Endocrine Pancreas

Question 1

• Endocrine cells of the pancreas are arranged into clusters called _
• These are innervated by _,_ and _ neurons
• What is the most predominant cell type and where in the cluster is it located + what does it secrete?
• What other cells are present and what do they secrete

Answer 1

• Islet’s of Langerhans
• Adrenergic (sympathetics), Cholinergic (parasympathetics), and Peptidergic neurons
• Beta cells-located in the center, secrete insulin
• Alpha cells-around periphery, secrete glucagon
• Delta cells-interspersed-secrete somatostain

Question 2

• Gap junctions allow for rapid cell-cell communication between what cell types?

Answer 2

• Alpha-alpha
• Beta-beta
• Alpha-beta

Question 3

Insulin and C Peptide are secreted in a _ to _ fashion

Answer 3

• 1 to 1
• C peptide can be used as a long term marker for insulin secretion

Question 4

How is insulin secreted?

What is the most important factor regulating glucose secretion?

Answer 4

• STEPS:
  
  • Glucose binds GLUT 2 on beta cells
  • Glucose goes thru TCA cycle and produces ATP
  • ATP closes ATP dependent K+ channel
  • Depolarization occurs
  • Ca2+ influx into cell
  • Increased Ca2+ stimulates exocytosis of insulin and C peptide
• Most important regulator of insulin secretion: Glucose

Question 5

• _ drugs promote closing of ATP dependent K+ channel (helps with insulin secretion and used to treat T2 Diabetes)
• _ is secreted in equimolar amounts with insulin and excreted unchanged in the urine (used to monitor endogenous B cell function)

Answer 5

• Sulfonylurea
• C peptide

Question 6

• Glucose stimulates the secretion of insulin in a _ manner
• _ is absent in a diabetic individual

Answer 6

• Biphasic
• Phase 1

Question 7

• Besides glucose, what other factors stimulate insulin release?
• What inhibits insulin release?
• Through which types of G protein coupled receptors do these molecules work?

Answer 7

• Stimulates:
  
  • Glucagon-Gs
  • GLP-1: Gs
  • CCK-Gq
  • ACh-Gq
• Inhibits:
  
  • Somatostatin-Gi

Question 8

• Before insulin enters the systemic circulation, it bypasses in bursts through the _
• What is significant about this?

Answer 8

• Liver
• Almost 80% of insulin that enters the liver stays in the liver
• The rest is sent in pulsations to the systemic circulation

Question 9

• How does insulin receptor signaling work?

Answer 9

• Insulin receptor is an RTK
• Insulin binding to receptor triggers autophosphorylation of the receptor and phosphorylation of IRS and substrate proteins
• Substrate proteins activate downstream signaling cascades that lead to growth and metabolic effects
• GLUT4 translocation to PM in Muscle Cells and Adipocytes
• GLUT 2 translocation to PM in Liver Cells

Question 10

• What are the actions of insulin in muscle cells

Answer 10

• Increase glucose uptake (GLUT4)
• Increase in glycogen synthesis (Activates glycogen synthase)
• Increases glycolysis and carb oxidation (Increased activity of hexokinase, phosphofructokinase and pyruvate dehydrogenase)
• Decreased gluconeogenesis
• Increase protein synthesis and decrease in protein breakdown

Question 11

• Alternative intracellular pathways for glucose uptake independent of insulin
• What is significant about this finding?

Answer 11

• Muscle contractions stimulate AMPK
• Results in translocation of GLUT4 to PM
• Exercise management can be used as part of treatment for patients with insulin resistance/diabetes

Question 12

• Insulin effects on triglyceride and fatty acid metabolisms in adipose tissue

Answer 12

Question 13

• How does an increase in insulin affect the following nutrients’ concentration in the blood?
  
  • Glucose
  • Fatty acids
  • Ketoacids
    Amino Acids

Answer 13

• ALL ARE DECREASED

Question 14

• Summary of insulin actions and the effect on blood levels

Answer 14

Question 15

• Summary of factors affecting insulin secretion

Answer 15

Question 16

• Type I Diabetes Mellitus
• What happens?
• What causes it?
• What are some key characteristics of the disease?

Answer 16

• Destruction of beta cells (usually d/t AID); does not show sx until 80% of cells are destroyed
• Increase in blood glucose
  
  • ​Decreased uptake of glucose
  • Decreased glucose utilization
  • Increase in gluconeogenesis in the liver
• Increase in Blood FA and Ketoacids
  
  • ​Decreased fatty acid synthesis
  • Decreased triglyceride synthesis
  • Increased triglyceride breakdown
  • Increased conversion of FA to ketoacids and decreased ketoacid utilization by tissues (DKA-metabolic acidosis)
• Increase in blood AAs
  
  • ​Increased protein breakdown
  • Decreased protein synthesis
  • Increased catabolism of aa’s (loss of lean body mass)
  • Increased ureagenesis
• Hyperkalemia
  
  • ​Shift of K+ out of cell
  • Even though K+ is high in plasma, is low total K+ b/c of polyuria and dehydration
  • OSMOTIC DIURESIS
    ​Increased BGL results in increased filtered load of glucose
  • Water and electrolyte absorption prevented (glucose reabsorption is prevented)
  • Polyuria-leads to excess excretion of Na+ and K+
  • Polydipsia

Question 17

• The goal of insulin replacement therapy for T1 DM is to recreate normal physiology using _
• Drawbacks of insulin replacement therapy?

Answer 17

• Basal and bolus insulin
• Drawbacks
  
  • Painful
  • Time consuming
  • Lag between glucose measurement and insulin dosing
  • Delayed absorption of insulin following subcutaneous injections
  • Poor BG control
    
    • Periods of hyperglycemia

Question 18

• T2 DM
  
  • ​Progressive exhaustion of _ cells d/t environmental factors (sedentary lifestyle, malnutrition, obesity)
  • Patients can make insulin, but not enough to overcome _
  • Initially, insulin levels are _
  • As the disease progresses, insulin levels are _

Answer 18

• Beta Cells
• Insulin resistance
• Normal or elevated
• Deficient
  
  • Reactive hyperinsulinemia followed by relative hypoinsulinemia

Question 19

• What are the three causes for obesity-induced insulin resistance?

Answer 19

1. Decreased GLUT 4 uptake of glucose
2. Decreased ability of insulin to repress hepatic glucose production
3. Inability of insulin to repress HSL or increase LPL in adipose tissue

Question 20

• Type II diabetics are not as prone to _ because the presence of some insulin secretion serves as protection
• In non-obese patients, type II diabetes can occur d/t _ in insulin release by the _ (varying degrees of insulin resistance can also occur)

Answer 20

• Ketoacidosis
• Decrease in insulin release by the pancreas

Question 21

• Treatment for Type II Diabetes

Answer 21

• Caloric restriction and weight reduction
• Insulin secretagogues:
  
  • sulfonylurea drugs
  • Incretin analog of GLP-1 (injection)
  • alpha glucosidase inhibitors
  • Amylin analogs
  • Insulin sensitizers
  • Biguanide drugs (EX: metformin): upregulate insulin receptors on target tissues

Question 22

• Incretin hormones
• Diabetic patients have a _ incretin effect

Answer 22

• Intestine derived hormones (EX: GLP-1, GIP, Short T1/2)
• Secreted in response to glucose and fat
• Stimulate insulin secretion (glucose dependent)
• Inhibit glucagon secretion
• Slow gastric emptying
• Diabetics have a reduced incretin effect

Question 23

• Summary of Type I versus Type II Diabetes

Answer 23

Question 24

• Glucagon is a 29 aa straight chain polypeptide and is members of the peptide family including _ and _ GI hormones
• Synthesized as _
• Undergoes processing in _ cells of the pancreas and _ cells of the intestine
• Stored in _ until alpha cells are stimulated (what is the major stimulus?)

Answer 24

• Secretin, GIP
• Proglucagon
• Alpha cells of pancreas and L cells of the intestine
• Dense granules (main stimulus is decrease in BGL)

Question 25

* **Besides low BGL, what else has stimulatory effects on glucagon secretion?** * **What has inhibitory effects on glucagon secretion?**

Answer 25

* Stimulatory: * Low BGL * Increase in AAs (**arginine and alanine)** * Fasting * CCK * Beta adrenergic agonists * ACh * Inhibitors: * Insulin (also inhibits synthesis) * Somatostatin * Increased fatty acid and ketoacid concentration

Question 26

* The major actions of glucagon are in the \_ * What happens?

Answer 26

* Liver * Increase in gluconeogenesis (by decreasing production of fructose 2,6 phosphate) * Increase in glycogenolysis (inhibits glycogen formation from glucose) * Increases lipolysis and inhibits fatty acid synthesis * Ketoacids are produced from fatty acids

Question 27

* Glucagon has what effect on the concentration of the following nutrients in the blood? * Glucose * Fatty Acids * Ketoacids

Answer 27

* INCREASES CONCENTRATION IN BLOOD FOR ALL OF THESE

Question 28

* Summary of factors regulating glucagon secretion

Answer 28

Question 29

* Summary of overall effects of glucagon secretion

Answer 29