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
I. Glucagon
1. What is glucagon?
Catabolic hormone that is produced by pancreatic α-cells
I. Glucagon
2. What is the role of glucagon?
- 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)
I. Glucagon
3. What is the primary target of glucagon?
The liver is the primary target organ of glucagon, with only small effects on peripheral tissues
II. Synthesis of glucagon
1. What are the steps in Synthesis of glucagon?
- 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
III. Regulation of glucagon secretion
1. What are the activating factors in regulation of glucagon secretion?
- 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
III. Regulation of glucagon secretion
2. What are inhibiting factors of glucagon secretion?
- 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
IV. Glucagon effects
1. What are the features of glucagon receptor?
- 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.
IV. Glucagon effects - Effects of glucagon in the liver
1. What does glucagon do to liver?
Glucagon activates PKC -> glycogen breakdown -> [glucose]IC↑ -> liver secretes
glucose
IV. Glucagon effects - Effects of glucagon in the liver
2. How much can liver store glycogen?
Limited storage of glycogen in the liver = 50g (only for 1-2 hours)
IV. Glucagon effects - Effects of glucagon in the liver
3. What is Gluconeogenesis?
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
IV. Glucagon effects - Effects of glucagon in the liver
4. What are the effects of glucagon in liver?
↑gluconeogenesis, ↑glycogenolysis, ↑lipolysis, ↓glycogenesis, ↓glycolysis
IV. Glucagon effects - Effects of glucagon in other tissues
5. What is the effect of glucagon in adipose tissue?
promotes lipolysis ( -> glycerol)
IV. Glucagon effects - Effects of glucagon in other tissues
6. What is the effect of glucagon in Muscle?
increases proteolysis (-> AAs)
V. Endocrine mechanisms protecting from hypoglycemia. - SYM and/or adrenal medullary activity (adrenalin)
1. How are catecholamines released?
Catecholamines (NE/E -> β-receptor -> [cAMP]↑) are released from SYM nerve endings and the adrenal medulla in response to decreased [glucose], stress and exercise.
V. Endocrine mechanisms protecting from hypoglycemia. - SYM and/or adrenal medullary activity (adrenalin)
2. What happen if there is hypoglycemia?
Decreased glucose levels (hypoglycemia) is primarily sensed by hypothalamic neurons, which initiate a SYM response to release catecholamines.
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?
catecholamines will affect:
- Liver
- Muscle
- Adipose tissue
- Pancreatic α-cells -> secrete glucagon
V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
4. What are the effects of adrenalin on liver?
(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)
V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
4. What are the effects of adrenalin on liver?
(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)
V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
5. What are the effects of adrenalin on adipose tissue?
- Decreased glucose uptake (-> glucagon↑)
- Lipolysis (hormone-sensitive lipase) -> release of FFA and glycerol in the circulation -> liver (gluconeogenesis)
V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
6. What are the effects of adrenalin on skeletal muscle?
- 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
V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
7. Give a general description of Cori cycle
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
V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
8. What are the Effect of adrenalin infusion on the muscle?
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)
V. Endocrine mechanisms protecting from hypoglycemia - Effects of adrenalin
9. What are the Effect of adrenalin infusion on the Liver glycogen?
Liver glycogen breakdown
=> appears in plasma as elevated [glucose]
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol)
10. What is the molecular mechanism of cortisol?
Cortisol will be released in response to a stressful stimuli (CNS -> stress -> ACTH -> cortisol => metabolic effects)
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol)
11A. What are the 3 main consequences of released cortisol?
- Insulin-resistance
-> sensitivity↓, insulin-receptor kinase activity↓, GLUT4-targeting to the PM↓ - Inhibit phosphodiesterase
- ↑cAMP -> PKA -> stimulation of hormone-sensitive lipase) - Permissive effects: β-receptor expression↑, gluconeogenetic enzyme expression in the liver↑, glucagon secretion↑
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
11B. What are the permissive effects of released cortisol?
β-receptor expression↑, gluconeogenetic enzyme expression in the liver↑, glucagon secretion↑