Abstract
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.
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Papers of particular interest, published recently, have been highlighted as: •• Of major importance
•• 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.
DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979, 237:E214–E223.
DeFronzo RA, Tripathy D: Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 2009, 32(Suppl 2):S157–S163.
DeFronzo RA, Gunnarsson R, Bjorkman O, et al.: Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985, 76:149–155.
Bonadonna RC, Groop L, Kraemer N, et al.: Obesity and insulin resistance in humans: a dose-response study. Metabolism 1990, 39:452–459.
Gulli G, Ferrannini E, Stern M, et al.: The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 1992, 41:1575–1586.
Mari A, Wahren J, DeFronzo RA, Ferrannini E: Glucose absorption and production following oral glucose: comparison of compartmental and arteriovenous-difference methods. Metabolism 1994, 43:1419–1425.
Eriksson J, Franssila-Kallunki A, Ekstrand A, et al.: Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989, 321:337–343.
Tripathy D, Lindholm E, Isomaa B, et al.: Familiality of metabolic abnormalities is dependent on age at onset and phenotype of the type 2 diabetic proband. Am J Physiol Endocrinol Metab 2003, 285:E1297–E1303.
Tripathy D, Carlsson AL, Lehto M, et al.: Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state. Diabetologia 2000, 43:1476–1483.
Defronzo RA, Banerji MA, Bray GA, et al.: Determinants of glucose tolerance in impaired glucose tolerance at baseline in the Actos Now for Prevention of Diabetes (ACT NOW) study. Diabetologia 2010, 53:435–445.
Weyer C, Bogardus C, Mott DM, Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999, 104:787–794.
Sriwijitkamol A, Christ-Roberts C, Berria R, et al.: Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. Diabetes 2006, 55:760–767.
Reyna SM, Ghosh S, Tantiwong P, et al.: Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 2008, 57:2595–2602.
Mullen E, Ohlendieck K: Proteomic profiling of non-obese type 2 diabetic skeletal muscle. Int J Mol Med 2010, 25:445–458.
Tripathy D, Eriksson KF, Orho-Melander M, et al.: Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in type 2 diabetes. Diabetologia 2004, 47:782–793.
Li S, Brown MS, Goldstein JL: Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci U S A 2010, 107:3281–3282.
Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993, 259:87–91.
Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest 2005,115:1111–1119.
Galic S, Oakhill JS, Steinberg GR: Adipose tissue as an endocrine organ. Mol Cell Endocrinol 2010, 316:129–139.
Karastergiou K, Mohamed-Ali V: The autocrine and paracrine roles of adipokines. Mol Cell Endocrinol 2010, 318:69–78.
Gerozissis K: Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 2008, 585:38–49.
Tschritter O, Preissl H, Hennige AM, et al.: The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc Natl Acad Sci U S A 2006, 103:12103–12108.
Richardson DK, Kashyap S, Bajaj M, et al.: Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 2005, 280:10290–10297.
Chavez AO, Kamath S, Jani R, et al.: Effect of short-term free fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. J Clin Endocrinol Metab 2010, 95:422–429.
Hwang H, Bowen BP, Lefort N, et al.: Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes 2010, 59:33–42.
Ozcan U, Cao Q, Yilmaz E, et al.: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004, 306:457–461.
Ozcan U, Yilmaz E, Ozcan L, et al.: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006, 313:1137–1140.
Boden G, Duan X, Homko C, et al.: Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 2008, 57:2438–2444.
Belfort R, Mandarino L, Kashyap S, et al.: Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 2005, 54:1640–1648.
Boden G, Lebed B, Schatz M, et al.: Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 2001, 50:1612–1617.
Tripathy D, Mohanty P, Dhindsa S, et al.: Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003, 52:2882–2887.
DeFronzo RA: Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004, 88:787–835, ix.
Gastaldelli A, Ferrannini E, Miyazaki Y, et al.: Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia 2004, 47:31–39.
Abdul-Ghani MA, Jenkinson CP, Richardson DK, et al.: Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 2006, 55:1430–1435.
Kahn SE, Haffner SM, Heise MA, et al.: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006, 355:2427–2443.
Tripathy D, Carlsson M, Almgren P, et al.: Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. Diabetes 2000, 49:975–980.
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.
Lencioni C, Lupi R, Del Prato S: Beta-cell failure in type 2 diabetes mellitus. Curr Diab Rep 2008, 8:179–184.
Eizirik DL, Cardozo AK, Cnop M: The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 2008, 29:42–61.
Cnop M, Igoillo-Esteve M, Cunha DA, et al.: An update on lipotoxic endoplasmic reticulum stress in pancreatic beta-cells. Biochem Soc Trans 2008, 36:909–915.
Matsuda T, Kido Y, Asahara S, et al.: Ablation of C/EBPbeta alleviates ER stress and pancreatic beta cell failure through the GRP78 chaperone in mice. J Clin Invest 2010, 120:115–126.
Palotay JL, Howard CF Jr: Insular amyloidosis in spontaneously diabetic nonhuman primates. Vet Pathol Suppl 1982, 7:181–192.
Ritzel RA, Meier JJ, Lin CY, et al.: Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets. Diabetes 2007, 56:65–71.
•• 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.
Drucker DJ: Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 2007, 30:1335–1343.
Nauck MA, Meier JJ: The enteroinsular axis may mediate the diabetogenic effects of TCF7L2 polymorphisms. Diabetologia 2007, 50:2413–2416.
Baggio LL, Drucker DJ: Biology of incretins: GLP-1 and GIP. Gastroenterology 2007, 132:2131–2157.
Nauck MA, Heimesaat MM, Orskov C, et al.: Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993, 91:301–307.
Elahi D, McAloon-Dyke M, Fukagawa NK, et al.: The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept 1994, 51:63–74.
Kjems LL, Holst JJ, Volund A, Madsbad S: The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003, 52:380–386.
Vilsboll T, Krarup T, Madsbad S, Holst JJ: Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia 2002, 45:1111–1119.
Altshuler D, Hirschhorn JN, Klannemark M, et al.: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000, 26:76–80.
Deeb SS, Fajas L, Nemoto M, et al.: A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998, 20:284–287.
Sladek R, Rocheleau G, Rung J, et al.: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007, 445:881–885.
•• 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.
Lyssenko V, Nagorny CL, Erdos MR, et al.: Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 2009, 41:82–88.
Saxena R, Hivert MF, Langenberg C, et al.: Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 2010, 42:142–148.
Disclosure
Dr. Devjit Tripathy has received research support from Takeda Pharmaceuticals. No other potential conflicts of interest relevant to this article were reported.
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Tripathy, D., Chavez, A.O. Defects in Insulin Secretion and Action in the Pathogenesis of Type 2 Diabetes Mellitus. Curr Diab Rep 10, 184–191 (2010). https://doi.org/10.1007/s11892-010-0115-5
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DOI: https://doi.org/10.1007/s11892-010-0115-5