Diabetes: A primer © R.J.Walters 2003
Diabetes is a condition caused by an inherent or acquired inability to finely regulate the free
concentration of blood sugar (primarily glucose). The cells of the human body, and especially those of
the nervous system, require the concentration of glucose to be maintained close to 5 milliMolar. Too
much blood glucose (hyperglycaemia) results from the failure of insulin to command the cells of the liver,
muscle and adipose (fat tissue) to take up sufficient of the surplus glucose in the diabetic condition,
which, left untreated, causes diabetic coma and eventually death. Similarly, too little blood glucose
(hypoglycaemia), which is caused by an excessive release of, or sensitivity to insulin, results in
insufficient fuel to support the vital activity of the cells of the central nervous system, which can
only use glucose (and ketone bodies) for fuel, resulting in coma and death. Thus mammalian life exists
upon the knife edge of the finely regulated blood sugar glucose concentration, and the hormones of the
pancreas which have evolved to regulate it.
The cells of the islet of Langerhans, embryologically derived from neural crest tissue (that in later
development gives rise to other nerve cells), constitute the endocrine tissue of the pancreas. There are
a number of cell types within the grape-like structure of the islet of Langerhans;
d (delta) cells, which release somatostatin
(a growth inhibitor); a (alpha) cells which
release glucagon, and the predominant b (beta) cells which release insulin. Glucagon and insulin
have classically antagonistic actions, glucagon mobilising glucose from cellular stores and stimulating
gluconeogenesis (the de novo synthesis of D-glucose), and insulin which stimulates glucose uptake
into tissues, fat and protein anabolism (construction) and the synthesis of glycogen (the water associated
with the storage form of glucose). As might be expected, glucagon release is triggered by low blood glucose
concentrations and insulin by high blood glucose concentrations.
A failure to control blood glucose levels may have a range of causes. An inadequate release of
insulin in response to a surge in blood sugar that follows a meal logically implicates a defect in the
b-cell's responsiveness to glucose. This might result from a defect in the cell's secretory machinery,
an insensitivity to glucose or a decrease in b-cell numbers (as occurs in type I diabetes that results
from the auto-immune destruction of b-cells). Most commonly, however, diabetes results from an insensitivity
of peripheral body tissues to insulin (type II diabetes). This is common in obesity, where over-eating
leads to a sustained release of insulin into the circulation in response to sustained elevations of
blood sugar, and this in turn leads to a decrease in the responsiveness of the peripheral tissues to
insulin. A vicious cycle ensues, where the b-cells release yet more insulin into the blood stream in
order to compensate, leading to yet a further desensitization of the response of the peripheral tissues
to insulin. Equally an over-sensitivity of the b-cell to glucose leads to excessive insulin release and
glucose uptake into peripheral tissues (or potentially an insufficient glucagon release from
a-cells and resulting failure to liberate
glucose from peripheral tissues), leading to hypoglycaemia.
The b-cell is a unique and intricate electrical glucose concentration sensor and regulator.
Blood glucose is rapidly taken up into the b-cell by a selective glucose transporter, where it is
immediately metabolised by the mitochondria of the b-cell into the universal currency of cell energy
, adenosine triphosphate (ATP). Classically a build up of ATP levels inside the cell closes the
ATP-sensitive potassium (KATP) channels present in the b-cell membrane, thereby depolarizing the
intracellular face of the membrane (making it more positively charged), which leads in turn to an
activation of ion channels in the b-cell membrane that are sensitive to membrane potential. These
ion channels are selectively permeable to calcium, and their opening causes an increase in calcium
concentration in the b-cell. This elevation in cellular calcium causes the insulin containing membrane
vesicles inside the b-cell to approach the outer cell membrane and fuse with it, thereby releasing
insulin into the blood stream. Recent evidence however (unpublished observations), strongly suggests
that glucose directly activates at least two different populations of voltage-activated calcium channels.
Unsurprisingly, the b-cell remains a central focus for diabetes research. An understanding of the
physiology and pharmacology of the ion channels and the sulphonylurea drug receptor that regulates
insulin secretion by the b-cell might allow new therapeutic strategies to be devised to manage the
diabetic state. Much research remains to be done to understand the cellular basis of all forms of
diabetes.
