Insulin Glucagon GLP-1 and Counter Regulatory hormones Flashcards
alpha cells of pancreas
secrete glucagon
beta cells of pancreas
secrete insulin
D (or delta) cells
secrete somatostatin
PPcells
secrete pancreatic polypeptide
Blood supply of pancreas
- fenestrated capillaries
- blood flows from core to periphery (so alpha and D cells are perfused with blood containing high conc of insulin
- secretion products pass into portal vein and go to liver first (more insulin and glucagon exposure in liver, then)
Innervation of pancreas
autonomic (symp/parasymp)
-mainly cholinergic
Insulin structure
- derived from pro-insulin by cleavage of connecting peptide (C-peptide) leaving A and B chains joined by disulfide bonds.
- C peptide is cleaved in secretory vesicles (then called secretory granules with crystalline insulin hexamers and two Zn atoms)
C peptide
- secreted along with endogenous insulin (can be measure in blood)
- exogenous insulin doesn’t have this.
Plasma insulin levels
5-10 microU/ml (0.5 ng/ml) fasting
maintained by secretion of 0.25-1.5 U insulin/hr into portal v.
Response to increased glucose
- biphasic
- exposure of islet cells to high glucose concentrations for 20 minutes or longer results in a rapid surge of insulin followed by a decline, then rise–sustained for as long as glucose is high
- docked vesicles (first phase)
- recruit cytoplasmic vesicles to docked position (second phase)
Initiators of insulin release
-stimulate insulin release on their own
glucose
aa
drugs like sulfonylureas
potentiators of insulin secretors
-stim insulin secretion only in the presence of glucose
glucagon
incretin peptides (like glucagon-like-peptide: GLP-1)
ACh
inhibitors of insulin secretion
diazoxide
somatostatin
alpha-adrenergics
Also:
long term basis: fatty acids
longstanding hyperglycemia
Glucose and insulin secretion
- Glucose take up by beta-cell through GLUT-2 transporter
- Glucose to G6P via glucokinase
- metabolized by glycolysis and TCA cycle.
- results in ATP production– generates an intracellular signal
- Metabolism of glucose depolarizes Beta cell by closing ATP regulated K channels (sulfonylureas act directly by blocking these channels)
- Depolarization leads to opening of voltage-dependent Ca channels in plasma membrane.
- leads to exocytosis of insulin.
other nutrients leading to insulin release
-plasma aa from food enter Beta cell and are metabolized to intermediate that stimulates insulin secretion
***fats do not stim insulin secretion
somatostatin and insulin secretion
-somatostatin from delta-cells in pancreatic islet decreases insulin release in a paracrine fashion
Epinephrine and insulin secretion
- inhibits insulin secretion by binding to alpha-adrenergic receptors on the Beta cells
- may be imp in stress, exercise
Stim of splanchnic nerves
- inhibits insulin secretion
- the liberated catecholamines interact with alpha-receptors on the Beta cell
Stim of vagal nerve
-releases ACh which increases insulin secretion
results in modest increase in insulin— sight/taste of food: cephalic phase of insulin release
Chronic high blood glucose
-leads to islet cell hypertrophy allowing the pancreas to produce high levels of insulin in people w/ insulin resistance
Alloxan and streptozotocin
destory islet cells (create experimental diabetes)
Insulin in liver
- stimulates glycogen synthesis
- stimulates fat synthesis
- reduces gluconeogenesis
-It does NOT increase glucose uptake in liver (because GLUT 2 transporters are not insulin responsive)
insulin in skeletal muscle
- stimulates glucose uptake (Glut-4)
- increases glycogen synthesis
insulin in adipose tissue
- stimulates glucose uptake
- stim fat synthesis
- inhibits fat breakdown (lipolysis)
insulin receptor
- belongs to epidermal growth factor family of membrane associated receptors
- receptor = heterotetramer (two extracellular alpha chains (insulin binding) and two memb spanning beta chains)
- beta chain has inherent tyrosine kinase activity
- the activated receptor binds to SH2 domains of various proteins and activates them primarily by phosphorylating various tyrosine residues
- phosphorylation of Insulin Receptor Substrates (IRS) (types 1-4) form main links for signal transduction between the receptor and downstream effector pathways
- Phosphorylated IRS then acts as a docking site for SH2 domain proteins
2 pathways of insulin signaling
PI-3 kinase –> metabolic effects
MAP kinase–> mitogenic effects
PI3K–> AKT –> GLUT4 translocation–>glucose uptake
PI3K–> AKT–> NO production–> vasodilation
MAPK–> ERK–> ET-1 –> vasoconstriction
MAPK–>ERK–> growth and mitogenesis
Insulin and glycogen production
-many steps are involved and phosphorylation on tyrosine residues is important in mediating these normal actions of insulin.
Mitogenic pathway key intermediate
key intermediate is MAP kinase
Insulin resistance
-takes a higher conc of insulin to get same levels of glucose disposal or reductions in liver glucose production (for ex)
Causes of insulin resistance
-not usually caused by problems with the insulin receptor
-most due to problems in insulin signaling pathways
-genetic/lifestyle factors combine to change cellular metabolism in a way that favors phosphorylation of serine and threonine residues on signaling molecules, making signaling along pathway less effective.
(tyrosine phos stimulates insulin signaling, serine and threonine phos reduces insulin signaling)
Where is glucagon synthesized?
- in alpha cells of pancreatic islets
- secreted into portal circulation, where liver is first target of action
Glucagon action
- binds to G-prot coupled receptor, increases cellular level of cAMP
- liver: increases in glycogenolysis and gluconeogenesis
- insulin and glucagon are reciprocally regulated
-glucagon also promotes lipolysis (breakdown of triglycerides in adipose tissue) and ketogenesis in liver
(fatty acids and ketone bodies are alternative fuels to glucose, used during starvation)
-glucagon inhibits hepatic glycolysis (so liver must rely on fatty acids and not glucose for energy during fasted states)
Glucagon secreted in response to
hypoglycemia
(inhibited by hyperglycemia)
-secretion of glucagon inhibited by entry of glucose into alpha cells via insulin-sensitive glucose transporters
(so glucagon secretion can be inappropriately high if insulin is low as in Type I diabetes or in insulin resistance as in Type 2 diabetes)
Glucagon metabolism (t1/2, degradation)
t1/2: 5 minutes
Mostly degraded in the liver.
Incretins
-Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)
GLP-1 production
- product of glucagon gene
- expressed in pancreatic alpha cells, Lcells of intestinal mucosa
- Lcell generates pro-glucagon, which is cleaved to release GLP-1 and GLP-2
GLP-1 secretion
-stimulated by nutrients in gut, but also throughout day correlated to release of insulin
-GLP-1 is a VERY POTENT insulin-releasing substance
(responsible for a large part of insulin response to oral glucose)
GLP-1 actions
-acts thru cell membrane associated receptor present on beta cells of the pancreas (and other cells).
Actions:
- potentiates glucose stimulated insulin secretion (if bg high, then GLP-1 stimulates insulin secretion, but if bg low it will not stimulate insulin secretion)
- inhibits glucagon secretion
- inhibits GI secretion and motility
- inhibits appetite and food intake
- promotes Beta cell proliferation
GLP-1 degradation
GLP-1 has a very short half life (mins)
- broken down by dipeptidyl peptidase-4 (DPP-4)
- meds have been developed that work like GLP-1 but are resistant to DPP-4 so have a longer half life.
Catecholamines and blood glucose
- epi/norepi increase blood glucose concentrations
- interact with Beta recep on liver: similar effects as glucagon– increase glycogenolysis, gluconeogenesis, and ketogenesis (and decrease glycolysis and glycogen formation)
- also: inhibit insulin secretion by interacting with alpha recep on Beta cells of pancreatic islets
- produce insulin resistance in skeletal muscle by stimulating glycogenolysis
cortisol/corticosteroids and blood glucose
- increases blood glucose levels
- slow
- increases supply of aa as substrates for gluconeogenesis by promoting muscle protein breakdown
- produces insulin resistance
- potentiates actions of glucagon and catecholamines
-so chronic increases in plasma cortisol levels are assoc with developing diabetes.
growth hormone
- produced by anterior pituitary gland
- a counterregulatory hormone that increases blood glucose levels.
- increased levels in blood in response to hypoglycemia and other stress.
- long term: promotion of lipolysis and stimulation of protein synthesis.
- anti-insulin effects, leads to decreased insulin sensitivity.
Insulin resistance in:
ppl going thru growth spurt (high GH)
tumors of pituitary (high GH)
Deficiency of ACTH and GH or with cortisol deficiency from adrenal gland failure: risk of developing hypoglycemia
Somatostatin
- in hypothal, inhibits GH release
- inhibitor of insulin and glucagon
- secreted by delta-cells of pancreas
- also inhibits gut motility, splanchnic blood flow, secretion of digestive enzymes and intestinal absorption
Pancreatic polypeptide
- function unknown
- stimulated by protein ingestion and vagal activity
- decreases secretion of pancreatic enzymes as well as contraction of the gall bladder.
