Gene therapy for type 1 and type 2 diabetes

Gene therapy for diabetes can be divided into four major approaches: 1) exp ansion of beta-cells or beta-cell precursors; 2) engineering of glucose-res ponsive insulin secretion; 3) altering peripheral insulin resistance in typ e 2 diabetes; and 4) immune modulation to prevent autoimmune destruction of pancreatic beta-cells during early stages of type 1 diabetes and to protec t islet grafts from an immune attack. The pathophysiology of type 1 and typ e 2 diabetes means that some gene therapy approaches can be applied for bot h variants of the disease, while others will be specific to each variant. F or example, insulin deficiency, a prominent feature of both variants, can b e approached by in vivo or ex vivo insertion of genes that stimulate the gr owth of pancreatic beta-cells or beta-cell precursors. An increasing number of genes that are involved in the process of beta-cell growth and differen tiation are being discovered. Induction of differentiation in early endocri ne precursors is an attractive, albeit difficult, approach for beta-cell ex pansion. An alternative is engineering of glucose-responsive insulin secret ion in non-beta-cells. Substantial progress has been made in this direction ; however, in the absence of intact insulin secretory apparatus, it is diff icult to achieve tight coupling between glucose stimulation and insulin sec retion. In type 2 diabetes, insulin resistance increases the secretory dema nd on failing beta-cells. Recent progress in our understanding of the regul ation of body weight, adiposity, and insulin resistance, as well as the int eraction between insulin resistance, hyperglycemia, and beta-cell dysfuncti on, opens a new window for gene therapy strategies to reduce insulin resist ance and to protect pancreatic beta-cells. Finally, gene therapy may be val uable for primary prevention of autoimmune destruction of pancreatic beta-c ells in type 1 diabetes and for the prevention of immune rejection, recurre nt autoimmunity, and apoptosis in transplanted islets.