Block 3 - glucose sensing and B-cell dysfunction (L7-8)

Question 1

In the pancreas, blood flows in what direction?

Answer 1

from the center to the periphery

Question 2

What three factors can modulate secretion from the endocrine pancreas?

Answer 2

humoral communication, cell-cell communication, neural communication

Question 3

How do insulin and glucagon module eachother?

Answer 3

insulin inhibits glucagon secretion
glucagon stimulates insulin secretion

Question 4

How does humoral communication modulate secretion from the pancres?

Answer 4

• from the systemic circulation (glucose, insulin, glucagon, FFAs)
• in the endocrine pancreas (insulin, glucagon, and somatostatin modulate secretion from the a, B, and gamma cells)

Question 5

How does cell-cell communication modulate secretion from the pancreas?

Answer 5

• use of gap junctions to allow transfer of factors

Question 6

How does neural communication modulate secretion from the pancreas?

Answer 6

• input from the sympathetic and parasympathetic nerves modulates secretion of insulin and glucagon

Question 7

How (increase or decrease) is insulin secretion influenced by glucose concentration, NE, ACh, and CCK?

Answer 7

glucose concentration - increase insulin
NE - decrease insulin
ACh - increase insulin
CCK - increase insulin

Question 8

Pancreatic B cells are innervated by…

Answer 8

postganglionic sympathetic neurons and postganglionic parasympathetic neurons

Question 9

Describe the sympathetic stimulation of pancreatic B cells

Answer 9

• sympathetic neurons secrete NE
• Ne binds to a-adrenergic receptors (GPCRs coupled to Gai)
• adenylate cyclase is inhibited
• reduction in cAMP, lower PKA, less secretion of insulin

Question 10

Describe the parasympathetic stimulation of pancreatic B cells

Answer 10

• parasympathetic neurons secrete ACh
• ACh binds to receptors (GPCRs coupled to Gq)
• stimulates PLC, formation of DAG and IP3
• DAG stimulates PKC, IP3 stimulates Ca++ release
• PKC and Ca++ promote the secretion of insulin

Question 11

Pancreatic islet a-cells break down proglucagon into…

Answer 11

GRPP, glucagon and the major proglucagon fragment

Question 12

Intestinal L cells break down proglucagon into…

Answer 12

glicentin, GLP1, IP2, and GLP2

Question 13

Describe glucagon secretion when glucose is low

Answer 13

• at low glucose, glucose entry via GLUT1 is low (associated with activation of Na+ channels)
• Na+ entry causes membrane depol and activation of voltage sensitive Ca++ channels
• Ca++ influx is associated with fusion of glucagon containing vesicles with plasma membrane and glucagon secretion

Question 14

Describe glucagon secretion when glucose is high

Answer 14

• at high glucose, glucose entry via GLUT1 is high (associated with inhibited Na+ channels)
• inhibition of Na+ leads to unchanged membrane potential
• voltage-sensitive Ca++ channels don’t open
• no Ca++ influx means vesicles do not migrate or fuse with the membrane
• a-cells remain quiescent

Question 15

Describe how glucagon secretion is modulated by neural input

Answer 15

• when sympathetic nerve activity is increased, there is more delivery of NE
• more activation of a-adrenergic receptors/Gq and increased Ca++
• fusion of glucagon vesicles and increased glucagon secretion

Question 16

A minor (not physiologically relevant) influence on glucagon secretion is that it increases with increase in…

Answer 16

essential amino acids

Question 17

A minor (not physiologically relevant) influence on insulin secretion is that it increases with increase in…

Answer 17

GLP-1 and glucagon

Question 18

How do insulin levels differ for those with Type 2 Diabetes vs. Impaired glucose tolerance?

Answer 18

• Impaired glucose tolerance has compensatory hyperinsulinemia, so insulin peaks much higher than those with T2D
• Those with T2D have relative B cell dysfunction, so even though blood glucose rises way higher than normal, the insulin only rises a little higher than normal

Question 19

Describe how increase plasma glucose and FFAs can cause compensatory hyperinsulinemia

Answer 19

• increase glucose/FFAs, increased ATP
• more K+ channels closed and more depolarization
• more Ca++ entry
• more exocytosis and secretion of insulin

Question 20

Describe how long-term oxidative stress can cause relative B cell dysfunction

Answer 20

• long term FFA and hyperglycemia exposure
• oxidative stress leads to decreased ATP
• less K+ channels closed, less depolarization, less Ca++ entry
• less secretion of insulin
• elevated FFA, TNF-a, and resistin can also inhibit insulin gene transcription

Question 21

Describe the mechanism for B cell apoptosis in the metabolic syndrome

Answer 21

• long term increase FFA, glucose, leptin, and cytokines
• increase caspace activity
• increase apoptosis (decrease B cells mass)

Question 22

How do sulfonylureas impact B cell function?

Answer 22

Metabolic syndrome and Type 2 diabetes cause dysfunctions in ATP production and closure of K-ATP.

Sulfonylureas bind to K-ATP to keep them closed, leading to insulin secretion even if there are upstream dysfunctions in energy metabolism

Question 23

In Type 2 Diabetes, describe the levels of glucose, glucagon, and insulin after a high carb meal or glucose drink

Answer 23

higher than normal glucose (shouldn’t go up that high)
higher than normal glucagon (should go down)
lower than normal insulin (should go up more)

Question 24

Describe the effect of sympathetic overactivity on glucagon secretion from a-cells

Answer 24

• increased SNS activity
• more NE delivery
• increase Ca++ release
• increase glucagon secretion