Insulin resistance is an important feature of type 2 diabetes, and failure of insulin action in the peripheral insulin sensitive tissues, skeletal muscle, and adipose tissue is a major part of disease pathogenesis. Rare inherited syndromes of extreme insulin resistance have been vital in identifying genes involved in the insulin signaling pathway. One of these, Rabson-Mendenhall syndrome, consists of pineal hyperplasia, facial dysmorphism, phallic enlargement in males, short stature, acanthosis nigricans, and premature dentition. Diabetes mellitus presents between 3 and 7 yr of age, with death from ketoacidosis in the second decade. The diabetes is highly insulin resistant. Survivors develop later widespread microvascular disease (69). The syndrome is caused by insulin-receptor mutations leading to defective binding capacity (70). A model of treatment for this condition has been described, using monoclonal antibodies acting as a substitute for the normal ligand, thereby activating the defective receptor (71). It is interesting that another inherited syndrome, leprechaunism (Donohue syndrome) is also associated with insulin-receptor mutations. This syndrome is characterized by intrauterine growth retardation and presentation in infancy with pachydermia, hypertri-chosis, acanthosis nigricans, reduced subcutaneous fat stores, and coarse facies (72). There is extreme hyperinsulinism, insulin resistance, and, paradoxically, often fasting hypoglycemia. Insulin binding to receptors is severely decreased. The diabetes is difficult to treat and may be complicated by renal disease similar to diabetic nephropathy (73). Over 50 insulin-receptor mutations have been described, the vast majority in association with these extreme insulin-resistance syndromes. These mutations either abolish insulin receptor binding, disrupt the tyrosine kinase activity of the receptor, or interfere with the synthesis and expression of the receptor (74). It is probable that lep-rechaunism, Rabson-Mendenhall syndrome, and type A insulin resistance (nonobese, nondysmorphic, severely insulin-resistant females with hirsutism, acanthosis nigricans, and menstrual disturbance) represent points on a continuum of increasingly severe receptor dysfunction, rather than completely distinct syndromes (71). Mutations in the insulin receptor do not make a major contribution to the insulin resistance seen in more common disorders such as type 2 diabetes. Interest is now being focused on peroxisome proliferator-activated-receptor gamma (PPARy), a nuclear receptor that is the target of thiazolidinedione drugs. Dominant negative mutations have been described in three individuals with diabetes mellitus as a result of severe insulin resistance and hypertension (75).
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All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.