pancreas and metabolic syndrome Flashcards
Microscopy of islet of langerhans
Alpha cells: make glucagon
Beta cells: make insulin
Delta cells: make SST (doesnt travel to the pituitary, just paracrine and inhibits alpha and beta cells)
Insulin is the storage hormone
Insulin is stimulated by an increase in the blood glucose, fatty acids and amino acids (essentially food by products in the blood)
Insulin then stimulates glucose uptake in the liver, adipose tissue and muscle to lower blood glucose back down to normal
Insulin also increases the uptake of fatty acids into adipose and amino acids into protein in muscles
Human proinsulin
Human proinsulin is cleaved in the Golgi apparatus in the pancrease beta cells to form connecting protein (C-peptide), and insulin (has an a and b chain), when stimulated, insulina and Cpeptide are secreted in equamolar amounts in granules with a small amount of proinsulin.
C-peptide is a marker of beta cell function
GLUTs
Glucose Transporters: work via facilitated diffusion
GLUT 1= placenta, brain, red cells, kidney and organs
GLUT 2= pancreas
GLUT 3= brain
GLUT 4= muscle and fat (insulin stimulated)
Km values tell you how much glucose is needed for glucose to be taken up by the GLUT:
1,4 low 3 very low 2 kinda high
Insulin receptor
Insulin binds to the alpha subunit of its receptor, which cause autophosphorylation of the beta subunit (induces tyrosine kinase activity)
The receptor kinase activity begins a cascade of phosphorylation that increases or decreases the activity of enzymes including the insulin receptor substrates (IRSs)
IRSs mediate the effcts of glucose on glucose/fat/protein metabolism (ie GLUTs are transported to the cell membrane)-insulin resistance is when GLUT cant get to the plasma membrane
Effects of insulin and plasma metabolites
Insulin is anabolic and inhibits catabolism in general
1. Muscle: insulin has a major effect on glucose and amino acid uptake in muscle. Muscle wont give up glucose into plasma and insulin inhibits the breakdown the muscle into amino acids (gluconeogenisis precursors)
- Adipose tissue: insulin stimulates glucose uptake and inhibits liplysis
- Liver: insulin stimulates glycogenisis (build glycogen) and glycolysis (use up glucose) b/c insulin decreases extracellular glucose in liver, when glycogen isnt there the liver uses up glucose, insulin will also decrease hepatic gluconeogenisis and ketogenisis
Control of insulin secretion
Stimulators: Glucose, Fatty acids, Amino acids (and GH and Cortisol indirectly) GH and Cort cause insulin resistance so glucose raises in plasma and insulin goes up
Inhibitors: SST (paracrine)-prevents overshoot
Amplifiers: GI hormones
Basic mechanism of glucsoe stimulation
Glucose travels in the GLUT transporter on the beta cell
Glucokinase converts glucose to G6P
Oxidation of G6P causes a depolarization which opens Ca cahnnelas that lead to insulin excretion
Glucagon effects
Glucagons major role is to prevent hypoglycemia (counterregulatory) and muscle is not a source of glucose production
Glucagon has no effects on muscle
Glucagon stimulates hepatic gluconeogenisis from amino acid precursors, it also stimulates lipolysis and the conversion of free fatty acids to ketoacids (a fuel) in the liver
Glucagon also stimulates glycogenolysis and inhibits glycolysis
Control of glucagon release
Alpha cell release of glucagon is inhibited by glucose, insulin, SST, ketones, FFA (inhibition of glycogenolysis in fed state)
Amino acids stimulate glucagon release (glucagon stimulates the conversion of AA to glucose in the liver and amino acids stimulating glucagon prevents insulin induced hypoglycemia after eating a pure protein meal)
Glucagon like peptides
GLPS:
Secreted from the gut in response to feeding
Acute-increases insulin response to glucose
Chronic- increases beta cell mass
Daily levels of blood glucose, glucagon and insulin
Glucagon won’t ever really go down because we usually are not hypoglycemic
Breakfast-> small increase in glucose but high increase in insulin (GLP)
Two larger meals -> sustained increase of blood glucose (even though insulin response wanes before glucose goes down) important because you dont want glucose uptake to exceed the glucose supply (reactive hypoglycemia due to insulin)
Prevention of reactive hypoglycemia: paracrine SST inhibition of insulin, GLP goes down quickly
Fed state vs fasted state
Fed state: insulin is increased to stimulate glucose uptake and counterregulatory hormones not stimulated
Fasted state: insulin is low-> counterregulatory hormones stimulate gluconeogenisis to maintain glucose supply for consumption in non-insulin dependent tissues (liver)
With true starvation, cortisol is required to maintain gluconeogenisis using AA precursors generated by muscle metabolism
Glucose tolerance curve in normal Vs Diabetes
Normal: fasted person given glucose, insulin levels go up, glucose goes back down to normal (glucose uptake is stimulated via insulin)
In diabetes either insulin is absent due to autoimmune islet cell destruction (Type 1) or there is a resistance to the action of insulin in target tissue (type 2)
Fasting diabetes will have high glucose, glucose given and a very large increase in plasma (inneffective/ absent insulin)
Gestational diabetes: insulin resistance from placental hormones
GH and cortisol excess cause insulin resistance and can lead to a fasting hyperglycemia
Pathogenisis of T2 diabetes
Genetic suscepptibility, development of obesity and exrcise (insulin resistance is worsened)
Primary cell defect-> decreased glucose uptake (insulin resistance
Primary liver defect-> decrease in hepatic glucose uptake failure to decrease gluconeogenisis
beta cell defect-> low insulin response
Therapies: target (increase glucose uptake, decrease hepatic gluconeogenisis and stimulate insulin release)
Excersice to improve insulin sensitivity
