Endocrine Pancreas Flashcards
What are the endocrine cells in the pancreas and what do they secrete?
alpha = glucagon
beta = insulin, C peptide
delta = somatostatin
How are the endocrine cells arranged in islets?
betas in the center
alpha and delta in the periphery
(alpha and delta get bathed in insulin)
What does sympathetic stimulation do to the pancreas?
Parasympathetic?
alpha adrenergic signal –> decreased insulin
ACh –> increased insulin
How do cells of pancreatic islets communicate with each other?
gap jxns = rapid cell-to-cell communication btw a-a, a-b, b-b
blood flows into center of islets first –> goes out = all cells get bathed in insulin
How do delta cells affect beta and alpha cells?
somatostatin inhibits insulin and glucacon secretion
How do beta cells affect alpha and delta cells?
beta cells inhibit alpha cells
alpha cells promote insulin
delta cells inhibit beta cells
How are the alpha and beta strands of insulin held together?
by 2 disulfide bridges
C peptide initially holds them together but is then cleaved to form the active hormone
What is the main stimulus for insulin?
carbohydrate or protein-containing meal –> high glucose levels
What is the difference between preproinsulin, proinsulin, and insulin?
preproinsulin = signal peptide, A and B chains, and connecting peptide
proinsulin = no signal peptide; C peptide, disulfide bridges form in ER –> packaged in vesicles in golgi
during packaging, proteases cleave proinsulin
What is the importance of C peptide?
insulin and C peptide are packed together in secretory vesicles –> secreted in 1:1 ration
C peptide can be used as long-term marker of Beta cell function and insulin secretion
How does glucose signal insulin release?
glucose binds glut2 – glucokinase –> G-6-P –> makes ATP –> closes K+ channels –> cell depolarizes –> voltage-gated Ca channels open –> exocytosis of insulin and C peptide
What do sulfonurea drugs do?
promote the closing of ATP-dependent K+ channels (glucose signals this) –> so that more insulin will be secreted
used to treat T2DM
How is insulin secreated in response to glucose?
biphasic manner
phase 1 = preformed vesicles released
phase 2 = preformed and newly synthesized insulin released
In diabetic ppl, what is the first thing to disappear?
the first phase/ acute insulin response
How do CCK and ACh contribute to insulin release?
both bind Gq receptor –> PLC –> IP3 and DAG –> both calcium and PkC signal insulin release
How does somatostatin contribute to insulin release?
binds Gi –> inhibits cAMP and PkA –> inhibits insulin release
How do glucagon and GLP-1 contribute to insulin release?
Binds Gs receptor –> cAMP –> PkA –> insulin release triggered
What happens (in general) when insulin binds its receptor?
receptor phosphorylates itself and other proteins –> insulin-receptor complex is internalized by target cell –> glucose transport, protein, fat, and glycogen synthesis; growth and gene expression
How does insulin affect its own receptor?
down regulates its own receptor
What is the relationship btw insulin and the liver?
insulin released from pancreas –> to liver, can take up insulin and receptor and cleave –> actual levels in systemic circulation are a lot less than what is initially released from the pancreas
What receptors do insulin upregulate in cell membranes?
GLUT4 in muscle and adipose tissue
GLUT2 in liver
other GLUTs
How does insulin induce metabolic effects?
binds receptor –> Piates –> IRS1-4 –> PI3K –> PIP3 –> pkB/AKT –> metabolic effects
*include GLUT translocation and activation of protein postphatases
How does insulin induce growth effects?
insulin + receptor –> Piates –> IRS1-4 –> SHC –> GRB/SOS –> RAS/GTP –> MAPK –> growth effects
How does insulin affect glycogen?
increases glucogen synthase
upregulates hexokinase (glucokinase in liver and beta cells)
activates glycogen synthase
How does insulin affect protein and fat metabolism?
increases protein synthesis and decreases protein breakdown
favors FAs –> triglycerides (lipogenesis)
inhibits triglycerides –> FAs by inhibiting hormone-sensitive lipase
How does excercise affect insulin and glucose metabolism?
muscle contractions stimulate AMPK –> GLUT4 into membranes –> helps uptake of glucose and decreases insulin resistance
How does insulin affect blood levels of nutrients?
decreases:
glucose, FAs, ketoacids, amino acids
(basically puts it all in cells)
How does insulin affect K+ levels?
increases K+ uptake into cells and lowers plasma K
glucose and insulin can be given to treat hyperkalemia
When do symptoms of T1DM become evident?
not until 80% of beta cells are destroyed
What occurs to induce diabetic ketoacidosis?
increased conversion of FA to ketoacids and decreased ketoacid utilization by tissues
What things do you see increased in the blood in T1DM?
glucose
fatty acids and ketoacids
amino acids
K+ (even though total body K is usually low)
What occurs to induce hyperkalemia in type 1 diabetics?
insulin doesn’t have effect on Na/K ATPase –> K shifts out of cells –> plasma levels become high, but total is usually low bc of polyuria and dehydration
What occurs in osmotic diuresis?
increased blood glucose –> increased filtered load of glucose, exceeding reabsorptive capacity of PCT
water and electrolyte reabsorption is also prevented
Polyuria: increased excretion of Na and K even though urine concentration of electrolytes is low
What are the main drawbacks of insulin replacement therapy?
lag btw glucose measurement and insulin dosing, delayed absorption of insulin following injection –> periods of hyperglycemia
What occurs in the progression of T2DM?
initially high insulin levels and insulin resistance –> progressive exhaustion of beta cells –> insulin deficiency later
What are teh 3 causes for obesity-induced insulin resistance?
decreased GLUT-4 uptake of glucose in response to insulin
decreased ability of insulin to repress hepatic glucose production
inability of insulin to repress hormone-sensitive lipase (HSL) or increase lipoprotein lipase (LPL)
What is the current understanding of insulin resistance?
not well understood
might be due to post-receptor signaling –> ultimately results in less gluts in membranes
*may be bc insulin receptor or downstream proteins aren’t Piated
What do biguanide drugs do?
upregulate insulin receptors on target tissues
(metformin)
What is the difference in effects of IV glucose vs oral glucose?
insulin is much more affected by oral glucose than IV
What are incretin hormones and what do they do?
intestine-derived, short T1/2
GLP-1, GIP
GI glucose and fat –> stimulate insulin secretion, inhibit glucagon, slow gastric emptying
What is the reduced incretin effect?
in type 2 diabetics, oral glucose fails to result a mich higher peak of insulin that is seen in normal ppl
bc incretins aren’t working to increase insulin
Which form of diabetes has more of a genetic component?
type 2 = 50% family link rather than 10-20 for type 1
What hormones have a hyperglycemic action?
glucagon
epinephrine
cortisol
growth hormone
What other hormones are part of the same family as glucagon?
How do they differ?
GLPs are in same family
proglucagon –> processing in alpha cells –> glucagon
proglucagon –> processing in intestinal L cells –> GLP-1 and GLP-2
How is glucagon stored?
in dense granules until alpha cells are stimulated
What is the main stimulus for glucagon secretion? How does it work?
low glucose
no glut signaling –> increased ATP –> K channel inhibited, Na and Ca channels open –> Ca stimulates glucagon release
Besides low glucose, what other things stimulate glucagon release?
amino acids
fasting
CCK
beta adrenergic agonists
ACh
What things inhibit glucagon synthesis and secretion?
insulin
somatostatin
increased FA and ketoacid concentration
What are the major actions of glucagon?
increases glycogen breakdown
Glucagon –> cAMP –> PKA –> inhibits production of fructose 2,6-biPi –> substrates directed toward glucose formation
How does glucagon affect lipid metabolism?
increases lipolysis and inhibits FA synthesis
shunts substrates toward gluconeogenesis
increased blood glucose, FAs, and ketoacids
What do F cells do?
release pancreatic peptide
acts like a satiety signal like neuropeptide Y
