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+ CAPS 301: Respiratory, Renal, GI, Endocrinology, Reproduction > Glucose Homeostasis > Flashcards

Glucose Homeostasis Flashcards

1
Q

Where is insulin stored?

A

in dense-core granules within pancreatic beta cell

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2
Q

Insulin Synthesis Process

A
  1. proinsulin synthesized on rough ER
  2. proinsulin travels to Golgi, then secretory granules
  3. PC 1/3 cleaves proinsulin at amino acids 32-33
  4. PC2 cleaves proinsulin at amino acids 65-66
  5. carboxypeptidase E (CPE) removes remaining basic residues

result: mature insulin and C-peptide

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3
Q

What are the two prohormone convertase enzymes?

A

PC 1/3

PC 2

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4
Q

Does proinsulin have any bioactivity?

A

has 5-10% of the bioactivity of insulin

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5
Q

What is the function of C-peptide?

A
  • biological action is still not clear – maybe because it is not highly conserved
  • measured as marker for insulin secretion from beta cells in diabetic patients
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6
Q

Regulation of Insulin Secretion

How is insulin stimulated by glucose?

A

in a concentration-dependent manner

  • steep dose response between 5 and 10 mM
  • beta cells are attuned to be sensitive in range where it is needed
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7
Q

Does blood insulin levels increase or decrease after eating a meal?

A

increase

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8
Q

How many phases of insulin release are there?

A

2

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9
Q

Insulin is secreted in what pattern?

A

oscillatory manner

  • initial spike within first 5 minutes
  • beta cells are stressed out or at risk if not oscillating properly
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10
Q

Intracellular Mechanisms Involved in Insulin Secretion by Beta Cells

Steps

A
  1. glucose enters beta cells via GLUT1 glucose transporters
  2. glucose is phosphorylated to glucose-6-phosphate
  3. glucose-6-phosphate is metabolized to produce ATP (glycolysis in mitochondria)
    - rate-limiting step: glucokinase
    - majority of ATP produced by OxPhos in mitochondria
  4. increased ATP:ADP ratio triggers closing of ATP-sensitiive K+ channels
  5. causes membrane depolarization
  6. opens voltage-dependent Ca2+ channels
  7. increased intracellular Ca2+ triggers exocytosis of insulin secretory granules
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11
Q

What ispersistent hyperinsulinemia and hypoglycemia in infants (PHHI) caused by?

A

mutations in ATP-sensitive K+ channel

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12
Q

What does Ca2+ response in a single human beta-cell exposed to high glucose look like on a graph?

A
  • initially basal level of Ca2+
  • huge spike in Ca2+
  • slow oscillating decrease in Ca2+
  • delay from 3 to 15 mM glucose – how long it takes cell to generate ATP to close K+ channel, then Ca2+ channel opens almost instantaneously
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13
Q

What happens in exocytosis of insulin secretory granules?

A

dense-core insulin granules fuse with plasma membrane and release insulin – mediated by SNARE proteins

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14
Q

What are the 2 phases of insulin release (exocytosis)?

A
  • 1st phase: thought to correspond to fusion of ‘docked’ granules
  • 2nd phase: requires mobilization from a reserve pool
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15
Q

Does insulin last a long time in the blood?

A

no – very short half-life, lasting only 4 minutes in bloodstream

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16
Q

Where does insulin clearance occur?

A

at liver and kidney

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17
Q

What happens to insulin released by beta cells?

A

1/2 taken up by liver on the first pass

  • insulin receptors in liver
  • insulin goes through liver, but doesn’t get absorbed by liver
  • too much insulin coming through, would oversaturate
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18
Q

What factors increase stimulation to islet beta cells to secrete insulin? (4)

A
  • increase in GI hormones (by food intake)
  • increase in parasympathetic stimulation (by food intake)
  • increase in blood amino acid concentration
  • increase in blood glucose concentration (major control)
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19
Q

What factors decrease stimulation to islet beta cells to secrete insulin? (1)

A

sympathetic stimulation (and epinephrine)

20
Q

What does insulin secretion do to:

  • blood glucose
  • blood fatty acids
  • blood amino acids
  • protein synthesis
  • fuel storage
A
  • decrease blood glucose
  • decrease blood fatty acids
  • decrease blood amino acids
  • increase protein synthesis
  • increase fuel storage
21
Q

What is insulin secretion tightly regulated by? (3)

A
  • nutrients
  • neural
  • hormonal
22
Q

How do nutrients tightly regulate insulin secretion?

A

glucose (most important), amino acids (ie. arginine) and fatty acids stimulate insulin secretion

23
Q

How does neural control tightly regulate insulin secretion?

A

increased sympathetic activity (­epinephrine) inhibits insulin secretion

increased parasympathetic activity (ie. response to food intake) stimulates insulin secretion

24
Q

How does hormonal control tightly regulate insulin secretion?

A

GI hormones stimulate insulin secretion – ie. glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1)

  • only WITH GLUCOSE can they release insulin secretion
  • release twice as much insulin
  • more insulin to drive glucose

islet hormones also regulate insulin secretion (ie. somatostatin inhibits insulin secretion)

25
Q

What are incretins?

A

group of metabolic hormones that stimulate a decrease in blood glucose level

26
Q

Incretin Concept

A
  • intravenous is more glucose intolerant

- intrajejunal glucose returns quicker to baseline due to greater glucose response (hormonal regulation)

27
Q

What is the insulin receptor composed of?

A

glycoprotein composed of two extracellular 𝛼-subunits and two 𝛽-subunits which span cell’s plasma membrane

28
Q

What are alpha and beta-subunits of insulin receptors joined by?

A

disulfide bonds

29
Q

What are insulin receptors?

A

kinase that phosphorylates scaffold proteins (ie. IRS-1, IRS-2)

30
Q

What are the short-term effects of increased insulin?

A 
glucose transport (immediate)
metabolic enzymes (minutes to hours)
31
Q

What are the longer-term effects of increased insulin?

A

cell differentiation/growth (many hours to days)

32
Q

What is GLUT4 for?

A
  • for tissues that are independent for glucose uptake
  • stimulation of GLUT4 translocation is one of the best studied effects of insulin
  • beta cells and many cells in brain are not glucose-independent
33
Q

Glucagon Synthesis

A
  1. proglucagon synthesized in alpha cells
  2. proglucagon cleaved in…
    - pancreas in alpha cells by PC2
    - OR in intestinal L cells by PC1/3

result: glucagon and other protein fragments

34
Q

What is glucagon secretion regulated by? (3)

A
  • nutrients
  • hormonal
  • neural
35
Q

How do nutrients regulated glucagon secretion?

A
  • low glucose (post-absorptive state) and amino acids (arginine – most important) stimulate glucagon secretion
  • high glucose (absorptive state) and fatty acids inhibits glucagon secretion (in presence of insulin)
36
Q

How does hormonal control regulate glucagon secretion?

A

GI hormones

  • GIP, CCK (stimulatory)
  • GLP-1, somatostatin (inhibitory)
37
Q

How does neural control regulate glucagon secretion?

A

activation of both sympathetic and parasympathetic (vagus) nerves stimulate glucagon secretion

38
Q

In general, how do regulators of insulin secretion compare to regulators of glucagon secretion

A

opposite to one another

39
Q

What is the role of glucagon in glucose metabolism?

A

opposes the effects of insulin on glucose metabolism

40
Q

Where is the major site of action of glucagon?

A

liver

41
Q

What are the important metabolic effects of glucagon in the liver for carbohydrates? (3)

A
  • increase gluconeogenesis (glucose production from amino acids and fatty acids)
  • increase glycogenolysis (glycogen breakdown)
  • decrease glycogen synthesis
42
Q

What are the important metabolic effects of glucagon in the liver for fat? (1)

A

increase ketogenesis (ketone production) – fatty acids turn into ketone bodies

43
Q

What are the important metabolic effects of glucagon in the liver for protein? (2)

A
  • decrease hepatic protein synthesis

- increase protein catabolism in liver

44
Q

When does glucagon increase glycogenolysis?

A

during exercise or fasting

45
Q

Glucagon Receptor Signalling

A
  • binding of glucagon to its receptor causes conformational change in G-protein (hydrolyzes GTP)
  • activation of adenylate cyclase increases cAMP via cAMP-dependent protein kinase A

+ CAPS 301: Respiratory, Renal, GI, Endocrinology, Reproduction (32 decks)

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