Metabolism
on-line - the virtual tutorial room
copyright © 2008 - 2015 David A Bender
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.)
What conclusions can you draw from these observations?
In the control incubations there is the expected increase in insulin secretion
in response to glucose; in the presence of mannoheptulose there is no increase
in insulin secretion in response to glucose. This suggests that the way in which
the pancreas senses increased blood glucose is not by binding to a receptor
on the cell surface, but by increased formation and metabolism of glucose 6-phosphate.
This problem concerns a small number of families with a clear pattern of dominant
inheritance of an unusual form of diabetes that develops in early childhood.
It is generally referred to as maturity-onset diabetes of the young (MODY),
although it is distinct from types 1 and 2 diabetes.
What is meant by a dominant pattern of inheritance?
Dominant inheritance means that the disease is manifest in heterozygotes, with
one normal and one abnormal gene. Commonly this is because the product of the
abnormal gene has undesirable effects, or because having only half the normal
amount of the enzyme or protein is not sufficient.
A recessive condition is where there must be two copies of the abnormal gene for the condition to be manifest because having only half the normal amount of enzyme does not have any effect.
As will be obvious by the time you have finished working through this problem,
MODY is a dominant condition because having only half the normal amount of an
enzyme does not permit adequate secretion of insulin in response to increasing
blood glucose.
Glucose enters the cells of most tissues by active transport, which is stimulated in response to insulin. In the absence of insulin, glucose transporters are sequestered in intracellular vesicles, which migrate to the cell surface and become active in the presence of insulin. This means that insulin promotes the uptake and utilisation of glucose in most tissues.
After entry, glucose is phosphorylated to glucose 6-phosphate before onward metabolism or use for synthesis of glycogen (in muscle) or fatty acids (in adipose tissue).
In the liver, glucose enters cells by passive diffusion and is then trapped
by phosphorylation to glucose 6-phosphate, which cannot cross cell membranes.
Glucose 6-phosphate is then either metabolised as a metabolic fuel or used to
synthesise glycogen and fatty acids.
Two isoenzymes catalyse the formation of glucose 6-phosphate from glucose