Endocrine Pancreas Flashcards
What is the major function of the endocrine pancreas?
Regulate glucose, fatty acids, and a.a. metabolism
How are endocrine cells of the pancreas arranged in?
clusters - islets of langerhans (1-2% of pancreatic mass)
Each Islet contains 2500 cells
What are the islets of Langerhans innervated by?
adrenergic, cholinergic, and peptidergic neurons
Describe beta cells of the pancreas
60-65% of the islet
secrete insulin and C peptide
Tend to be located in the central core
Describe alpha cells of the pancreas
20% of islet
Secrete glucagon
tend to be located near the periphery of the islet
Describe delta cells of the pancreas
5% of the islet
Secrete somatostatin
Interspersed between alpha and beta cells
neuronal appearance, send dendrite-like processes to beta cells
What do gap junctions permit in islets of Langerhans?
rapid cell-to-cell communication
a-a
b-b
a-b
Describe the blood supply in the islets of Langerhans
islets receive about 10% of total pancreatic blood flow
Blood flows first to capillaries in the center and pick up insulin beta cells
Blood flows to periphery of islets, and bathes the other types of cells
What is the main stimulatory factor of insulin secretion
Glucose
insulin secreted in response to carbohydrate and/or protein-containing meal
Describe preproinsulin
4 peptides (signal peptide, A and B chains of insulin, and connecting peptide: C peptide)
Describe proinsulin
no signal peptide
C peptide still attached to insulin
Disulfide bridges form in ER
Packed into secretory vesicles in the Golgi
What happens to proinsulin while being packed into secretory vesicles
proteases cleave proinsulin
Insulin and cleaved C peptide packed together
What is C peptide used to test for?
Test Beta cell function in type I DM pts receiving insulin injections
What transporter does Glucose use to get into beta cells of the pancreas?
GLUT 2
How does Glucose cause Insulin to be secreted?
Glucose enters the cell
Glucose –(glucokinase)->G6P
Oxidation leads to ATP increase
ATP increase closes K channels causes the membrane to depolarize and open Ca channels
Increase intracellular Ca causes exocytosis of insulin and C peptide
What do sulfonylurea drugs do?
promote the closing of ATP-dependent K channels
This increases insulin secretion; used in the treatment of type II DM
How much C peptide is secreted compared to insulin?
in equimolar and is excreted unchanged in urine
Glucose stimulates insulin secretion in a _____ manner
biphasic
What type of receptor is the insulin receptor?
Tyrosine kinase receptor
Insulin-receptor complex is internalized by its target cell. What downregulates the receptor?
Insulin itself
How often is insulin released from the pancreas?
release oscillates with a period of 3-6 min
Blood concentration from 800 pmol/l to 100
What Tyrosine kinase pathway activates the metabolic effects of insulin?
Ras-independent pathway
IRS->PI3K->PIP3->PKB
What tyrosine kinase pathway activates the growth effects of insulin?
The Ras-dependent pathway
IRS->GRB/SOS->RAS/GDP->GTP->MAPK
What do endocrine cells of the pancreas secrete?
insulin, glucagon, and somatostatin
What glucose transporter is inserted into membrane after insulin activation of adipose tissue, resting skeletal m, and other tissues?
GLUT 4
What are the insulin actions in muscles?
Glucose uptake increased via GLUT 4
Increase glycogen synthesis by increasing hexokinase (or glucokinase in liver and b cells), PFK, and pyruvate DH
Increase glycogen synthase
Decrease protein breakdown and gluconeogenesis
What are the effects of insulin of TGs and FA metabolism in adipose tissue
Inhibits breakdown of TGs by inhibiting hormone sensitive lipase
Promote glucose ->A-glycerol-P+FA’s->TGs
Increase TGs storage and export (VLDLs)
Describe the actions of insulin in liver
GLUT2 increase
Increase glucokinase, glycogen synthesis, glycolysis (increase acetyl CoA, and FA synthesis)
Decrease gluconeogenesis and glucose-6-phosphatase
Increase TG storage and export
Increase protein synthesis and decrease degradation
Describe the actions of insulin in adipose tissue
Increase GLUT 4, glycolysis (increase a-glycerol phosphate, acetyl CoA, and FA synthesis)
Increase TGs and lipoprotein lipase for uptake
Decrease HPL to decrease lipolysis
Describe insulin actions in muscle
Increase GLUT 4, glycogen synthesis, glycolysis, protein synthesis, and TGs
What are the effects of insulin on blood levels?
Decrease glucose, a.a., F.A., ketoacid, and K
What are factors that stimulate insulin secretion?
increase [glucose], [a.a.], [F.A] and [Ketoacid] Glucagon Cortisol GIP Vagal: ACh K Sulfonylurea drugs obesity
What are factors inhibiting insulin secretion ?
decrease blood [glucose], fasting, exercise, somatostatin, alpha-adrenergic agonists, diazoxide
Describe the pathophysiology of insulin in T1DM?
inadequate insulin secretion
Destruction of beta cells - usually autoimmune
Symptoms not there until 80% of beta cells are destroyed
Describe what happens in DMT1 to glucose levels
inadequate insulin secretion causes increase in blood glucose concentration
- decrease uptake of glucose
- decrease glucose utilization
- increase gluconeogenesis
Describe what happens in DMT1 to FA and Ketoacid levels
Increase blood FA and Ketoacid concentrations
- decrease FA synthesis
- Decrease TG synthesis
- Increase TG breakdown
- Increase level of circulating free FA
- Conversion of FA to ketoacids and decrease ketoacid usage by tissues = DKA
Describe what happens in DMT1 to a.a. levels
Increase
- increase protein breakdown
- decrease protein synthesis
- increase catabolism of a.a. : loss of LBM
- increase ureagenesis
Describe what happens in DMT1 with osmotic diuresis
Increase blood [glucose] results in increase filtered load of glucose, exceeds capacity of proximal tubule
Water and electrolyte reabsorption prevented
Polyuria: increase excretion of Na and K
Thirst
Describe what happens in DMT1 to K levels?
Shift K out of cell causing hyperkalemia
- intracellular concentration low
- lack of insulin effect on Na/K - ATP pump
- plasma levels above normal but total body K usually below normal due to polyuria and dehydration
What is the Tx for T1DM?
insulin replacement: recreate normal physiology (basal and bolus insulin)
What are the drawbacks of insulin replacement therapy?
painful and time consuming
lag btwn glucose measurement and insulin dosing
delayed absorption of insulin following subcutaneous injection
poor blood glucose control: periods of hyperglycemia
What is the pathophysiology of insulin in TIIDM?
insulin resistance
- vast majority of diabetes is type II
Pts make insulin but not enough to overcome insulin resistance
normal or elevated insulin concentration initially; relative insulin deficiency (reactive hyperinsulinemia followed by relative hypoinsulinemia)
What are the 3 causes for obesity-induced insulin resistance?
Decrease GLUT-4 uptake of glucose in response to insulin release
Decreased ability of insulin to repress hepatic glucose production
Inability of insulin to repress hormone-sensitive lipase or increase LPL in adipose tissue
In DMTII there is a (Hyper/Hypo) glucagonemia
hyper
What are the Tx of DMTII?
- Caloric restriction and weight reduction
- insulin secretagogues: sulfonylurea drugs and incretin analog of GLP-1 (exenatide); injection needed
- slow absorption of Carbs: alpha-glucosidase inhibitors and amylin analogs
- insulin sensitizers: biguanide drugs: upregulate insulin receptors on target tissues
Describe glucagon
single straight-chain polypeptide with 29 a.a.
Member of a family of peptide that includes GI hormones secretin and GIP
Synthesized as preproglucagon
Stored in dense granules until alpha cells are stimulated
What is the major stimulatory factor of glucagon secretion? What else also stimulates glucagon secretion?
Decrease in blood glucose concentration Increase in a.a. (arginine and alanine) Fasting CCK B-adrenergic agonists ACh
What inhibits the synthesis and secretion of glucagon?
Insulin
Somatostatin
Increase in F.A. and ketoacid concentration
What is the process of release of glucagon from alpha-cells?
Mitochondria increases the amount of ATP Inhibits K-ATPase pump Membrane depolarizes Na channels open VDCC channels open allowing Ca influx Granules released
Where are the major actions of glucagon?
in the liver
What are the actions of glucagon in the liver?
Increase glucogenolysis and inhibits glycogen formation
Increase gluconeogenesis by decreasing production of F2,6-BP via cAMP/PKA pathway
What is the effect of glucagon on blood levels?
increased glucose, FA, and ketoacid levels
Glucagon increases lipolysis and inhibits FA synthesis - shunts substrates towards gluconeogenesis
FA->ketoacids
In insulin resistance, the ability of insulin to suppress _____ in adipose tissue and ______ secretion by alpha cells in the islet results in ___________ gluconeogenesis
lipolysis
glucagon
increase
What are the incretin hormones?
intestine derived hormones
GLP-1, GIP
Short T1/2
Secreted in response to GI glucose and fat
What do incretin hormones do?
stimulate insulin secretion (glucose dependent)
inhibit glucagon secretion
slow gastric emptying
What transporter does the liver use?
GLUT 2
