Endocrine Pancreas

Question 1

Describe insulin

Answer 1

Major historical discovery and major anabolic hormone

Secrete in response to o CHO and/or protein digestion

Question 2

What is the major stimulatory factor of insulin secretion?

Answer 2

Glucose

Question 3

What are the precursors to insulin?

Answer 3

Pre-proinsulin —> proinsulin —> insulin and C peptide

Question 4

What is pre-proinsulin?

Answer 4

Signal peptide with A and B chains with connecting peptide (C peptide) and no disulfide bonds

Question 5

What is proinsulin?

Answer 5

No signal peptide
Still attached in insulin
Package into secretory granules
Proteases here cleave proinsulin

Question 6

What are the steps of insulin release?

Answer 6

Glucose enters cell via GLUT2 and is phosphorylated by glucokinase
G6P is oxidized promoting ATP generation
ATP closes the inward rectifying K channel
Plasma membrane is depolarized
Activation of voltage gated Ca channels
Ca enters the cell and initiates mobilization of insulin (and C peptide)

Question 7

A rise in ATP levels will close what?

Answer 7

K channels (ATP dependent K channels)

Question 8

Describe sulfonylurea receptors

Answer 8

Associated with ATP dependent K channels
Increase insulin secretion
Causes membrane depolarization to occur more easily
More Ca entry
Used for treatment of T2DM

Question 9

Describe the biphasic release of insulin

Answer 9

Initial spikes within minutes
Further increase in half hour to an hour later
First phase of insulin secretion is lost first in T2DM

Question 10

Where does insulin resistance primarily occur?

Answer 10

In adipose tissue and skeletal muscle

Occurs very early in disease progression

Question 11

What are the intracellular steps of insulin signaling?

Answer 11

Insulin binding to receptor
Substrate proteins phosphorylate and activate/inactivate downstream pathways P13/Akt/mTOR and MAP kinases (these mediate metabolic and mitogenic responses)
Translocation of vesicles containing GLUT4 to membrane (muscle and adipose)
Glucose enters via facilitated diffusion

Question 12

What are the stimulatory factors for insulin secretion?

Answer 12

ACh, CCK, GIP, GLP
Glucagon (inhibited by insulin but modulates insulin action)
Cortisol 
K+ 
Obesity 
Sulfonylurea drugs

Question 13

What are some inhibitory factors for insulin secretion?

Answer 13

Fasting, exercise
Somatostatin
NE

Question 14

What are the actions of insulin on skeletal muscle?

Answer 14

increased glucose uptake, glycogen synthesis, glycolysis and CHO oxidation, protein synthesis and decreased protein breakdown

Question 15

What are the actions of insulin on the liver?

Answer 15

promotes glycogen synthesis, glycolysis and CHO oxidation, decreases gluconeogenesis, increases hexose monophosphate shunt, increase pyruvate oxidation, increases lipid storage and decreases lipid oxidation, increases protein synthesis and decrease protein breakdown

Question 16

What are the actions of insulin on adipose tissue?

Answer 16

increased glucose uptake, glycolysis and uptake of FAs; decreased lipolysis

Question 17

Which ion does insulin effect the concentrations of?

Answer 17

Increases uptake of K into cells —> decreased K in blood

Question 18

Describe the effects of blood sugar and insulin

Answer 18

Muscle contraction stimulates glucose uptake independent of insulin (activation of AMP kinase (AMPK) results in GLUT4 translocation to plasma membrane)
Blood sugar usually roughly normal (except for long distance aerobics)
Insulin may decrease
Eating too close to exercise can disrupt glucose homeostasis

Question 19

Describe beta cells

Answer 19

60-65% of the islets of langerhans
Centrally located
Secrete insulin and C peptide

Question 20

Describe alpha cells

Answer 20

20% of islet
Peripherally located
Secrete glucagon

Question 21

Describe delta Ellis

Answer 21

5% of islet
Interspersed between alpha and beta cells
Secrete somatostatin
Neuronal appearance and send dendrite like processes to beta cells

Question 22

Describe F cells (PP cells)

Answer 22

Secrete pancreatic polypeptide

Acts like a satiety signal (neuropeptide Y of the peptide YY family)

Question 23

How do cells of islets communicate with each other?

Answer 23

Ion concentrations changes signal

Gap junctions allow for rapid cell to cell communication between alpha-alpha, beta-beta and alpha-beta cells

Question 24

Describe the blood supply to the islets of langerhans

Answer 24

Islets receive 10% of pancreatic blood flow
Venous blood from beta cells carries insulin to alpha and delta cells
Blood flows first to the center (for insulin)
Flows through periphery (on alpha cells inhibits glucagon release)

Question 25

Blood glucose reflects balance between what?

Answer 25

Hypoglycemic actions of insulin and hyperglycemic actions of anti-insulin hormones

Question 26

Describe glucagon

Answer 26

Increases blood glucose Substrates are directed toward glucose formation Increases gluconeogenesis, lipolysis and glycogenolysis Inhibits glycogen synthesis

Question 27

Describe the secretion of glucagon

Answer 27

Release stimulated by decreased blood glucose (major | Also stimulated by increasing AA (arginine and alanine), fasting, CCK, beta adrenergic agonists and ACh

Question 28

What inhibits the secretion of glucagon?

Answer 28

Insulin and high blood glucose levels | Somatostatin, FAs and keto acids

Question 29

What is the incretin effect?

Answer 29

Incretins are a group of metabolic hormones that stimulate a decrease in glucose levels The incretin effect is abolished in T2DM

Question 30

Which factors contribute to the development of T2DM?

Answer 30

Multiple genes coupled with environment, environmental exposures, adipose tissue dysfunction and chronic systemic inflammation

Question 31

Which ethnicities are at a greater risk for T2DM?

Answer 31

African American, Hispanic and Native American

Question 32

Which environmental exposures are involved in the development of T2DM?

Answer 32

Caloric intake excessive, sedentary behavior, maternal disease and nutrition, rapid postnatal growth, sleep debt, other endocrine disruptions, chronic inflammation

Question 33

Describe adipose tissue dysfunction involved with development of T2DM

Answer 33

Adipose tissue is inflamed and recruits M1 macrophages causing release of more inflammatory markers Disposition of adipokines (i.e. adiponectin and leptin) Release of FAs IL-6 and other pro inflammatory cytokines (i.e. TNF-alpha, IFN-gamma and CRP)

Question 34

Describe the progression of insulin resistance to T2DM

Answer 34

1. Systemic insulin resistance 2. Reactive hyperinsulinemia: postprandial glucose levels are normal but more insulin is required to do the job (reactive hyperinsulinemia) 3. Postprandial hyperglycemia 4. Disrupted response to oral glucose tolerance test 5. Blunted incretin release (don't need to known within this timeline) 6. Chronic elevated insulin levels 7. Mild-moderate chronically elevated glucose levels 8. Frank hyperglycemia Timeline of development can be 5-30 years

Question 35

What are some treatment options for T2DM?

Answer 35

Caloric restriction, weight reduction and physical activity/exercise Insulin sensitizers and secretagogues Slow absorption of CHO Bariatric surgery

Question 36

Describe type 1 DM

Answer 36

Inadequate insulin secretion T cell mediated destruction of beta cells often from autoimmune disease (no insulin or C peptide produced) Sx do not become evident until >80% of beta cells are destroyed Increase blood glucose, FAs, keto acids, amino acids, increased conversion of FA to keto acids Decreased utilization of ketoacids results in DKA Hyperkalemia and osmotic diuresis/glucosuria can occur

Question 37

Describe the hyperkalemia that occurs during T1DM

Answer 37

Shift of K out of cells (intracellular concentration is low) Lack of insulin effect on Na/K ATPase Plasma levels may be normal but total K is usually low due to polyuria and dehydration

Question 38

Describe the osmotic diuresis/glucosuria that can occur during T1DM

Answer 38

Increased blood glucose increases filtered load of glucose, exceeds reabsorptive capacity of proximal tubule Water and electrolyte reabsorption also blunted Polyuria - increases excretion of Na and K even though urine concentration of electrolytes is low Thirst (polydipsia)

Question 39

What are some environmental factors that contribute to the development of T1DM?

Answer 39

Breast feeding - early exposure to cow’s milk may predispose Vitamin D deficiency Wheat gluten (increased risk in celiac disease pts) Few childhood infections Obesity Viral infections (mumps, rubella, enterovirsues, retroviruses, CMV)

Question 40

What is the treatment for T1DM?

Answer 40

Goal is to recreate normal physiology (basal and bolus insulin) Timing insulin dose to meal consumption to mimic physiologic response

Question 41

T2DM causes increased risk for what other diseases?

Answer 41

CVD/ischemic heart disease, ischemic vascular disease (i.e. stroke), non-alcohol fatty liver disease and steatohepatitis, kidney failure, blindness, skin ulcers and amputations, peripheral neuropathy Reduced wound healing