Type 2 Diabetes and Nuclear Receptors for Developing New Therapy

iHumans.com <http://ihumans.com>

25 January, 2001

Type 2 Diabetes and Nuclear Receptors for Developing New Therapy

Diabetes and obesity are responsible for a major deaths in developed countries. These diseases have complex causes involving genetic and nutritional factors. Nutritional factors are emphasized typically for the occurrence of diabetes that may be referred to as diseases from contemporary life style. These diseases arising from nutritional factors are rapidly increasing in the number of patients. Diabetes results from high glucose level in the blood and is of two types, type 1 arising from insulin deficiency due to genetic defect of the patient and type 2 from yet unknown causes but often arising from insensitivity to insulin action.

Diabetes mellitus offers pharmaceutical industry a major target for the drug development. Worldwide sales of anti-diabetics is now US$8 billions. In diabetes, the type 2 is increasingly important as the number of patients is increasingly rapidly worldwide. It has been difficult to treat type 2 diabetes. Most recent regimen for this chronic disease condition is the use of compounds referred to as glitazones that induce responsiveness to insulin action in the patient who does not do so even when the glucose level is high in the blood. High level of glucose leads to various complications such as neurosis, nephropathy and retinopathy. However, glitazones have serious side-effect. The first drug, troglitazone (Rezulin), of this kind has recently been retracted from the market, for typically in about 1.9% of patients hepatotoxicity has occurred, which may be severe and even fatal (Kohlroser J et al, 2000: uid=10638596). Thus while there is a high market demand, it has been a difficult endeavor to develop excellent drugs against type 2 diabetes.

Modern concepts of biomedicine lead to new venues for drug development. One of them is the remarkable development made in recent years in the area of nuclear receptors. There are a large number of receptors in the nucleus of the cell that receive signals carried by small molecules (ligands) from outside to induce specific cell functions. Hormones and their receptors are an example. There are a number of nuclear receptors whose ligands are not known thus referred to as "orphan" receptors. Thanks to intensive research, these orphans are getting legitimized, and revealed functions are extremely interesting, and important particularly for the mechanistic characterizations of type 2 diabetes.

Nuclear receptors form dimeric complexes with the particular nuclear receptor partner termed RXR to be active for the induction of specific gene functions. A few of the dimeric receptor complexes have been delineated to the physiological activities related to the regulation of glucose levels in the blood. For example, a nuclear receptor PPARgamma forms the dimeric complex RXR/PPARgamma that induces sensitization to insulin action and lowers the glucose level. Small molecular ligands that specifically bind to each nuclear receptor are now hotly pursued in an aim to develop novel drugs against type 2 diabetes. These ligands are mostly analogs of RXR compounds that bind to and activate RXR.

Insulin Resistance
Insulin resistance (poor response to insulin action) can be caused by abnormalities of glycogen synthesis and by increased free fatty acids that inhibit glucose transport. In subjects with type 2 diabetes, glycogen concentrations are reduced and the rate of glucose synthesis is increased in the liver (Shulman GI, 1999: uid=10418851). This possible mechanism of insulin resistance may lead to therapy with agents that reverse the pathophysiology of type 2 diabetes. Thiazolidinediones have been developed that appear to increase glucose clearance by peripheral tissues, and also compounds such as biguanide metformin that appear to lower glucose by suppressing hepatic glucose production.

Troglitazone (Rezulin, Sankyo, USA in 1997), rosiglitazone maleate (Avandia, SmithKline, USA in 1999), and pioglitazone hydrochloride (Actos, Takeda, USA in 1999) are a new class of oral anti-diabetic agents developed in recent years. These anti-hyperglycemic agents (thiazolidinediones, collectively termed as glitazones) can improve glycemic control primarily by improving insulin sensitivity, namely reducing insulin resistance of type 2 diabetes, in muscle and adipose tissues. Their efficacy is clearly demonstrated by the marked reductions of blood glucose. They are dependent on the presence of insulin for activity, but do not stimulate the secretion of insulin.

Recently there is increasing evidence that a group of closely related nuclear receptors, called peroxisome proliferator-activated receptors (PPARs) are somehow involved in type 2 diabetes. PPARs may be activated by specific ligands such as glitazones for PPARgamma and fibrates for PPARalpha. PPARgamma regulates the expression of several genes involved in metabolism, and controls adipocyte differentiation, lipid storage, and insulin sensitization. But it is not known which genes are directly involved in the insulin-sensitizing action mediated by PPARgamma activation. In addition to PPARgamma, insulin resistance may also be decreased via PPARalpha. Fibrates that exert their lipid-lowering activity via PPARalpha were shown to improve insulin sensitivity in two rodent models of high fat diet-induced C57BL/6 mice or genetically obese Zucker rats (Guerre-Millo M, 2000: uid=10828060).

Finally, a totally new approach may now be possible to elucidate the occurrence of insulin resistance and to design of novel compounds against it. Thinking that PPARgamma is an adipocyte factor, Steppan et al (Nature 409, 307 - 312: 2001) screened genes that are induced during adipocyte differentiation but downregulated when exposed to glitazones, and discovered a unique signalling molecule, resistin, that is increased in diet-induced and genetic forms of obesity. Type 2 diabetes is strongly associated with obesity. Resistin mRNA and its circulating levels are increased in type 2 diabetes, and decreased by rosiglitazone. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Further, resistin was cloned from mouse and humans. Direct proof remains to be obtained but evidence accumulates that PPARgamma activaction is at least one of the molecular mechanisms to reduce insulin resistance that is accompanied by downregulation of resistin.

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