Glucose-Stimulated Genes and Prospects of Gene Therapy for Type I Diabetes*

GLUCOSE is an important modulator of gene expression in practically all living cells and organisms, procaryotes as well as eucaryotes, yeasts as well as multicellular plants or animals. However, the molecular mechanisms underlying the action of glucose on the transcriptional machinery have remained relatively obscure until recently and are still imperfectly understood. In vertebrates, glucose action can be direct, being mediated by glucose itself or by glucose metabolism, or indirect, secondary to glucose-dependent modifications of hormone secretion, mainly of insulin and glucagon. However, the insulin and glucose pathways, although interdependent, have recently been better defined, and glucose-response elements have been described in various genes specific to the endocrine pancreas, liver, and adipocytes (1–3). Insulin-dependent diabetes mellitus (IDDM), or type I diabetes, is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic β-cells. In the United States, the lifetime prevalence of IDDM is about 0.4 %. Thus, with a population of 250 million, approximately 1 million Americans have IDDM (4). Exogenous insulin the-rapy, which is the main treatment, does not permit a glycemic control as precise as that provided by natural secretion from functional islet β-cells, and acute decompensations and long-term complications are always present. It is therefore appropriate to look at possible alternative therapeutic strategies for IDDM.