Gene therapy for type 1 and type 2 diabetes

Gene therapy for diabetes can be divided into four major approaches: 1) expansion of β-cells or β-cell precursors; 2) engineering of glucose-responsive insulin secretion; 3) altering peripheral insulin resistance in type 2 diabetes; and 4) immune modulation to prevent autoimmune destruction of pancreatic β-cells during early stages of type 1 diabetes and to protect islet grafts from an immune attack. The pathophysiology of type 1 and type 2 diabetes means that some gene therapy approaches can be applied for both variants of the disease, while others will be specific to each variant. For example, insulin deficiency, a prominent feature of both variants, can be approached by in vivo or ex vivo insertion of genes that stimulate the growth of pancreatic β-cells or β-cell precursors. An increasing number of genes that are involved in the process of β-cell growth and differentiation are being discovered. Induction of differentiation in early endocrine precursors is an attractive, albeit difficult, approach for β-cell expansion. An alternative is engineering of glucose-responsive insulin secretion in non-β-cells. Substantial progress has been made in this direction; however, in the absence of intact insulin secretory apparatus, it is difficult to achieve tight coupling between glucose stimulation and insulin secretion. In type 2 diabetes, insulin resistance increases the secretory demand on failing β-cells. Recent progress in our understanding of the regulation of body weight, adiposity, and insulin resistance, as well as the interaction between insulin resistance, hyperglycemia, and β-cell dysfunction, opens a new window for gene therapy strategies to reduce insulin resistance and to protect pancreatic β-cells. Finally, gene therapy may be valuable for primary prevention of autoimmune destruction of pancreatic β-cells in type 1 diabetes and for the prevention of immune rejection, recurrent autoimmunity, and apoptosis in transplanted islets.