Block 3 - glucose sensing and B-cell dysfunction (L7-8) Flashcards
In the pancreas, blood flows in what direction?
from the center to the periphery
What three factors can modulate secretion from the endocrine pancreas?
humoral communication, cell-cell communication, neural communication
How do insulin and glucagon module eachother?
insulin inhibits glucagon secretion
glucagon stimulates insulin secretion
How does humoral communication modulate secretion from the pancres?
- 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)
How does cell-cell communication modulate secretion from the pancreas?
- use of gap junctions to allow transfer of factors
How does neural communication modulate secretion from the pancreas?
- input from the sympathetic and parasympathetic nerves modulates secretion of insulin and glucagon
How (increase or decrease) is insulin secretion influenced by glucose concentration, NE, ACh, and CCK?
glucose concentration - increase insulin
NE - decrease insulin
ACh - increase insulin
CCK - increase insulin
Pancreatic B cells are innervated by…
postganglionic sympathetic neurons and postganglionic parasympathetic neurons
Describe the sympathetic stimulation of pancreatic B cells
- 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
Describe the parasympathetic stimulation of pancreatic B cells
- 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
Pancreatic islet a-cells break down proglucagon into…
GRPP, glucagon and the major proglucagon fragment
Intestinal L cells break down proglucagon into…
glicentin, GLP1, IP2, and GLP2
Describe glucagon secretion when glucose is low
- 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
Describe glucagon secretion when glucose is high
- 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
Describe how glucagon secretion is modulated by neural input
- 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
A minor (not physiologically relevant) influence on glucagon secretion is that it increases with increase in…
essential amino acids
A minor (not physiologically relevant) influence on insulin secretion is that it increases with increase in…
GLP-1 and glucagon
How do insulin levels differ for those with Type 2 Diabetes vs. Impaired glucose tolerance?
- 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
Describe how increase plasma glucose and FFAs can cause compensatory hyperinsulinemia
- increase glucose/FFAs, increased ATP
- more K+ channels closed and more depolarization
- more Ca++ entry
- more exocytosis and secretion of insulin
Describe how long-term oxidative stress can cause relative B cell dysfunction
- 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
Describe the mechanism for B cell apoptosis in the metabolic syndrome
- long term increase FFA, glucose, leptin, and cytokines
- increase caspace activity
- increase apoptosis (decrease B cells mass)
How do sulfonylureas impact B cell function?
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
In Type 2 Diabetes, describe the levels of glucose, glucagon, and insulin after a high carb meal or glucose drink
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)
Describe the effect of sympathetic overactivity on glucagon secretion from a-cells
- increased SNS activity
- more NE delivery
- increase Ca++ release
- increase glucagon secretion
