frequently in older people and which results from relative insulin deficiency and insulin
resistance, frequently arising from obesity which causes impaired insulin action. Insulin
is the mainstay of therapy for Type I diabetes. For Type II diabetes, however, weight
reduction is the first line of therapy, not the administration of drugs. Nevertheless, oral
hypoglycemic agents, and sometimes even insulin, are used in Type II diabetes.
Managing the Complications of Diabetes.Diabetes is more than just a disorder of
elevated glucose; it is a systemic disease that affects many organ systems. In addition
to the metabolic problems there are numerous neurological, circulatory, and renal
complications, even when the blood glucose level is properly controlled. The main
reason is the unnatural administration of insulin by injection, instead of the constant
secretion by the pancreas in response to changing blood glucose levels. Diabetics have
a predisposition of atherosclerosis, with an increased risk for heart attacks and stroke.
Another complication of diabetes is blindness, which is due to blood vessel damage
at the back of the eye (proliferative retinopathy); this accounts for about 12% of all
blindness. In hyperglycemia, fructose is only slowly metabolized, and sorbitol accu-
mulates in tissues. Because aldose reductase is found in kidneys, optic nerve, and
peripheral neurons, retinopathy and painful neuropathies develop in poorly controlled
or long-standing diabetes as a result of sugar alcohol (sorbitol) accumulation. Aldose
reductase inhibitors,such as tolrestat (5.129) or sorbinil (5.130), have been evaluated
as agents to ameliorate these additional symptoms of diabetes.
370 MEDICINAL CHEMISTRY