillary dysfunction in target organs (microvascular disease). The pathways are discussed below. and neuropathy. although the primacy of any one over the others is unclear. resulting in diabetic retinopathy.Slide 4 Pathophys of Hyperglycaemia Complications Acute: •Diabetic Ketoacidosis •Hyperglycaemic Hyperosmolar State Chronic: •Advanced Glycation End-Products •Activation of PKC •Polyol Pathway Disturbance •Hexosamine Pathway Crash Course! The morbidity associated with long-standing diabetes of either type results from several serious complications. Macrovascular disease causes accelerated atherosclerosis among diabetics. nephropathy.

Slide 5 Diabetic Ketoacidosis (DKA) Someone else .

will eventually lead to dehydration. and lactic acidosis may itself cause coma. weight loss. or coma. tachycardia. Accumulation of lactate in the blood (lactic acidosis) may also complicate diabetic ketoacidosis if the tissues become hypoxic. lethargy. The body's cells become progressively dehydrated as water is taken from them and excreted and electrolyte imbalances are also common. the hyperosmolarity of the plasma causes unconsciousness (hyperosmolar coma). the plasma glucose can be elevated to such a degree that independent of plasma pH. High BGL Glycosuria High Blood Osmolarity Dehydration of Cells CNS Failure Coma in diabetes can be due to acidosis and dehydration.Slide 6 Hyperglycaemic Hyperosmolar State Typical HHS: •elderly individual with type 2 DM •Several-week history of polyuria. . water is osmotically drawn out of cells into the blood and there is glycosuria. •Ex: profound dehydration and hyperosmolality and reveals hypotension. --. combined with the loss of water. However. the osmotic effect of high glucose levels. and altered mental status. If fluid is not replaced. and diminished oral intake •Culminates in mental confusion. This results in loss of water and an increase in blood osmolarity.CNS sensitive to osmolarity Cause: When a person with a very high (usually considered to be above 300 mg/dl (16 mmol/L)) BGL.

which alters their structure and inhibits their function.and extracellular proteins. . AGE cause: •Bind to AGE receptors (RAGE) on leukocytes. via the nonenzymatic glycosylation of intra. Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins.Slide 7 Advanced Glycosylation End-Products Elevated intracellular levels of glucose cause a non-enzymatic covalent bonding with proteins. which bind to a cell surface receptor. endothelium and vascular smooth muscle •Cross-link proteins (esp ECM) Effects: •Cytokines from intimal macrophages •ROS in endothelium •Procoagulant activity •Proliferation of SM and ECM synthesis •Decreased vessel elasticity •Proteolytic resistance and protein deposition enhancement •Reduce NO synthesis •Endothelial Dysfunction •Glomerular dysfunction Contribution to microangiopathy and hence neuropathy Increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs).

and both contribute to the long-term complications of diabetic microangiopathy. leading to increased deposition of extracellular matrix and basement membrane material •Production of PAI-1. and hence causes activation of PKC. leading to reduced fibrinolysis and possible vascular occlusion •Production of pro-inflammatory cytokines by the vascular endothelium Activation of intracellular protein kinase C (PKC) by Ca*2++ ions and the second messenger diacyl glycerol (DAG) is an important signal transduction pathway in many cellular systems. It should be evident that some effects of AGEs and activated PKC are overlapping. due to decreased expression of endothelial nitric oxide synthase •Production of profibrogenic factors like TGF-β. implicated in the neovascularization characterizing diabetic retinopathy •Elevated levels of endothelin-1 and decreased levels of NO.Slide 8 Activation of PKC Hyperglycaemia stimulates synthesis of DAG from glycolytic intermediates (DAG required for PKC activation) Abnormal PKC activity causes: •Production of proangiogenic vascular endothelial growth factor (VEGF). . The downstream effects of PKC activation are numerous. Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates.

lenses. blood vessels ICF Glucose Aldose Reductase NADPH NAD Sorbitol Glycolysis etc NADPH required for reduced glutathione regeneration (antioxidant) Effects: •Redox potential -> ROS generation •Inc cellular osmolality In some tissues that do not require insulin for glucose transport (e. kidneys. kidneys. Increased sorbitol concentration alters redox potential. Hyperglycemia increases glucose metabolism via the sorbitol pathway. but when increased. nerves. Minimal effect though? . blood vessels). lenses.Slide 9 Polyol Pathway Disturbance Some tissues don’t require insulin for glucose transport – nerves. persistent hyperglycemia in the extracellular milieu leads to an increase in intracellular glucose.g. generates reactive oxygen species.. increases cellular osmolality. some glucose is converted to sorbitol by the enzyme aldose reductase. Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis.

Slide 10 Hexosamine Pathway ICF hyperglycaemia increases flux through the hexosamine pathway via F6P synthesis (glycolysis intermediate). -> O-linked glycosylation and proteoglycan production Effects: •Glycosylation of endothelial NO synthase •Changes in gene expression of TGF and PAI-1 A fourth theory proposes that hyperglycemia increases the flux through the hexosamine pathway. The hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor (TGF-) or plasminogen activator inhibitor-1 (PAI-1). a substrate for O-linked glycosylation and proteoglycan production that alters signalling pathways and TF inductino. . which generates fructose-6-phosphate.

but it would have taken all day.Slide 11 Synthesis of Everything = everything goes wrong I was going to go through an example (e. Wikipedia is actually quite accurate on each topic .g. Diabetic retinopathy) that went through it all.

Slide 12 References • Lecture material. Professional Edition. •Something else I forgot to write down . Updated Edition. 8th ed. 2nd ed. •Hall: Guyton and Hall Textbook of Medical Physiology. 2012 •Harrison's Online •Boron: Medical Physiology. •Kumar: Robbins and Cotran Pathologic Basis of Disease. 12th ed.

The direction of blood flow is preferentially from the center of the islet to the periphery. Identify the disease states caused by oversecretion. dietary glucose absorption. Although islets represent only 1–2% of the mass of the pancreas. Normal pancreatic function involving the production and release of the hormones insulin and glucagon is essential for the physiologic control of glucose homeostasis. sympathetic.. and pancreatic polypeptide. and glucose uptake and disposal from skeletal muscle and adipose tissue. Following first-pass hepatic metabolism. undersecretion. The pancreatic hormones insulin and glucagon play central roles in regulating each of these processes and their overall effects are in part modified by other hormones such as growth hormone. Maintenance of glucose homeostasis is similar to the maintenance of calcium balance discussed in Chapter 6. Sympathetic nerve stimulation inhibits basal and glucose-stimulated insulin secretion and somatostatin release and stimulates glucagon and pancreatic polypeptide secretion. cortisol. surrounded by . pituitary adenylate cyclase–activating polypeptide. The arterial blood supply to the pancreas is derived from the splenic artery and the superior and inferior pancreaticoduodenal arteries. This arrangement plays a role in the cell-to-cell paracrine regulation of hormone release. Therefore. and storage of energy substrates. somatostatin. and gastrinreleasing peptide are released from the parasympathetic nerve terminals. small clusters of endocrine cells called the islets of Langerhans. Identify the time course for the onset and duration of the biologic actions of insulin and glucagon.AccessMedicine | Print: Chapter 7. . and describe the principal manifestations of each. Most of the pancreatic mass is composed of exocrine cells that are clustered in lobules (acini) divided by connective tissue and connected to a duct that drains into the pancreatic duct and into the duodenum.and -cells are exposed to high concentrations of hormones produced by the -cells (ie.and -cells. and epinephrine. and their chemical nature. their cells of origin. contributing to the inhibition of glucagon release by high local insulin concentrations. with the -cells located centrally. Parasympathetic. the pancreatic endocrine hormones are distributed to the systemic circulation. and hormonal mechanisms that regulate pancreatic hormone release. FUNCTIONAL ANATOMY The pancreas is a retroperitoneal gland divided into a head. PANCREATIC HORMONES Insulin mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Endocrine Pancreas Page 1 of 17 Endocrine Physiology. galanin. and sensory nerves richly innervate the pancreatic islets. The -cells constitute about 73–75% of the total mass of endocrine cells. Understand the nutrient. or decreased sensitivity to insulin. and pancreatic polypeptide. Vagal nerve activation stimulates the secretion of insulin. which is secreted into the small intestine to aid in the digestive process. amylin. and an even smaller number of cells (1%) secrete pancreatic polypeptide. This chapter focuses on the endocrine function of the pancreas through the release of insulin and glucagon and the mechanisms by which these hormones regulate events central to maintaining glucose homeostasis. 3e > Chapter 7. the endocrine pancreas also secretes somatostatin. and their principal secretory product is insulin. Endocrine Pancreas > OBJECTIVES Identify the principal hormones secreted from the endocrine pancreas. the liver. they receive about 10–15% of the pancreatic blood flow. and neuropeptide Y are released from sympathetic nerve terminals. the process involves a regulated balance among hepatic glucose release (from glycogen breakdown and gluconeogenesis). Norepinephrine. and tail and is located near the duodenum. In the case of glucose. in which several tissues and hormones interact in the regulatory process. List the principal target organs for insulin and glucagon action and their major physiologic effects. 5/17/2012 . The rich vascularization by fenestrated capillaries allows ready access to the circulation for the hormones secreted by the islet cells. ENDOCRINE PANCREAS: INTRODUCTION The pancreas is a mixed exocrine and endocrine gland that plays a central role in digestion and in the metabolism. insulin). Acetylcholine. is exposed to the highest concentrations of pancreatic hormones. Venous blood from the pancreas drains into the hepatic portal vein. The localization of these cell types within the islets has a particular pattern. and the respective neurotransmitters and neuropeptides released from their nerve terminals exert important regulatory effects on pancreatic endocrine hormone release. body. The -cells account for about 18–20% of the endocrine cells and are responsible for glucagon secretion. vasoactive intestinal polypeptide. Embedded within the acini are richly vascularized. Therefore. glucagon.. a principal target organ for the physiologic effects of pancreatic hormones. In addition to secreting insulin and glucagon. utilization. A small number of -cells (4–6%) secrete somatostatin. neural. in which 2 endocrine cell types ( and ) predominate.ch. The product of the pancreatic exocrine cells is an alkaline fluid rich with digestive enzymes.tmp\0071613013.

. This release of insulin granules from different pools leads to a biphasic pattern of insulin release in response to stimulation of the -cell by glucose. which accumulate in the -cell cytosol and are coreleased in response to glucose stimulation. Shown are portal insulin concentrations during basal state (left) and after ingestion of a mixed meal (right) in normal patients. generating proinsulin (Figure 7–1). Grofte T. Insulin release occurs in a biphasic mode and is derived from secretory granules that are immediately available for release (<5%). A. Insulin circulates in its free form and has a half-life of 3–8 minutes. Ca++. Figure 7–1. C. Human insulin release processes measured by intraportal sampling. Rossle M. Most of the granules (more than 95%) belong to a reserve pool and need to be chemically modified. Am J Physiol Endocrinol Metab. Veldhuis JD. as discussed in Chapter 1 (Figure 1–5). C-peptide links the .AccessMedicine | Print: Chapter 7.. About 5% of the granules are stored in a readily releasable pool. with permission.ch. allowing proper folding of the molecule and the formation of disulfide bonds between the 2 chains. 5/17/2012 .282(3):E695–E702. from granules that must undergo a series of preparatory reactions including mobilization to the plasma membrane (>95%). Insulin is degraded mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Insulin is composed of 2 chains. and a connecting peptide in the middle known as the C-peptide.and -chains. Endocrine Pancreas Page 2 of 17 INSULIN SYNTHESIS The process involved in the synthesis and release of insulin. B. The active form of insulin is produced by modification of proinsulin by cleavage of the C-peptide structure linking the and chains. Mengel A. Vilstrup H. ADP and. Figure 4 of article. an chain of 21 amino acids and a chain of 30 amino acids.) Stimulation of the pancreatic -cell leads to exocytosis of the contents of the secretory granules. In the endoplasmic reticulum. Insulin and the free C-peptide are packaged into secretory granules in the Golgi apparatus and are released together. Juhl C. These secretory granules accumulate in the cytoplasm. A third disulfide bond is present within the chain. from: Porksen N. or even physically translocated. (Reproduced. Insulin synthesis starts with the translation of insulin mRNA into an inactive protein called preproinsulin. Schmitz O. proinsulin is processed by specific endopeptidases known as prohormone convertases.tmp\0071613013. Preproinsulin undergoes cleavage of its signal peptide during insertion into the endoplasmic reticulum. Both insulin and the cleaved C-peptide are packaged in secretory granules. 2002. with the resulting release of equal amounts of insulin and C-peptide into the portal circulation. a polypeptide hormone. Removal of the C-peptide exposes the end of the insulin chain that interacts with the insulin receptor. by the -cells of the pancreas is similar to that of other peptide hormones. These granule preparatory or maturation processes are modulated by intracellular levels of ATP. Proinsulin consists of an amino-terminal chain. a carboxy-terminal -chain. Insulin release in response to a meal is characterized by increased frequency and amplitude of pulsatile release. which cleave the C-peptide to generate the mature form of insulin. Insulin levels in the circulation average 43–186 pmol/L (6–26 U/mL) in the fasting state. Preproinsulin undergoes post-translational modification in the endoplasmic reticulum (ER) to form proinsulin. Greisen J. to become immediately available for release. Only a small proportion of the cellular stores of insulin are released even under maximal stimulatory conditions. The chains are held together by 2 disulfide (S-S) bonds.

and glucose-induced changes in the extracellular potassium concentration and in nitric oxide. In particular. the relatively long half-life of the peptide (35 minutes) allows its release to be used as an index of the secretory capacity of the endocrine pancreas. Additional degradation of insulin occurs in the kidneys as well as at target tissues by insulin proteases following endocytosis of the receptor-bound hormone. Endocrine Pancreas Page 3 of 17 predominantly by the liver during its first pass. which extracts about 40–80% of insulin delivered. some of the proposed mechanisms include gap junctions between the pancreatic -cells. glucagon-like peptide-1 (GLP-1). In the past. The importance of C-peptide is that unlike insulin. somatostatin.AccessMedicine | Print: Chapter 7. membrane depolarization. Insulin release rises after a meal in response to the increases in plasma levels of glucose and amino acids.. C-peptide. and substrate factors have been shown to play an important role in the pulsatile pattern of insulin release. hormonal. mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Figure 7–2. The synchronized increase in insulin release is thought to be the result of recruitment of -cells to release insulin. REGULATION OF INSULIN RELEASE The release of insulin throughout the day is pulsatile and rhythmic in nature.tmp\0071613013. Glucose is the principal stimulus for insulin release from the pancreatic -cells. intrapancreatic neural. The amino acid sequence of insulin is highly conserved among species. porcine and bovine insulin were used to treat patients with diabetes. and epinephrine). The pulsatile release of insulin is important for achieving maximal physiologic effects. Although it is not clear how the -cells communicate with each other to synchronize the release of insulin. In addition. and neurotransmitters (norepinephrine and acetylcholine) (Figure 7–2). appears to have some biological action as recent evidence indicates that replacement of C-peptide improves renal function and nerve dysfunction in patients with type 1 diabetes. it appears to be critical in the suppression of liver glucose production and in insulin-mediated glucose disposal by adipose tissue. avoiding problems such as the development of antibodies to nonhuman insulin.ch. aiding the propagation of the synchronization between the cells. 2 identifiable rhythms occur with periods of 5–10 and 60–120 minutes (Figure 7–1). allowing the passage of ions and small molecules. human recombinant insulin is available and has replaced animal-derived insulin. The pancreatic -cell functions as a fuel sensor that responds to changes in plasma levels of energy substrates releasing insulin in response to integrated signals from nutrients (glucose and amino acids). which was previously thought to be biologically inert. hormones (insulin. it is not readily degraded in the liver. Thus. and in addition exerts a permissive effect for the other modulators of insulin secretion.. Secretion is the result of a combination of an increase in the total amount of insulin released in each secretory burst (by about 50%) and an increased pulse frequency of a similar magnitude Figure 7–1). The receptor and signaling mechanisms involved in mediating these responses are still under investigation. Currently. 5/17/2012 .

phospholipase C. Glucose enters the -cell through a membrane-bound glucose transporter (GLUT-2). cholecystokinin. As a result. activation (opening) of voltage-dependent Ca2+ channels. This is the basis for the therapeutic use of sulfonylurea drugs in the treatment of diabetes.ch. AC. All rights reserved. It is important to note that the regulation of K+ channels by ATP is mediated by the sulfonylurea receptor. and increased Ca2+ influx. glucagon-like peptide-1. Glucose enters the -cell by a specific glucose-transporter protein (GLUT-2) and is immediately phosphorylated by glucokinase. an increase in the ATP/ADP ratio in the cytosol. GLP-1. Figure 7–3. including hormones (glucagon-like peptide-1) and neurotransmitters (acetylcholine).. mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Endocrine Pancreas Page 4 of 17 Regulation of insulin release. the generation of metabolic intermediates. This process results in membrane depolarization. NEJM. the enzyme glucokinase phosphorylates glucose in the initial step of glycolysis. Copyright © Massachusetts Medical Society.345:971.) The glucose-induced stimulation of insulin release is the result of glucose metabolism by the -cell. with permission. there is an increased influx of extracellular Ca2+ as well as mobilization of Ca2+ from intracellular stores leading to the fusion of insulin-containing secretory granules with the plasma membrane and the release of insulin (and C-peptide) into the circulation. 2001. Mechanisms of disease: Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. 5/17/2012 . Glucose is the principal stimulus for insulin release from the pancreatic -cell. and a rise in intracellular Ca2+ (Figure 7–3). CCK. (Modified. The rise in intracellular Ca2+ concentrations triggers the exocytosis of insulin secretory granules and the release of insulin into the extracellular space and into the circulation. reducing the efflux of K+. The increased concentrations of ATP and resulting greater ATP/adenosine diphosphate (ADP) ratio leads to inhibition and closure of the ATP-sensitive K+ channels (the target of sulfonylurea drugs). PLC. Glucose synergizes with these mediators and enhances the secretory response of the -cell to these factors.AccessMedicine | Print: Chapter 7. adenylate cyclase.. The resulting increase in intracellular ATP levels inhibits (closes) the ATPsensitive K+ channels (KATP) in the -cell. leading eventually to the generation of acetyl-coenzyme A (CoA) and adenosine triphosphate (ATP) by the Krebs cycle. Formation of glucose-6-phosphate in the first step of glycolysis initiates the glycolytic metabolism of glucose followed by the Krebs cycle leading to generation of adenosine triphosphate (ATP). resulting in depolarization of the plasma membrane and opening of the voltage-dependent Ca2+ channels.tmp\0071613013. Addition factors can also stimulate insulin release from the -cell. Once inside the -cell. from Fajans SS et al.

Signaling pathways including the phosphatidylinositol-3-kinase (PI3-K) and the mitogen-activated protein kinase (MAPK) cascades The -cell Ca2+ concentrations can also be elevated by amino acids through their metabolism and ATP generation. This results in downstream activation of cellular events mediated through the phosphorylation of insulin receptor substrates. Then p85 is constitutively bound to the catalytic subunit (p110). Copyright © Massachusetts Medical Society. one of the immediate effects of insulin is the active recruitment of GLUT-4. Activation of phosphoinositide-3-kinase is a major pathway in the mediation of insulin-stimulated glucose transport and metabolism. Endocrine Pancreas Page 5 of 17 contribute to the overall effects of insulin. stored in intracellular vesicles to the cell surface. These substrates form complexes with docking proteins such as phosphoinositide-3-kinase at its 85-kDa subunit (p85) by means of SH2 (Scr homology region 2) domains.tmp\0071613013. from Shepherd PR. All rights reserved. Insulin binding to the receptor activates the intrinsic kinase activity of the intracellular domain of the receptor. Insulin binds to its receptor in the plasma membrane.AccessMedicine | Print: Chapter 7. Exercise can also stimulate glucose transport by pathways that are independent of phosphoinositide-3-kinase and thought to involve 5'-AMP-activated kinase. or by direct mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Glucose transporters and insulin action: Implications for insulin resistance and diabetes mellitus.341(4):248–257. with permission.) Insulin-receptor signaling.ch.. (Reproduced.. 1999. resulting in phosphorylation of the receptor and insulin-receptor substrates such as the IRS molecules. Kahn BB. 5/17/2012 . NEJM. As shown in the insert.

GLP-1 raises levels of cyclic adenosine monophosphate (cAMP) and activates cAMP-dependent protein kinase A. and an intracellular segment that has intrinsic tyrosine kinase activity controlled by insulin binding to the extracellular -subunit. early (within minutes). adipose tissue. This biphasic response to glucose is a major characteristic of glucose-stimulated insulin secretion.tmp\0071613013. and liver Lipid metabolism Fatty acid and triacylglycerol synthesis in tissues Uptake of triglycerides from the blood into adipose tissue and muscle Rate of cholesterol synthesis in the liver Protein metabolism Amino acid transport into tissues Protein synthesis in muscle... Overall. The short-term regulation of insulin release is mediated through modification of proinsulin mRNA translation. and the insulin-related receptor. all of which are involved in cell division. and GLP-1. diacylglycerol. metabolism. a transmembrane segment. The activated receptor phosphorylates tyrosine residues of several proteins known as insulin-receptor su strates (IRS-1. the release of insulin in response to glucose is biphasic. These IRS proteins facilitate the interaction of the insulin receptor with intracellular substrates by serving as a mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Ca2+ influx across the cell membrane. 5/17/2012 ." which consists of a gradually increasing rate of secretion to a plateau level. Acetylcholine and cholecystokinin promote phosphoinositide breakdown. and arachidonic acid and the activation of protein kinase C amplify the Ca2+ signal by decreasing Ca2+ uptake by cellular stores and promoting both the phosphorylation and activation of proteins that trigger the exocytosis of insulin. Endocrine Pancreas Page 6 of 17 depolarization of the plasma membrane." which consists of a rapid burst of release to a high peak and then a steep decline to a low secretion rate. and Protein Meta olism Meta olic effects Carbohydrate metabolism Insulin stimulates Glucose transport in adipose tissue and muscle Rate of glycolysis in muscle and adipose tissue Glycogen synthesis in adipose tissue. Insulin binding to the receptor triggers receptor autophosphorylation on tyrosine residues in the cytoplasmic domain ( -chain). inhibition of adenylate cyclase. the second over an hour or more. Insulin Effects on Car ohydrate. An elevation in plasma glucose concentrations is followed by a transient stimulation of insulin secretion known as "first-phase secretion. liver. with an initial rapid release of preformed insulin followed by a more sustained release of newly synthesized insulin. Over longer periods. the actions of insulin at target organs are anabolic and promote the synthesis of carbohydrate. and these effects are mediated through binding to the insulin receptor (Table 7–1). and protein. -3. cholecystokinin. which includes the insulin receptor. linked by disulfide bonds. The insulin receptor is a heterotetrameric glycoprotein membrane receptor composed of 2 . Catecholamines and somatostatin inhibit insulin secretion through G protein–coupled receptor (GPCR) mechanisms. and other tissues Insulin inhi its Glycogen breakdown in muscle and liver Rate of glycogenolysis gluconeogenesis in the liver Lipolysis in adipose tissue.and 2 -subunits. such as the modulation of ion (K+) and glucose transport into the cell. PHYSIOLOGIC EFFECTS OF INSULIN Insulin produces a wide variety of effects that range from immediate (within seconds). with a consequent mobilization of Ca2+ from intracellular stores. The first phase occurs over a period of minutes.4. The -chain consists of a short extracellular region. and modification of Ca2+ and K+ channel gating.5-trisphosphate. lowering the plasma fatty acid level Fatty acid oxidation in muscle and liver Ketogenesis Protein degradation in muscle Urea formation INSULIN RECEPTOR The insulin receptor is part of the insulin-receptor family. Fat. As mentioned above. such as the regulation of metabolic enzyme activity. inositol 1. muscle. This is followed by "second-phase secretion. such as the modulation of enzyme synthesis.ch. to delayed (within hours to days). and activation of protein kinase C. Other factors (shown in Figure 7–2) that amplify the glucose-induced release of insulin from the -cell include acetylcholine. The second phase would require mobilization of -granules from a storage pool to replenish the readily releasable pool of granules before -granule docking and exocytosis. 2. The -chain is the extracellular portion and is the site for insulin binding. gastrointestinal peptide. -4). such as the effects on growth and cellular differentiation. glucose also increases proinsulin mRNA content by both stimulating proinsulin gene transcription and stabilizing the mRNA. with the first phase representing the readily releasable pool of granules already docked at the -cell plasma membrane that does not require additional movement along microtubules. fat. The subsequent generation of cAMP. moderate (within minutes to hours). The mechanism may involve insulin release from 2 separate pools of granules. These substances all bind to cell surface receptors and activate adenylate cyclase and phospholipase C.AccessMedicine | Print: Chapter 7. Ta le 7–1. Several hypotheses have been proposed to explain the biphasic nature of insulin secretion. and development (Figure 7–3). the insulin-like growth-factor receptor.

The affinity of the receptor for insulin is increased following a period of decreased insulin levels and during adrenal insufficiency. Chronic exposure to high insulin levels. promoting cell survival. Main Features of Glucose Transporters Transporter E pression GLUT-1 Ubiquitous. including glucose transport. and kidney -cells. Insulin binding to its receptor results in recruitment of GLUT-4 from mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. with their own unique tissue distribution. when activated. with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessels of the brain. and glycogen synthesis. The activated ligand-receptor complex is internalized into endosomes. The PI3-kinase pathway involves phosphorylation of inositol phospholipids and the generation of phosphatidylinositol3. Function Glucose uptake by skeletal muscle and fat under basal conditions Functions in the glucose sensor system and ensures that glucose uptake by pancreatic -cells and hepatocytes occurs only when circulating glucose levels are high Together. Signal transduction by the insulin receptor is not limited to its activation at the cell surface. The Pl3-kinase pathway is involved predominantly in mediating the metabolic effects of the hormone. Although signaling cascades in this pathway do not appear to play a significant role in the metabolic effects of insulin. catalyze some of the cellular effects of insulin. diet. exercise and starvation upregulate the number of receptors. Low-affinity glucose transporter present in pancreatic liver. insulin dissociates from its receptor. and other hormones. the great majority (80–90%) of which occurs in skeletal muscle. Approx mately 90% of GLUT-4 is sequestered intracellularly Insulin-stimulated glucose transport is mediated through GLUT in the absence of insulin or other stimuli such as exercise. attract serine kinases to the plasma membrane. Spermatozoa and small intestine GLUT-5 Predominantly a fructose transporter . and plays a crucial role in the regulation of protein synthesis by insulin. in turn. mainly the phosphatidylinositol-3-kinase (PI3-kinase) and the mitogen-activated protein kinase (MAPK) pathways (Figure 7–3). intestine.5-trisphosphate and phosphatidylinositol-3. obesity. In contrast to the other GLUT isoforms. insulin. 5/17/2012 . Moreover... and excess growth hormone all lead to a downregulation of insulin receptors.ch. INSULIN EFFECTS AT TARGET ORGANS Early effects Although the expression of insulin receptors is widespread. Ta le 7–2. The movement of glucose into the cell is mediated by a family of carrier proteins. ending the insulin receptor–mediated phosphorylation events and promoting the degradation of insulin by proteases such as the acidic insulinase. The other main signaling pathway that is activated by insulin binding to its receptor is the MAPK pathway. where it becomes available for insulin binding again.tmp\0071613013. In contrast.4. this pathway is involved in cell growth and transmits a strong antiapoptotic signal. which. These products. including the phosphoinositide-dependent kinase and different isoforms of protein kinase B. The main transporters and their predominant tissue distributions are summarized in Table 7–2. which are primarily localized on the cell membrane.4-bisphosphate. Endocrine Pancreas Page 7 of 17 scaffold for recruitment of proteins involved in signal transduction to downstream pathways. The insulin receptor can then be recycled into the cell surface. Endocytosis of activated receptors is thought to enhance the insulin receptor tyrosine kinase activity on substrates that are distant from those readily accessible at the plasma membrane. Expressed in skeletal muscle and fat.AccessMedicine | Print: Chapter 7. Following acidification of the endosomal lumen. GLUT-4 transporter proteins are sequestered in specialized storage vesicles that remain within the cell's interior under basal conditions. or glucose transporters. The result is coupling of insulin receptor activation to signaling pathways. GLUT-1 and GLUT-3 are crucial in allowing glucose to cross the blood-brain barrier and enter neurons The major insulin-responsive transporter GLUT-2 GLUT-3 Primarily in neurons GLUT-4 Predominantly in striated muscle and adipose tissue. glycolysis. they are involved in mediating the proliferative and differentiation effects elicited by insulin. The number of available insulin receptors is modulated by exercise. Insulin mediates about 40% of glucose disposal by the body. the specific effects of insulin on skeletal muscle glucose utilization dominate insulin action.

. and liver (Figure 7–4). and glycolysis. Endocrine Pancreas Page 8 of 17 cytosolic vesicular compartments to the plasma membrane.AccessMedicine | Print: Chapter 7. Glucagon and insulin effects on hepatic glucose metabolism. 5/17/2012 . Figure 7– . dephosphorylation of hormone-sensitive lipase inhibits the breakdown of triglycerides to fatty acids and glycerol.and glucagon-mediated effects are presented.tmp\0071613013. This is the underlying mechanism by which insulin stimulates glucose transport into fat and muscle cells.. In the adipocytes. The principal target enzymes for insulin. Intermediate effects The intermediate effects of insulin are mediated by modulation of protein phosphorylation of enzymes involved in metabolic processes in muscle. fat.ch. Insulin antagonizes catecholamine-induced lipolysis through the phosphorylation and activation of phosphodiesterase. Accumulation of GLUT-4 at the membrane is the net result of increased translocation through targeted exocytosis and decreased rate of GLUT-4 endocytosis. insulin inhibits lipolysis and ketogenesis by triggering the dephosphorylation of hormone-sensitive lipase and stimulates lipogenesis by activating acetyl-CoA carboxylase. This process thereby reduces the amount of substrate that is available for ketogenesis. gluconeogenesis. In fat. the rate-limiting step in the release of free fatty acids mediated by lipolysis. The overall mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Binding of glucagon and insulin to their respective receptors stimulates a cascade of protein phosphorylation steps that activate (or inhibit) key enzymes involved in the regulation of glycogenolysis. leading to a decrease in intracellular cAMP levels and a concomitant decrease in protein kinase A activity.

PEP. phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) (Figure 7–5). ADP. glucokinase. glucagon. adenosine diphosphate. In the liver.tmp\0071613013.AccessMedicine | Print: Chapter 7. G.ch.. insulin stimulates the gene expression of enzymes involved in glucose utilization (eg. adenosine triphosphate. and lipogenic enzymes) and inhibits the gene expression of enzymes involved in glucose production (eg. In addition. 5/17/2012 . insulin. ATP. mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Endocrine Pancreas Page 9 of 17 result is an increase in hepatic glucose output. pyruvate kinase. Insulin stimulates glycogen synthesis by increasing phosphatase activity. leading to the dephosphorylation of glycogen phosphorylase and glycogen synthase. insulin-mediated dephosphorylation of inhibitory sites on hepatic acetyl-CoA carboxylase increases the production of malonyl-CoA and simultaneously reduces the rate at which fatty acids can enter hepatic mitochondria for oxidation and ketone body production. I. phosphoenolpyruvate.. Figure 7– .

and cortisol combine to increase the activity of hormone-sensitive lipase. increase the release of free fatty acids. epinephrine. and decrease the activity of acetyl-coenzyme A (CoA) carboxylase.tmp\0071613013. Insulin deficiency and high levels of counterregulatory hormones glucagon.. thereby impairing the reesterification of free fatty acids and promoting fatty acid conversion into ketone bodies. Endocrine Pancreas Page 10 of 17 Process of ketogenesis in insulin deficiency.. The excess supply of fatty acetyl-CoA and the deficiency in oxaloacetate increase the oxidation to ketone bodies.AccessMedicine | Print: Chapter 7.ch. 5/17/2012 . with the mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92.

FA. kidney. Although this pathway of insulin action is not as well elucidated as the effects that are mediated through the activation of IRS. In muscle. stomach. excess visceral fat. Vagal (parasympathetic) PHYSIOLOGIC EFFECTS OF GLUCAGON The principal target tissues for glucagon are the liver and adipose tissue. these actions counteract the effects of insulin (Figure 7–5). overall.. and phosphorylation of effector proteins. In addition. Endocrine Pancreas Page 11 of 17 resulting release of ketone bodies into the blood. Epinephrine stimulates release of glucagon through a 2-adrenergic mechanism (while it suppresses insulin release from stimulation increases glucagon release. insulin favors lipid storage in muscle as well as in adipose tissue. -cells through an 2 -adrenergic mechanism).. and vascular tissues. Glucagon GLUCAGON SYNTHESIS Glucagon. a decrease in lipid storage. and high energy intake. and kidney. fatty acid.tmp\0071613013. resulting in negative nitrogen balance and muscle wasting. Glucagon's main physiologic effect is to increase plasma glucose concentrations by stimulating de novo hepatic glucose production through gluconeogenesis and glycogen breakdown. Glucagon binding activates adenylate cyclase and results in intracellular accumulation of cAMP.ch. the proliferative effects of chronic hyperinsulinemia influence vascular smooth muscle cells. evidence is now surfacing on the pathophysiologic effects of chronic elevations of insulin on specific cell populations. such as enteroendocrine cells in the intestinal tract and in the brain. high waist-to-hip ratio. including hypertension. mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Glucagon has a short half-life (5–10 minutes) and is degraded mostly in the liver. which are responsible for the maintenance of vascular tone. Long-term effects MAP Sustained insulin stimulation enhances the synthesis of lipogenic enzymes and the repression of gluconeogenic enzymes. Chronic hyperinsulinemia has been linked to increased risk of cancers including endometrium. is a 29–amino acid polypeptide hormone secreted by the -cells of the islets of Langerhans. As discussed later.AccessMedicine | Print: Chapter 7. high body mass index. The primary sequence of glucagon is almost perfectly conserved among vertebrates. atherosclerosis. The glucagon receptor is expressed in liver. insulin deficiency leads to glucose accumulation in blood. The molecular basis of insulin's effect on vascular smooth muscle cell growth and its association with hypertension are currently unclear. HMG. and protein loss. The role of glucagon receptors in the rest of the tissues is still unclear. Glucagon release is inhibited by hyperglycemia (high blood glucose levels) and stimulated by hypoglycemia (low blood glucose levels). as well as in some regions of the brain. 5/17/2012 . Insulin levels are high during the development and early stages of type 2 diabetes. protein kinase A activation. HSL. High amino acid levels following an amino acid–rich meal stimulate glucagon release. sedentary lifestyle. the processing of the prohormone differs among tissues. parathyroid hormone. pancreatic -cells. A meal rich in carbohydrates suppresses glucagon release and stimulates insulin release from the -cells through intestinal release of GLP-1. colon. and it is structurally related to the secretin family of peptide hormones. These cells play an important role in the pathogenesis of several diseases. In addition. Conditions that cause elevated insulin levels include high waist circumference. and dyslipidemia. mobilization of intracellular Ca 2+. vasoactive intestinal polypeptide. and adrenal glands. Glucagon mediates its effects by binding to the glucagon Gs protein–coupled receptor. which plays an important role in the regulation of glucose homeostasis by producing antagonistic effects on insulin action. heart. Both MAPK and particularly the chronic activation of extracellular receptor kinase by insulin receptor binding lead to excessive cell growth. post-menopausal breast. However. insulin stimulates glucose uptake and favors protein synthesis though phosphorylation of a serine/threonine protein kinase known as mammalian target of rapamycin. The plus sign (+) denotes steps that are favored by insulin deficiency. GLP-1 is produced in the intestine in response to a high concentration of glucose in the intestinal lumen. cardiovascular disease. 3-hydroxy-3-methylglutaryl. Somatostatin also inhibits glucagon release. The glucagon-receptor complex undergoes endocytosis into intracellular vesicles. The 2 main products of proglucagon processing are glucagon in the -cells of the pancreas and GLP-1 in the intestinal cells. Glucagon is synthesized as proglucagon and then proteolytically processed to yield glucagon. The growth-promoting and mitogenic effects of insulin are long-term responses mediated through the path ay. GLP-1 is known as an incretin. a mediator that amplifies insulin release from the -cell in response to a glucose load. GLUCAGON RECEPTOR The glucagon and GLP-1 peptide receptors belong to a family of GPCRs that include those for secretin. REGULATION OF GLUCAGON RELEASE The mechanisms involved in the regulation and stimulus-secretion coupling of glucagon release are not as well understood as those for insulin. where glucagon is degraded. adipose tissue. all of which are closely associated with insulin resistance and hyperinsulinemia. and also in other tissues. hormone-sensitive lipase. The prohormone proglucagon is expressed in the pancreas. and growth hormone–releasing factor. Plasma glucagon concentrations average 50–100 ng/L (50–100 pg/mL). calcitonin.

The key enzymatic steps regulated by glucagon that mediate the stimulation of hepatic glucose output are summarized in Table 7–3. PEPCK. Endocrine Pancreas Page 12 of 17 GLUCAGON EFFECTS AT TARGET ORGANS The principal physiologic effects of glucagon are mediated in the liver. Glucagon binds to G protein–coupled receptor (GPCR) on target cells.) Ta le 7–3. The effects of glucagon on adipose tissue are relevant primarily during periods of stress or food deprivation. glucose-6-phosphatase.tmp\0071613013. Figure 7– . particularly when insulin release is suppressed. phosphatidylinositol 4. PIP2. from Guoqiang Jiang. phosphoenolpyruvate carboxykinase.284:E671–E678. Zhang.5biphosphate. The principal effects of glucagon are mediated in hepatocytes where glucagon through activation of adenylate cyclase. Effects of Glucagon on Hepatic Glucose Meta olism Effect on target en yme Increased expression of glucose-6-phosphatase Suppression of glucokinase Meta olic response Frees glucose to enter the circulation Decreases glucose entry into the glycolytic cascade Stimulates glycogenolysis Inhibits glycogen Phosphorylation (activation) of glycogen phosphorylase Inhibition of glycogen synthase mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Glucagon receptor–mediated cellular effects. Glucagon and regulation of glucose metabolism. peroxisome proliferator–activated receptor-coactivator-1. Figure 1 of article. Am J Physiol Endocrinol Metab. Glucagon stimulates hepatic glucose output by stimulating glycogen breakdown and gluconeogenesis and decreasing glycolysis Figure 7–6).ch. PGC-1.AccessMedicine | Print: Chapter 7. Bei B.. elevation in cAMP leads to increased protein kinase A activity leading to phosphorylation of enzymes responsible for control of glucose metabolism. 5/17/2012 . G-6-Pase. with permission. The ultimate result is an increase in hepatic glucose production through increased gluconeogenesis and glycogenolysis. 2003. (Reproduced..

AccessMedicine | Print: Chapter 7. Circulating amylin is increased in obesity.6-BPase) is the phosphatase activity of Stimulates the bifunctional regulatory enzyme. and gestational diabetes. ketogenesis is regulated by the balance between the effects of glucagon and insulin at their target organs. and even unconsciousness. suppressing the postprandial secretion of glucagon and slowing gastric emptying. Amylin is the main component of pancreatic islet amyloid. and particularly protein-rich meals. the importance of endogenous paracrine inhibition of insulin and glucagon release is not well established.ch. Somatostatin Somatostatin is a 14–amino acid peptide hormone produced by the -cells of the pancreas. It is produced in the endocrine type F cells located in the periphery of pancreatic islets and is released into the circulation after ingestion of food. The regulation of its release is not well studied because of the difficulty in analyzing the small number of islet cells that produce this hormone. convulsions. Pancreatic polypeptide crosses the blood-brain barrier and has been postulated to play a role in regulating feeding behavior. as seen in uncontrolled diabetes (discussed later).. 5/17/2012 . sweating. Its release is stimulated by highfat.6-bisphosphatase (F-2. pancreatic somatostatin may have a limited contribution toward physiologic control of insulin and glucagon release. exercise. aggressiveness. calcitonin gene-related peptide.6-bisphosphatase (PFK-2/Fgluconeogenesis 2. with insulinoma being the most frequent. the secretion of amylin is impaired before that of insulin. Glycerol released into the circulation can be utilized in the liver for gluconeogenesis or for reesterification. Excessive glucagon production by the tumor may mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. thereby increasing lactate production. or islet amyloid polypeptide. Amylin is synthesized as a small precursor. In the liver. an effect mediated by transmembrane proteins known as receptor activity– modifying proteins (RAMPs). Amylin appears to work with insulin to regulate plasma glucose concentrations in the bloodstream. which includes calcitonin. glucagon stimulates protein kinase A–mediated phosphorylation (activation) of hormone-sensitive lipase. Glucagonomas are unusual tumors that may produce symptoms of diabetes. phosphofructokinase-2/fructose-2. Somatostatin has a generalized inhibitory effect on virtually all gastrointestinal and pancreatic exocrine and endocrine functions.tmp\0071613013. Endocrine Pancreas Page 13 of 17 synthesis Stimulation of phosphoenolpyruvate carboxykinase expression Stimulates gluconeogenesis Inactivation of phosphofructokinase-2 (PFK-2) and activation of fructose-6-phosphatase.6-BPase). Thus. found in the vast majority of patients with noninsulin-dependent (type 2) diabetes mellitus. However. free fatty acids are used for reesterification or they can undergo -oxidation and conversion into ketone bodies. In type 2 diabetes. The importance of this balance is evident during insulin deficiency and glucagon excess. undergoes posttranslational modification (amidation). and growth hormone. palpitations. Because -cells are located in the periphery of the -cells and because blood flows from the center of the islets of Langerhans toward the periphery. releasing them into the circulation. is stored in -granules. PFK-2 is Inhibits glycolysis the kinase activity and fructose-2. cortisol. DISEASES ASSOCIATED ITH PANCREATIC HORMONES Hormone-Producing Tumors Excess pancreatic hormone production and release are usually due to hormone-producing tumors. confusion. and vagal stimulation. high-carbohydrate. glucagon.. and is thought to contribute to destruction of the pancreatic -cell.or glucagon-producing tumors. modulation of gastric acid secretion. The modified calcitonin receptor has higher affinity for amylin. Pancreatic Polypeptide Pancreatic polypeptide is a 36–amino acid peptide hormone that belongs to a peptide family including neuropeptide Y and peptide YY. The effects of pancreatic polypeptide include inhibition of pancreatic exocrine secretion. Plasma amylin concentrations increase after a meal or glucose infusion. gallbladder contraction. exogenous administration of somatostatin does suppress the release of both insulin and glucose and is used in the clinical setting for the management of insulin. it is low or absent in type 1 diabetes mellitus. Amylin binds to a variant of the calcitonin GPCR. These symptoms are mostly observed before breakfast and following physical exercise. Suppression of activity of the pyruvate kinase Decreases glycolysis In the adipocyte. Free fatty acids are used as fuel by most tissues. hypertension. and gastrointestinal motility. Further. and is inhibited by insulin. In muscle. is a 37–amino acid peptide hormone that belongs to the calcitonin family. and is released along with insulin and C-peptide. amylin opposes glycogen synthesis and activates glycogenolysis and glycolysis. predominantly skeletal muscle and liver. Amylin Amylin. and adrenomedullin. the enzyme that breaks down triglycerides (stored fat) into diacylglycerol and free fatty acids. The compensatory or counterregulatory response of the body includes the release of catecholamines. and patients present with episodes of hypoglycemia. Insulinomas produce excessive amounts of insulin.

leading to severe weight loss and anorexia. The resulting dehydration triggers compensatory mechanisms such as thirst (polydipsia). releasing fatty acids into the circulation Liver Liver Catalyzes the conversion of acetyl-CoA to malonyl-CoA. cortisol. Type 1 diabetes.AccessMedicine | Print: Chapter 7. Fatty acids released into the circulation undergo -oxidation to acetyl-CoA in the liver. which is then reduced to 3-hydroxybutyrate. Endocrine Pancreas Page 14 of 17 also result in an overall catabolic effect on fat and muscle. increase the release of free fatty acids. Somatostatinoma is a rare tumor that may cause moderate diabetes. The diagnosis of diabetes is based on plasma glucose levels obtained in the fasting state (greater than 126 mg/dL). if severe. Dia etic etoacidosis Diabetic ketoacidosis is an acute pathologic event characterized by elevated blood glucose levels and ketone bodies and metabolic acidosis. and conversion of acetoacetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA and then to acetoacetate. It rarely leads to ketoacidosis. Diabetic ketoacidosis is precipitated by infections. can result in diabetic coma. acetyl-CoA is diverted from entering the Krebs cycle and is used preferentially for ketone body formation or ketogenesis. It is usually associated with obesity in adults and is characterized by mild hyperglycemia. The lack of insulin and the high levels of counterregulatory hormones glucagon. Three Principal En ymes In ol ed in En yme Hormone-sensitive lipase Acetyl-CoA carboxylase HMG-CoA synthase Tissue Function etogenesis Adipocytes Breaks down triglycerides. new-onset (untreated) diabetes. a highly fat-soluble compound that is excreted slowly by the lungs and is responsible for the fruity odor of the breath of individuals with diabetic ketoacidosis. discontinuation of or inadequate insulin use. leading to the buildup of ketone bodies in the blood (diabetic ketoacidosis) and their urinary excretion. polydipsia. These exceed the liver's capacity for their metabolic utilization. The steps involved in ketogenesis are -oxidation of fatty acids to acetyl-CoA. insulin mediates the majority of the body's glucose disposal through its effects on skeletal muscle. The excess blood glucose increases osmolarity. Type 1 diabetes is characterized by the development of ketoacidosis in the absence of insulin therapy. Type 2 diabetes is often part of "syndrome X" or "insulin resistance syndrome. thus decreasing its availability for condensation with acetyl-CoA. oxaloacetate is preferentially used for gluconeogenesis. The 2 forms of diabetes." a metabolic syndrome characterized by hypertension. and other events such as the stress associated with surgery. stimulating hunger (polyphagia) and triggering the activation of compensatory responses to increase the release and availability of fuel substrates though activation of lipolysis and proteolysis. Diabetes can also present as random plasma glucose levels higher than 200 mg/dL in association with symptoms of diabetes (polyuria. Actely-CoA condenses with oxaloacetate to form citrate in the entry step to the Krebs cycle (citric acid cycle or tricarboxylic cycle). thereby impairing the reesterification of free fatty acids and promoting fatty acid conversion into ketone bodies (Figure 7–6). juvenile-onset diabetes. Ta le 7– . In diabetic ketoacidosis. During insulin deficiency and excess glucagon. The inability of the cells to utilize glucose resembles a state of cellular starvation. The enzymes involved in ketogenesis are summarized in Table 7–4. and growth hormone. This process results in increased plasma osmolarity and urinary loss of glucose. formation of acetoacetyl-CoA. and decrease the activity of acetyl-CoA carboxylase. The insulin deficiency causes glucose to accumulate in the blood. gluconeogenesis in the liver proceeds unopposed by the physiologic presence of insulin. Acetoacetate can be spontaneously decarboxylated to acetone. It accounts for 2–5% of cases and it occurs more frequently in younger people. 2 hours after glucose ingestion). As a result. and polyphagia) or as persistent elevations in plasma glucose levels following an oral glucose load (greater than 200 mg/dL. which. accompanied by excess loss of water and sodium (polyuria). resulting directly from decreased insulin availability and simultaneous elevations of the counterregulatory hormones glucagon.. type 1 and type 2. As mentioned earlier. epinephrine. Type 2 diabetes results from a loss of normal regulation of insulin secretion and accounts for more than 90% of diabetes cases. the primary substrate of fatty acid biosynthesis Involved in the conversion of acetyl-CoA to acetoacetate mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Lack of insulin results in increased circulating levels of free fatty acids and gluconeogenic amino acids. atherosclerosis. hence its other name. also known as insulin-dependent diabetes mellitus. the process by which fatty acids are transformed into acetoacetate and 3hydroxybutyrate in hepatocyte mitochondria. Dia etes Mellitus The most common disease resulting from impaired pancreatic hormone release is diabetes mellitus. are characterized by impaired insulin release.. and cortisol combine to increase the activity of hormone-sensitive lipase.ch. and central obesity. catecholamines. 5/17/2012 . The pathophysiology of the disease involves impaired entry of glucose into the cells and accumulation of glucose in the blood. is the result of -cell destruction.tmp\0071613013.

The slow post-translational and nonenzymatic glycation of hemoglobin provides a measure of chronic glycemia. particularly after dinner. the earliest physiologic indication of -cell dysfunction is a delay in the acute insulin response to glucose. and a high ratio (3:1 or higher) of 3hydroxybutyrate to acetoacetate is generated because of the highly reduced state of hepatic mitochondria. insulin resistance precedes the onset of the disease by several years. Patients with type 2 diabetes secrete normal amounts of insulin during fasting. In mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. In patients with type 2 diabetes. The measurement of glycosylated hemoglobin is used to monitor glycemic control in patients with known diabetes. the pancreas compensates by secreting increased amounts of insulin. As insulin resistance increases. The combination of insulin resistance and impaired -cell function characterizes clinical type 2 diabetes. and erratic. dissociate completely. but in response to a glucose load (or a meal). Treatment of the Dia etic Patient The goal of therapy is tight glycemic control. All 3 of these components have been targeted for pharmacologic treatment of diabetic patients. AMP-activated protein kinase is activated during exercise and has been termed a master metabolic switch because it phosphorylates key target proteins that control flux through metabolic pathways. The increase in glucose transport resulting from exercise is not mediated through the insulin receptor. At physiologic pH. impaired glucose tolerance develops. processing. Because type 1 diabetes is characterized by -cell destruction. The resulting liberation of H+ from ketone body metabolism exceeds the blood's buffering capacity. The signaling pathways involve increased cytosolic Ca2+ and the enzyme AMP-activated protein kinase. and peripheral insulin resistance. decreasing the sensitivity of tissues to insulin action and producing a state of insulin resistance. and kidneys. Some of the approaches used. During diabetic ketoacidosis. abnormalities in glucose transport. This abnormality results in significantly higher levels of fasting glucose in these patients. they secrete considerably less insulin (70%) than nondiabetic patients. This initial period of sustained hyperinsulinemia downregulates the insulin receptors.ch. 5/17/2012 . To maintain euglycemia. to a lesser extent. ketone bodies. Compensating for insulin resistance by an increase in insulin release is effective only temporarily.. failure or exhaustion of the pancreatic -cell results in decreased insulin secretion. warrant mention because they affect the physiologic mechanisms of pancreatic hormone release and target organ effects on the control of glucose. Ultimately. Endocrine Pancreas Page 15 of 17 CoA.. Insulin Resistance Insulin resistance is the inability of peripheral target tissues to respond properly to normal circulating concentrations of insulin.AccessMedicine | Print: Chapter 7. hyperglycemia (fasting glucose at least 126 mg/dL or random glucose at least 200 mg/dL) is the diagnostic criterion and a main prognostic parameter in diabetes. If severe. abnormal insulin synthesis. storage. sluggish. and skeletal muscle and adipose tissue glucose uptake and disposal. this condition can lead to coma. These ketone bodies can freely diffuse across cell membranes and serve as an energy source for extrahepatic tissues including the brain. coenzyme A. which has been shown to delay the development of microvascular complications associated with diabetes. Clinical E aluation of Dia etes According to the American Diabetes Association. this approach is ineffective in those patients. with pulses that are significantly smaller. which in turn produces a compensatory and exaggerated second-phase hyperinsulinemic response. leading to metabolic acidosis with an increased anion gap. Type 2 Dia etes Type 2 diabetes is the result of inadequate responsiveness of the -cells to glucose. skeletal muscle. or secretion).tmp\0071613013. Values of glycosylated hemoglobin are strongly correlated with the average blood glucose level over the preceding 1–3 months and can be obtained in the nonfasted state. Glucose homeostasis results from the regulated balance among hepatic glucose release. Exercise has been demonstrated to increase glucose transport in skeletal muscle and to decrease insulin resistance in patients with type 2 diabetes. glycogenolysis) and increase insulin-stimulated glucose uptake in skeletal muscle and adipocytes. HMG. with the exception of acetone. high amounts of ketone bodies are released into the blood. Ketone bodies are filtered and reabsorbed in the kidney. The defect in the initial response to a glucose load leads to an excessive rise in plasma glucose. Regardless of the etiology (eg. 3-hydroxy-3-methylglutaryl. defective -cell secretory function. which is later followed by a net reduction in -cell mass and a decreased responsiveness of peripheral tissues to insulin action. Biguanides Biguanides such as metformin reduce hepatic glucose output (primarily through inhibition of gluconeogenesis and. in addition to conventional insulin. Sulfonylureas Sulfonylureas increase insulin release by closing K + ATP channels in the pancreatic -cell membrane. dietary glucose absorption. In addition to a reduction in insulin release. The main pathologic defects in diabetes are excessive hepatic glucose production. This action is mediated by binding of the drug to the sulfonylurea receptor subunit of the channel. the pattern of insulin release is also altered following a meal.

15:412.113(suppl 6A):23S. fatty acetyl-CoA synthase.AccessMedicine | Print: Chapter 7. fatty acid transporter protein. Thia olidinediones Thiazolidinediones reduce insulin resistance in skeletal muscle by activation of the -isoform of the peroxisome proliferator–activated receptor in the nucleus. Zierath JR.tmp\0071613013. Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. ev. 2002. Kirpichnikov D. 2001. and inhibit lipolysis. 2002.. GLP-1 increases insulin biosynthesis -cells. iabetes Metab es ev. Am J Med. Sowers JR. Metformin: an update. Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. glucokinase. SUGGESTED READINGS Bergsten P. iabetes Metab lin her. Alpha-glucosidase inhi itors Alpha-glucosidase inhibitors delay the intestinal absorption of carbohydrates through inhibition of the brush-border enzymes that hydrolyze polysaccharides to glucose. thereby affecting the transcription of several genes involved in glucose and lipid metabolism and energy balance.137:25. [PMID: 11394726] es ev. metformin facilitates glucose transport by increasing tyrosine kinase activity in insulin receptors and enhancing glucose transporter trafficking to the cell membrane. Porksen N et al. Evaluation of alternative strategies for optimizing glycemia: progress to date. Derave W. Wojtaszewski JFP. 2002.171:249. McFarlane SI. and the GLUT-4 glucose transporter. Among the genes that are affected are those that code for lipoprotein lipase. malic enzyme. 2001.282:E695. Glucagon-li e peptide GLP-1 amplifies glucose-induced insulin release. 2000. 2002. Richter EA. exercise and insulin: emerging concepts. Endocrine Pancreas Page 16 of 17 insulin-sensitive tissues (such as skeletal muscle). Acta Physiol cand.. iabetes Metab es mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92. Glucose. [PMID: 9914469] LeRoith D. Pathophysiology of impaired pulsatile insulin release. Am J Med. suppress hepatic glucose production. and hormonal regulation. [PMID: 10634967] Lang J.259:3. 2002.23:646. The mode of action of thiazolidinediones. Glucagon antagonizes insulin's effects by stimulating hepatic glucose release. and the MAPK pathway is mostly involved in mediating the proliferative responses. [PMID: 11412137] iochem. The PI3-kinase pathway mediates most of insulin's metabolic effects. Gerich JE.18(suppl 2):S10. adipocyte fatty acid–binding protein. A disruption in the balance of insulin and glucagon leads to ketogenesis and hyperosmolar coma. neural. Am J Physiol Endocrinol Metab. pathophysiology and application of monitoring to diabetes. Ketone bodies: A review of physiology.113(suppl 6A):3S. Eur J 1999. Hauner H. and insulin gene expression and has tropic and antiapoptotic effects on the pancreatic EY CONCEPTS Insulin release is under nutrient. Human insulin release processes measured by intraportal sampling. The principal metabolic effects of insulin are to increase glucose utilization in skeletal muscle. Ryder JW. 5/17/2012 . In addition.16:179. [PMID: 10867718] Cefalu WT.ch. J Physiol. Chibalin AV. The pancreatic -cell functions as a glucose sensor in the process of insulin release.535(Pt 2):313. Intracellular mechanisms underlying increases in glucose uptake in response to insulin or exercise in skeletal muscle. Matching treatment to pathophysiology in type 2 diabetes. 2001. 1999. Ann Intern Med. [PMID: 12093242] Laffel L.

rends ell iol. [PMID: 11849969] iabetes Metab es ev. Pessin JE. [PMID: 12469359] < mk:@MSITStore:C:\Users\Ridhwan\AppData\Local\Temp\7zOAD92..18:451. Endocrine Pancreas Page 17 of 17 Saltiel AR. 5/17/2012 .AccessMedicine | Print: Chapter 7. 2002..tmp\0071613013. Glucose-stimulated signaling pathways in biphasic insulin secretion.ch. Straub SG.12:65. Insulin signaling pathways in time and space. 2002. Sharp GWG.

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