7.5. Glucagon secretion and the regulation of the secretion. Endocrine mechanisms protecting from hypoglycemia. Endocrine and metabolic changes related to starving and physical exercise Flashcards

1
Q

I. Glucagon
1. What is glucagon?

A

Catabolic hormone that is produced by pancreatic α-cells

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2
Q

I. Glucagon
2. What is the role of glucagon?

A
  • Increases blood glucose levels through its effects on liver glucose output
  • Glucagon promotes production of glucose through ↑glycogenolysis + gluconeogenesis and ↓glycolysis + glycogenesis (also ↓lipogenesis in liver)
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3
Q

I. Glucagon
3. What is the primary target of glucagon?

A

The liver is the primary target organ of glucagon, with only small effects on peripheral tissues

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4
Q

II. Synthesis of glucagon
1. What are the steps in Synthesis of glucagon?

A
  • The precursor, pre-proglucagon, harbors the AA sequences for glucagon, GLP-I and GLP-II (glucagon- like peptide)
  • The latter 2 go to the intestine
  • Pre-proglucagon is proteolytically cleaved in the α-cell to glucagon
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5
Q

III. Regulation of glucagon secretion
1. What are the activating factors in regulation of glucagon secretion?

A
  • Hypoglycemia
  • Basic amino acids (Arg, Lys): this effect is ↓ when [glucose] is high
  • SYM NS (+ stress = ↑ glucagon secretion, β-adrenergic effect,  [cAMP]↑)
  • Catecholamines
  • Cortisol (permissive effect)
  • GH
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6
Q

III. Regulation of glucagon secretion
2. What are inhibiting factors of glucagon secretion?

A
  • Glucose (GLUT4 transporter – can inhibit glucagon if insulin is present)
  • Insulin (glucose transport + gene transcription of glucagon↓)
  • Somatostatin (inhibits both glucagon and insulin secretion)
  • FFA
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7
Q

IV. Glucagon effects
1. What are the features of glucagon receptor?

A
  • Glucagon receptor is a Gs-coupled receptor (Gs -> ↑activity of AC -> ↑[cAMP] -> ↑PKA- activity).
  • The receptor is primarily expressed in the liver, but is also very important in the β- cell. In the liver, its effects are pretty much the opposite to that of insulin.
  • Its main goal is to make more transport nutrients available in the blood.
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8
Q

IV. Glucagon effects - Effects of glucagon in the liver
1. What does glucagon do to liver?

A

Glucagon activates PKC -> glycogen breakdown -> [glucose]IC↑ -> liver secretes
glucose

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9
Q

IV. Glucagon effects - Effects of glucagon in the liver
2. How much can liver store glycogen?

A

Limited storage of glycogen in the liver = 50g (only for 1-2 hours)

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10
Q

IV. Glucagon effects - Effects of glucagon in the liver
3. What is Gluconeogenesis?

A

From pyruvate (lactate) + glycerol + AAs, we will have the fuel for glucose production and delivery to circulation for a prolonged time – when we do not have excess to glucose

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11
Q

IV. Glucagon effects - Effects of glucagon in the liver
4. What are the effects of glucagon in liver?

A

↑gluconeogenesis, ↑glycogenolysis, ↑lipolysis, ↓glycogenesis, ↓glycolysis

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12
Q

IV. Glucagon effects - Effects of glucagon in other tissues
5. What is the effect of glucagon in adipose tissue?

A

promotes lipolysis ( -> glycerol)

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13
Q

IV. Glucagon effects - Effects of glucagon in other tissues
6. What is the effect of glucagon in Muscle?

A

increases proteolysis (-> AAs)

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14
Q

V. Endocrine mechanisms protecting from hypoglycemia. - SYM and/or adrenal medullary activity (adrenalin)
1. How are catecholamines released?

A

Catecholamines (NE/E -> β-receptor -> [cAMP]↑) are released from SYM nerve endings and the adrenal medulla in response to decreased [glucose], stress and exercise.

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15
Q

V. Endocrine mechanisms protecting from hypoglycemia. - SYM and/or adrenal medullary activity (adrenalin)
2. What happen if there is hypoglycemia?

A

Decreased glucose levels (hypoglycemia) is primarily sensed by hypothalamic neurons, which initiate a SYM response to release catecholamines.

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16
Q

V. Endocrine mechanisms protecting from hypoglycemia. - SYM and/or adrenal medullary activity (adrenalin)
3. What happen if there is increased SYM and/or adrenal medullary activity?

A

catecholamines will affect:
- Liver
- Muscle
- Adipose tissue
- Pancreatic α-cells -> secrete glucagon

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17
Q

V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
4. What are the effects of adrenalin on liver?

A

(same effect as glucagon):
- Gluconeogenesis: from AAs and glycerol
- Proteolysis
- Ketogenesis: from acetyl-CoA, which is
provided by FFA + AAs
- Glycogenolysis (for 1-2 hours only)

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18
Q

V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
4. What are the effects of adrenalin on liver?

A

(same effect as glucagon):
- Gluconeogenesis: from AAs and glycerol
- Proteolysis
- Ketogenesis: from acetyl-CoA, which is
provided by FFA + AAs
- Glycogenolysis (for 1-2 hours only)

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19
Q

V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
5. What are the effects of adrenalin on adipose tissue?

A
  • Decreased glucose uptake (-> glucagon↑)
  • Lipolysis (hormone-sensitive lipase) -> release of FFA and glycerol in the circulation -> liver (gluconeogenesis)
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20
Q

V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
6. What are the effects of adrenalin on skeletal muscle?

A
  • Glycogenolysis (but glucose cannot appear
    directly from glycogen to the circulation)
  • Decreased glucose uptake (-> glucagon↑)
  • No gluconeogenesis (no tools for it)
  • Glycolysis -> lactate ( -> Cori cycle)
    +) source of lactate is glycogen, because when there is SYM activity, the low level/absence of insulin does not allow significant entry of glucose into the cell
    +) lactate will leave the muscle cell
  • Krebs cycle: from acetyl-CoA received from ketone bodies + FFA + glycolysis
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21
Q

V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
7. Give a general description of Cori cycle

A

Glycolysis -> lactate ( -> Cori cycle)
+) source of lactate is glycogen, because when there is SYM activity, the low level/absence of insulin does not allow significant entry of glucose into the cell
+) lactate will leave the muscle cell

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22
Q

V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
8. What are the Effect of adrenalin infusion on the muscle?

A

Muscle glycogen breakdown (cannot produce glucose, but produces lactate)
-> [lactate] increases rapidly
-> appears in the blood
-> enters the circulation via the portal vein in the liver
-> taken up in the liver
-> converted to liver glycogen (can now be converted to glucose when needed)

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23
Q

V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
9. What are the Effect of adrenalin infusion on the Liver glycogen?

A

Liver glycogen breakdown
=> appears in plasma as elevated [glucose]

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24
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol)
10. What is the molecular mechanism of cortisol?

A

Cortisol will be released in response to a stressful stimuli (CNS -> stress -> ACTH -> cortisol => metabolic effects)

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25
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol)
11A. What are the 3 main consequences of released cortisol?

A
  1. Insulin-resistance
    -> sensitivity↓, insulin-receptor kinase activity↓, GLUT4-targeting to the PM↓
  2. Inhibit phosphodiesterase
    - ↑cAMP -> PKA -> stimulation of hormone-sensitive lipase)
  3. Permissive effects: β-receptor expression↑, gluconeogenetic enzyme expression in the liver↑, glucagon secretion↑
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26
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
11B. What are the permissive effects of released cortisol?

A

β-receptor expression↑, gluconeogenetic enzyme expression in the liver↑, glucagon secretion↑

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27
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
12. Make a schematic diagram of Glucocorticoids (cortisol) effects?

A
28
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
13. What are the effects of cortisol on Muscle (+bone, lymphoid tissue, CT, skin, etc.)?

A
  • Decreased (GLUT4-mediated) glucose uptake
  • Increased proteolysis
29
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
14. What are the effects of cortisol on (Subcutaneous) adipose tissue?

A
  • Decreased (GLUT4-mediated) glucose uptake
  • Increased lipolysis: (hormone-sensitive lipase) liberate glycerol + FFA -> substrate for gluconeogenesis in the liver
30
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
15. What are the effects of cortisol on Liver?

A
  • Gluconeogenesis: from AAs (proteolysis)
  • Ketogenesis: from FFA and glycerol
  • Glycogenesis(!!!): Glucocorticoid-effect -> ↑ the glycogen-content of liver
    +) Glycogen in the liver – the most immediate source of glucose production
    +) Glucocorticoids are important, because they maintain this readily available source of glucose
31
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
16. What are the causes for GH secretion?

A

Hypoglycemia, AAs, fasting, physical exercise, stress, sleep

32
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
17A. What are the direct effects of of GH secretion?

A
  1. [glucose]plasma↑:
    - Insulin sensitivity↓
    - Pancreas α-cell: glucagon secretion↑
  2. Adipose tissue:
    - Glucose uptake↓
    - lipolysis↑
    -> FFA
  3. Liver:
    - Protein synthesis↑
    - IGF-1 secretion
33
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
17B. What are the direct effects of of GH secretion on [glucose] plasma?

A

[glucose]plasma↑:
- Insulin sensitivity↓
- Pancreas α-cell: glucagon secretion↑

34
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
17C. What are the direct effects of of GH secretion on Adipose tissue?

A
  • Glucose uptake↓
  • lipolysis↑
    => FFA
35
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
17D. What are the direct effects of of GH secretion on liver?

A
  • Protein synthesis↑
  • IGF-1 secretion
36
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
18. What are the indirect effects of of GH secretion?

A

Indirect effects: (GH -> IGF-1 -> indirect effects)
Occurs in skeletal muscles, bones, heart, lungs, cartilage.
- AA uptake↑
- Protein synthesis↑ (insulin-like effect)

37
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
19. How are Effects of GH on the intermediary metabolism influenced?

A

Effects of GH on the intermediary metabolism (whether direct or indirect effects dominate) are significantly influenced by the simultaneous presence of insulin or cortisol.

38
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
20. Make a schematic diagram of effects of GH

A
39
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
21. What is molecular mechanism of GH in case Direct effect (when [GH] is abnormally high): (hypoglycemia)?

A
  • GH secretion, glucagon secretion, SYM (β-AR) activation and cortisol secretion will be stimulated by hypoglycemia – BUT not insulin
  • In the absence of insulin and presence of all other hormones (especially cortisol), the direct effect of GH will be dominant (-> ↑[glucose])
40
Q

V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
21. What is molecular mechanism of GH in case Indirect effect: (hyperglycemia)?

A
  • When we eat proteins + glucose + fat, insulin is there, because it gets activated by hyperglycemia and AAs.
  • GH will also appear – together with insulin, the IGF-mediated indirect effect will prevail (=> ↑AA uptake)
41
Q

V. Endocrine mechanisms protecting from hypoglycemia
22. What are hormonal responses which protect against hypoglycemia?

A
42
Q

V. Endocrine mechanisms protecting from hypoglycemia
23. What are the hormones increasing plasma glucose concentration? What are their effects?

A
43
Q

VI. Thyroid hormones (T3/T4)
1. What is the role of Thyroid hormones (T3/T4)?

A

Acts on the intermediary metabolism, but is not influenced by [glucose]plasma!

44
Q

VI. Thyroid hormones (T3/T4)
2. What are the effects of thyroid hormones (T3/T4)?

A
  • Lipolysis↑
  • Gluconeogenesis↑
  • Glucose absorption (from intestine) ↑
  • Protein synthesis↑ (if more than normal TH present = proteolysis)
  • BMR↑
45
Q

VI. Thyroid hormones (T3/T4)
3. What are the permissive effects of thyroid hormones (T3/T4)?

A

Permissive effects: (hyperthyroidism)
- Expression of β-receptor/catecholamines↑ -> glucagon↑ -> ↑glucose
- Insulin sensitivity↓

46
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Hormonal changes related with feeding
1. What are hormonal changes when we have carbohydrate-rich meal?

A

Carbohydrate-rich meal: insulin/glucagon = 30-40
- Glucose level↑ -> insulin↑ -> inhibit glucagon secretion
- After the meal, the hormonal alterations will normalize
- Insulin helps glucose to get into the α-cell, the α-cell glucagon secretion will be inhibited when the glucose will
be taken up
- The rapid insulin secretion is also dependent on GLP + GIP: they reduce the fluctuation of [glucose]

47
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Hormonal changes related with feeding
2. What are hormonal changes when we have Protein-rich meal?

A
  • [protein]↑ in blood, but [glucose]↓ (hypoglycemia)
    => Prevented by glucagon: secreted simultaneously as insulin activates the glucose discharge/secretion
    => [glucose]plasma ≈ unchanged, because insulin + glucagon are secreted in response to AAs
48
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Hormonal changes related with feeding
3A. Why do we need to have changes of intermediary metabolism during fasting?

A
49
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Hormonal changes related with feeding
3B. What are regulators in changes of the intermediary metabolism during fasting?

A
50
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Hormonal changes related with feeding
3C. What are the major effectors in changes of the intermediary metabolism during fasting?

A
  1. Liver
  2. Adipose tissue
  3. Skeletal muscle
  4. Brain
    (+ other tissues)
51
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
4. What is the main aim of fasting?

A
  • In fasting period, the main aim is to keep the blood glucose level in a normal range for the organs that can only consume glucose (RBC, cornea, lens, neurons [at lesast until they adapt to use ketones]).
  • This means we have to find other possible sources of energy for some more flexible organs.
52
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
5. What are the 3 stages of fasting?

A
  1. Early fasting (0-24 hours)
  2. Short-term fastin (24-72 hours)
  3. Long-term fasting (>72 hours)
53
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
6A. How does early fasting affect liver?

A
  • (liver) glycogen -> glycogenolysis -> glucose (75%) RBC, brain
  • Gluconeogensis -> glucose (25%) from lactate produced in the muscle (glycolysis) and glycerol produced in the adipose tissue (lipolysis)
54
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
6B. How does early fasting affect Muscle?

A

glycolysis
-> lactate
-> liver (gluconeogensis)

55
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
6C. How does early fasting affect Adipose tissue?

A

Lipolysis:
- Glycerol -> liver (gluconeogenesis)
- FFA -> skeletal cardiac muscle (glucose consumption↓)

56
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
6D. Make a schematic diagram to demonstrate the effects of early fasting on tissues?

A
57
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Short-term fasting (24-72 hours)
7A. What are the effects of short-term fasting on liver?

A
  • No more (liver) glycogen
  • Gluconeogenesis -> glucose (100%): from lactate produced in the muscle (glycolysis), glycerol prodced in the adipose tissue (lipolysis) and AAs prodced from the muscles (proteolysis)
  • Ketogenesis: formation of ketone bodies from FFA released from lipolysis in the
    adipose tissue
58
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Short-term fasting (24-72 hours)
7B. What are the effects of short-term fasting on muscle?

A
  • Glycolysis -> lactate -> liver (gluconeogenesis)
  • Proteolysis↑↑ -> AAs -> liver (gluconeogenesis)
59
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Short-term fasting (24-72 hours)
7C. What are the effects of short-term fasting on Adipose tissue?

A

Lipolysis:
- Glycerol -> liver (gluconeogenesis)
- FFA -> skeletal, cardiac muscle (glucose consumption↓↓)

60
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Short-term fasting (24-72 hours)
7D. Make a schematic diagram to demonstrate the effects of short-term fasting on tissues?

A
61
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Long-term fasting (>72 hours)
8A. What is the general effect of .Long-term fasting (>72 hours) on tissues?

A

Inactivity, BMR↓

62
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Long-term fasting (>72 hours)
8B. What are the effects of Long-term fasting (>72 hours) on Liver?

A
  • No more (liver glycogen)
  • Gluconeogenesisglucose (100%): from glycerol produced in the adipose tissue
    (lipolysis) and AAs produced from the muscles (proteolysis ↓a little bit) -> (50% of
    brain energy soruce)
  • Ketogenesis: formation of ketone bodies (50% of brain energy source) from FFA
    released from lipolysis in the adipose tissue
63
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Long-term fasting (>72 hours)
8C. What are the effects of Long-term fasting (>72 hours) on Muscle?

A

Proteolysis
-> AAs
-> liver (gluconeogenesis)

64
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Long-term fasting (>72 hours)
8D. What are the effects of Long-term fasting (>72 hours) on Adipose tissue?

A

Lipolysis:
- Glycerol -> liver (gluconeogenesis)
- FFA -> skeletal, cardiac muscle (very low glucose consumption)

65
Q

VII. Endocrine and metabolic changes related to starving and physical exercise - Long-term fasting (>72 hours)
8E. Make a schematic diagram to demonstrate the effects of long-term fasting on tissues?

A
66
Q

VII. Endocrine and metabolic changes related to starving and physical exercise
9. Explain the Stress-induced catabolic response

A
  • The changes partially remind to those observed during fasting, but the metabolic changes are primary!
  • In response to stress (hypoxia, thermal stress, fighting with someone) -> SYM activation (↑catecholamines) and release of glucocorticoids (adrenal cortex) -> will have many effects (see picture)
67
Q

VII. Endocrine and metabolic changes related to starving and physical exercise
10. Explain the metabolic response of physical exercise

A
  • The metabolic response of physical exercise is pretty much the same as fasting, with the addition of GLUT-4 transposition in the PM of active muscle, even though the insulin level is low.
  • This allows the muscles to receive a sufficient amount of glucose for anaerobic energy production.
  • In inactive or moderately active muscles, the glucose uptake and consumption is decreased. FFA is provided as an alternative energy source.