Etiology

Underutilization of glucose is thought by most researchers, and investigators to be the operative mechanism in idiopathic diabetes mellitus.

An absolute lack of insulin is thought to exist due to failure of secretory capacity of the beta cells of the islets of Langerhans. However, this point of view has ben challenged by Soskin, and others in the 1950s, while favoring the hypothesis that there exists only a relative lack insulin, and that the prevailing mechanism in diabetes is " overproduction " of glucose from adrenal and pituitary overactivity.

Again, overproduction could be interpreted either as excess gluconeogenesis, or as inhibition of glucose oxidation with piling up of unused sugar, as a result of the pituitary or adrenal hormonal effects.

In the late 1940s, and in the 1950s, Stetten examined both hypotheses experimentally in rats. He produced insulin lack by injury to the beta cells of the pancreas with alloxan, and renal diabetes with losses of sugar via the urine, with phlorizin. No greater loss of sugar resulted from lack of insulin than occurred with renal glycosuria.

This suggest that overproduction does not follow insulin deprivation. However, such study does not rule out the possibility that pre-existing overproduction may be a cause of eventual failure of the pancreas in human diabetics.

Such a possibility is suggested by the fact that total pancreatectomy in non-diabetics results in a diabetes of only mild severity; since an average of 50 units of insulin restors carbohydrate metabolism to normal after operation, whereas many spontaneous diabetics, especially when infections exists, may require far larger amounts of insulin.

However, the higher insulin requirements of spontaneous diabetes are also taken into account by the " underutilization " theory, in view of the possibilities of either increased tissue needs for insulin, or of insulin inactivation, in the severe diabetic.

Since the advent of insulin many decades ago: New and more modern hypoglycemic, and hyperglycemic medication has been develpoed, and are used in the treatment of controlling diabetes. These medication are in a series of pill form. Nevertheless, insulin is still widely used. Physiology

In the event glucose is not used by the body tissues because of lack of insulin, a chain of events occurs.

First, a rise in blood glucose (sugar)takes place above the normal limits of 80-120 mg. per 100 cc., due to inability of renal tubular phosphorylation to keep pace with the excess of sugar.

In diabetes of long standing, however, adaptation apparently takes place, and glycosuria may not appear with blood levels up to 0.25 - 0.3 Gm. per 100 cc. The sugar available for excretion is first derived from ingested glucose. This normally would be oxidized, converted to liver and muscle glycogen, or used in the synthesis of amino acids and fatty acids.

Failure of utilization soon results in glycolysis of the liver glycogen. By an unknown mechanism, a falling liver glycogen results in increased mobilization of fats as fatty acids to be brought to the liver. Similarly, failure of amino acid ( and thus protein)synthesis prevents correction of the breakdown of tissue proteins required to provide amino acids to the liver for gluconeogenesis.

The excessive mobilization of fat has two consequences. The normal end products of fat metabolism in the liver are acetic acid and acetoacetic acid. These normally enter the blood and are burned primarily in the muscles, at a rate equal to that of their formation. In the presence of diabetes the formation of these products is in excess of that which can be handled.

Interconversion of acetic acid excess then occurs in the liver to form ketone acids and acetone.

The " underutilization " theory currently does not imply, as formerly, that glucose utilization stops completely. The brain and other tissues have an inherent, though limited, capacity to use sugar independently of insulin.

Insulin

Insulin is secreted from the beta cells of the islets of Langerhans in the pancreas. It is an incomplete protein lacking in methionine, rich in cystine, and depending on the disulfied bonds of cystine for its activity. Its molecular weight is about 35,000. The immediate consequence of insulin lack is hyperglycemia, while an excess causes hypoglycemia.

The mechanisms of action of the hormone are largely unknown. The main metabolic disorder for which insulin is used therapeutically is diabetes mellitus. Here, too, the pathologic mechanism which results in the disorder are obscure.

In general, insulin opposes those other endocrane secretions which serve to mobilize glucose or decrease its utilization. The metabolism of carbohydrate, fat, and protein are highly interrelated. Thus, derangement in the metabolic pathway of one ultimately causes serious interference with the metabolism of the others.

Secretion Of Insulin

The secretion of insulin is thought to be under endocrine, nervouis, and chemical control. Young has shown that certain anterior pituitary extracts increase the size and insulin content of the islets of Langerhans in dogs, the so called insulinotropic effect. Mirsky has found that chronic injections of insulin lead in time to atrophy of the beta cells of the islets.

Also, transient diabetes is known to follow the removal of an insulin-secreting pancreatic adenoma which had caused hypoglycemia. These observation suggest that there may be a possible reciprocal relationship between the insulinothropic function of the anterior pituitary and insulin secretion.