Recent Advances in Therapeutic Approaches to Type 2 Diabetes

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John M. Nuss1 and Allan S. Wagman2 Exelixis, Inc.1, South San Francisco, CA 94080 Chiron Corporation2, Emeryville, CA 94608

Introduction - Diabetes mellitus is the only non-infectious disease designated as an epidemic by the World Health Organization (1). The prevalence of all types of diabetes is estimated to be 2.3% of the world's population, with the number of diabetics increasing by 4-5% per annum. It is projected that as many as 40-45% of persons aged 65 or older have either Type 2 diabetes or its precursor state, impaired glucose tolerance (IGT). In the US -10% of the diabetic population suffer from Type 1 diabetes, an autoimmune disease characterized by the loss of pancreatic P-ceil function and an absolute deficiency of insulin. The remainder of the diabetic population suffers from Type 2 diabetes or IGT, which, although related to the body's inability to properly respond to insulin, have a more complex etiology (2). Diabetes can be treated by a combination of lifestyle change, dietary change and medication. However, the metabolic disorder underlying diabetes also affects protein and lipid metabolism, leading to serious complications, including peripheral nerve damage, kidney damage, impaired blood circulation, and damage to the retina of the eye. Diabetes is the leading cause of blindness and amputation in western populations, and the direct medical costs alone were estimated to be ~$44bn in the US alone in 1998 (2).

The United Kingdom Prospective Diabetes Study (UKPDS), a long term study of Type 2 diabetics, has shown that rigorous management of blood glucose levels (measured as glycosylated hemoglobin, HbAic), and blood pressure substantially reduce the incidence of complications (3). The current therapeutic strategies for Type 2 diabetes are very limited, and involve insulin therapy and oral hypoglycemic agents (OHAs) such as sulfonylureas, metformin, and the thiazolidinediones. Combination therapy with one or more of these agents is now a viable option as target blood glucose levels become harder to maintain with monotherapy (3,4). While a wide variety of therapeutic approaches are now being examined for Type 2 diabetes, these can generality be classified in one of the following categories: 1) insulin or insulin mimetics; 2) agents which effect the secretion of insulin; 3) inhibitors of hepatic glucose production; 4) insulin sensitizers; and 5) agents which inhibit glucose absorption. The current chapter focuses on some of the most interesting, recent (post 1998) medicinal chemistry approaches that have been taken for the treatment of Type 2 diabetes.

INSULIN, INSULIN ANALOGUES OR MODIFIED INSULIN/IMPROVED DELIVERY

Insulin/Modified Insulins - Early or timely initiation of insulin therapy, either as monotherapy or in combination with other agents, can establish good glycemic control in a majority of Type 2 patients, and this mode of therapy does not adversely effect the quality of life of these patients (4,5). Short-acting analogs of insulin such as insulin lispro, an analog of insulin which has favorable pharmacokinetics, and is useful in the control of post-prandial glucose levels, have been reviewed (6).

Improved Delivery Vehicles - Inhalable, oral, intranasal, and transdermal forms of insulin offer considerably more convenience than do the traditional s.c. injectable forms of the drug, along with having more favorable pharmacokinetic characteristics. These alternatives have been extensively reviewed (7,8).

Insulin Mimetics - The natural product L-783,281 1, a non-peptidyl fungal metabolite, has been shown to selectively activate the insulin receptor in vitro, and oral adminstration of this agent showed a 40% lowering of blood glucose when administered orally for 7 days (9). The mechanism of action of likely involves intracellular activation of the insulin receptor tyrosine kinase (IRTK). A second report of simplified synthetic analogs of these compounds, e.g., 2, has appeared (10).

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