Postprandial Glucose Metabolism - Pancreatic Function Flashcards
What is the endocrine role of the pancreas?
1-2% of weight in Islets of Langerhans; production and secretion of insulin, amylin, glucagon, somatostatin, and pancreatic polypeptide
What is the exocrine function of the pancreas?
98-99%; production and secretion of bicarbonate, amylase, trypsin, chymotrypsin, and carboxypeptidase for digestion
What is the structure of the pancreatic islets?
50-500um diameter sphere of 50-300 cells of 4 types: alpha, beta, delta, and theta; beta cells are 80% of the population and comprise the core; the other 3 comprise the outside
Beta cells secrete
(80%) insulin and amylin
Alpha cells secrete
(10%) glucagon
Delta cells secrete
(<5%) somatostatin
Theta cells secrete
(<5%) pancreatic polypeptide
Insulin is synthesized as a
preprohormone
Insulin is cleaved by
PC2 (pre) and PC1 (pro)
The cleaved segment of insulin gene is
C-peptide (connecting peptide)
Insulin forms from
disulphide bonds between the alpha and beta chains of the insulin gene with C-peptide cleaved from between them
Insulin is packaged into
secratory granules containing endopeptidase enzymes
Secretion of insulin is stimulated by
nutrients eg glucose
What are the 2 phases of insulin secretion?
sharp rise (2-5mins) of surface quick-released vesicles; prolonged secretion (for duration of stimulus)
How is the insulin release profile altered in type 2 diabetes?
1st/rapid phase of insulin secretion disappears
Which GLUT receptor takes up glucose into beta cells?
GLUT2
What is unique about GLUT2 and glucokinase?
They both have high Kms; they increase in proportion to the concentration of sugar present
How are beta cells signalled to secrete insulin?
Glucose enters cell via GLUT2; phosphorylated to G6P by glucokinase; enters glycolysis & TCA; increases ATP/ADP ratio which closes a K+ channel; causes depolarization of the membrane and opening of a Ca2+ channel; Ca2+ influx signals vesicle release
GLUT2 and glucokinase are only expressed in
beta cells and liver
How do amino acids trigger insulin secretion by beta cells?
taken up by specific AA transporters; enter TCA as does G6P to increase ADP/ATP ratio, triggering membrane depolarization, Ca2+ influx, and vesicle release (like glucose does)
How do fatty acids trigger insulin secretion by beta cells?
burning of FAs results in an increase in malonyl-CoA which inhibits entry of fats into mitochondria via the carnatine transporter for beta-oxidation; somehow this causes insulin secretion; also a FA receptor FFA1R
more insulin is secreted when glucose is administered _______ than when administered ________
orally; intravenously - this phenomenon is called the incretin effect and is explained by the presence of incretin hormones from the gut causing insulin secretion
What are incretins?
gut derived hormones that are secreted in response to nutrients (glucose, FAs, AAs) that increase insulin production
What are the incretins?
glucagon-like peptide 1 (GLP-1) and glucose-induced insulinotropic polypeptide (GIP)
GIP comes from the
upper small bowel
GLP-1 comes from the
lower small bowel
GLP-1 is a fragment of the
glucagon gene - processed to different hormones depending on tissue
GLP-1 stimulates insulin secretion only when
glucose is high
GLP-1 is secreted from
L-cells in small intestine in response to glucose and FA
GLP-1 binds to
receptor on beta cells
What are the actions of GLP-1?
stimulates insulin release and proinsulin/insulin biosynthesis (only if glucose is low); inhibits gastric emptying; inhibits glucagon secretion; promotes beta cell proliferation, differentiation, and maturation
Why can’t GLP-1 be used directly in treatment of T2D?
half-life is only 2-3mins
What are the incretin-based therapies?
DPP-4 inhibitors - incretin enhancers that inhibit the enzyme that degrades GLP-1; GLP-1R agonists -incretin mimetics eg exenatide
What is exenatide?
byetta - GLP-1R agonist in the tx of T2D; causes a drop in HbA1c and some weight loss
What is the concern over incretin-based therapies?
DPP-4 inhibitors and GLP-1R agonists may cause increases in pancreatitis and pancreatic cancer
GIP is secreted from
K cells of duodenum in response to glucose and FAs
What are the actions of GIP?
stimulates insulin release; activates lipoprotein lipase to enhance fat clearance from the blood; its effects are dependent on plasma glucose concentration
GIP binds to
a receptor on beta cells
Amylin is released from
beta cells
What are the actions of amylin?
inhibits glucagon secretion; delays gastric emptying; inhibits food intake
In type 1 diabetes, amylin
is deficient because the beta cells are destroyed
Glucagon is secreted from
alpha cells in response to low blood glucose
What is the action of glucagon?
stimulates liver to release glucose to restore normal blood glucose
Pancreatic polypeptide is secreted from
theta cells after a meal
What are the actions of pancreatic polypeptide?
inhibits food intake; increases energy expenditure; inhibits secretion of pancreatic enzymes; blocks contraction of gallbladder
Somatostatin is released from
delta cells following a mixed meal
What are the actions of somatostatin?
inhibits insulin and glucagon secretion; inhibits pancreatic exocrine function; main function to prevent exaggerated hormonal responses to a meal
