Physiology Block 3 Week 15 11 Pancreas Flashcards Preview

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Flashcards in Physiology Block 3 Week 15 11 Pancreas Deck (33)
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Cells of Islet of Langerhans and what each produces

Islets of Langerhans release hormones into ducts directly



Insulin Function

Insulin is the storage hormone

1. Insulin release is stimulated by an increase in blood glucose

2. Insulin stimulates glucose uptake in the liver, adipose tissue, and muscles
--lowers blood glucose to normal levels

3. 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

Very High Km


Glucose uptake of the muscles

High Km--insulin stimulated glucose uptake


Insulin Binding Receptor, The Cascade, and Effects

Insulin binds alpha receptor
--autophosphorylation of beta subunits
--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:

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:
--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

-hepatic gluconeogenesis from AA precursors
-lipolysis and conversion of fatty acids to ketoacids
--glycogenolysis (glycogen breakdown)



Control of Glucagon Release

Inhibition of glucagon release:
-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

-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:
-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

-has fasting hyperglycemia
-Blood glucose increases and stays up and comes down slowly over hours

-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

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:

-Lipid Overload

**The defect is POST-RECEPTOR**

The activity of insulin receptor substrates (IRS) is interfered with limiting glucose uptake