Therapeutic approaches to preserve islet mass in type 2 diabetes.
Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in beta-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances beta-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands beta-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve beta-cell mass, although it remains unclear whether TZDs affect beta-cell mass via direct mechanisms. Complementary approaches to regeneration of beta-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in beta-cell mass that is characteristic of the natural history of type 2 diabetes.
Baggio
Laurie L
LL
Department of Medicine, Toronto General Hospital, Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
Drucker
Daniel J
DJ
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D004815:Epidermal Growth Factor / Q000502:physiology; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology; D005755:Gastrins / Q000502:physiology; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D018027:Receptors, Glucagon / Q000819:agonists; D045162:Thiazolidinediones / Q000494:pharmacology
C000593833:GLP1R protein, human; D005755:Gastrins; D005765:Gastrointestinal Agents; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D045162:Thiazolidinediones; D005749:Gastric Inhibitory Polypeptide; D004815:Epidermal Growth Factor; D018819:Dipeptidyl Peptidase 4