Physiology Block 3 Week 15 11 Pancreas Flashcards
Cells of Islet of Langerhans and what each produces
Islets of Langerhans release hormones into ducts directly
Alpha–glucagon
Beta–insulin
Delta–somatostatin
Insulin Function
Insulin is the storage hormone
- Insulin release is stimulated by an increase in blood glucose
- Insulin stimulates glucose uptake in the liver, adipose tissue, and muscles
- -lowers blood glucose to normal levels - Insulin release stimulated by fatty acids and amino acids and increases uptake
Very important function in the fetus
–fetal insulin important for fetus to get glucose from the mother
How is Insulin synthesized?
Insulin is not synthesized directly–pro-hormone
Pro-insulin is cleaved in the Golgi Apparatus of pancreatic beta cells
It is post-translationally processed to 2 hormones:
- C Peptide
- insulin (A and B chains connected by disulfide bonds)
C Peptide and insulin packaged in granules and secreted
C-Peptide = clinical marker of beta cell function
Glucose Transporters (GLUTs) and mode of function
Facilitated Transport
Follows concentration Gradient
Km = Michaelis constant
Low Km = high affinity; better for low glucose concentrations
High Km = low affinity; better for high glucose concentrations
Glucose Uptake in the brain
Brain does not want to be insulin deprived–otherwise will die
Glucose uptake in the brain is NOT primarily insulin dependent
–allows maintenance of glucose uptake during periods of starvation (low ambient glucose and insulin concentration)
GLUT 1–low Km–basal glucose uptake (on blood brain barrier)
GLUT 3–low Km–basal glucose uptake (in brain itself)
Glucose uptake of the liver
GLUT 2
Very High Km
Glucose uptake of the muscles
GLUT 4
High Km–insulin stimulated glucose uptake
Insulin Binding Receptor, The Cascade, and Effects
Insulin binds alpha receptor
- -autophosphorylation of beta subunits
- -induces TYROSINE KINASE ACTIVITY
- -phosphorylation cascade on Insulin Receptor Substrate (IRS) enzymes:
- growth and gene expression
- glycogen synthesis
- fat synthesis
- protein synthesis
- translocation of glucose transporters to cell membrane
Effect of Insulin on Muscle
Increased glucose and Amino Acid uptake
Muscle is NOT a source of glucose efflux into plasma
–muscle will burn glucose in glycolysis
Insulin inhibits breakdown of muscle for AA release (gluconeogenic precursors)
Effect of Insulin on Adipose Tissue
Insulin stimulates glucose uptake
Inhibits lipolysis and release of free fatty acids for beta-ketoacidosis
Effect of Insulin on Liver
Decrease extracellular glucose concentration in the liver
Insulin stimulates:
- glycogenesis
- glycolysis
There is a finite supply of glycogen storage
–when stores are full, burns glucose in glycolysis to prevent release of glucose into plasma
Prevents release of glucose to: Muscle --prevents AA formation Adipose tissue --prevents release of fatty acids and ketoacids
Stimulators of Insulin
Plasma Glucose
Amino Acids (Protein)
Fatty Acids
Indirect (GH/Cortisol):
–GH and cortisol increase glucose production
–important in starvation; prevents insulin from increasing glucose uptake
Amplifier of Insulin
GI Hormones
When drink glucose vs inject, ALWAYS a bigger insulin response to oral glucose because stimulates GI hormones
Ex. Glucagon-like peptide (GLP) and glucose insulinotropic peptide (GIP)
- -released when chyme moves into the stomach and small intestine
- -amplifies effect of glucose on insulin release
Inhibitors of Insulin
Somatostatin (paracrine)
Prevents overshoot of glucose-stimulated insulin release
Released from delta cells in islets of Langerhan
- -inhibits insulin release by a paracrine effect
- -inhibits GH release
Mechanism of glucose stimulation of insulin secretion
Glucose enters into cell via GLUT 2
Leads to cellular depolarization and Ca2++ influx and insulin release
Insulin released during lots of glucose around in fed state
The effects of glucagon
Prevents hypoglycemia
- -increases glucose production
- -muscle is NOT A SOURCE of glucose production
Stimulates:
- hepatic gluconeogenesis from AA precursors
- lipolysis and conversion of fatty acids to ketoacids
- -glycogenolysis (glycogen breakdown)
Inhibits:
-glycolysis
Control of Glucagon Release
Inhibition of glucagon release:
- glucose
- ketones
- free fatty acids
- insulin (fed state)
- somatostatin (fed state)
Stimulation of Glucagon release:
- Amino acids
- -cortisol is up, breaks down muscle, releases AA, stimulates gluconeogenesis
- -AA stimulation of glucagon prevents insulin-induced hypoglycemia after eating a pure protein meal
Ex. Hyena eats protein meal, if it didn’t stimulate glucagon, it would pass out from hypoglycemia because insulin also stimulated
Glucagon-Like Peptides (GLPs)
Secreted from gut in response to feeding
Acute–increases insulin response to glucose
Chronic–increases beta-cell mass
Amplifiers (incretins)–amplify glucose response to a meal
Temporal Profile of Blood Glucose, Glucagon, and Insulin in a healthy adult.
What happens during breakfast?
What happens during lunch?
What happens during dinner?
Glucagon does not change because subject never becomes hypoglycemia
Breakfast:
- small increase in glucose
- large increase in insulin due to increase of GLP from feeding which has amplification effect
Lunch (large meal):
- sustained increase in glucose
- insulin response waned before glucose decreased to baseline
- *if insulin didn’t come down, glucose would keep going down, and would get hypoglycemia after every meal–reactive hypoglycemia
Dinner (larger meal):
- glucose goes way up
- insulin comes up and then down before glucose absorbed
- *Removing GLUT from cell membrane (think slowing down at a stop sign)
Insulin and Counterregulatory Hormones in Fed vs Fasted State
Counterregulatory Hormones:
- epinephrine
- glucagon
- glucocorticoids
- growth hormones
Fed State:
- insulin increased = stimulates glucose uptake
- counterregulatory hormones not stimulated
Fasted State:
- insulin low
- counterregulatory hormones stimulate gluconeogenesis to maintain glucose supply for consumption in non-insulin dependent tissues
Starvation (Super Fasted):
-cortisol required to maintain gluconeogenesis using AA precursors from muscle catabolism
Glucose Curve in Patient with Diabetes Mellitus vs Healthy
After an overnight fast, glucose given to patient orally
DM:
- has fasting hyperglycemia
- Blood glucose increases and stays up and comes down slowly over hours
Healthy:
- Glucose increases and is restored to normal (even dips below)
- an increase in insulin stimulates glucose uptake
Diabetes Mellitus Type I
Insulin is absent due to autoimmune islet cell destruction
Islet cell destruction
Diabetes Mellitus Type II
There is resistance to the action of insulin in target cells
Insulin resistance
Where does glucose go in patients with diabetes mellitus?
After a glucose load and no response to insulin, the blood glucose stays up and slowly comes down over hours
The glucose goes to the brain, heart, and mostly urine
Gestational Diabetes
Due to insulin resistance from placental hormones (human placental lactogen) in pregnant women who have a propensity for insulin resistance
Excess Cortisol and Growth Hormone
Causes insulin resistance and can lead to significant fasting hyperglycemia
Current View of Pathogenesis of Type I Diabetes Mellitus
Genetic Susceptibility + Environment (viral infection?)
Autoimmune attack of beta cell by lymphocytes and immunoglobulins
Permanent Loss of insulin secretion
Hypothetical Pathogenesis of Type II Diabetes Mellitus
Strongly associated with obesity and lack of exercise
Therapies target increased glucose uptake, decreased hepatic gluconeogenesis, and stimulate insulin release (decreased response to insulin)
Most effective tx is diet and exercise
Primary Cellular Defect
–decreased glucose uptake (insulin resistance)
Primary Liver Defect
- -decrease in hepatic glucose uptake
- -failure to decrease gluconeogenesis
Relative beta cell Defect
–inadequate insulin response
- ->Hyperglycemia (Insulin resistance with increased insulin–hyperinsulinemia
- –the beta cells will eventually overwork and die out
Long Term Complications of Diabetes
Retinopathy Nephropathy Neuropathy Cardiovascular Disease Skin (poor wound healing) Pregnancy--increase size of baby due to more glucose to fetus, increasing fetal insulin (a fetal growth factor)
Two Possible Mechanisms of Insulin Resistance
Leads to failure of insulin to increase glucose uptake:
- Inflammation
- Lipid Overload
The defect is POST-RECEPTOR
The activity of insulin receptor substrates (IRS) is interfered with limiting glucose uptake
Metabolic Syndrome
Made up syndrome for patients that are pre-diabetic
Insulin resistance (High fasting glucose) and 2 of the following:
- hypertension
- dyslipidemia
- obesity (visceral)
- microalbuminuria (early renal dysfunction)
Adipose tissue is CENTRAL to this syndrome (overeating and sedentary lifestyle)
–releases cytokines, adipokines, PROTHROMBOTIC factors (embolisms), and free fatty acids that lead to insulin release
Lipotoxicity
Liver and Muscle:
-ectopic deposition of fat induces insulin resistance
Beta cells:
-ectopic deposition of fat leads to relative insulinopenia
If insulin was able to increase enough, it could restore plasma glucose to normal
HOWEVER, although insulin increases, it doesn’t increase as much as it should if beta cell function were normal–blood glucose remains elevated
Which of the following will NOT have an increase in blood insulin levels?
Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus (early in the disease) Metabolic syndrome Cushing’s syndrome Acromegaly
Type 1 Diabetes Mellitus
Insulin is absent due to autoimmune islet cell destruction
