5.

03 Hormones & Metabolism Regulation II

Suzette M. Mendoza, MD | March 5, 2018 
 

● Major target organs:

OUTLINE  → Liver
IV. Clinical Correlation → Skeletal muscles
A. Insulin Deficiency or → Adipose tissues
I. Overview Resistance ● Normal blood glucose level: ​80-100 mg% (5 mM)
A. Review of Hormones B. Diabetes Mellitus Type ● Dependent on glucose for all or part of energy needs
B. Glucose Homeostasis 1 → Brain
II. Insulin C. Diabetes Mellitus Type → Mature RBC
A. Metabolic Effects 2 → Adrenal medulla
B. Structure D. Gestational Diabetes → Exercising skeletal muscles
C. Biosynthesis E. Monogenic Forms of ● Total glucose requirement per day: ​190 g
D. Insulin Release DM → Brain: 150 g
E. Insulin Receptor V. Glucagon → Other tissues: 40 g
F. Degradation A. Biologic Effects
III. Signaling Pathway of B. Synthesis II. INSULIN
Insulin C. Structure
A. Proximal IR Signaling D. Receptor A. METABOLIC EFFECTS
Events E. Regulators of Release
B. Downstream Signaling F. Secretion ● The insulin signaling system coordinates systemic growth &
Events VI. Signaling Cascade of development with peripheral & central nutrient homeostasis,
C. Regulation of Signaling Glucagon fertility and lifespan.
Cascades VII. Summary of Hormonal ● At the molecular level, insulin regulates many pathways:
Regulation → Stimulation of protein synthesis (in muscle & liver)
VIII. Incretins → Decrease protein degradation
→ Lipid synthesis and storage (liver & adipose tissue)
OBJECTIVES → Glycolysis & glucose storage (muscle and liver)
→ Inhibition of ketogenesis and gluconeogenesis (liver)
1. Review the physiologic effects of Insulin and Glucagon. → Increasing glucose uptake primarily in skeletal muscles &
2. Expound the biochemistry of Insulin and Glucagon. adipocytes via GLUT4
3. Correlate the signaling pathways of Insulin and Glucagon with → Glucose utilization and storage
their metabolic effects. → Decreasing hepatic glucose output (via decreased
4. Analyze the biochemical bases of different diseases due to glycogenolysis and gluconeogenesis)
Insulin deficiency/resistance. → Decreasing FA release from TAGs in adipocytes & muscles
5. Describe the factors that can terminate the signaling pathway of
Insulin and Glucagon. B. STRUCTURE
6. Discuss the functions of Incretins to regulate metabolism.

I. OVERVIEW

A. REVIEW OF HORMONES

● Major hormones that regulate fuel metabolism:

→ Insulin
→ Glucagon Figure 1. ​Structure of Insulin
→ Epinephrine & Norepinephrine
→ Glucocorticoid ● Polypeptide hormone w/ 2 chains of 51 amino acids (AAs)
→ Thyroid hormones → A chain (21 AAs): B chain (30 AAs)
→ Growth hormone ● Linked by 3 disulfide (S-S) bridges contributed by Cysteine
→ Somatostatin → 2 Inter-chain S-S bridges connect A7 to B7, & A20 to B19
→ Incretins → 3rd intra-chain S-S bond connects AAs 6 to 11 of the A chain

B. GLUCOSE HOMEOSTASIS

● Life ➝ continuous provision of energy (glucose, FAs and AAs)

● Glucose homeostasis
→ Maintenance of blood glucose near 4.5 mM at all times
through the combined actions of major hormones regulating
fuel metabolism Insulin, Glucagon, Epinephrine, and Cortisol
on metabolic processes in many body tissues

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 C. BIOSYNTHESIS Second Phase 
● Synthesis of new Insulin and released in response to ↑ cytosolic
Acyl CoA

Figure 2.​ Biosynthesis of Insulin

Figure 4. ​Phases of Insulin Release
● Preproinsulin
→ MW = 11,500 kD ● First Phase: Faster and higher peak as a result of increased
→ “​Pre” or “Leader” sequence​: 23 hydrophobic amino acids oral glucose
→ The reason why the Glucose Tolerance Test or GTT is
that directs the molecule into the cisternae of RER
performed orally and not via IV
● Proinsulin
● Second Phase: Lower peak as a result of other secretagogues
→ MW = 9000 kD
aside from increased glucose
→ Provides the conformation for the proper location of the
disulfide (S-S) bridges
→ Sequence: B chain – ​C (connecting) peptide​ – A chain
ATP-Gated K​+​ Channels in β Cells of the Pancreas 
● Mature Insulin
→ Difficult to measure because of the short half-life on insulin
(3-5 minutes)
→ Always couple with Zinc

D. INSULIN RELEASE

Figure 5.​ ATP-gated K+ channels in ​β cells of the Pancreas

● Octamer
● 4 Kir6.2 subunits:
→ Selectivity filter
→ ATP-gating mechanism
● 4 SUR1 subunits:
→ Closes when Sulfonylurea is present → Insulin release

Insulin Release Regulation 

● Only Insulin & Glucagon are synthesized and released in direct
response to changing levels of fuel in the blood.
● Threshold for Insulin release: 80 mgs%; proportional to the
concentration of glucose up to 300 mgs%
Figure 3.​ Insulin Release
Table 1.​ Regulators of Insulin Release
First Phase  Regulators Effect
1. Glucose entry via GLUT 2 into β cells ➝ Complete oxidation via Major Regulator
Glycolysis ➝ TCA ➝ Oxidative Phosphorylation ➝ Increased
Glucose +
[ATP]/[ADP]
Minor Regulators
2. Closure of ATP-dependent K+ channels ➝ Depolarization of
cell membrane Amino acids +
3. Opening of L-type Ca​2+​ channels ➝ Ca​2+​ influx ➝ Activation of Neural input +
Ca​2+​ dependent proteins GIT hormones (Incretins, GIP, +
4. Release of preformed Insulin by Exocytosis GLP-1)
Epinephrine (Adrenergic) -

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 Figure 6.​ Pattern of Glucose, Insulin and Glucagon Release
After a High Carbohydrate Meal Figure 7. ​Insulin Receptor

● Throughout the day, a person will get a pattern of insulin levels

(shown in Figure 6) in relation to food intake.
F. DEGRADATION
● After a high carbohydrate meal, there is a subsequent increase
● Half-life: 3-5 minutes
of Insulin around 1 hour after meals. Insulin starts to go up as
● Sites: ​Liver​, kidneys, placenta
early as 45 minutes while Glucagon is decreased.
→ 50% of the degradation takes place in the liver
● The graph shows that there is never a time where glucagon
● 2 enzymes:
levels is zero. This is why there is a Insulin/Glucagon ratio.
→ Protease (Insulinase)
→ Glutathione-Insulin transhydrogenase:​ ​↓​disulfide bonds
E. INSULIN RECEPTOR ● Endocytosis of Insulin-receptor complex
→ Degradation of enzymes
● Chromosome 19
● Family of homologous receptor tyrosine kinases(RTK)
→ e.g. IGF [Insulin-like Growth Factor] and IRR [Insulin III. Signaling Pathway of Insulin
Receptor-Related Receptor]
● Proteolytic cleavage of a single polypeptide chain precursor A.PROXIMAL IR SIGNALING EVENTS
→ α & β chains linked by disulfide bonds
● Biologically active α2β2 receptor heterotetramer ● Once activated via phosphorylation, IR phosphorylates a no. of
● Preformed tetramer: important proximal substrates on Tyr which includes
→ 2 extra-cellular α sub-units: Insulin binding domains 1. IRS 1,2 & 4: IRS 4 is found in the hypothalamus &
▪ Inhibits the tyrosine kinase activity of the β subunit thymus
→ 2 transmembrane β sub-units: Tyrosine Kinase activity and 2. Shc adapter proteins
auto-phosphorylation sites; joined by S-S bridges 3. SIRP family members: Gab-1, Cbl, & APS
▪ 2 domains 4. Effector molecules with Src homology 2(SH2) domains:
− Transmembrane domain small adapter CHONs Grb2, Nck, SHP2 protein tyrosine
− Intracytoplasmic domain(contains the ATP binding site phosphatase, & the regulatory sub-unit of PI3-K
and where the RTK property resides) ● Insulin Signaling Pathway
● Only 3 are expressed in human → Insulin receptor is active after phosphorylation of critical
→ IRS1 and IRS2 tyrosine residues (this is the start of any cascade)
▪ Expressed in the brain, muscle, heart, adipocyte, liver, → Activated tyrosine receptors will phosphorylate insulin
kidney, ovary and mammary gland receptor substrates (IRS) 1, 2,4 (more important are 1 and 2)
▪ Contribute to a broad array of physiologic functions → IRS must have phosphotyrosine domains which are the ones
including: to be phosphorylated to give activated IRS
− Pancreatic β cell growth and function ▪ IRS: immediate downstream substrate of a
− Central nutrient sensing phosphorylated/active insulin receptor
− Neurodegeneration → Inhibitors of phosphorylation of IRS:
− Cancer progression and lifespan ▪ Phosphotyrosine phosphatase (PTP)
→ IRS4 ▪ SHP
▪ Largely restricted to the Hypothalamus and Thymus ▪ SRC homologue phosphatase
● Type-1 diabetes is characterized by the inability to synthesize
insulin, whereas in type-2 diabetes the body becomes resistant

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 to the effects of insulin, presumably because of defects in the → PI-3K-independent pathway​:
insulin signaling pathway. ▪ IR-mediated tyr phosphorylation of ​Cbl ​proto-oncogene
B. DOWNSTREAM SIGNALING EVENTS (encodes for ubiquitination factor) in the presence of ​APS
(adapter protein) and ​CAP ​(Cbl Associated Protein)
● Insulin-stimulated GLUT4 translocation: ▪ specific to adipocytes
→ PI-3K-dependent pathway​:
▪ Serine-threonine kinase Akt/PKB
▪ Atypical PKC​ζ/λ
▪ 3 main pathways regulated
− AGC ​family of ​ser/thr ​protein kinases
− guanine nucleotide-exchange proteins of ​Rho GTPase
family
− Tec​ family of tyrosine kinases

● CrkII is constitutively associated with the Rho-family guanine

nucleotide exchange factor, C3G

Figure 8.Downstream SIg​naling Event

▪ Site: Skeletal muscles containing PDK1 and Akt2

downstream of PI3k

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 C. REGULATION OF SIGNALING CASCADES ● An autoimmune condition that destroys β cells in the pancreas
which are responsible for production of insulin
1. Serine-threonine kinases phosphorylate IRS-4 → ↓susceptibility ● More commonly diagnosed during childhood or adolescence
to phosphorylation by insulin receptor(Akt/PKB, Protein period (< 20 years old)
phosphatase 2A - PP2A) ● Characterized by the mobilization of TAGs from adipocytes
2. Phosphotyrosine phosphatase 1B(PTP1B) : contributes to which are then oxidized and produce acetyl CoA and ketone
termination of insulin action bodies
3. Phosphatase & Tensin homologue on chromosome 10(PTEN) : → Production of high levels of ketone bodies (ketogenesis) ->
a 3’ phosphatase lower blood pH (can be fatal)
4. Family of SRC homology 2 containing inositol 5’ phosphatase (2 ● Maintenance requires regular intake of INSULIN
gene products SHIP1 & 2) → degrade PIP2 & PIP3 → Only insulin can be used as treatment
5. Negative feedback inhibition from Akt/PKB, PKC​ζ, p70S6K &
MAPK ​ → phosphorylation of Ser & inactivation of Insulin C. DIABETES MELLITUS TYPE 2
signaling
6. Internalization & degradation of insulin- insulin receptor complex ● Adult onset (> 40 years old) diabetes: most common type of
in endosomes diabetes (90%)
● Impairment of pancreatic 𝛃 cell function
IV. CLINICAL CORRELATION → Peripheral insulin resistance
● Etiology: multifactorial
A. INSULIN DEFICIENCY OR RESISTANCE → 2 main risk factors:
▪ Family history (gene susceptibility)
● Diabetes Mellitus is characterized by increased blood glucose − Heritability ​> 50%
level (hyperglycemia) due to the absence or insufficient ▪ Obesity
production of insulin − Insulin resistance first presents as ​hyperinsulinemia
● May result from the combination of genetic and environmental with normal glucose concentration
factors (e.g. lifestyle) − 𝛃 cells compensate for peripheral insulin resistance
● Type 1 DM, Type 2 DM and Gestational Diabetes constitute the − Failed compensation: increase in plasma glucose
three major types of diabetes during fasting
● Risk factors − Further insulin resistance and consequent impairment
→ Obese(>20% above their IBW) of insulin secretion leads to T2DM.
→ Have a relative with DM − IFG (impaired fasting glucose) and IGT (impaired
→ Belong to a high-risk ethnic population(African-American, glucose tolerance) are predictors for T2DM
Native American, Hispanic or Native Hawaiian) ● Treatment: lifestyle modifications
→ Have been diagnosed with gestational diabetes or have
delivered a baby weighing >9 lbs (4kg) Table 3.​ Genes associated with T2DM
→ Have high BP (>=140/90 mmHg) GENE FUNCTION ASSOCIATION
→ Have a high density lipoprotein cholesterol level <= to 35 WITH T2DM
mg/dL and/or a triglyceride level > or equal to 250 mg/dL PPAR​𝛾 - Differentiation & Involved in the
→ Have had impaired glucose tolerance test (GTT) or impaired (Peroxisomal functioning of brown & improvement of
fasting glucose on previous testing proliferator white adipocytes insulin resistance
activated - Promotes the
Table 2. ​Receptor-related mechanism of Insulin receptor 𝛾) accumulation of lipids
Deficiency/Resistance in the adipocytes
Site of Resistance Abnormality Comment IRS-1 -Mediated control of Impaired peripheral
Pre-receptor IR antibodies Rare cellular process by response to Insulin
Abnormal molecule insulin
Receptor ↓ number or affinity Not significant in KCJN11 - codes for 2 CHONs: associated with
of IR DM (K-inwardly-rectif ATP sensitive K neonatal DM
Post-receptor Defects in signal Post receptor ying channel channel (part of - Affects insulin
transduction: resistance is the subfamily J sulfonylurea receptor secretion
Defective tyr P most common type member 11) complex)
mutations in genes of insulin resistance
coding for IRS-1,
PI-3K, defective
translocation of WFS1​ (Wolfram -codes for Wolframin: detected in patients
GLUT4, ↑FAs syndrome 1 CHON w/ D.I. & juvenile
DM, deafness and
B. DIABETES MELLITUS TYPE 1 optic atrophy
HNF1A & - codes for Associated with
● Type 1 DM is also known as insulin-dependent diabetes or HNF1B ​(HNF1 transcription factor Maturity Onset
juvenile diabetes homeobox A/B) Diabetes in the
Young (MODY 3/5)
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 SLC30A8 -codes for Zinc Risk for T2DM → Leprechaunism
transporter → Rabson-Mendenhall syndrome
FTO -Fat mass & obesity Associated with → Lipoatrophic diabetes
associated protein obesity → Mutations in the PPAR𝛾 gene
GCKR & IGF1 Associated with insulin resistance ● Forms associated with defective insulin secretion
→ Mutations in insulin or proinsulin genes
Table 4.​ Comparison between T1DM and T2DM → Mitochondrial gene mutations
TYPE 1 DM TYPE 2 DM → Maturity-onset diabetes of the young (MODY)
▪ HNF-4ɑ (MODY 1)
Onset < 20 years old >40 years old
▪ Glucokinase (MODY 2)
Insulin absent due to immune Preserved:
− Most common
Synthesis destruction of β-cells combination of
− Non-functioning glucokinase → glucose
insulin resistance
phosphorylation in β-cells → no ATP increase →
and impaired
K-channels do NOT close →​ ​channels always open
β-cells
channel = no insulin secretion
Plasma insulin Low to zero Low, normal or high
▪ HNF-1ɑ (MODY 3)
concentration
▪ IPF1 (MODY 4)
Genetic Yes Yes ▪ HNF-1β (MODY 5)
susceptibility ▪ NeuroD1/BETA2 (MODY 6)
Islet β cell Yes no
antibodies at
V. GLUCAGON
diagnosis
Obesity Uncommon Common A. BIOLOGIC EFFECTS
Ketoacidosis Yes Rate, can be
precipitated by
major metabolic
stress
Treatment Insulin Hypoglycemic
drugs & insulin

D. GESTATIONAL DIABETES

● Pregnancy: decreases insulin sensitivity → provide adequate

glucose for the fetus
→ Hyperglycemic during pregnancy
● GDM: additional decrease in insulin sensitivity in 14% of
pregnant women and inability to compensate with increased
insulin secretion
● Increased resistance to insulin - mediated glucose transport in
skeletal muscle Figure 9​. Effects of glucagon on different organs.
→ Overexpression of plasma membrane glycoprotein 1 ​(PC-1)​:
inhibits tyr kinase activity by direct interaction with ɑ subunits ● Major counter-regulatory hormone that opposes the effect of
→ blocking insulin-induced transformation change insulin (contra-insulin)
● Excessive phosphorylation of ser-thr residues in skeletal ● Target organ​: liver, adipocytes
muscles’ insulin receptors → down-regulation of tyr kinase → Skeletal muscles: NO GLUCAGON RECEPTOR
activity ● Half-life​: 3-5 minutes
● Decreased expression and (P) of tyr residues of IRS-1 in ● Stimulation of :
skeletal muscles → Mobilization of fuel reserves
→ Defect in insulin action not insulin receptor binding affinity → Glycogenolysis
→ 30-50% → T2DM after pregnancy especially in the obese → Gluconeogenesis
● Glucose is available to glucose-dependent tissues in between
meals (fasting)
● Increased sensitivity of target cells to other insulin counter
E. MONOGENIC FORMS OF DM regulatory hormones

● Only 1 gene is associated

→ Neonatal diabetes: monogenic vs. T2DM: polygenic
● Basic problem: issue with insulin receptor gene
● Hyperglycemia is common through all
● Forms associated with insulin resistance
→ Mutations in the insulin receptor gene
→ Type A insulin resistance

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 ▪ Pancreas → glucagon (29 AA)
▪ Intestine → glucagon-like peptide (GLP)
→ Release of Glucagon
▪ Glucose enters into alpha cell of GLUT 1
▪ Low Glucose → moderate activity of K​ATP channels
​
→ activation of voltage-dependent T & N type and I-type
Calcium and Sodium Channels → Action Potentials →
Calcium Influx
▪ Exocytosis of Glucagon granules

Figure 10. ​Effects of glucagon on muscles, adipocytes, and liver.

Table 5.​ Glucagon Effects on Fuel Metabolism (adapted for ppt)

LIVER ADIPOSE TISSUE TISSUE
LIPOLYSIS
Glucose output ↑↑
Ketogenesis ↑
Gluconeogenesis ↑ Fat synthesis
Glycogenolysis ↑↑ No effect ↑
Glycogenesis ↓ Figure 11. ​How glucagon is produced from preproglucagon.
Protein synthesis -
C. STRUCTURE
Table 6.​ Covalent Modification by Glucagon
ACTIVE when INACTIVE when ● Polypeptide hormone: 29 AA (single polypeptide chain)
phosphorylated phosphorylated ● Degradation: liver and kidneys (cleavage between Ser 2 and
● Glycogen ● PFK 1 Gln 3 from the N-end)
phosphorylation ● Pyruvate kinase
● Phosphorylase ● Glycogen synthase
kinase ● PFK 2
● Fructose 2, 6 ● PDH
bisphosphate ● Acetyl CoA
● Hormone sensitive carboxylase
lipase
Key regulatory enzymes regulated by covalent modification are
phosphorylated by glucagon.

● Induction of enzymes by glucagon

1. G-6-phosphatase (gluconeogenesis) Figure 12. ​Glucagon is a 29 amino acid.
2. F 1,6-BP* (gluconeogenesis)
3. PEPCK* (gluconeogenesis)
D. RECEPTOR
4. Pyruvate carboxylase* (gluconeogenesis)
5. PDH kinase ● Glucagon receptor: G-protein coupled receptor (​GPCR​) in
6. Aminotransferase plasma membrane (trimeric protein)
7. HMG-CoA synthase (ketogenesis) → Has 7 hydrophobic plasma membrane spanning domains
8. CPT1 (FA beta oxidation) ● Stimulates synthesis of intracellular second messenger (cAMP)
→ Activates PKA → phosphorylation of key enzymes
B. SYNTHESIS
E. REGULATORS OF RELEASE
● Synthesized by the​ ɑ cells​ of the islets of pancreas and ​L​ ​cells
of the intestines. Table 7.​ Major and Minor regulators of Glucagon Release (adapted
→ Preproglucagon from ppt)
▪ 160 amino acids REGULATOR EFFECT
▪ synthesized in the RER of ɑ cells MAJOR REGULATORS
▪ enter the lumen of the ER → proteolytic cleavage →
Glucose -
proglucagon
Insulin -
→ Proglucagon
Amino acids +
▪ Undergoes proteolytic cleavage at various sites
MINOR REGULATORS
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 Cortisol + ● Inactivation occurs due to the intrinsic GTPase activity of ​G​α
Neural (stress) + subunit
Epinephrine + → G​α ​ bound to GDP will reassociate with G​ ​βγ ​to form an
inactive G protein that can again associate with the
receptor
F. SECRETION 
2. Adenylate cyclase activation which catalyzes the conversion of
ATP to cAMP, thereby increasing cAMP levels
Low glucose conditions 
● ATP is complexed with Mg2+ since it plays a role in the
● Low activity of​ K​ATP​ results to its partial opening
stability of all polyphosphate compounds
→ Efflux of K+ leads to hyperpolarization
● Phosphodiesterase catalyzes the breakdown of cAMP to
→ Nearby Tetrodotoxin-sensitive Na+ channel is activated
5’AMP
→ Voltage-gated T-type Ca2+ channels depolarizes the
● cAMP is the major second messenger of glucagon
membrane
glycosylation, exerting excitatory effects on pancreatic alpha
→ Membrane potential reaches action potential threshold
cells by two pathways:
→ Large population of L-type, N-type, and P/Q-type Ca2+
→ cAMP-dependent PKA pathway
channels is able to enter the conductive state
→ Non-cAMP-dependent protein kinase pathway
→ Calcium influx
→ GLUCAGON SECRETION
● T-type Ca2+ channels open in response to mild depolarization cAMP-dependent PKA pathway 
steps, whereas P/Q-type, L-type, and N-type Ca2+ channels ● PKA has 2 regulatory (RR) and 2 catalytic (CC) subunits
are activated by strong depolarization → Each RR subunit binds to 2 molecules of cAMP (4 molecules
of cAMP total) and CC is then released
→ CC catalyzes the phosphorylation and activation of target
High glucose conditions 
enzymes
● Increased cytosolic ATP/ADP ratio causes closure of ​K​ATP
→ Target enzymes will elicit the response
channels
● Phosphorylated proteins can be degraded by phosphatases
→ Depolarized membrane potential
→ Large portion of Tetrodotoxin-sensitive Na+ are inactive and
enter a nonconductive state non-cAMP-dependent PKA pathway 
→ T-type Ca2+ channels are also inactive 1. Activated PKA translocates to the nucleus via nuclear pores
→ Low-amplitude action potential spikes are generated 2. This phosphorylates and activates cAMP-regulated proteins
→ Reduced calcium influx (CREB)
→ INSUFFICIENT TO TRIGGER GLUCAGON SECRETION 3. Activated CREB activates and binds to CREB-binding protein
(CBP)/p300
● The p300-CBP coactivator family is composed of two closely
related transcriptional co-activating proteins
● They interact with numerous transcription factors to increase
the expression of target genes
4. Activated CBP/p300 controls expression of genes with
cAMP-sensitive regulatory elements (CRE) on DNA
5. Synthesis of proteins for glucose production

Down-regulation of GPCR/cAMP/PKA signaling 

● Dissociation of hormone from the receptor
● Hydrolysis of GTP by ​G​α ​ due to GTPase activity
● Hydrolysis of cAMP via cAMP phosphodiesterase (PDE)
● Phosphorylation and desensitization of receptors by kinases
such as PKA and beta-adrenergic receptor kinase (​βARK)
● GPCRs removed from the membrane by vesicular uptake

Figure 13​. Glucose control of glucagon secretion VII. SUMMARY OF HORMONAL REGULATION 

● Glucose homeostasis is directed towards the maintenance of

VI. SIGNALING CASCADE OF GLUCAGON constant BG levels.
● Insulin and glucagon are the two major hormones that regulate
1. Glucagon binds to Gs receptor on target cell membrane
the balance between fuel mobilization and storage. They
● High-affinity receptors on cell membrane not present in
maintain BG near 80-100 mg%, despite varying CHO intake
muscle
during the day.
● Mainly expressed in liver and in kidney, with lesser amounts
● If dietary intake of all fuels is in excess of immediate need, it is
in heart, adipose tissue, spleen, thymus, adrenal glands,
stored as either glycogen or TAGs
pancreas, cerebral cortex, and GI tract
● Insulin is released in response to to CHO ingestion and
● When activated, G ​ ​α ​dissociates from G
​ ​βγ
promotes glucose use as fuel and glucose storage. Insulin
● G​α bound to GTP is active, and can diffuse along the
​
secretion is regulated principally by blood glucose levels.
membrane

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● Glucagon promotes glucose production via glycogenolysis and
gluconeogenesis
● cAMP activates PKA, which phosphorylates the key regulatory
enzymes, activating some and inhibiting others
● Insulin acts via a receptor tyrosine kinase and leads to the
dephosphorylation of key enzymes, activating some and
inhibiting others
● Hormones that antagonize insulin action, known as
counterregulatory hormones which include glucagon,
epinephrine, and cortisol
[BIOCHEMISTRY] 2019/03/05. ​Regulation of Metabolism by
Insulin & Glucagon. ​Suzette M. Mendoza, M.D., MHSE
2021B Trans
2021C Trans
Baynes, Clinical Biochemistry (4th Edition)
Harper’s Illustrated Biochemistry (30th Edition)
Mark’s Basic Medical Biochemistry (5th Edition)

VII. INCRETINS

● Gut-derived metabolic hormones, ​members of the​ glucagon

peptide superfamily,​ that stimulate a ​decrease​ in blood
glucose levels
● Released after eating and augment the secretion of​ insulin
released from ​pancreatic beta cells​ by a ​blood
glucose-​dependent mechanism
● 2 main candidate molecules that fulfill criteria for an incretin are
the ​intestinal peptides glucagon-like peptide-1 (GLP-1)​ and
gastric inhibitory peptide (GIP, also known as
glucose-dependent insulinotropic peptide)
● Incretin effect
→ Increased stimulation of insulin secretion elicited by oral as
compared with IV administration of glucose under similar
plasma glucose levels
→ GLP-1 ​and​ GIP, cholecystokinin, ​and​ vasoactive
intestinal polypeptide (VIP) ​potentiates insulin secretion
→ secreted by increased glucagon concentration in the gut
● GLP-1 and GIP: act via GPCR
→ Results to increased insulin secretion, (+) ​β-cell proliferation,
decreased apoptosis
● Slow the rate of absorption of nutrients by reducing gastric
emptying and may directly reduce food intake
● Some incretins (GLP-1) also inhibit glucagon
● GLP-1 and GIP are rapidly inactivated by the enzyme
dipeptidyl peptidase-4 (DPP-4​).

REVIEW QUESTION

1. What is the main regulator of insulin release?

a. GUT hormones
b. Epinephrine
c. Glucose
d. Amino acids
2. Which organ/s is/are affected by glucagon?
a. Adipocyte
b. Skeletal muscle
c. Liver
d. both A & C
3. ​Which of the following sub-unit/s does insulin binds?
a. Alpha
b. Beta
c. Delta
d. Both A & B

Answers: c, d, a

REFERENCES 
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