Metabolism on-line - the virtual tutorial room
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An unusual cause of diabetes - how the pancreas senses a rise in blood glucose
There are two common types of diabetes mellitus
Type 1 diabetes (also known as insulin-dependent diabetes or juvenile onset diabetes)
Here the problem is one of failure to secrete adequate amounts of insulin, and patients are dependent on injection of insulin to maintain control over their blood glucose concentration. The condition usually develops in childhood and progresses with loss of pancreatic beta islet cells until there is almost no secretion of insulin.
Type 2 diabetes (also known as non-insulin-dependent diabetes or maturity onset diabetes)
Here the problem is one of loss of sensitivity of tissues to insulin action; the secretion of insulin may be normal or greater than normal. Although injection of insulin helps to maintain good control over blood glucose concentration, patients are not strictly dependent on an exogenous source of insulin. The problem usually develops in adult life and is commonly associated with obesity, especially abdominal obesity.
What are the main ways in which insulin acts to lower blood glucose?
Insulin stimulates uptake of glucose into muscle and adipose tissue. It achieves this by recruitment of glucose transporters from intracellular vesicles to the cell surface.
In the presence of insulin, glucose becomes major fuel for muscle contraction. There is increased synthesis of glycogen as a result of activation of glycogen synthase and inactivation of glycogen phosphorylase.
In adipose tissue, glucose is used for the synthesis of fatty acids and and the triacylglycerol for storage, as a result of increased activity of fatty acid synthase and decreased activity of hormone-sensitive lipase.
Liver uptake of glucose is not affected by insulin, but insulin stimulates the synthesis of glycogen from glucose, as in muscle, as a result of activation of glycogen synthase and inactivation of glycogen phosphorylase.
What are the main adverse effects of poor glycaemic control and hyperglycaemia?
Either failure of insulin secretion or decreased sensitivity of insulin receptors leads to elevated blood glucose (hyperglycaemia). Glucose reacts non-enzymically with amino groups in proteins, including:
collagen (hence increased arthritis and damage to epithelial basement membrane leading to damage to blood vessels, and contributing to circulatory problems, retinal damage and renal damage)
proteins in low density lipoprotein (hence increased risk of developing atherosclerosis)
crystallin in the lens of the eye ( hence the development of cataracts)
proteins in myelin (hence nerve damage)
haemoglobin – not a pathological problem, but diagnostically useful to monitor long-term control of blood glucose by measurement of glycated haemoglobin (haemoglobin A1c)
In addition, hyperglycaemia may lead to osmotic imbalance and dehydration. Glucose may also be reduced to sorbitol in nerve and other tissues, again leading to osmotic damage.
The beta-islet cells of the pancreas secrete insulin in response to an increase
in blood glucose. This problem is concerned with the way in which the beta-cells
detect the increased concentration of glucose.
One early hypothesis was that there is a glucose receptor on the outer surface of the beta -cell membrane, and when this binds glucose it initiates a series of intracellular events that lead to secretion of insulin.
Coore & Randle (1964) measured the secretion of insulin by rabbit pancreas
incubated in vitro with two concentrations of glucose, with and without the
addition of the 7-carbon sugar mannoheptulose, which they had previously shown
to be an inhibitor of phosphorylation of glucose to glucose 6-phosphate. Their
results are shown below.
Secretion of insulin (µg /minute /incubation) by rabbit pancreas incubated in vitro with 3.3 or 16.6mol /L glucose. (3.3 mmol /L is the glucose
concentration that would be seen in relatively prolonged fasting; 16.6 mol /L
is about the concentration that would be seen in the hepatic portal
vein after a moderately carbohydrate-rich meal):
| incubated with: | control |
+ mannoheptulose to inhibit phosphorylation
of glucose |
| 3.3 mmol /L glucose | 3.5 |
3.5 |
| 16.6 mmol /L glucose | 12.5 |
3.5 |
(From data reported by Coore HG & Randle PJ, Biochemical Journal 93: 66 – 77, 1964.)