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↑
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
12. Make a schematic diagram of Glucocorticoids (cortisol) effects?
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.)?
- Decreased (GLUT4-mediated) glucose uptake
- Increased proteolysis
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
14. What are the effects of cortisol on (Subcutaneous) adipose tissue?
- Decreased (GLUT4-mediated) glucose uptake
- Increased lipolysis: (hormone-sensitive lipase) liberate glycerol + FFA -> substrate for gluconeogenesis in the liver
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of cortisol
15. What are the effects of cortisol on Liver?
- 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
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
16. What are the causes for GH secretion?
Hypoglycemia, AAs, fasting, physical exercise, stress, sleep
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
17A. What are the direct effects of of GH secretion?
- [glucose]plasma↑:
- Insulin sensitivity↓
- Pancreas α-cell: glucagon secretion↑ - Adipose tissue:
- Glucose uptake↓
- lipolysis↑
-> FFA - Liver:
- Protein synthesis↑
- IGF-1 secretion
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?
[glucose]plasma↑:
- Insulin sensitivity↓
- Pancreas α-cell: glucagon secretion↑
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?
- Glucose uptake↓
- lipolysis↑
=> FFA
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?
- Protein synthesis↑
- IGF-1 secretion
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
18. What are the indirect effects of of GH secretion?
Indirect effects: (GH -> IGF-1 -> indirect effects)
Occurs in skeletal muscles, bones, heart, lungs, cartilage.
- AA uptake↑
- Protein synthesis↑ (insulin-like effect)
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
19. How are Effects of GH on the intermediary metabolism influenced?
Effects of GH on the intermediary metabolism (whether direct or indirect effects dominate) are significantly influenced by the simultaneous presence of insulin or cortisol.
V. Endocrine mechanisms protecting from hypoglycemia - Glucocorticoids (cortisol) - Effects of Growth hormone (GH)
20. Make a schematic diagram of effects of GH
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)?
- 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])
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)?
- 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)
V. Endocrine mechanisms protecting from hypoglycemia
22. What are hormonal responses which protect against hypoglycemia?
V. Endocrine mechanisms protecting from hypoglycemia
23. What are the hormones increasing plasma glucose concentration? What are their effects?
VI. Thyroid hormones (T3/T4)
1. What is the role of Thyroid hormones (T3/T4)?
Acts on the intermediary metabolism, but is not influenced by [glucose]plasma!
VI. Thyroid hormones (T3/T4)
2. What are the effects of thyroid hormones (T3/T4)?
- Lipolysis↑
- Gluconeogenesis↑
- Glucose absorption (from intestine) ↑
- Protein synthesis↑ (if more than normal TH present = proteolysis)
- BMR↑
VI. Thyroid hormones (T3/T4)
3. What are the permissive effects of thyroid hormones (T3/T4)?
Permissive effects: (hyperthyroidism)
- Expression of β-receptor/catecholamines↑ -> glucagon↑ -> ↑glucose
- Insulin sensitivity↓
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?
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]
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?
- [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
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?
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?
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?
- Liver
- Adipose tissue
- Skeletal muscle
- Brain
(+ other tissues)
VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
4. What is the main aim of fasting?
- 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.
VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
5. What are the 3 stages of fasting?
- Early fasting (0-24 hours)
- Short-term fastin (24-72 hours)
- Long-term fasting (>72 hours)
VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
6A. How does early fasting affect liver?
- (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)
VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
6B. How does early fasting affect Muscle?
glycolysis
-> lactate
-> liver (gluconeogensis)
VII. Endocrine and metabolic changes related to starving and physical exercise - Stages of fasting
6C. How does early fasting affect Adipose tissue?
Lipolysis:
- Glycerol -> liver (gluconeogenesis)
- FFA -> skeletal cardiac muscle (glucose consumption↓)
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?
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?
- 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
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?
- Glycolysis -> lactate -> liver (gluconeogenesis)
- Proteolysis↑↑ -> AAs -> liver (gluconeogenesis)
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?
Lipolysis:
- Glycerol -> liver (gluconeogenesis)
- FFA -> skeletal, cardiac muscle (glucose consumption↓↓)
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?
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?
Inactivity, BMR↓
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?
- No more (liver glycogen)
- Gluconeogenesisglucose (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
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?
Proteolysis
-> AAs
-> liver (gluconeogenesis)
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?
Lipolysis:
- Glycerol -> liver (gluconeogenesis)
- FFA -> skeletal, cardiac muscle (very low glucose consumption)
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?
VII. Endocrine and metabolic changes related to starving and physical exercise
9. Explain the Stress-induced catabolic response
- 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)
VII. Endocrine and metabolic changes related to starving and physical exercise
10. Explain the metabolic response of physical exercise
- 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.
