Therapeutic perspectives for type 2 diabetes mellitus: Molecular and clinical insights

Current antidiabetic agents do not suppress insulin resistance, do not rein state physiological insulin secretion and fail to prevent the gradual loss of beta -cell function. Thus, these molecules are unable to maintain long t erm euglycemia in all type 2 diabetic patients and there is a need for new antidiabetic drugs. Thiazolidinediones (TZD) are a new class of insulin sen sitizers recently approved in Europe, in combination therapy with sulfonylu reas or/and metformin, for the treatment of type 2 diabetes. TZD show benef icial effects on insulin action, glucose homeostasis and lipid metabolism d espite a substantial weight gain. Their potential protective effect on beta -cell function and on the development of macrovascular complication is of particular interest. Non TZD PPAR gamma agonists are also under clinical tr ials. Other interesting therapeutic perspectives to treat insulin resistanc e lie in the development of inhibitors of protein tyrosine phosphatases and in the promotion of non insulin-dependent contraction-like muscle glucose uptake via stimulation of AMP protein kinase (AMPK). As to new insulin secr etagogues, the phenylalanine derivative nateglinide is a first phase insuli n secretion enhancer primarily intented at controlling post-prandial hyperg lycemia. The most promising perspective to improve beta -cell function lies in the development of glucagon-like peptide-1 (GLP-1) analogs. Clinical st udies show beneficial effects on glucose homeostasis in type 2 diabetics an d efficacy in sulfonylurea resistant patients without risk of hypoglycaemia . Animal studies predict beneficial effects on beta -cell mass. Finally we will discuss the potential use of gene therapy to treat insulin resistance and beta -cell dysfunction.