Diabetes Insulin

Question 1

What is the relationship between insulin and glucose?

Answer 1

Excursions mirror one another over 24 hours

Question 2

What unit is insulin given in?

Answer 2

micro-IU/mL or pmol/L

Question 3

What do some propose is the ideal fasting insulin levels?

Answer 3

8.4 microIU/mL

Question 3

What does the head and tail of the pancreas connect to?

Answer 3

Head = duodenum
Tail = tapers to left side of abdomen, near spleen

Question 3

What is the pancreas?

Answer 3

Narrow 6-inch long gland, left side of abdominal cavity

Question 4

What Type of gland is the pancreas? What secretions does it produce?

Answer 4

Heterocrine glan; Endocrine and exocrine

Question 5

What cells make up the endocrine portion of the pancreas?

Answer 5

small bundles of Langerhans cells (red stain)

Question 6

What cells make up the exocrine portion of the pancreas?

Answer 6

Acini (blue stain)

Question 7

How many islets are found in a healthy, adult pancreas?

Answer 7

1 million

Question 8

What types of cells are found in the islets?

Answer 8

beta, alpha, delta, PP (or gamma) and epsilon cells

Question 8

What is found inside islets?

Answer 8

3000-4000 clusters of cells per iselt

Question 9

Describe the blood and nerve supply to the islets

Answer 9

Highly vascularised; receive 15% of total pancreatic blood supply

Autonomic nerve fibers (terminals with acetylcholine and norepinephrine)

Question 10

Differentiate between mouse and human lslets of Langerhans

Answer 10

Mouse:
Red: insulin
Green: glucagon
Very organized
β-cells = 80%

Human:
Red: insulin
Green: glucagon
Less organized
β-cells = 50-60%

Question 10

What do the 5 different pancreatic cell types secrete?

Answer 10

1. alpha cells = glucagon
2. beta cells = insulin and amylin
3. D cells = somatostatin
4. Epsilon cells = ghrelin
5. PP cells = pancreatic polypeptide

Question 11

How is insulin biosynthesised?

Answer 11

Question 12

Describe what occurs in beta cells at rest.

Answer 12

1. Low glucose in the blood
2. Metabolism slows
3. ATP decreases
4. kATP channels open
5. Cell is at resting potential and no insulin is released

Question 13

What happens when a beta cell is secreting insulin?

Answer 13

1. High glucose levels in blood
2. Metabolism increases
3. ATP increases
4. kATP channels close
5. Cell depolarises and calcium channels open
6. Ca2+ entry acts as an intracellular signal (ligand)
7. Ca2+ signal triggers exocytosis, and insulin is secreted.

Question 14

What is the biphasic nature of glucose-induced insulin release?

Answer 14

• With each cellular response to glucose, there are 2 phases of insulin release that follow
• First phase = rapid, transient and there is a pronounced increase in insulin levels which quickly declines
• Second phase = Gradual, sustained and less pronounced increase in insulin levels compared to the first phase

Question 15

Why does the 2nd phase of insulin release take longer than the first?

Answer 15

Needs time to synthesize and release new insulin-containing granules/vesicles

Question 16

Why does the first phase of insulin release take a shorter amount of time than the second?

Answer 16

There is a readily available of pool of insulin-containing vesicles in the cell

Question 17

What do potentiators (factors) of insulin secretion do?

Answer 17

Modulate insulin secretion but are separate to nutrient effects like glucose

Question 18

What is the difference between a potentiator and initiator?

Answer 18

• Initiator: Starts/triggers the secretion of insulin (glucose)
• Potentiator: Modulates the secretion of insulin (incretin)

Question 19

Under normoglycemic conditions, what effect do potentiators have?

Answer 19

• Little to no effect
• Limit potential of developing harmful hypoglycaemia

Question 20

What are incretins?

Answer 20

• Metabolic hormones that stimulate insulin release
  to decrease blood glucose levels
• Examples: glucagon-like peptide-1 (GLP-1)
  AND
  glucose-dependent insulinotropic peptide (GIP)

Question 21

What is the impact of GLP1 on glycaemic control?

Answer 21

* GLP-1 has specific effects on glycemic control (how well glucose is cleared from the body) * All together these affects lead to Glycemic control improvement 1. Promotes satiety in brain 2. Delays gastric emptying 3. stimulates insulin secretion, B-cell proliferation, inhibits B-cell apoptosis and inhibits glucagon secretion 4. Overall improves glycaemic control and reduces body weight

Question 22

Describe the dose-response curve of glucose-induced insulin secretion

Answer 22

* Sigmoidal * Glucokinase in pancreatic β–cell acts as glucose sensor & couples insulin secretion to prevailing glucose levels *Glucose concentrations below 5 mmol/L do not affect insulin release, but progressive increase 5-15 mmol/L range *Potentiators amplify insulin response at stimulatory concentrations of glucose

Question 23

The regulation of insulin secretion is affected by many factors. What are these factors and do they positively or negatively control insulin secretion (via islet B-cell stimulation)?

Answer 23

1. High BG [ ] is a major control + 2. High GI hormones + 3. Parasympathetic stimulation + 4. Sympathetic stimulation - 5. Epinephrine -

Question 24

What happens metabolically when insulin is secreted (5)?

Answer 24

1. Blood glucose lowers 2. Blood fatty acids lower 3. Blood amino acids lower 4. Protein synthesis increases 5. Fuel storage increases

Question 25

What are the effects of insulin on target tissue?

Answer 25

* Insulin = released and transported in circulation * Effects specific target tissues * Increased plasma insulin in response to nutrients * Consider liver: glucose uptake and insulin facilitates conversion of glucose into glucose 6 phosphate. Insulin facilitates anabolic reactions in storage. Glucose converted into glycogen or undergoes metabolism forming pyruvate, acetyl-coA and fatty acids * Consider fat cells: insulin directly facilitates glucose uptake through specific transporters. Lipogenesis occurs in these tissues producing fatty acids. Insulin can also facilitate FA and monoglyceride uptake by affecting transport proteins involved which is stored. * Muscle: AA also taken up under influence of insulin under transport proteins. Stored in muscle proteins. Muscle is major site of glucose uptake and a specific GLUT activated directly by insulin signalling involved in glucose uptake into muscle. Glucose stored as glycogen or used in metabolism. * Red arrows = decreased insulin levels

Question 26

Describe this important mechanism, which includes muscle glucose uptake.

Answer 26

1. Receptor tyrosine kinase (RTK) is found on the sarcolemma cell surface. 2. Insulin binds RTK --> Phosphorylation occurs 3. Signal cascade is initiated 4. IRS1 = recruited to the sarcolemma and phosphorylated by the activated insulin receptor 5. IRS1 becomes activated 6. Active IRS1 converts PI3 kinase into active form 7. *Akt = next kinase in the cascade and is phosphorylated and activated 8. Akt activates and facilitates translocation of GLUT4 containing vesicles 9. GLUT4 is insulin responsive transporter 10. In rested state: GLUT4 = contained within intracellular vesicles 11. In activated state: vesicles = stimulated to move to sarcolemma and fuses to sarcolemma 12. Glucose = taken up into myocytes

Question 27

Describe this important mechanism (how the liver indirectly regulated glucose uptake) in the FED STATE

Answer 27

Hepatocytes in fed state: 1. Insulin does not directly regulate GLUT2 in the liver 2. Liver: GLUT2 always remains on the cell membrane (unlike GLUT4 for muscle) 3. Insulin activates hexokinase that catalyzes the conversion: glucose to glucose-6-P 4. Thus insulin lowers liver intracellular glucose levels vs. plasma levels 5. As a result, there is a concentration gradient that allows glucose diffusion – via GLUT2 - from plasma into liver cells 6. If GLUT2 was not present on cell membrane in fasted state, then glucose would be unable to exit liver cells to enter into circulation

Question 28

Describe this important mechanism (how the liver indirectly regulated glucose uptake) in the FASTED STATE

Answer 28

Hepatocyte in fasted state: 1. Glycogenolysis and gluconeogenesis occurs --> liberates glucose and produces glucose in hepatocyte which is exported. 2. Works via concentration gradient. 3. Glucose levels = maintained at homeostatic levels during fasting state.

Question 29

How does insulin promote glucose storage when in a fed/absorptive state?

Answer 29

1. Overall, insulin in fed state decreases plasma glucose

Question 30

How does glucagon respond in the fasted state?

Answer 30

Low plasma glucose stimulates liver cells to secrete glucagon which stimulates glycogenolysis and gluconeogenesis to increase plasma glucose

Question 31

Which hormone dominates in the fed and fasted state? Note that these hormones are opposing and synergistic.

Answer 31

Fed = Insulin (move glucose out of blood into cells) Fasted = Glucagon (move glucose out of cells into blood)