Diabetes Mellitus
!
Hyperglycaemia, Insulin and Insulin Action!
Diabetes Mellitus: syndrome characterised by chronic hyperglycaemia, and relative insulin deficiency, resistance or
both. Affects >120 million people worldwide (and expected to affect 220 million by 2020). Usually irreversible!
Insulin Structure and Secretion!
Insulin = key hormone involved in storage and controlled release within the body of chemical energy available from
food. !
Insulin coded for on chromosome 11; synthesised in beta-cells of pancreas!
After secretion, insulin enters the portal circulation and is carried to the liver. About 50% of secreted insulin is extracted
and degraded in the liver; the residue is broken down by the kidneys. !
C-peptide is only partially extracted by the liver, but is mainly degraded by the kidneys.!
Outline of glucose metabolism!
Blood glucose levels are closely regulated in health; rarely stray outside the range of 3.5-8.0mmol/L (63-144mg/dL),
despite varing demands of food, fasting and exercise. !
Principal organ of glucose homeostasis = liver; absorbs and stores glucose (as glycogen) in the post-absorptive state, and
releases it into the circulation between meals to match the rate of glucose utilisation by peripheral tissues.!
Liver also combines 3C-molecules from the breakdown of fat (glycerol), muscle glycogen (lactate) and protein (alanine)
into 6C glucose (by gluconeogenesis)!
Glucose Production: !
200g glucose produced and utilised each day. >90% is derived from liver glycogen and hepatic gluconeogenesis;
remainder from renal gluconeogenesis!
Glucose Utilisation: !
Brain = major consumer of glucose; !
Requirement=1mg/kg bodyweight per minute, or 100g daily in 70kg man!
Glucose uptake by brain = obligatory; not dependent on insulin. Glucose is oxidised to CO2 and water.!
Other tissues e.g. muscle and fat = facultative glucose consumers.!
The effect of insulin peaks associated with meals is to lower threshold for glucose entry into cells.!
Glucose taken up by muscle is stored as glycogen/ is broken down to lactate, which re-enters the circulation and
becomes a major substrate for hepatic gluconeogenesis. !
Glucose: used by fat tissue as a source of energy; substrate for TG synthesis. Lipolysis releases fatty acids from TG,
together with glycerol.!
Hormonal Regulation!
Insulin = major regulator of intermediary metabolism, although its actions are modified by other hormones.!
- Actions in fasting and post-prandial states differ!
- In fasting state: main action - regulate glucose release by the liver!
- Post-prandial state: facilitates glucose uptake by fat and muscle!
The effect of counter-regulatory hormones (glucagon, adrenaline, cortisol and growth hormone) - cause greater
production of glucose from the liver and less utilisation of glucose in fat and muscle for a given level of insulin.!
Glucose Transport!
Cell membranes are not inherently permeable to glucose. A family of specialised glucose-transporter (GLUT) proteins
carry glucose through the membrane into cells.!
- GLUT-1: enables basal non-insulin stimulated glucose uptake into many cells!
- GLUT-2: transports glucose into the beta-cell = pre-requisite for glucose sensing!
- GLUT-3: enables non-insulin-mediated glucose uptake into brain neurones!
- GLUT-4: enables much of peripheral action of insulin. It is the channel through which glucose is taken up into
muscle/adipose tissue cells following stimulation of insulin receptor!
Insulin Receptor !
Insulin receptor = glycoprotein; 400kDa; coded for on short arm of chromosome 19; dimer of 2 alpha-subunits (includes
binding site for insulin) and 2 beta-subunits (traverse cell membrane)!
Insulin binds alpha-subunit; induces a conformational change in beta-subunits; results in activation of tyrosine kinase
and initiation of cascade response, including movement of GLUT4 to the cell surface and increased transport of glucose
into the cell. The insulin-receptor complex is internalised by the cell, insulin is degraded and the receptor is recycled to
!
the cell surface.
DIABETES - SIOBHAN PAGE 1
!
Hyperglycaemia, Insulin and Insulin Action!
Diabetes Mellitus: syndrome characterised by chronic hyperglycaemia, and relative insulin deficiency, resistance or
both. Affects >120 million people worldwide (and expected to affect 220 million by 2020). Usually irreversible!
Insulin Structure and Secretion!
Insulin = key hormone involved in storage and controlled release within the body of chemical energy available from
food. !
Insulin coded for on chromosome 11; synthesised in beta-cells of pancreas!
After secretion, insulin enters the portal circulation and is carried to the liver. About 50% of secreted insulin is extracted
and degraded in the liver; the residue is broken down by the kidneys. !
C-peptide is only partially extracted by the liver, but is mainly degraded by the kidneys.!
Outline of glucose metabolism!
Blood glucose levels are closely regulated in health; rarely stray outside the range of 3.5-8.0mmol/L (63-144mg/dL),
despite varing demands of food, fasting and exercise. !
Principal organ of glucose homeostasis = liver; absorbs and stores glucose (as glycogen) in the post-absorptive state, and
releases it into the circulation between meals to match the rate of glucose utilisation by peripheral tissues.!
Liver also combines 3C-molecules from the breakdown of fat (glycerol), muscle glycogen (lactate) and protein (alanine)
into 6C glucose (by gluconeogenesis)!
Glucose Production: !
200g glucose produced and utilised each day. >90% is derived from liver glycogen and hepatic gluconeogenesis;
remainder from renal gluconeogenesis!
Glucose Utilisation: !
Brain = major consumer of glucose; !
Requirement=1mg/kg bodyweight per minute, or 100g daily in 70kg man!
Glucose uptake by brain = obligatory; not dependent on insulin. Glucose is oxidised to CO2 and water.!
Other tissues e.g. muscle and fat = facultative glucose consumers.!
The effect of insulin peaks associated with meals is to lower threshold for glucose entry into cells.!
Glucose taken up by muscle is stored as glycogen/ is broken down to lactate, which re-enters the circulation and
becomes a major substrate for hepatic gluconeogenesis. !
Glucose: used by fat tissue as a source of energy; substrate for TG synthesis. Lipolysis releases fatty acids from TG,
together with glycerol.!
Hormonal Regulation!
Insulin = major regulator of intermediary metabolism, although its actions are modified by other hormones.!
- Actions in fasting and post-prandial states differ!
- In fasting state: main action - regulate glucose release by the liver!
- Post-prandial state: facilitates glucose uptake by fat and muscle!
The effect of counter-regulatory hormones (glucagon, adrenaline, cortisol and growth hormone) - cause greater
production of glucose from the liver and less utilisation of glucose in fat and muscle for a given level of insulin.!
Glucose Transport!
Cell membranes are not inherently permeable to glucose. A family of specialised glucose-transporter (GLUT) proteins
carry glucose through the membrane into cells.!
- GLUT-1: enables basal non-insulin stimulated glucose uptake into many cells!
- GLUT-2: transports glucose into the beta-cell = pre-requisite for glucose sensing!
- GLUT-3: enables non-insulin-mediated glucose uptake into brain neurones!
- GLUT-4: enables much of peripheral action of insulin. It is the channel through which glucose is taken up into
muscle/adipose tissue cells following stimulation of insulin receptor!
Insulin Receptor !
Insulin receptor = glycoprotein; 400kDa; coded for on short arm of chromosome 19; dimer of 2 alpha-subunits (includes
binding site for insulin) and 2 beta-subunits (traverse cell membrane)!
Insulin binds alpha-subunit; induces a conformational change in beta-subunits; results in activation of tyrosine kinase
and initiation of cascade response, including movement of GLUT4 to the cell surface and increased transport of glucose
into the cell. The insulin-receptor complex is internalised by the cell, insulin is degraded and the receptor is recycled to
!
the cell surface.
DIABETES - SIOBHAN PAGE 1
