Defects in Insulin Secretion and Action in the Pathogenesis of Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin action and insulin secretion. Although insulin resistance manifests early during the prediabetic state, a failing β-cell function unable to overcome insulin resistance at target tissues determines the onset of T2DM. This review focuses on recent advances in the molecular mechanisms of insulin resistance and β-cell dysfunction. The role of mitochondrial dysfunction, impaired regulation of the enteroinsular axis, and endoplasmic reticulum stress are currently the subjects of intensive research. In addition, the adipose tissue has emerged as a major endocrine organ that secretes a growing list of adipocytokines with diverse central and peripheral metabolic effects. The role of a growing number of candidate genes and transcription factors regulating insulin action and secretion is also discussed.
KeywordsType 2 diabetes mellitus Insulin resistance Insulin secretory defects Mitochondrial dysfunction Free fatty acids Adipokines Incretins
Dr. Devjit Tripathy has received research support from Takeda Pharmaceuticals. No other potential conflicts of interest relevant to this article were reported.
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 1.•• Defronzo RA: Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009, 58:773–795. This recent comprehensive review describes in detail all new players in the pathogenesis of T2DM.Google Scholar
- 33.DeFronzo RA: Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004, 88:787–835, ix.Google Scholar
- 38.Turner RC, Cull CA, Frighi V, Holman RR: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999, 281:2005–2012.Google Scholar
- 45.•• Guardado-Mendoza R, Davalli AM, Chavez AO, et al.: Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons. Proc Natl Acad Sci U S A 2009, 106:13992–13997. This describes in detail the pancreatic islet morphology and the role of IAPP and α-cell hyperplasia in islets.Google Scholar
- 56.•• Lyssenko V, Lupi R, Marchetti P, et al.: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 2007, 117:2155–2163. This is the best study thus far describing in detail the physiology of the TCF7L2 gene.Google Scholar