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Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes

Key Points

  • Type 2 diabetes is often associated with obesity and occurs as a consequence of a combined impairment in insulin secretion and insulin action. This results in loss of metabolic control, leading to increased concentrations of glucose and lipids in the circulation.

  • The decrease in insulin action — known as insulin resistance — is caused by several factors, including direct deleterious effects of excess lipids and other metabolic fuels on organs and tissues, enhanced inflammatory signalling, and activation of endoplasmic reticulum (ER) stress pathways.

  • Different tissues respond to excess metabolic fuels in different ways. Thus, excess glucose and lipid supplies in the liver favour the partitioning of lipids away from oxidative pathways in the mitochondria and into esterification pathways to produce lipids with signalling properties that can activate Ser kinases, which then phosphorylate and inactivate key insulin signalling molecules.

  • In muscle, excess lipids enhance fatty acid oxidation but do not coordinately induce the downstream tricarboxylic acid cycle. This leads to the accumulation of incompletely metabolized lipids in the mitochondria that can impair insulin signalling.

  • Glucose-stimulated insulin secretion from the β-cells of the pancreatic islets involves both triggering and amplifying signals. The triggering signal involves glucose-stimulated generation of ATP, inhibition of ATP-sensitive K+ channels and influx of Ca2+, whereas new evidence suggests that the amplifying signal is derived from anaplerotic pyruvate cycling pathways that include mitochondrial and cytosolic components.

  • β-cell failure of type 2 diabetes has a metabolic component, wherein exposure to excess lipids abrogates the normal glucose-induced increase in pyruvate cycling.

  • Overnutrition causes a demand for high rates of insulin secretion, ultimately leading to ER stress in β-cells that results in loss of β-cell mass. Amylin, another product of pancreatic islets, is hypersecreted under these conditions and accumulates as amyloid plaques, leading to β-cell damage and death. Metabolic stress, ER stress and amyloid-mediated cytotoxicity represent a 'perfect storm' that leads to β-cell failure, heralding the onset of full-blown type 2 diabetes.

  • Given the multiple organs that are affected by these diverse mechanisms, it is not surprising that there is currently no single drug that delivers fully efficacious and long-lasting therapy for type 2 diabetes. Future work must focus on battling the root causes of this disease, including excessive food intake, energy imbalance and inflammatory responses.

Abstract

Nearly unlimited supplies of energy-dense foods and technologies that encourage sedentary behaviour have introduced a new threat to the survival of our species: obesity and its co-morbidities. Foremost among the co-morbidities is type 2 diabetes, which is projected to afflict 300 million people worldwide by 2020. Compliance with lifestyle modifications such as reduced caloric intake and increased physical activity has proved to be difficult for the general population, meaning that pharmacological intervention may be the only recourse for some. This epidemiological reality heightens the urgency for gaining a deeper understanding of the processes that cause metabolic failure of key tissues and organ systems in type 2 diabetes, as reviewed here.

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Figure 1: Metabolic overload in the liver and skeletal muscle.
Figure 2: Biochemical mechanisms of glucose-stimulated insulin secretion, including roles of the pyrvuate cycling pathways of the β-cell.
Figure 3: Mechanisms of β-cell failure in type 2 diabetes.

References

  1. Cohen, P. The twentieth century struggle to decipher insulin signalling. Nature Rev. Mol. Cell Biol. 7, 867–873 (2006). A useful review of insulin signalling as it relates to metabolic control.

    CAS  Google Scholar 

  2. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature Rev. Mol. Cell Biol. 7, 85–96 (2006). Detailed review of the molecular pathway of insulin signalling.

    CAS  Google Scholar 

  3. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Science 372, 425–432 (1994).

    CAS  Google Scholar 

  4. Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

    CAS  PubMed  Google Scholar 

  5. Trujillo, M. E. & Scherer, P. E. Adipose tissue-derived factors: impact on health and disease. Endocr. Rev. 27, 762–778 (2006).

    CAS  PubMed  Google Scholar 

  6. Sethi, J. K. & Vidal-Puig, A. J. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J. Lipid Res. 48, 1253–1262 (2007).

    CAS  PubMed  Google Scholar 

  7. Reitman, M. L. & Gavrilova, O. A-ZIP/F-1 mice lacking white fat: a model for understanding lipoatrophic diabetes. Int. J. Obes. Relat. Metab. Disord. 24 (Suppl. 4), S11–S14 (2000).

    CAS  PubMed  Google Scholar 

  8. Gavrilova, O. et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J. Clin. Invest. 105, 271–278 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. & Goldstein, J. L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76 (1999).

    CAS  PubMed  Google Scholar 

  10. Ebihara, K. et al. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 50, 1440–1448 (2001).

    CAS  PubMed  Google Scholar 

  11. Colombo, C. et al. Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes 51, 2727–2733 (2002).

    CAS  PubMed  Google Scholar 

  12. Oral, E. A. et al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med. 346, 570–578 (2002).

    CAS  PubMed  Google Scholar 

  13. Abel, E. D. et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409, 729–733 (2001).

    CAS  PubMed  Google Scholar 

  14. Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005).

    CAS  PubMed  Google Scholar 

  15. Sivitz, W. I., Desautel, S. L., Kayano, T., Bell, G. I. & Pessin, J. E. Regulation of glucose transporter messenger-RNA in insulin-deficient states. Nature 340, 72–74 (1989).

    CAS  PubMed  Google Scholar 

  16. Muoio, D. M. & Newgard, C. B. Metabolism: A is for adipokine. Nature 436, 337–338 (2005).

    CAS  PubMed  Google Scholar 

  17. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKKβ. Science 293, 1673–1677 (2001).

    CAS  PubMed  Google Scholar 

  19. Kim, J. K. et al. Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest. 108, 437–446 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, M. & Robertson, R. P. Effects of prostaglandin synthesis inhibitors on human insulin secretion and carbohydrates tolerance. Prostaglandins 18, 557–567 (1979).

    CAS  PubMed  Google Scholar 

  21. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nature Med. 11, 183–190 (2005). Demonstrates that hepatic inflammatory pathways contribute to insulin resistance.

    CAS  PubMed  Google Scholar 

  22. Arkan, M. C. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nature Med. 11, 191–198 (2005). Demonstrates the importance of myeloid cells in inflammatory pathways of insulin resistance.

    CAS  PubMed  Google Scholar 

  23. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen, A. et al. Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes. Res. 13, 1311–1320 (2005).

    CAS  PubMed  Google Scholar 

  25. McGarry, J. D. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51, 7–18 (2002).

    CAS  PubMed  Google Scholar 

  26. Li, X., Monks, B., Ge, Q. & Birnbaum, M. J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator. Nature 447, 1012–1016 (2007).

    CAS  PubMed  Google Scholar 

  27. Griffin, M. E. et al. Free fatty acid induced insulin resistance is associated with activation of protein kinase Cθ and alterations in the insulin signaling cascade. Diabetes 48, 1270–1274 (1999).

    CAS  PubMed  Google Scholar 

  28. Chavez, J. A., Holland, W. L., Bar, J., Sandhoff, K. & Summers, S. A. Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. J. Biol. Chem. 280, 20148–20153 (2005).

    CAS  PubMed  Google Scholar 

  29. Chavez, J. A. & Summers, S. A. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch. Biochem. Biophys. 419, 101–109 (2003).

    CAS  PubMed  Google Scholar 

  30. Neschen, S. et al. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice. Cell Metab. 2, 55–65 (2005).

    CAS  PubMed  Google Scholar 

  31. Abu-Elheiga, L., Oh, W., Kordari, P. & Wakil, S. J. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc. Natl Acad. Sci. USA 100, 10207–10212 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Savage, D. B. et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J. Clin. Invest 116, 817–824 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007). Pharmacological or genetic inhibition of ceramide synthesis protected rodents against insulin resistance induced by administration of dexamethasone or lipid infusion with saturated fatty acids.

    CAS  PubMed  Google Scholar 

  34. Petersen, K. F. et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54, 603–608 (2005).

    CAS  PubMed  Google Scholar 

  35. Hulver, M. W. et al. Skeletal muscle lipid metabolism with obesity. Am. J. Physiol. Endocrinol. Metab. 284, E741–E747 (2003).

    CAS  PubMed  Google Scholar 

  36. Shulman, G. I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu, L. et al. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J. Clin. Invest. 117, 1679–1689 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Muoio, D. M. & Newgard, C. B. Obesity-related derangements in metabolic regulation. Annu. Rev. Biochem. 75, 367–401 (2006).

    CAS  PubMed  Google Scholar 

  39. Koves, T. R. et al. Peroxisome proliferator-activated receptor-γ co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J. Biol. Chem. 280, 33588–33598 (2005). Provides key evidence for association of muscle insulin resistance with high rates of incomplete fat oxidation and accumulation of fatty acid-derived acylcarnitines.

    CAS  PubMed  Google Scholar 

  40. An, J. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nature Med. 10, 268–274 (2004).

    CAS  PubMed  Google Scholar 

  41. Koves, T. R. et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7, 45–56 (2008).

    CAS  PubMed  Google Scholar 

  42. Kelley, D. E., Goodpaster, B., Wing, R. R. & Simoneau, J. A. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am. J. Physiol. 277, E1130–E1141 (1999). This paper introduces the concept of 'metabolic inflexibility', or the failure of obese, insulin-resistant individuals to switch normally from glucose to lipid oxidation in an overnight fast.

    CAS  PubMed  Google Scholar 

  43. Finck, B. N. et al. A potential link between muscle peroxisome proliferator-activated receptor-a signaling and obesity-related diabetes. Cell Metab. 1, 133–144 (2005).

    CAS  PubMed  Google Scholar 

  44. Savage, D. B., Petersen, K. F. & Shulman, G. I. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol. Rev. 87, 507–520 (2007). This review provides a strong case for hepatic steatosis as an important element of liver insulin resistance.

    CAS  PubMed  Google Scholar 

  45. Ritov, V. B. et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 54, 8–14 (2005).

    CAS  PubMed  Google Scholar 

  46. Patti, M. E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc. Natl Acad. Sci. USA 100, 8466–8471 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003). Describes the coordinate regulation of key oxidative enzymes by PGC1 α.

    CAS  PubMed  Google Scholar 

  48. Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002). Demonstrates the impaired function of the electron transport chain in skeletal muscle mitochondria from obese and type 2 diabetic individuals.

    CAS  PubMed  Google Scholar 

  49. Morino, K., Petersen, K. F. & Shulman, G. I. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55 (Suppl. 2), S9–S15 (2006).

    CAS  PubMed  Google Scholar 

  50. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).

    CAS  PubMed  Google Scholar 

  51. Perseghin, G., Petersen, K. & Shulman, G. I. Cellular mechanism of insulin resistance: potential links with inflammation. Int. J. Obes. Relat. Metab. Disord. 27, S6–S11 (2003).

    CAS  PubMed  Google Scholar 

  52. Saltiel, A. R. & Pessin, J. E. Insulin signaling pathways in time and space. Trends Cell Biol. 12, 65–71 (2002).

    CAS  PubMed  Google Scholar 

  53. Shoelson, S. E., Lee, J. & Yuan, M. Inflammation and the IKKβ/I-κB/NF-κB axis in obesity- and diet-induced insulin resistance. Int. J. Obes. Relat. Metab. Disord. 27 (Suppl. 3), S49–S52 (2003).

    CAS  PubMed  Google Scholar 

  54. Nagle, C. A. et al. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. J. Biol. Chem. 282, 14807–14815 (2007).

    CAS  PubMed  Google Scholar 

  55. Hammond, L. E. et al. Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs. J. Biol. Chem. 280, 25629–25636 (2005).

    CAS  PubMed  Google Scholar 

  56. Samuel, V. T. et al. Inhibition of protein kinase Cɛ prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest 117, 739–745 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kim, J. K. et al. PKC-θ knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest 114, 823–827 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Serra, C. et al. Transgenic mice with dominant negative PKC-θ in skeletal muscle: a new model of insulin resistance and obesity. J. Cell Physiol. 196, 89–97 (2003).

    CAS  PubMed  Google Scholar 

  59. Gao, Z. et al. Inactivation of PKCθ leads to increased susceptibility to obesity and dietary insulin resistance in mice. Am. J. Physiol. Endocrinol. Metab. 292, E84–E91 (2007).

    CAS  PubMed  Google Scholar 

  60. Felig, P., Wahren, J., Hendler, R. & Brundin, T. Splanchnic glucose and amino acid metabolism in obesity. J. Clin. Invest. 53, 582–590 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Krebs, M. et al. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes 51, 599–605 (2002).

    CAS  PubMed  Google Scholar 

  62. Tremblay, F. et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54, 2674–2684 (2005).

    CAS  PubMed  Google Scholar 

  63. Krebs, M. et al. Direct and indirect effects of amino acids on hepatic glucose metabolism in humans. Diabetologia 46, 917–925 (2003).

    CAS  PubMed  Google Scholar 

  64. Um, S. H., D'Alessio, D. & Thomas, G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab. 3, 393–402 (2006).

    CAS  PubMed  Google Scholar 

  65. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    PubMed  Google Scholar 

  66. Ozcan, U. et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137–1140 (2006). Provides strong evidence for ER stress as a major component of insulin resistance, including studies showing the reversal of diabetes using small-molecule chemical chaperones.

    PubMed  PubMed Central  Google Scholar 

  67. Newgard, C. B. & McGarry, J. D. Metabolic coupling factors in pancreatic β-cell signal transduction. Annu. Rev. Biochem. 64, 689–719 (1995).

    CAS  PubMed  Google Scholar 

  68. Newgard, C. B. & Matschinsky, F. M. Handbook of Physiology Vol. II (eds Jefferson, J. & Cherrington, A.) 125–152 (Oxford University Press, 2001). A comprehensive overview of pathways of fuel-stimulated insulin secretion.

    Google Scholar 

  69. Henquin, J. C., Ravier, M. A., Nenquin, M., Jonas, J. C. & Gilon, P. Hierarchy of the β-cell signals controlling insulin secretion. Eur. J. Clin. Invest. 33, 742–750 (2003). An elegant model for organizing stimulus- and secretion-coupling factors for insulin secretion into triggering and amplifying signals.

    CAS  PubMed  Google Scholar 

  70. Nenquin, M., Szollosi, A., Aguilar-Bryan, L., Bryan, J. & Henquin, J. C. Both triggering and amplifying pathways contribute to fuel-induced insulin secretion in the absence of sulfonylurea receptor-1 in pancreatic β-cells. J. Biol. Chem. 279, 32316–32324 (2004).

    CAS  PubMed  Google Scholar 

  71. Khan, A., Ling, Z. C. & Landau, B. R. Quantifying the carboxylation of pyruvate in pancreatic islets. J. Biol. Chem. 271, 2539–2542 (1996).

    CAS  PubMed  Google Scholar 

  72. MacDonald, M. J. Estimates of glycolysis, pyruvate (de)carboxylation, pentose phosphate pathway, and methyl succinate metabolism in incapacitated pancreatic islets. Arch. Biochem. Biophys. 305, 205–214 (1993).

    CAS  PubMed  Google Scholar 

  73. Schuit, F. et al. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in β cells. J. Biol. Chem. 272, 18572–18579 (1997).

    CAS  PubMed  Google Scholar 

  74. Lu, D. et al. 13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS). Proc. Natl Acad. Sci. USA 99, 2708–2713 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. MacDonald, M. J. Feasibility of a mitochondrial pyruvate malate shuttle in pancreatic islets. Further implication of cytosolic NADPH in insulin secretion. J. Biol. Chem. 270, 20051–20058 (1995).

    CAS  PubMed  Google Scholar 

  76. Boucher, A. et al. Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue. J. Biol. Chem. 279, 27263–27271 (2004). Demonstrates abrogation of the normal glucose-induced increment in pyruvate cycling during lipid-induced functional impairment of the β-cell.

    CAS  PubMed  Google Scholar 

  77. Cline, G. W., Lepine, R. L., Papas, K. K., Kibbey, R. G. & Shulman, G. I. 13C NMR isotopomer analysis of anaplerotic pathways in INS-1 cells. J. Biol. Chem. 279, 44370–44375 (2004).

    CAS  PubMed  Google Scholar 

  78. Jensen, M. V. et al. Compensatory responses to pyruvate carboxylase suppression in islet β-cells. Preservation of glucose-stimulated insulin secretion. J. Biol. Chem. 281, 22342–22351 (2006).

    CAS  PubMed  Google Scholar 

  79. Joseph, J. W. et al. The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion. J. Biol. Chem. 281, 35624–35632 (2006).

    CAS  PubMed  Google Scholar 

  80. Ronnebaum, S. M. et al. A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion. J. Biol. Chem. 281, 30593–30602 (2006). Demonstrates a key role for a pyruvate–isocitrate cycle in the control of glucose-stimulated insulin secretion.

    CAS  PubMed  Google Scholar 

  81. Joseph, J. W. et al. Normal flux through ATP-citrate lyase or fatty acid synthase is not required for glucose-stimulated insulin secretion. J. Biol. Chem. 282, 31592–31600 (2007).

    CAS  PubMed  Google Scholar 

  82. MacDonald, M. J. et al. Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. Am. J. Physiol. Endocrinol. Metab. 288, E1–E15 (2005). A thorough and insightful review from one of the leaders in the field.

    CAS  PubMed  Google Scholar 

  83. Kibbey, R. G. et al. Mitochondrial GTP regulates glucose-stimulated insulin secretion. Cell Metab. 5, 253–264 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Rabaglia, M. E. et al. α-ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice. Am. J. Physiol Endocrinol. Metab. 289, E218–E224 (2005).

    CAS  PubMed  Google Scholar 

  85. Unger, R. H. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44, 863–870 (1995).

    CAS  PubMed  Google Scholar 

  86. Finegood, D. T. et al. β-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 50, 1021–1029 (2001).

    CAS  PubMed  Google Scholar 

  87. Butler, A. E. et al. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003). Important demonstration of the loss of β-cell mass in human type 2 diabetes.

    CAS  PubMed  Google Scholar 

  88. Stoehr, J. P. et al. Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci. Diabetes 49, 1946–1954 (2000).

    CAS  PubMed  Google Scholar 

  89. Winter, W. E., Nakamura, M. & House, D. V. Monogenic diabetes mellitus in youth. The MODY syndromes. Endocrinol. Metab. Clin. North Am. 28, 765–785 (1999).

    CAS  PubMed  Google Scholar 

  90. Chen, C., Hosokawa, H., Bumbalo, L. M. & Leahy, J. L. Regulatory effects of glucose on the catalytic activity and cellular content of glucokinase in the pancreatic β cell. Study using cultured rat islets. J. Clin. Invest. 94, 1616–1620 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Khaldi, M. Z., Guiot, Y., Gilon, P., Henquin, J. C. & Jonas, J. C. Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose. Am. J. Physiol. Endocrinol. Metab. 287, E207–E217 (2004).

    CAS  PubMed  Google Scholar 

  92. Poitout, V. & Robertson, R. P. Minireview: secondary β-cell failure in type 2 diabetes — a convergence of glucotoxicity and lipotoxicity. Endocrinology 143, 339–342 (2002).

    CAS  PubMed  Google Scholar 

  93. Prentki, M., Joly, E., El-Assaad, W. & Roduit, R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in β-cell adaptation and failure in the etiology of diabetes. Diabetes 51 (Suppl. 3), S405–S413 (2002).

    CAS  PubMed  Google Scholar 

  94. Zhou, Y. P. & Grill, V. E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J. Clin. Invest. 93, 870–876 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhou, Y. P. & Grill, V. E. Palmitate-induced β-cell insensitivity to glucose is coupled to decreased pyruvate dehydrogenase activity and enhanced kinase activity in rat pancreatic islets. Diabetes 44, 394–399 (1995).

    CAS  PubMed  Google Scholar 

  96. Segall, L. et al. Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells. Am. J. Physiol. 277, E521–E528 (1999).

    CAS  PubMed  Google Scholar 

  97. Liu, Y. Q., Tornheim, K. & Leahy, J. L. Glucose-fatty acid cycle to inhibit glucose utilization and oxidation is not operative in fatty acid-cultured islets. Diabetes 48, 1747–1753 (1999).

    CAS  PubMed  Google Scholar 

  98. Assimacopoulos-Jeannet, F. et al. Fatty acids rapidly induce the carnitine palmitoyltransferase 1 gene in the pancreatic β-cell line INS-1. J. Biol. Chem. 272, 1659–1664 (1997).

    CAS  PubMed  Google Scholar 

  99. Liu, Y. Q., Jetton, T. L. & Leahy, J. L. β-cell adaptation to insulin resistance. Increased pyruvate carboxylase and malate-pyruvate shuttle activity in islets of nondiabetic Zucker fatty rats. J. Biol. Chem. 277, 39163–39168 (2002).

    CAS  PubMed  Google Scholar 

  100. Medvedev, A. V. et al. Regulation of the uncoupling protein-2 gene in INS-1 β-cells by oleic acid. J. Biol. Chem. 277, 42639–42644 (2002).

    CAS  PubMed  Google Scholar 

  101. Joseph, J. W. et al. Free fatty acid-induced β-cell defects are dependent on uncoupling protein 2 expression. J. Biol. Chem. 279, 51049–51056 (2004).

    CAS  PubMed  Google Scholar 

  102. Zhang, C. Y. et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes. Cell 105, 745–755 (2001).

    CAS  PubMed  Google Scholar 

  103. Chan, C. B., Saleh, M. C., Koshkin, V. & Wheeler, M. B. Uncoupling protein 2 and islet function. Diabetes 53 (Suppl. 1), S136–S142 (2004).

    CAS  PubMed  Google Scholar 

  104. Joseph, J. W. et al. Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51, 3211–3219 (2002).

    CAS  PubMed  Google Scholar 

  105. Moore, P. C., Ugas, M. A., Hagman, D. K., Parazzoli, S. D. & Poitout, V. Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion. Diabetes 53, 2610–2616 (2004).

    CAS  PubMed  Google Scholar 

  106. Robertson, R. P. & Harmon, J. S. Diabetes, glucose toxicity, and oxidative stress: a case of double jeopardy for the pancreatic islet β cell. Free Radic. Biol. Med. 41, 177–184 (2006).

    CAS  PubMed  Google Scholar 

  107. Harding, H. P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in Perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153–1163 (2001).

    CAS  PubMed  Google Scholar 

  108. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001).

    CAS  PubMed  Google Scholar 

  109. Scheuner, D. et al. Control of mRNA translation preserves endoplasmic reticulum function in β cells and maintains glucose homeostasis. Nature Med. 11, 757–764 (2005). Demonstrates a potential role for ER stress pathways in the development of β-cell failure of type 2 diabetes.

    CAS  PubMed  Google Scholar 

  110. Westermark, P., Wernstedt, C., O'Brien, T. D., Hayden, D. W. & Johnson, K. H. Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. Am. J. Pathol. 127, 414–417 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Cooper, G. J. et al. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc. Natl Acad. Sci. USA 84, 8628–8632 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Matveyenko, A. V. & Butler, P. C. β-cell deficit due to increased apoptosis in the human islet amyloid polypeptide transgenic (HIP) rat recapitulates the metabolic defects present in type 2 diabetes. Diabetes 55, 2106–2114 (2006). Demonstrates that overproduction of human amylin in a rodent model can lead to β-cell failure resembling that of human diabetes.

    CAS  PubMed  Google Scholar 

  113. Sano, H. et al. Rab10, a target of the AS160 rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metab. 5, 293–303 (2007).

    CAS  PubMed  Google Scholar 

  114. Lazar, D. F. & Saltiel, A. R. Lipid phosphatases as drug discovery targets for type 2 diabetes. Nature Rev. Drug Discov. 5, 333–342 (2006).

    CAS  Google Scholar 

  115. Delibegovic, M. et al. Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B (PTP1B). Mol. Cell. Biol. 27, 7727–7734 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Xue, B. et al. Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. J. Biol. Chem. 282, 23829–23840 (2007).

    CAS  PubMed  Google Scholar 

  117. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Uno, K. et al. Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science 312, 1656–1659 (2006).

    CAS  PubMed  Google Scholar 

  119. He, W., Lam, T. K., Obici, S. & Rossetti, L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nature Neurosci. 9, 227–233 (2006).

    CAS  PubMed  Google Scholar 

  120. Lam, T. K., Gutierrez-Juarez, R., Pocai, A. & Rossetti, L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943–947 (2005).

    CAS  PubMed  Google Scholar 

  121. Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).

    CAS  PubMed  Google Scholar 

  122. MacDonald, P. E. et al. Antagonism of rat β-cell voltage-dependent K+ currents by exendin 4 requires dual activation of the cAMP/protein kinase A and phosphatidylinositol 3-kinase signaling pathways. J. Biol. Chem. 278, 52446–52453 (2003).

    CAS  PubMed  Google Scholar 

  123. Dulubova, I. et al. A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? EMBO J. 24, 2839–2850 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Shibasaki, T., Sunaga, Y., Fujimoto, K., Kashima, Y. & Seino, S. Interaction of ATP sensor, cAMP sensor, Ca2+ sensor, and voltage-dependent Ca2+ channel in insulin granule exocytosis. J. Biol. Chem. 279, 7956–7961 (2004).

    CAS  PubMed  Google Scholar 

  125. Briscoe, C. P. et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 278, 11303–11311 (2003).

    CAS  PubMed  Google Scholar 

  126. Itoh, Y. et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 422, 173–176 (2003).

    CAS  PubMed  Google Scholar 

  127. Steneberg, P., Rubins, N., Bartoov-Shifman, R., Walker, M. D. & Edlund, H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab. 1, 245–258 (2005).

    CAS  PubMed  Google Scholar 

  128. Latour, M. G. et al. GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo. Diabetes 56, 1087–1094 (2007).

    CAS  PubMed  Google Scholar 

  129. Ostenson, C. G., Gaisano, H., Sheu, L., Tibell, A. & Bartfai, T. Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients. Diabetes 55, 435–440 (2006).

    CAS  PubMed  Google Scholar 

  130. Kohlroser, J., Mathai, J., Reichheld, J., Banner, B. F. & Bonkovsky, H. L. Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am. J. Gastroenterol. 95, 272–276 (2000).

    CAS  PubMed  Google Scholar 

  131. Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457–2471 (2007).

    CAS  PubMed  Google Scholar 

  132. Bray, G. A. & Ryan, D. H. Drug treatment of the overweight patient. Gastroenterology 132, 2239–2252 (2007).

    CAS  PubMed  Google Scholar 

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Correspondence to Christopher B. Newgard.

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DATABASES

OMIM

MODY1

MODY2

MODY4

Entrez Gene

leptin

Degs1

Xbp1

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Glossary

Hyperglycaemia

An abnormal elevation in blood glucose levels. The American Diabetes Association currently considers a fasting blood glucose of >126 mg ml−1 as the cut-off for diabetes.

Adipokine

A peptide hormone or cytokine that is produced and secreted by adipocytes, which regulate fuel use and storage in other peripheral tissues.

Hyperphagia

Abnormal or continuous food ingestion.

Hyperlipidaemia

An abnormal elevation of circulating lipids, including triglycerides, free fatty acids and low-density lipoproteins, often accompanied by a decrease in high-density lipoprotein.

Hypoglycaemia

An abnormally low blood glucose level. Humans with blood glucose levels below 50 mg ml−1 are considered to be hypoglycaemic and manifest symptoms that are related to an inadequate delivery rate of glucose to the brain.

Hepatic steatosis

The accumulation of stored lipids, most notably triglycerides, to abnormally high levels in the liver.

Vagotomy

Division of fibres of the vagus nerve by surgery, a technique that is used to diminish acid secretion of the stomach.

Acylcarnitine

One of a family of carnitine esters that are derived from acetyl CoA and acyl CoA intermediates of fatty acid and amino acid catabolism.

Unfolded protein response

A transcriptional program that functions to slow protein synthesis and promote protein degradation in response to the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum.

Anaplerotic

Repletion of the tricarboxylic acid cycle with intermediates that can condense with acetyl CoA to form citrate.

Pyruvate cycling

The exchange of pyruvate with intermediates from the tricarboxylic acid cycle.

Insulinoma cell line

A cell line that is derived from rodent pancreatic islet β-cells that are transformed by oncogene expression or another means of transformation.

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Muoio, D., Newgard, C. Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9, 193–205 (2008). https://doi.org/10.1038/nrm2327

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