Intermediary Metabolism

Question 1

Glucose homeostasis

Answer 1

Maintenance of plasma glucose concentrations within a relatively narrow range (60-150 mg/ml) is critical to survival; glucose is the predominant fuel utilized by the CNS. The hormones involved include:
• Insulin
• Glucagon
• Catecholamines
• Glucocorticoids
• Growth Hormone
• Hormones of the Gut

Question 2

Insulin (Chemistry and synthesis)

Answer 2

Insulin consists of 2 peptide chains held together by S-S bridges. The whole molecule is needed for activity. There are some species differences but most insulins have comparable activities. Synthesis occurs in β−cells of the Islets of Langerhans. The initial product of mRNA translation is pre-proinsulin which is enzymically cleaved to proinsulin.
Cleavage of proinsulin yields insulin and C-peptide.

Question 3

Control of Insulin Secretion

Stimulus

Answer 3

• Primary stimulus: high blood glucose level (this also stimulates insulin synthesis).
• Other stimulants include: certain amino acids (especially arginine), ketones, glucagon, gut peptide hormones.

Question 4

Control of Insulin Secretion

Inhibitors

Answer 4

• Catecholamines
• sympathetic nervous system
• somatostatin

Question 5

Glucose stimulation of Insulin

Answer 5

• Secretion involves a glucose sensor (glucokinase), glucose metabolism and coupling of glucose metabolism via the ATP/ADP ratio leading to ionic events in the β−cell membrane governing insulin secretion.
• The key factor for insulin secretion is the
calcium ion concentration.

Question 6

Inactivation of Insulin

Answer 6

• Half-life ~ 10 min
• degraded primarily by hepatic proteolytic enzymes.
• The half-life of proinsulin is 20 min; degraded by kidney enzymes.

Question 7

Mechanism of Action of Insulin

Answer 7

• Insulin binds to a cell surface receptor (a transmembrane protein).
• In the presence of its ligand the receptor can function as a tyrosine kinase.
• This leads to autophosphorylation of the receptor and phosphorylation of key docking proteins (IRS and Shc).
• This results in the activation of a series of parallel downstream events that involve a cascade of covalent phosphorylation reactions and protein-protein interactions, which ultimately results in
modulation of specific cell functions including glucose transport, glycogen and protein synthesis
and mitogenesis.

Question 8

Physiological Actions of Insulin on Muscle

Answer 8

1. Stimulation of glucose transport into the cell.
2. Enhancement of glycogen synthesis.
3. Stimulation of amino acid uptake.
4. Stimulation of protein synthesis.
5. Inhibition of proteolysis.

NB: Exercise also stimulates glucose transport into muscle cells.

Question 9

Physiological Actions of Insulin on Adipose Tissue

Answer 9

1. Stimulation of glucose uptake into the cells.
2. Promotion of fat synthesis.
3. Activation of lipoprotein lipase.
4. Inhibition of hormone-sensitive lipase.
5. Enhancement of glycogen synthesis.
6. Enhancement of amino acid uptake and protein synthesis

Question 10

Physiological Actions of Insulin on Liver

Answer 10

1. Stimulation of glucokinase and glycogen synthetase activity.
2. Stimulation of activities of key rate limiting glycolytic enzymes (glucokinase, phosphofructokinase, pyruvate kinase and pyruvate dehydrogenase).
3. Inhibition of activities of the key rate limiting gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-diphosphate phosphatase, phosphoenolypyruvate carboxykinase and pyruvate carboxylase).
4. Stimulation of fatty acid synthesis and increase in activities of key lipogenic enzyme.

Question 11

Glucagon

Chemistry and synthesis

Answer 11

• 29 amino acid polypeptide chain

* Synthesized in the a-cells of Islets of Langerhans. • Initial product is pre-proglucagon.

Question 12

Secretion of Glucagon

Answer 12

• Primary stimulus: low blood glucose level.

* Other stimulators include amino acids, gut hormones, catecholamines

Question 13

Distribution and degradation of Glucagon

Answer 13

• Degraded very rapidly in liver and thus it is questionable whether any glucagon normally reaches peripheral circulation.
• Proglucagon, however, is degraded in kidney and its biological activity is minimal.

Question 14

Glucagon receptors

Answer 14

Cell surface receptors have been identified in liver, fat, myocardial cells and pancreatic islet β−cells.

Question 15

Physiological action of glucagon

Answer 15

1. Stimulates hepatic glycogenolysis (it is the most powerful hyperglycogenolytic agent known).
2. Inhibits glycogen synthetase.
3. Stimulates gluconeogenesis.
4. Stimulates hepatic lipolysis.
5. Inhibits fatty acid synthesis.
6. Increases hepatic ketogenesis.

All these effects are mediated via cAMP.

Question 16

Catecholamines

Synthesis

Answer 16

Synthesized from tyrosine in:

1. adrenal medulla (secreted product is primarily epinephrine (E));
2. postganglionic sympathetic nerve endings (norepinephrine (NE)).

Question 17

Regulation of Catecholamine synthesis

Answer 17

1) tonic inhibition by NE in cytosol. The inhibition is removed when nerve stimulation releases this NE.
2) chronic nerve stimulation induces the enzymes tyrosine hydroxylase, and dopamine-β-hydroxylase (involved in catecholamine synthesis)
3) ACTH and cortisol may also enhance synthesis.

Question 18

Release of catecholamines

Answer 18

Major stimulus is acetylcholine, and stimulation releases catecholamines from both the adrenal gland and sympathetic nerve endings.

Question 19

Degradation of catecholamines

Answer 19

• Very rapidly degraded (half-life in plasma <1 min) by enzymes in plasma, liver and kidneys.
• Also they can be taken up and recycled at nerve
terminals and excreted unchanged by the kidneys

Question 20

Receptors of catecholamines

Answer 20

• On cell surface of target cells.
• Two major categories, α and β plus many subtypes. β-receptors, which result in the synthesis of cAMP, are implicated in the metabolic effects.
• Recent evidence suggests that some a-receptors that release Ca++ may also be involved.
• Both E and NE bind to all receptors, although with different affinities.

Question 21

Physiological actions of catecholamines

skeletal muscle

Answer 21

1. Stimulation of glycogenolysis and lactate production.

2. Inhibition of glycogen synthesis and glucose uptake.

Question 22

Physiological actions of catecholamines

adipose tissue

Answer 22

Stimulation of lipolysis via the hormone-sensitive lipase.

Question 23

Physiological actions of catecholamines

liver

Answer 23

Identical with those of glucagon but much less potent mole for mole

1. Stimulation of glycogenolysis.
2. Inhibition of glucose oxidation.
3. Inhibition of glycogen synthesis.
4. Stimulation of gluconeogenesis.
5. Stimulation of lipolysis.

Question 24

Glucocorticoids, Growth Hormone and Somatostatin

Answer 24

These hormones are also involved in the maintenance of blood glucose levels but probably
to a much lesser extent than insulin, glucagon and catecholamines in the unstressed healthy
individual.

Question 25

Glucocorticoids

Answer 25

Glucocorticoids are among the “counter-regulatory” hormones that protect the body from
insulin-induced hypoglycemia. They do this by:
1. stimulating hepatic gluconeogenesis;
2. permissively by enhancing the stimulatory effect of glucagon and catecholamines on
gluconeogenesis and glycogenolysis;
3. inhibiting peripheral glucose utilization;
4. promoting liver glycogen synthesis thus storing substrate for acute responses to
glycogenolytic agents.
5. Stimulating lipolysis

Question 26

Growth Hormone

Answer 26

1. Stimulates lipolysis.
2. Inhibits tyrosine-amino transferase.
3. Stimulates acutely glucose uptake in muscle and fat.

Question 27

Somatostatin (SRIF)

Answer 27

• SRIF is a potent inhibitor of many polypeptide hormones including insulin, glucagon, growth
hormones.
• Very effective pharmacological agent; its physiological significance is unclear
(probably dubious)