2407: Exam Report

Outline the control of blood glucose

60% of candidates passed this question.

This question required candidates to discuss the role of the pancreas and liver in the homeostasis of blood glucose.

This included how the pancreas senses high or low glucose levels, the mechanism of secretion of insulin and glucagon and subsequent effects on the liver.

The response in early fasting when glucagon stores are depleted was expected as well as the role of other organs in this setting such as muscle glycogen and hypothalamus driven satiety.

A brief mention other hormonal responses in the setting of hypoglycaemia was also expected (including ACTH, cortisol, adrenaline, growth hormone and thyroid hormones).

U1iii / 24A07: Outline the control of blood glucose

  • Normal blood glucose levels-4.0 – 7.8 mmol/L
  • It is maintained in the normal range by a feedback system involving the pancreatic islets, liver, muscle and fat.

Mediated by

  • Directly by release of hormones – Insulin, glucagon
  • Indirectly by Neural influence- resulting in hormonal regulation
  • Hypothamlamus driven satiety- regulates food intake

Part A

When blood glucose levels are high (threshold ~5–6 mmol/L)

Processes activated

  • Glycogenesis
  • Glycolysis

Processes inhibited

  • Gluconeogenesis
  • Glycogenolysis

Insulin is

  • A polypeptide stored in beta islets of pancreas
  • The main regulatory hormone responsible for fluctuations in blood glucose.

Stimulatory factors

  • High/increased blood glucose level
  • Increased amino acid level
  • Increased fatty acid & ketoacid level
  • Glucagon
  • Glucagon-like peptide-1 (GLP-1)
  • Cortisol
  • Vagal stimulation – acetylcholine
  • Potassium
  • Sulphonylurea drugs

Inhibitory factors

  • Decrease blood sugar level
  • Fasting
  • Exercise
  • Somatostatin
  • α-adrenergic agonists

Stimuli for insulin release

1. Substrates

  1. Glucose is the principal stimulus: Glucose metabolism in the β cells increases intracellular ATP> blocks the ATP-sensitive K+ channels > resulting in depolarization of the cell membrane and Ca2+ influx> exocytosis of insulin
  2. Amino acids like arginine, lysine, lucine, phenylalanine

2. Hormonal

  • Stimulants- glucagon
  • Ppost prandial- glucagon-like peptide-1 (GLP-1, secreted by enteroendocrine L cells) gastrin, secretin and cholecystokinin 

  • Inhibitors- somatostatin, leptin

3. Neural

Sympathetic- inhibits

    • Alpha 2 receptors

Parasympathetic- stimulates

    • Ach

Secretion of insulin occurs in two phases:

    • An initial rapid phase due to release of stored insulin and a slow,
    • Sustained phase due to secretion of both stored and newly synthesized insulin

Its effect is to decrease blood glucose by

    • Increased glucose uptake into cells via facilitated diffusion by GLUT -4 recruitment and enhanced glycogen synthesis,
    • Decreased gluconeogenesis-liver and glycogenolysis-liver, muscle.

Mechanism

  • Mediated by insulin receptors, located in the cell membrane> two α and two β chains held together by disulphide bridges. α chain -extracellular insulin-binding site and β chain-intracellular -tyrosine kinase activity> undergoes autophosphorylation of tyrosine residues of insulin receptor substrates (IRSs) > activates downstream pathways- PI3 kinase, MAPK>activate enzymes that catalyze glycolysis, glycogen transport
    • Increases permeability of the membrane to glucose occurs in muscle and adipose cells, but not in the brain, red blood cells and liver via recruitment of glucose transporter protein (GLUT-4)
    • In liver, insulin stimulates gene expression of enzymes involved in glucose utilization (eg., glucokinase) and inhibits that of involved in glucose production (eg., Glu-6-phosphatase)

Part B

When blood glucose levels are low (less than 3 mmol/L)

Processes activated

  • Gycogenolysis- mainly liver, muscle
  • Gluconeogenesis- mainly liver, renals

Processes inhibited

  • Glycognesis
  • Glycolysis

Glucose enhancing hormones are released:

  •  Glucagon
  • Catecholamines
  • Glucocorticoids
  • GH
  • Thyroid hormones

Glucagon

  • Poypeptide released from alpha islets of pancreas
  • Enhanced glycogenolysis and gluconeogenesis.

Stimulatory factors

  • Fasting
  • Low blood sugar levels
  • Increased plasma amino acids (especially arginine and alanine) levels
  • Cholecystokinin (CCK)
  • β-adrenergic agonists
  • Acetylcholine

Inhibitory factors

  • Insulin
  • Somatostatin
  • Increased fatty acid and ketoacid plasma levels

Glucocorticoids

  • Reduce glucose uptake and utilization by the cells and increase blood glucose concentration.

GH

  • An anti-insulin effect

Catecholamines

  • Enhanced glycogenolysis and reduced glucose uptake.

Oestrogen / Progesterone

  • Mild insulin resistance

Thyroxine

  • Released from thyroid
  • Increased GI absorption of glucose

Author: Nazma Navilehal Rajasab