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Pancreatic Hormones & Antidiabetic Drugs (Katzung)

Pancreatic Hormones & Antidiabetic Drugs (Katzung)

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Published by: Paula Giselle Pabalan Gutierrez on Sep 01, 2014
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PANCREATIC HORMONES & ANTIDIABETIC DRUGS

INTRODUCTION
 Pancreatic hormones products (secretory products)
1. Insulin – storage & anabolic hormone of body
2. Islet amyloid polypeptide – AKA Amylin (IAPP)
- Modulates appetite, gastric emptying, and
glucagon and insulin secretion
3. Glucagon – Hyperglycemic factor w/c mobilizes glycogen
store
4. Somatostatin – universal inhibitor of secretory cells
5. Gastrin – stimulates gastric acid secretion
6. Pancreatic peptide – small protein w/c facilitates
digestive by mechanism not yet clarified

 Pancreas – DUAL FUNCTION GLAND
o Exocrine (acinar cells) – en zyme rich juice
- Produces digestive enzyme
(trypsin, chymotrypsin, pancreatic lipase &
amylase)
- Enzyme help breakdown of CHO, proteins
and fat
o Endocrine – TOPIC NOW 
- Consists of approx. 1million islets of
langerhans
- Islets of langerhans: 1-2% pancreatic mass

 ISLETS CELLS
CELL TYPES APPROX % OF
ISLET MASS
SECRETORY
PRODUCTS
Alpha (A) 20% Glucagon,
Proglucagon
Beta (B) 75% Insulin, C-peptide,
prinsulin, amylin
Delta (D) 3-5% Somatostatin
G cell 1% Gastrin
F (PP Cell) 1% Pancreatic
polypeptide (PP)


 DIABETES
- Major cause of heart disease & stroke
- Leading cause kidney failure, notraumatic
lower-limb amputation, and new cause of
blindness among (some) of adults
- 7th leading cause of death in USA
o DIABETES MELITUS
- Serious DO of CHO metab
- Elevated blood glucose assoc. Secretion
inadequate pancreatic insulin secretions
- w/ or w/out concurrent impairment of
insulin action
o 4 Category Types
 TYPE 1 – insulin-dependent diabetes
 TYPE 2 – non-insulin-dependent diabetes
 TYPE 3 – other specific causes
 TYPE 4 – gestational diabetes melitus

o 3 Cardinal signs of DM
 Polyuria – huge output
 Polydipsia – excessive thirst
 Polyphagia – excessive hunger & food consumption

o Markers of Immune detruction
 Islet cells autobodies (ICA)
 Autoantibodies to insulin (IAA)
 Autoantibodies to tyroime phosphatases : 1A-2 &
1A-2B

o TYPE 1 DM
- Selective B cell destruction
- Severe / absolute insulin deficiency
- Causes :
 Immune:
o cell mediated autoimmune destryctuib
if B cells : childhood + adolescence
o Most common form : insulin
dependent / Juvenile onset diabetes
o Can occur at any age
o Prone to :
 Grave’s dx – addison
 Hashimoto – vitiligo
 Pernicious anemia

 Idiopathic – suffers from episodic ketoacidosis but
no evidence of insulin def <-> episodes

- B cell failure at outset
- Insulin dependent
- Beta cells destroyed – no insulin produced
o chronic fusted state
o Melting flesh
o ketosis, acidosic, diuresis & coma
- Insulin replacement therapy is necessary:
o Admin :
SC  manual injection device
 insulin pump
o Interruption : causes – diabetic
ketoacidosis & death
o Diabetic ketoacidosis : insuff. Absent of
insulin
o Then resulting to excess release of F.A
& subsequent formation of toxic level
of ketoacids
 1st manifestation
 Residual Bcell func. To prevent
o TYPE 2 DM
- Tissue resistance to the action of insulin
combined w/ relative deficiency in insulin
secretion
- May have more resistance or more B-Cells
deficiency and abnormalities may be mild /
severe
- Impaired insulin action affects ? :
o Fat metabolism
↑ FA flux & triglyceride levels
↓ level of high-density 1.poprotein
(HDL)
- May not require insulin to survive BUT 30%
more benefits from insulin therapy 
control blood glucose
- Latent autoimmunr diabetes of adults (LADA)
o have both type 1 & 2
o or slow progressing Type 1
o Requires FULL INSULIN REPLACEMENT
- Ketoacidocis may occur : due to stress like:
o E.g. : cotricosteroids
 Infection
 Medication use w/c enhance
resistance
- Diabetic ketoacidosis : may not develop
unless medication use w/c enhance
resistance
- nonKetotic hyperosmolar Coma
o due to result of dehydration w/
untreated
o blood glucose : 6-20x (may rise) the
normal range
 develop altered mental state
o urgent care & rehydrated : required

o TYPE 3 DM
- Multiple other causes of elevated blood
glucose
o Pancreatectomy
o Pancreatitis
o Nopancreatic dx - causes
o Drug therapy - causes


 Genetic defects of B cell funct.
- Onset hyperglycemia at an early age (<2s)
- Referred as : maturity onset diabetes of
young (MODY)
- Impaired insulin secretion w/ minimal / no
defects in insulin action
- Inherited in autosomal dominant pattern
- Genetic defects @
o Chromosome 12, HND – 1a (MODY3)
 most common form
o Chromosome 7, Glucokinase (MODY 2)
 defective glucokinase mol.
o Chromosome 20, HNF-4a (MODY 1)
o Initochondrial DNA
- Hepatic transcription factor : HEPATOCYTE
NUCLEAR FACTOR
- HND 4a : transcription factor involved in
regulation of expression of HND 1a
- MELAS syndrome
o Mitochondrial myopathy
o Encephalopathy
o Lactic acidosis
o Stroke-like form
 Genetic defects in insulin action
- Type A insulin resistance enarged, cystic
ovaries in women
- Leprecchaunism 2
- Robson-menderhall syndrome Pedia
Syndr
- Lipoatrophic diabetes
- Range from hyperinsulinemia & modest
hypergly to severe diabetes

 Disease of Exocrine Pancreas
- Pancreatitis
- Trauma / Pancreatectomy
- Cystic Fibrosis If extensive
- Hemochromatosis enough,
Damage Bcells, &
impair insulin secr
- Fibrocalculous Pancreatopathy
o Abdominal pain radiating to back &
pancreatic calcifications of x-ray
 Endocrinepathies : several hormones antagonize
insulin action
- Acromegaly ------------- Excess amount of
- Cushing’s synd hormones such
- Glucagonoma as: Growth, E,
- Pheochromocytoma Cortisol,Glucagon
- Hyperthyroidism
- Somatostatinoma induced hypokal.
- Aldosteronoma (-) insultion secr.
 Drug / Chemical induced : impair insulin  ppt
diabetes w/ insulin resistance
- Vacor – rat poison ----- permanently
- Pentamidin – IV Pancreatic Bcell
- Nicotinic acid ----------- Impair Insulin
- Glucocorticoids action
- Thyroid hormone
- Diazoxide
- B-adrenergic agonist
- Thiazides
- Vilantin
- A-interferm
 Infections:
- Congenital rubella
- Cytomagelovirus
- Coxsacki virus B
- Adenovinis
- Mumps

o Uncommon forms of immune-mediated DIABETES
 Stiff-man Syndrome
- autoimmne DB of CNS characterized by
stiffness of axial muscle w/ painful spasm
- usually w/ ↑ titers of GMD
 Anti-Insulin receptor antibodies :
- Binding to insulin receptor  Bind of insulin
to receptor in target tissues
- Occassionally in px w/ SLE
 Acanthosis Nigricans : Type B insulin resistance

o Other Genetic Syndrome sometimes assoc w/
 Down’s synd ---------|Chromosal Abnormalities
 Kinefelter’s synd
 Turner’s Synd --------
 Wolfram’s synd – autosomal receisive DO  insulin
deficit
 Friedreich ataxia
 Huntington’s Chorea
 Laurence – moon – Bical syn
 Myotonic dystrophy
 Porphyria 0 Praderwilli synd.

 TYPE 4 DM
o GDM
- Any abnormalities in glucose levels noted for
the first time during pregnancy
- Any defree of glucose intolerance w/ onset/
first recognition during pregnancy
o Placenta & Placental hormones create insulin resistance
during pregnancy
o Categories :
- Diabetes
- IFG
- IGT
- Hormoglycemia
o Maternal Compli :
- ↑ rate cesarean delivery
- Chronic HTN
o Impaired glucose Tolerance (IGT)
o Impaired Fasting Glucose (IFG)
- Metabolic stage intermediate bet. Normal
glucose homeostasis & diabetes
- AKA : Prediabetes

 INSULIN : hormon of nutrient abundance
- Small protein w/ mw: 5808g/mol
- Has 51 amino acid arranged in 2 chains
linked by disulfide bridges
- Proinsulin – has mild hypoglycemic action
:: long single-chain protein mol
:: processed w/in Golgi apparatus of
Bcell & packaged into granules
:: hydrolyzed into insulin & C-Peptide
 residual connecting segment
:: Proinsulin  insulin + C-Peptide –
due to removal of 4AA
- Insulin secretagogues : small qty of
unprocessed or partially hydrolyzed
- Proinsulin is released
- Present insulin standard : 28 unit / mg
- Synthesized as part of PROINSULIN (86AA)
-  excised by enzymes  insulin(51AA) + C-
Peptide (29AA)
o Insulin Structure
- Large polypeptide : 51AA (5808g/mol)
- Two chains linked by DISULFIDE BONDS
o A. CHAIN (21AA)
o B. CHAIN (30AA)
o 3. Disulfide Bonds
o Insulin Synthesis
- Preproinsulin : insulin gene encodes large
precursor of insulin
- Proinsulin : during translation, signal peptide
is cleared
- Proinsulin  insulin + C-Peptide
↓ during packaging in granules
o Insulin Secretion
- Released from pancreatic B cells # low basal
rate and @ much higher stimulated rate

- Stimulants :
o sugars (mannose)
o AA ( gluconeogenic AA: leucine,
arginine)
o Hormones (glucagon-like polypeptide-
1)
 Glucagon
 Glucose dependent
insulinatropic
 Chloecystokinin
 FA
- B-Adrenergic Symph Ac.
- Stimulatory drugs:
o Sulfonylureas
o Meglitinide
o Nateglinide
o Isoproteronol
o ACH

- Inhibitory Signals
o Insulin
o Leptin
o A-Adrenergic symp
o Elevated glucose

- Inhibitory Drugs
o Diazoxide
o Phenytoin
o Vinblastine
o Colchicine
- Sulfonylureas (-) K-Channel ; (x), depolanze
- Glucose conc ↑
= ↑ ATP Prod (1)
= K Channel doses (2)
= Result : depolarization (3)
- Depolarization = Ca enters more (4)
- Ca Enters
= ↑ Intracell Ca
+
(5)
= ↑ insulin secretion (6)
- Insulin secretagogues : close ATP dependent
potassium channel (7)
o Sulfonylurea (8)
o Meglitinides = depolarized membrane
(9)
o D-phenotalanine
= ↑ insulin release(10)

o Stimulators of iNSULIN secretion
 ↑ serum glu
 ↑ serum AA
 ↑ serum FA (Free)
 ↑ Ketone bodiees

 Hormones :
- Gastroinhibitory peptide (GIP)
- Glucagon
- Gastrin
- Cholecystokinin
- Secretin
- Vasoactive intestinal peptide
- Epinephrine (B-receptor)
 Parasympathetic NS

 (-) of INSULIN secretion :
 ↓ glucose
 ↓ AA
 ↓ Free FA
 Hormones :
- Somatostatin
- Epinephrinie (A-receptor)
 Sympathetic NS

 INSULIN Degradation
o 2 Main organ that remove insulin
 LIVER :
- Clears blod 60% of insulin released in
pancreas
- Remove 30-40%
 KIDNEY :
- Removing 35-40% endogenous hormone
- Clears exogenous insulin (60%)
o T1/2 of insulin : 3-5mins

 Circulatory Insulin
- Basal insulin values
5-15µU/mL (30-90pmol /L)
- Peak
60-90µU/mL (360-540 pmol/L)

 INSULIN receptor
o Primary target tissues :Identifies biologic response
promoted by insulin receptor complex
 Liver
 Muscle
 Adipose tissue
o Insulin receptor  bind insulin in picomolar range
 A – extra cellular
 Β – contains tyrosine
o Network of Phosphorylation w/in cell : Insulin’s 2nd
messenger
o Insulin ↑
 Glucose uptake
 Glycogen formation
 Protein synthesis
 Lipogenesis
 DNA Synthesis, cell growth, division

o Steps :
1. Activates receptor by binding of insulin mol. To a
subunit @ outside surface of cell
2. Brings catalytic loop of opposing cytoplasmic β-
subunit into closer proximity thru comformational
change
3. Mutual phosphorylation of tyrosine residues on β-
subunits & tyrosine kinase activity directed at
cytoplasmic proteins
a. 1st protein to be phosphorylated
i. Docking protein
ii. Insulin receptor substrates (IRS)
4. IRS mol. Bind & activate other kinases
a. Phosphatidylinositol – 3-kinase
5. Bind to an adaptor protein :
a. Growth factor receptor – binding protein 2
i. Translate insulin signal to (GNRF)
Guanine Nucleotide-Releasing
Factor
b. GNRF : activates GTP binding protein in
RAS, Mitogen-Activated Protein Kinase
system (MAPK)
6.

o Insulin resistance : Phosphorylation of Threonine &
Serine

 Glucose Transporters
o GLUT 1 :
 All Tissues (red cells, brain)
 1-2 : Glu Km
 Func
- Basal uptake of glucose
- Transport across BBB
o GLUT 2 :
 Betacell of pancreas ; liver, kidney, gut.
 15-20 mmol / L
 Func
- Regulates insulin release
o GLUT 3 :
 Brain, lacenta
 <1
 Uptake into neurons
o GLUT 4 :
 Muscle, Adipose
 ~5
 Insulin mediated uptake of glucose
o GLUT 5 :
 Gut, Kidney
 1-2
 Absorpt. Of Fructose

 EFFECTS of INSULIN on its TARGET
o LIVER
 Reversal of catabolic features of insulin def.
- (-) glycogenolysis
- (-) conversion of FA. & AA to ketoacids
- (-) conversion of AA to glucose
 Anabolic actions
- Promote glucose storage as glycogen
- Induce
o Glycokinase
o Glycogen Synthase
- (-) Phosphorylase
o MUSCLE
 ↑ Triglyceride storage
- Lipoprotein lipase is induced & activated by
insulin to hydrolize triglycerides from
lipoproteins
- Glucose transport into cell provides glycerol
phosphate to permit esterification of FA
- Intracellular lipase is inhibited by insulin

AVAILABLE INSULIN PREPARATIONS
 TYPE OF INSULIN
o For Type 1 & 2 DM,
- Rapid-acting : very fast onset & short DOA
- Short-acting : rapid onset of action
- Intermediate-acting ------ 50% absorpt
- Long-acting : slow onset
o Terms:
 NPH (Neutral Protamine Hagedorn insulin)
 Goal of SC insulin therapy
- Replicate normal physiologic insulin secr.
- Replace background / basal as well as bohis /
prandial
 Intensive Therapy “tight control”
- Restore near normal glucose patterns while
minimizing risk of hypoglycemia
- Use long acting - provide basal (overnight
fasting bet. Meal)
- Rapid acting : meal time (prandial)

o Latter insulin : supp doses to correct transient hypergly
Conventional Therapy : split dose inj. Of mixtures of rapid
or short & intermediate

1. RAPID-Acting insulin : PRADIAL
- Mimic normal endogenous prandial than in
regular
- Benefit :
o Taken immediately before meal
o Don’t sacrifice glucose control
- DOA : 4-5Hrs
- ↓ risk of late postmeal hypoglycemia
- Aborption
o 5%
o Regular, 25%
- Preferred insulin for use in continuous SC
insulin infusion device
A. Insulin LISPRO, humalog (Lilly)
- Source : human analog : Conc : UIOO
- First monomeric insulin analog
- Produced by recombinant technology
o 2AA neaer carboxyl terminal of B-Chain
have been reversed in position
o Proline : B28  (move) B29
o Lysine : B29  B28
- Advantage : very low prpensity
- To enhance shelf life : cresol preservative
- When injected SC  quickly dissociates into
monomer  rapidly absorbed  onset : 5-
15mins – peak=1hr
B. Insulin As part , NOVOLOG (NOVO Nordisk)
- By substitution of B28 proline w/ (-) charged
aspartic acid
- Reduces normal ProB28 & Gly B23 monomer
interaction –monomer
- (-) insulin self-aggression
- Absorpt : same as LISPRO
- More reproducible than regular insulin
- Has binding properties, activities
- Source : Human Analog
- Conc: UIOO
C. Insulin Glulisine , Apidra (Avents)
- Source : Human Analog
- Conc: UIOO
- By substituting lysine for aspargine @ B3 and
glutamic acid for lysine @ B29
- Absorpt: similar as LISPRO

2. SHORT-acting : Regular Insulin
a. Regular NOVOLIN R (Novo Nordisk)
b. Regular Humulin R. (Lilly)
- Source : Human
- Conc:
o UIOO : NOVOLIN
o UIOO, U500 : Humulin R.
- Effect : w/in 30mins
- Peak: 2-3hrs
- Last : 5-8hrs after SC inj
- Hexameric nature
- Molecules self-aggregate in antiparallel
fashion forming dimers w/c stabilize around
Zn ions creating HEXAMERS
- Hexamic nature : cause of delayed onset &
prolong time to peak
- Admin & mealtime
= blood glucose rises faster than insulin
= Result : early postprandial Hypergly
: ↑ risk of late postprandial
HYPOGLYCEMIA
- Should be inj = 30-45mins before meal
- Absorpt : 35%
- Only type w/c should be admin. IV due to
dilution cause hexameric insulin to
immediate dissociate to monomers
- Useful for IV therapy in ketoacidosis
management
- Also when insulin requirement changing
rapidly
- After surgery / during acute inf.

3. INTERMEDIATE acting
A. NPH Insulin
- Absorpt & onset are delayed by combining
appropriate amount of INSULIN &
PROTAMINE so that neither is present in
uncomplexed from “ISOPHANE”
- Onset : 2-5hrs
- Duration : 4-12hrs
- Usually mixed w/ regular, LISPRO, aspart or
Glulisine insulin & given 2-4x / day for insulin
replacemnet
- After SC : Proteolytic Tissue enzyme degrade
protamine  permiting absorption
- Dose : regulates profile action
: small dose : lower, earlier peaks &
short DOA w/ converse true for large
dose
- Absorp: 50%
o NPH Humulin N. (Lilly)
o NPH Novolin N (Novo Nordisk)
- Source : Human
- Conc: UIOO

4. LONG acting
A. Insulin Glargine : LANTUS
- Soluble. “Peakless” (broad plasma conc.)
- Designed to provide reproducible convenient
background insulin replacement
- The attachment of 2 arginine & substitutes of
glycine for asparagine @ A21 POS. Created
an analog w/c is soluble in acidic solution but
ppt. In more neutral body PH after SC
- Onset: 1-1.5hrs
- Max effect : 4-6hrs
- Max activity : 11-24hrs maintained
- OD (some benefit from split BID)
- PH-4 : acidic : to maintain solubility
- Should not be mixed w/ other insulin
- Has 6-7 fold greater binding than native
insulin to the insulin – like growth factor
receptor
B. Insulin determir, LEVEMIR
- Most recently developed
- The terminal THREONINE is dropped from
B30 position & myristic acid is attached to
terminal B29 lysine
- MYSTIRIC ACID : C-KIFA chain
- Prolongs availability  ↑both self-
aggression in SC tissue & reversible albumin
binding
- Has most reproducible effect of intermediate
& long acting
- Use is assoc. w/ less hypoglycemia than NPH
- Dose-dependent
- Onset: 1-2hrs conc: UIOO
- DOA: >12hrs source: Human Analog
- BID :  to obtain smooth background insulin
lvl
5. MIXTURE of insulin
- LISPRO / aspart / Glulisine + NPH
- w/out affecting rapid absorpt.
- Premix – are unstable
- NPL : Neutral Protamine Lispro
- NPH : Neutral Protamine Aspart
- NPL & NPA DOA: same as NPH to remedy
unstableness
- NPL + Insulin LISPRO
- NPA + Insulin Aspart
- Glargine & detemir : given as separate inj
- Not miscible Conc. UIOO
A. Novolin 70 NPH + 30 regular -------------------- Human
B. Humulin 70 NPH + 30 regular (Lilly) -----------
C. 75/25 NPL + LISPRO (Lilly) ---------- Human Analog
D. 70/30 NPL + Aspart -------------------
o Insulin Production
- Mass production by recombinant DNA
techniques is carried out by inserting human
/ modified human proinsulin into E. Coli /
yeast & treating
- Conc entration : UIOO & U500
- Insulin Delivery Systems
 Standard delivery
- SC inj using conventional disposable needles
& syringe
 Portable Pen injectors :
- To facilitate multiple SC inj of insulin
particularly during intensive
- Contains cartridges of insulin & replaceable
needles
- Disposable insulin pens : also avail. For
selected formulations
o Regular insulin
o Lispro
o Aspart
o Gulisine
o Glargine
o Detemir
o Several mix of NPH w/ regular LISPRO
& Aspart
o Due to that they eliminate need to
carry syringes & bottles
 Continuous SC insulin Infusion devices
- CS11 / Insulin PUMPS :
- External open-loop pumps for insulin delivery
- Have user programmable pump w/c delivers
individualized basal & bolus insulin
replacement doses based on blood glucose
self-monitoring results
- 24hrs : basal rates are programmed
: constant
A. Insulin Pumps
- Contains insulin reservoir , program chip,
keypad , and the display screen is the size of
a paper
- Abdoben : favored site
- Change : 2-3 days
B. CSII delivery : most physiologic method of insulin
replacement
- Boluses : used to correct ↑ blood glucose lvl
: to cover mealtime insulin
requirement bassed on CHO content
- Use is encouraged for people unable to
obtain target control while on multiple
injection regimen & for excellent glycemic
control (e.g during pregnancy)
- Aspart, lispro, glulisine : approve for pump
use & prefer pump w/out ↑ risk of
hypoglycemia
- Portable pen injectors : contain cartridges of
insulin & replaceable needles
- Inhaled insulin : not yet applicable
o Benefit of Glycemic control in DM
 Exception from this is the Px w/ advanced renal dx
 due to risk of hypoglycemia
 Insulin Regimens
o Intensive Insulin Therapy
- Prescribed for almost everyone w/ TYPE-1
DM & TYPE-2 DM
- 0.55x person’s wt (Kg) : total daily reg
- Insulin-to-CHO ratio : refers to how man
grams CHO will be disposed OK by 1 unit of
rapid-acting
o Conventional Insulin Thrapy
- Prescribed only for certain people w/ TYPE-2
DM who felt not to benefit from intensive
glucose control
- Insulin regimen : one inj/d to many inj/d 
intermediate or long-acting alone or w/ short
/rapid acting or premixed

 Insulin Tx on Special Circumstances
1. Diabetic Ketoacidosis
- Life-threatening medical emergency caused
by inadequeate /absent insulin replacement
w/c occurs in people w/ TYPE-1 DM &
infrequent w/ TYPE-2 DM
- Occurs in newly diagnosed TYPE-1 px or
those who have experienced interrupted
insulin replacement
- Rarely in people w/ TYPE-2
 Signs&Symp
- Vomiting
- Nausea
- Abdominal pain
- Deep slow breathing : Kussmaul
- Change in mental status
- Elevated blood & urinary ketones & glucose
- Arterial blood pH - < 7.3
- Low HCO3

( <15 mmol/L )
 Tx
- Aggresive intravenous hydration
- Insulin therapy
- Maintenance of K & other electrolyte
- Fluid therapy : begins w/ normal salive
- Regular insulin : IV  0.1 IU /Kg/h

2. Hyperosmolar Hyperglycemic Syndrome
- Diagnosed in persons w/ TYPE-2 DM
- Characterized by profound hyperglycemia &
dehydration
- Assoc. w/ inadequate oral hydration esp. In
elderly px
- Use of medication w/c elevates blood sugar /
cause dehydration
- Drugs w/c ↑ BS / cause dehydration
o Phenytoin
o Steroids
o Diuretics
o Β Blocker
o Peritoneal Dialysis
o Hemodialysis
- Person w/ HHS are not acidotic unless DKA is
also present
- TX: Low-dose insulin therapy
COMPILATION of INSULIN THERAPY
1. Hypoglycemia
- Most common complication
- Result from inadequate cito, unusual physical
exertion, too large of insulin dose
A. Mech. & Diagnosis
 Sign
- Autonomic hyperactivity
- Sympathetic
o Tachycardia
o Palpitation
o Sweating
o Tremulousness
- Parasympathetic
o Nausea
o Hunger
- Convulsion *if untreated*
- Coma *if untreated*
 Hypoglycemic unawareness :
- Dangerous acquired condition
- Px lack early warning signs of ↓ blood
glucose
- Manifestation of untreated hypoglycemia
o Confusion
o Weakness
o Bizarre behavior
o Coma
o Seizure
o And @ point w/c not able to procure /
safely swallow glucose-containing
foods
B. TREATMENT :
 Glucose administration
 Simple glucose / sugar only  liquid (prefer)
 Mild hypogly :
- Dextrose tabs
- Glucose gel
- Any sugar-containing beverage/food
 Sever Hypogly :
- 20-50mL of 50% glucose soln by IV inf (2-
3mins)
- 1mg glucagon (SC /1m)
- Restore consciousness for 15mins
- Honey/syrup into
o Buccal
o Small amount

2. IMMUNOPATHOLOGY of INSULIN THERAPY
- 5mol class of insulin antibodies produced in
diabetics
o IgA
o IgD
o IgE
o IgG
o IgM


o Two (2) Major Types
A. Insulin Allergy
- Immediate type hypersensitivity
- Rare condition in w/c local / systemic uricaria
results from histamine release from tissue
most cell sensitized by: anti insulin IgE
antibody
- Anaphylaxis result in severe case
- Human & analog insulin : reduced incidence
of insulin allergy due to sensitivity is often to
non-insulin protein contaminants
B. Immune insulin resistance
- Low titer of circulating IgG anti-insulin
antibody w/c neutralizes action of insulin to
negligible extent develops in most insulin-
treated px.
- Rarely, titer of insulin antibody : leads to
insulin resistance & may be assoc w/ LE

3. LIPODYSTROPHY @ Injection Sites
- Inj of animal insulin : led to atrophy of SC
fatty tissue @ site of inj
- Hypertrophy of SC fatty-tissue: if injected
repeatedly @ same site
- May be corrected by avoiding specific site of
liposuction

4. INCREASED CANCER RISK
- Attributed to insulin resistance &
hyperinsulinemia
- Hyperinsulinemia : Indiv w/
o Insulin resistance
o Prediabetes
o TYPE-2 DM
- Tx w/c ↑ circulating insulin lvl:
- Insulin & sulfonylureas

ORAL ANTIDIABETIC AGENTS
 7 Categories : for tx of TYPE-2 DM
1. Insulin secretogogues
: ORAL ANTIDIABETIC AGENTS insulin secetion
from B cell
 Sulfonylureas : longest, traditional tx choice
 Meglitinides
 D-phenylalanines Derivatives

2. Biguanides : longest, traditional tx
3. Thiazolidinediones : reduce insulin resistance
4. A-Glucosidase (-)
- Slows digestion & absorpt of starch &
disaccharides
5. Incretin-based therapies
- Control post-meal glucose
- Excursions by ↑ insulin release & glucose ↓
glucagon secretion
6. Amylin Analog : ↓ postmeal glucose lvl & reduce
appetite
7. Bile acid – binding sequaterant ↓ glucose effect


 Sulfonylureas
o Tolbutamide (orinase) – Glipizide (glycliazinamide)
- (glucotrol, glucotrol XL)
o Tolazamide (Tolinase) – Glimepiride
o Chlorpropamide (Diabinese)
o Glyburide (Glibenclamide) (diabeta, micronase, glynase
prestab)

A. INSULIN SECRETAGOGUES
1. Sulfonylureas
 MOA: ↑ insulin release from pancreas
- Reduction of serum glycagon level
- Closure of K channels in extrapancreatic
tissue
 ↑ from pancreatic β cell
- Bind to 140-Kda high affinity sulfonylurea
receptor assoc. w/ B cell inward rectifier ATP-
sensitive w/ B cell inward rectifier ATP-
sensitive K channel
- (-) efflux of K ions thru channel – result :
depolarization
- Depolarization : open voltage-gated Ca
Channel  result : Ca influx : release
preformed insulin
 Reduction of Serum-glycagon concentrations
- Long-term admin to TYPE-2 : reduce
glucagon lvl
 result : Hypoglycemic effect
- Indirect (-) due to enhanced release OK both
insulin & somatostatin
 result (-) A cell secretion
- Efficacy & Safety
o Divided to first gen and 2nd gen
o 1st Gen : increasing difficulty to
procure
o 2nd Gen : generic & less expensive
A. First Generation :
 Tolbutamide (Orinase)
- Well absorbed but rapidly metabolized in
liver
- DOA: (SHORT) 6-12hrs
- Dose : (daily) : 0.5-2g in divided dose
- T1/2 : 4-5hrs
- Best admin in divided dose
- Safest sulfonylurea for elderly
- ADR : prolonged hypoglycemia (rare)
o In px w/ drugs:
 Dicumanol
 Phenylbutazone
 Some sulfonamide
o (-) metabolism

 Chlorpropamide (Diabinese)
- T1/2 : 32hrs
- Slowly metab : by liver
- Excreted : 20-30% unchanged in urine
- Also interacts w/ drugs in tolbutamide w/c
depend on hepatic oxidative catab
- CI: px w/ hepatic /renal insuf
- DOA: up to 60hrs
- Dose : 0.1-0.5g / single dose
: >500mg : ↑ risk of jaundice
- Average maintenance dosage. 250mg/d
 single dose in mornings
- ADR : prolonged hypoglycemic : in elderly
(common)
o Hyperemic flush after a/c ingestion in
preisposed Dx
o Dilutional Hyponatremia
- Hematologic Toxicity : transient leukopenia
o Occur <11% px thrombocytopenia
 Tolazamide (Tolinase)
- Comparable to chlorpropamide in potency
- DOA : 10-14hrs
- More slowly absorbed than other
sulfonylurea
- T1/2 : 7hrs
- Metabolized to several cmpds w/c retain
hypoglycemic effect
- If >500mg /d : -BID shoudl be divided

B. 2nd Generation
- Pescribed more freq.
- Fewer effect (ADR) & DI
- Caution : px whom hypoglycemia as
dangerous
o Glyburide (Glibenclamide) (Glynase prestab Diabeta,
micronase)
- Metab in liver into products w/ very low
hypoglycemic activity
- Starting dose : <2-5mg/d
- Ave Dose : 5-15mg/d
: Single morning dose
- Maintenance dose : 20mg/d
- >20mg/d 1  not recommended
- Glynase prestab “micronized glyburide”
- ADR:
o Flushing (rarely) after ethOH ingestion
o Enhance free water clearance
o Glypizide (glydiazinamide) (Glucotrol, Glucotrol XL)
- Shortest t1/2 : 2-4hrs
- For max effect : ingested 30min before bfast
- Absorption delays w/ drug is taken w/ food
- Starting : 5mg/d – 15mg/d – single dose
- Max dose by manuf : 40mg/d
- Max therapeutic effect : 15-20mg
- Daily dose : 8-30mg
o 20mg : glucotrol XL
- Glucotrol XL : provide 25hr action after once
daily morning dose
o Low propensity fore severe
hypoglycemia compared w/ long-
activity
- Produce less hypoglycemia
- 90% metab in liver
- 10% is excreted
- CI : px w/ significant hepatic / renal
impairment


o Glimepiride
- OD use as monotherapy / combi w/ insulin
- ↓ Blood glucose w/ lowest dose
- DOA: 12-24hrs
- Daily dose : 1-4mg
- Recommended max daily dose : 8mg
- T1/2 : 5hrs
- Completely metab by liver

2. Meglitinide
o Rapeglinide (Prandin)
- DOA: 4-7hrs
- Oral dose : 0.25-4mg before meal
- First member of meglitinide grp
- Modulate B cell insulin release by regulating
K influx thry K chanel
- Very fast onset of action
- Peak effect w/in : 1hr after ingestion
- Hepatically cleared by CYP3A4
- T1/2 : 1hr
- Use in controlling post prandial glucose /
skipped / contain inadequate CHO
- Caution : px w/ renal & hepatic impairment
- Approve as monotherapy / combi w/ bi
guanides
- Use in TYPE-2 DM w/ sulfur / sulfonylurea
allergy
3. D-Phenylalanine Derivative
A. Nagletinide (starlix)
- DOA : 4hrs
- Oral dose: 60-120mg
- Before meal taken
- Latest insulin secretagogue
- Stimulates very rapid & transient release of
insulin from B cell  thru ATP-sensitive K
+

channel
- Partially restore initial insulin chosure release
in response is IV glucose tolerance
- Use w/ isolated postprandial hyperglycemia
- Efficacious when given alone / combi w/ non
secretagogue oral agent (metformin)
- Absorbed : w/in 20mins
- T1/2 : 1hr – metab by liver by : CYP2C9
: CYP3A4
- Amplifies insulin secretory response to
glucose overload
- Markedly diminished effect in presence of
normoglycemia
- Safe w/ very reduced renal fume

B. Bigulanides
1. Metformin (Glucophage , Glucophage XR)
- MOA:
o reduce hepatic glucose production
through activation of enzyme AMP-
activated protein kinase (AMPK)
o Impairment of renal glucopheogenesis
o Slowing of glucose absorption from GIT
o ↑ glucose to lactae conversion by
enterocytes
o Direct stimulation of glycolysis in
tissues
o ↑ glucose removal from blood
o ↓ plasma glucagon level
- Px w/ TYPE-2 DM have less fasting
hyperglycemia
- As well as power postprandial hyperglycemia
- AKA “euglycemic” agents
- T1/2 : 1.5 – 3 hrs
- Not nound to plasma protein
- Not metab
- Excreted by kidney as active cmpd
- Impair hepatid metab of lactic acid
- ↑ risk of lactic acidosis in px w/ renal insuf
- First line therapy for TYPE-2 Dm
- Insulin-sparing agent
- Do not ↑ BW / provoke hypoglycemia
- ↓ risk of macrovascular & microvascular dx
- Combined also w/ insulin secretagogues or
thiazolidinediones in TYPE-2 in whom
monotherapy is inadequate
- Useful in TYPE-2 prevention
- Dose : 500mg
: 2.55g/d : max
- OD : before meal / bedtime
- Common sched for fasting hyperglycemia
o Single 500mg (bedtime for 1wk)
o 500mg (evening meal added)
- If dose ↑ : 500mg (bfast/midday meal)
- Largest dose : 850mg (BID/TID)
- 1000mg : provokes GI ADR
- Reduce risk of some cancer
- ADR:
o Anorexia
o Nausea
o Vomiting
o Abdominal discomfort
o Diarrhea
o Alcoholism
o Hepatic dx
o Conditions predisposing o tissue
anoxia
- CI: px w/ renal dx
o Thiazolidinediones
- ↓ insulin resistance
- Ligands of peroxisome proliferator-activated
receptor gamma (PPAR-y : part of steroid
thyroid)
o Found in muscle, fat
- PPARy
o Modulate expression of genes involved
in linid & glucose metab, insulin signal
transduction & apidocyte & other
tissue differentiation
o Oncogenic effect are complex and may
be both tumorigenic & antitumorigenic
- Adipose tissue
o Major site of Txd
o Promotes glycose uptake & utilization
& modulates synthesis of lipid
hormone
- Regulate adipogite apoptosis
o Pioglitazone (Actos)
- Oral dose : 15-45mg OD
- Has PPAR-a & PPAR-y activity
- Absorbed w/in 2hrs (food-delay uptake)
- Metab by: CYP2C8 & CYP3A4
- Starting dose : 15-30mg/d
- Max : 45mg/d
- ↓ triglyceride
- Approved as monotherapy & in combi w/
melformin, sulfonylureas & insulin
- Tx for TYPE-2
- ↑ dose : risk of bladder cancer

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