In starvation, glucose utilization is abnormally low because of inadequate glucose supplies. In diabetes mellitus, glucose utilization is similarly low, but it is low because the hormonal stimulus to glucose utilization--namely, insulin--is defective. As a result, glucose is present in excessive amounts in the blood, but in deficient amounts in the cells of peripheral tissues. The consequences of insulin deficiency are comparable to those of starvation in revealing important aspects of interorgan metabolic relationships.

Diabetes mellitus is not a single disease but rather a family of diseases.

Insulin-dependent diabetes often involves autoimmune destruction of the B cells of the pancreas, which can be caused by various factors, including viral infection.

Some forms of diabetes have a genetic origin. Mutations in insulin structure can render the hormone inactive, and other mutations cause defects in the conversion of preproinsulin or proinsulin to the active hormone. In these cases, treatment involves administration of insulin.

Some forms of the disease involve mutations in the structure of the cellular insulin receptor or in its intracellular activities that promote glucose utilization. These latter forms of the disease are called insulin-resistant diabetes, because patients cannot respond to therapeutic doses of insulin.

The failure of insulin to act normally in promoting glucose utilization by cells, with resultant glucose accumulation in the blood, starves the cells of nutrients and promotes metabolic responses similar to those of fasting (Figure 23.5). Liver cells attempt to generate more glucose by stimulating gluconeogenesis. Most of the substrates come from amino acids, which in turn come largely from degradation of muscle proteins. Glucose cannot be reused for resynthesis of amino acids or of fatty acids, so a diabetic may lose weight even while consuming what would normally be adequate calories in the diet.

As cells attempt to generate usable energy sources, triacylglycerol depots are mobilized in response to high glucagon levels. Fatty acid oxidation is elevated, with concomitant generation of acetyl-CoA. Activity of the citric acid cycle may decrease, due to accumulation of reduced electron carriers and/or Oxaloacetate limitation. In liver, both effects accelerate ketone body formation, generating increased levels of organic acids in the blood. These acids can lower the blood pH from the normal value of 7.4 to 6.8 or lower. Decarboxylation of acetoacetate, which is stimulated at low pH, generates acetone, which can be smelled on the breath of patients in severe uncontrolled diabetic situations.

Excessive concentrations of glucose in body fluids generates other metabolic problems. At blood glucose levels above 10 mM, the kidney can no longer reabsorb all of the glucose in the blood filtrate, and glucose is spilled into the urine, sometimes in amounts approaching 100 grams per day. Glucose excretion creates an osmotic load, which causes large amounts of water to be excreted as well. Under these conditions the kidney cannot reabsorb most of this water. As a result, the earliest indications of diabetes are often frequent and excessive urination, coupled with excessive thirst.

When diabetes strikes in childhood (the insulin-dependent form of the disease, representing about 10% of all cases), the metabolic imbalance is usually more severe and difficult to control than in the milder and more common adult-onset form. The latter can often be controlled by dietary restriction of carbohydrate, whereas treatment for juvenile diabetes usually involves daily self-injection of insulin.