Endocrinology, lecture on Glucose Balance
XXVI. Pancreatic Hormones and Glucose Balance
A. Endocrine pancreas primarily secretes 2 hormones: insulin and glucagon
1. exocrine pancreas secretes digestive enzymes into
the lumen of the intestine
2. insulin and glucagon are secreted from the
islets of Langerhans (1% of the organ)
a. insulin from b or B cells
i. 2 polypeptide chains 21aa (A) & 30aa (B)
connected by disulfide bridges, MW = 6000
(1) can aggregate as dimer ® hexamer (zinc)
(2) from proinsulin (MW = 9000) = continuous chain
from N-terminal at B chain to C-terminus with A
ii. even found in invertebrates, but there are major
variations in sequences between species of vertebrates
b. glucagon from a2 cells (= A cells)
i. 29 aa, very conservative
(homologies with secretin, VIP, GIP)
c. F or PP cells secrete pancreatic polypeptide
i. 36 aa
d. D or a1 or d secrete somatostatin
i. inhibits both insulin and glucagon
e. islets organised with a2 cortical (~15%),
then d (~10%), b medullary (~75%)
i. a2, b and d work together as a
functional secretory unit
1) many gap junctions / tight junctions between cells
2) releases suitable proportions of glucagon and
insulin to regulate minute-to-minute [glucose]
a) modulate metabolism toward
anabolism or catabolism in
accordance with physiological needs
ii. innervated by sympathetic (from VMH; NE)
& parasympathetic (VLH; ACh)
B. Insulin
1. Stimulated by Glucose, aa, fatty acids
a. Glucose is transported into b cells via GLUT2 glucose transporters
i. ATP induces closure of ATP-sensitive K+ channels
(1) cell membrane depolarization.
b. voltage-gated Ca++ channels open
c. Ý intracellular Ca++ ® exocytosis of insulin
i. incretins ® Ý cAMP Ý cytosolic Ca++
1) incretins are peptide hormones
released from the gut
ii. glucose also Ý biosynthesis of insulin
d. Amino acids, especially Arg (R), stimulate insulin release
2. Incretins, GI peptides (GLP1, GIP), stimulate insulin secretion and inhibit Glucagon (during hyperglycemia)
a. GIP/GLP1cooperatively ¯blood sugar by reducing gastric emptying
b. GLP1 = glucagon-like peptide 1 and GIP (gastric inhibitory peptide) releasd after eating
i. dipeptidyl peptidase 4 (DPP4) inactivates incretins
1) DPP4 inhibitors used to treat diabetes 2
c. also by glucagon
3. Insulin is stimulated by the parasympathetic NS:
VLH ® Vagal N. ® vagus nerve Ý ACh
a. inhibits glucagon
b. hypothalamus integrates balance of sympathetic/parasympathetic regulation of islet
4. Insulin is inhibited by NE, Epi, galanin, pancreostatin (Pst) & somatostatin (Sst)
a. and insulin
5. Insulin membrane receptor of 2 x 2 polypeptide chains
from a single chain precursor
a. insulin (2) binds to two a subunits
i. results phosphorylation of the b (2x): tyrosine PK
1) substrate is IRS1 (insulin receptor substrate 1)
a) IRS1 activates
phosphatidylinositol 3 kinase (PI3-K)
b) and GRB2 (growth factor receptor bound protein-2)
which activates the Sos gene product
+ SHP2 (Src homology protein tyrosine phosphatase-2)
i) gene expression and cell growth
PI3-K ® PI-3,4,5-P æ
c) Sos ® Ras ® Raf1 ® MEK ® MAP K
d) MAP K ® Phosphatase 1 ®
® Glycogen synthase ® glucose storage
æ transcription factors æ Ý glycogen
e) PI3-K ® Akt ® mToR ® AS160 ® GLUT4 vesicle
ii. receptor also binds G protein ® Ý PDE
1) degrades cAMP, blocks glycogen conversion
to glucose
iii. Tyr PK phosphorylates CAP-Cbl-Crk
1) pCrk translocates GluT4 to the cell membrane
b. Ý glucose uptake follows I-R ® PI3-K + TC10 (GTP binding protein) ®
® translocating GLUT4 to membrane
c. I-R desensitization results in type II diabetes
d. insulin receptor family includes the receptor of IGF1
C. Glucagon
1. inverse relationship between extracellular [glucose]
and glucagon secretion - low [glucose]: high glucagon secretion
a. inhibited by fatty acids and somatostatin
b. stimulated by aa,
c. Ý by NE, Epi from sympathetic NS,
via VMH ® N.Solitary Tract ® splanchnic nerve ®
® celiac ganglion ® mixed pancreatic nerve
d. paracrine insulin inhibits, endocrine insulin stimulates
2. membrane receptor: Gs/AC/cAMP/PKA
D. Function: Insulin and Glucagon have opposing actions
1. insulin stimulates anabolism, energy storage;
glucagon ® catabolism and energy mobilization
a. insulin ® Ý glycogen, protein, & lipid synthesis
i. blood sugar ¯
b. glucagon ® Ý glycogenolysis, gluconeogenesis,
ketogenesis, proteolysis
i. blood sugar Ý
c. in the liver, but also in muscle and adipose tissue
XXVI.v. Malfunction: Diabetes mellitus (running through honey)
A. Two types: 1. Loss of Insuling Production, 2. Reduced Receptor Sensitivity
1. Type 1 = Insulin-dependent (juvenile-onset)
a. islet b-cells destroyed ® insulin deficiency
b. 5-10% of diabetes
2. Type 2 = insulin-independent (maturity-onset)
a. 90% of all diabetes cases
b. b-cells still functional ® elevated insulin secretion
i. progression ® inability to maintain glucose homeostatsis
yields hyperglycemia
c. decreased sensitivity to insulin = insulin resistance
i. ¯ I-R
3. Secondary types develop fro complications of other diseases
a. affecting the pancreas
b. hormone disturbances
i. glucocorticoids
c. drugs
i. exogenous corticosteroids
4. gestational diabetes (GDM)
a. hyperglycemia
i. but also hypertension
or preeclampsia (with edema and proteinuria)
and hydramnios (too much amniotic fluid)
b. 7% of pregnancies
B. Pathophysiology - causes of diabetes mellitus
1. Type 1: NOT diet or lifestyle
a. Family History: heritable
i. Zinc transporter 8 (ZnT8) - a novel islet autoantigen
1) participates in insulin biosynthesis and release
2) expressed in insulin secretory vesicles
a) also in deteriorated b-cell function
i) 22-80% of Type 1 patients
3) ZnT8 indirectly regulates insulin homeostasis
through Zn regulation in b cells
b. primarily via autoimmune reactions
i. loss of insulin-producing b cells of the pancreas
c. Treatment: exogenous insulin
2. Type 2: Primarily a product of diet, lifestyle and genetics
a. High carbohydrate and fat diet I:I-R ® cellular uptake
i. over time fills liver and cellular glycogen stores
1) I:I-R converts glycogen to fatty acids
2) fatty acids cirulated to adipose tissue
b. I-R in glycogen-full cells are decommissioned
i. Insulin-induced I-R downregulation
ii. I-R involuted in the cell - receptor number is decreased by 50%
1) internalized I-R cannot bind additional Insulin
a) glycogen synthesis is blocked
2) I-R catabolized
iii. I-R desensitized
1) I-R lose insulin-sensitive tyrosine kinase
2) autophosphorylation is attenuated
3) IRS protein is negatively regulated
4) serine phosphorylation
c. Management and Treatment
i. Diet: low saturated fat, low refined carbohydrates
high in fiber and monounstaturated fats
ii. Expercise: aerobic exercise 90-150 min/week
iii. Medications
1) preference for therapies that do not induce hyperglycemia
a) Metformin (Glucophage, Glumetza, Riomet...)
i) reduces sugar absorption and production
ii) increases sensitivity to Insulin
2) sodium-glucose co-transporter-2 inhibitors (SGLT2): empagliflozin
a) ¯ blood sugar
b) ¯cardiovascular events with diet and exercise
3) dipeptidyl peptidase-4 (DPP-4) inhibitors
(sitagliptin, saxagliptin, linagliptin, alogliptin)
a) stimulates insulin/¯ glucacon
when [glucose] high
b) longer lasting in bloodstream
4) glucagon-like peptide-1 (GLP-1) receptor agonists
(exenatide, liraglutide, lixisenatide)
a) non-insulin medication to combine with diet and exercises
b)¯ blood [glucose]
¯ Glycated hemoglobin - hemoglobin A1C,
test for 3 month [glucose] average
5) to reduce microvascular complications
a) Angiotensin-converting enzyme (ACE) therapies
b) Angiotensin Recepor Blocker (ARB) therapies
