Carbohydrate metabolism and control of blood glucose Flashcards
Learning outcomes
- Explain the central role of glucose in carbohydrate metabolism.
- Describe the actions of insulin in terms of glucose storage and utilisation, and its role in moderating blood glucose levels.
- Show how insulin secretion is regulated.
- Show how blood glucose levels can be raised through; dietary sources, gluconeogenesis, glycogenolysis, the activity of glucocorticoids, adrenaline and other hormones.
- Show how hyperglycaemia produces osmotic changes and cellular toxicity.
- Show the causes of ketoacidosis.
- Predict the effects of hypoglycaemia.
- Distinguish between type 1 and type 2 diabetes.
Glucose- recap from Y1
- Glucose can be synthesized from fat (β-oxidation) and amino acids (gluconeogenesis). (Glycolysis> TCA cycle> oxidative (+O2) phosphorylation (CO2+H2O)
- Glucose is a large molecule (180 g/mol), it cannot easily diffuse and is transported across cell membranes by facilitated diffusion
Where are fructose and galactose converted to glucose?
Fructose & galactose are converted to glucose in the liver
• Carbohydrates are absorbed as monosaccharides (glucose, galactose, fructose).
• Glucose is the predominant form (~80% of total carbohydrate absorption).
• Monosaccharides undergo enzymatic interconversion in the liver.
• Hepatocytes contain large amount of glucose 6-phosphatase.
• 95% circulating monosaccharides = glucose
• Glucose is the final common pathway for the transport of carbohydrates into tissue cells.
Glucose transporters
• A family of glucose transporters (GLUT) mediate the concentration driven uptake of glucose into various tissues (peripheral blood glucose is 4-6 mM).
GLUT1- Found in most tissues (brain, rbc’s, cornea)- 1mM, function = basal glucose uptake
GLUT2- Found in liver, kidney, pancreatic B cells, 15-20 mM, function = removes excess glucose from blood (liver) regulates insulin release (pancreas)
GLUT3- Found in CNS and other tissues, 1 mM, function = basal glucose uptake
GLUT4- Found in skeletal muscle and adipose tissue, 5 mM, function = insulin increases GLUT4 at the plasma membrane, also increased by exercise
GI absorption differs and requires active sodium glucose co-transport (SGLT receptors)
Insulin- characteristics
- Insulin is a large polypeptide (M.W. 5808) made of two amino acid chains (A and B) connected by disulphide bridges.
- Produced by pancreatic β-cells in islets of Langerhans.
- Secretion is mainly stimulated by increasedblood glucose.
- Circulating half-life ~6 min.
- Mainly degraded in the liver by insulinase.
Mechanism for insulin secretion
- Glucose binds to GLUT-2 in beta cell, initiates TCA cycle
- ATP released from TCA cycle causes K+ channels to close (influenced by sulfonylureas), leading to membrane depolarisation and Ca2+ channels to open
- Ca2+ channels release calcium used in insulin/proinsulin production under influence from glucagon-like peptide (GLP-1) causes insulin secretion signal to release insulin
- Insulin released into bloodstream, controlled by norepinephrine and somatostatin
In tandem with insulin being produced in insulin producing machinery, preproinsulin (er) > proinsulin (golgi) > insulin
Insulin secretion and factors affecting it
- Rapid rise in plasma insulin levels after a meal from preformed insulin.
- After ~15 min. steady rise in insulin for 2-3 hrs. due to newly synthesized insulin.
- Insulin secretion increases linearly with glucose concentration between (~5.5-17 mM glucose).
- Reduced blood glucose levels rapidly turns off insulin secretion – key feedback mechanism.
Factors affecting insulin:
•Amino acids stimulate insulin secretion which increases tissue protein uptake
•GI hormones e.g. gastrin, CCK, GIP – anticipatory response
•Autonomic nervous system –feeding enhances, stress decreases
• Weak individual effects but together strongly potentiate the effect of glucose on insulin
Insulin and its metabolic effects
Adipose tissue: ↑glucose uptake, ↑lipogenesis
↓ lipolysis
Liver: ↑Glycogen synthesis,↑ lipogenesis
↓ gluconeogenesis
Striated muscle: ↑ Glucose uptake ↑ protein uptake ↑ protein synthesis
How does insulin affect the facilitated diffusion of glucose?
It increases it:
• Under fasting conditions energy is provided by fatty acids
• Muscle GLUT4 does not take up glucose at low levels
• Insulin increases GLUT4 levels and glucose uptake 15 to 20 fold.
• Exercise enhances glucose uptake in muscle in an insulin independent manner due to muscle contraction.
• Post meal:
• Muscles active - glucose used for energy generation
• Muscles inactive - glucose stored as glycogen
What is insulin’s impact on hepatic glucose metabolism?
High insulin
• Increases glucokinase which increases glucose 6-phosphate and glucose uptake.
• Increases glycogen synthetase which increases glycogen storage (up to 5-6 %).
Low insulin
• Increases glycogen phosphorylase which increases glycogen breakdown.
• Increases glucose 6-phosphatase which decreases glucose 6-phosphate and increases glucose release.
What is insulin’s impact on glucose metabolism in the brain?
- Insulin has minimal effect on glucose uptake by the brain.
- Brain cells (GLUT1) readily take up glucose and use it as their primary energy source.
- Normal blood glucose: 3.4-6.2 mmol/L
- Hypoglycaemiatypically causes nervous irritability and can lead to fainting, convulsions, and coma if prolonged.
What factors alter normal blood glucose levels?
Increasing blood glucose concentration:
Glucagon
Adrenaline/ noradrenaline •α-adrenergic activation increases glycogenolysis •β- adrenergic activation increases lipolysis
Cortisol
Growth hormone- • stimulate hepatic gluconeogenesis
• decrease tissue glucose uptake
• increase lipolysis
Stress hormones are protective of hypoglycaemia
Decreasing blood glucose concentration:
Insulin
Glucagon
- Glucagon is a large polypeptide (M.W. 3485) comprising a single chain of 29 amino acids.
- Produced by pancreatic α-cells in islets of Langerhans.
- Secretion is mainly stimulated by decreased blood glucose.
- Counter regulates the metabolic actions of insulin.
It promotes release of glucose from the liver:
• Glucagon receptor signalling increases cyclic AMP and PKA to stimulate glycogen phosphorylase promoting glycogen breakdown (glycogenolysis) and glucose release.
• Potent activation via cascade amplification.
How is glucagon secretion regulated?
• Glucagon secretion is stimulated by:
- Decreased blood glucose.
- Increased circulating amino acids (alanine, arginine) leading to gluconeogenesis.
- Exercise increases glucagon secretion –this mechanism is not understood but could involve effect of interleukin-6 on α-cells.
- Glucagon secretion is inhibited by somatostatin (δ-cells).
- Somatostatin exerts a general suppressive action on metabolism (decreases GI function, decreases insulin) that extends the time that nutrients can be used.
Diabetes mellitus
Type 1 Diabetes (~10 % of cases) • Insulin-dependent •β- cell dysfunction • Viral infection, autoimmune, hereditary • Juvenile onset typically ~14 years
Type 2 Diabetes (~90 % of cases) • Non-insulin dependent • Insulin resistance • Obesity-related • Adult onset typically >30 years
Adverse effects of hyperglycaemia include: lethargy, frequent urination, blurred vision, hunger and thirst, sudden weight loss, slow healing wounds, peripheral neuropathy
