Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Insulin action and resistance in obesity and type 2 diabetes

Nature Medicine volume 23, pages 804–814 (2017)Cite this article

Subjects

Abstract

Nutritional excess is a major forerunner of type 2 diabetes. It enhances the secretion of insulin, but attenuates insulin's metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes, pointing to a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity seems to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletal muscle. These and other advances over the past 5 years offer exciting opportunities and daunting challenges for the development of new therapeutic strategies for the treatment of type 2 diabetes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A model for how HFD feeding and obesity induce insulin resistance, thereby resulting in hyperglycemia and hyperlipidemia.
Figure 2: Effect of a HFD and/or obesity on liver and adipose metabolism.
Figure 3: A model for how HFD feeding and obesity induce hyperinsulinemia and thereby result in insulin resistance, hyperglycemia and hyperlipidemia.
Figure 4: The effects of modulating insulin levels on energy expenditure, adipose browning glucose intolerance and the liver in mice on a high-fat diet.
Figure 5: Adipocyte pathways downstream of insulin signaling to Akt disrupted by HFD feeding and obesity (denoted by asterisks) may contribute to systemic insulin resistance in mice and humans.

Similar content being viewed by others

References

  1. Reaven, G.M. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu. Rev. Nutr. 25, 391–406 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. US Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014 (CDC, 2014); available at https://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf.

  3. Klöting, N. et al. Insulin-sensitive obesity. Am. J. Physiol. Endocrinol. Metab. 299, E506–E515 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. DeFronzo, R.A., Bonadonna, R.C. & Ferrannini, E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15, 318–368 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Kim, S.H. & Reaven, G.M. Insulin resistance and hyperinsulinemia: you can't have one without the other. Diabetes Care 31, 1433–1438 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McGarry, J.D. What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258, 766–770 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Shanik, M.H. et al. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31 (Suppl. 2), S262–S268 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Pories, W.J. & Dohm, G.L. Diabetes: have we got it all wrong? Hyperinsulinism as the culprit: surgery provides the evidence. Diabetes Care 35, 2438–2442 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Corkey, B.E. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes 61, 4–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Boucher, J., Kleinridders, A. & Kahn, C.R. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 6, a009191 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Parker, V.E., Savage, D.B., O'Rahilly, S. & Semple, R.K. Mechanistic insights into insulin resistance in the genetic era. Diabet. Med. 28, 1476–1486 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Klotz, L.O. et al. Redox regulation of FoxO transcription factors. Redox Biol. 6, 51–72 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ryder, J.W., Gilbert, M. & Zierath, J.R. Skeletal muscle and insulin sensitivity: pathophysiological alterations. Front. Biosci. 6, d154–d163 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Pendergrass, M. et al. Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals. Am. J. Physiol. Endocrinol. Metab. 292, E92–E100 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Nakae, J., Barr, V. & Accili, D. Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. EMBO J. 19, 989–996 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gross, D.N., van den Heuvel, A.P. & Birnbaum, M.J. The role of FoxO in the regulation of metabolism. Oncogene 27, 2320–2336 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Titchenell, P.M. et al. Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production. Cell Metab. 23, 1154–1166 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qu, S. et al. Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology 147, 5641–5652 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Ozcan, L. et al. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab. 15, 739–751 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Banks, A.S. et al. Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice. Cell Metab. 14, 587–597 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, W. et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 281, 10105–10117 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Perry, R.J. et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160, 745–758 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cherrington, A.D., Edgerton, D. & Sindelar, D.K. The direct and indirect effects of insulin on hepatic glucose production in vivo. Diabetologia 41, 987–996 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Rebrin, K., Steil, G.M., Mittelman, S.D. & Bergman, R.N. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J. Clin. Invest. 98, 741–749 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schoiswohl, G. et al. Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice. Endocrinology 156, 3610–3624 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kimmel, A.R. & Sztalryd, C. The perilipins: major cytosolic lipid droplet-associated proteins and their roles in cellular lipid storage, mobilization, and systemic homeostasis. Annu. Rev. Nutr. 36, 471–509 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Puri, V. et al. Cidea is associated with lipid droplets and insulin sensitivity in humans. Proc. Natl. Acad. Sci. USA 105, 7833–7838 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gandotra, S. et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N. Engl. J. Med. 364, 740–748 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rubio-Cabezas, O. et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol. Med. 1, 280–287 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhou, L. et al. Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice. Nat. Commun. 6, 5949 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Lotta, L.A. et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat. Genet. 49, 17–26 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Tran, T.T., Yamamoto, Y., Gesta, S. & Kahn, C.R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Min, S.Y. et al. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat. Med. 22, 312–318 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Biddinger, S.B. et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 7, 125–134 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brown, M.S. & Goldstein, J.L. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95–96 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Caron, A., Richard, D. & Laplante, M. The roles of mTOR complexes in lipid metabolism. Annu. Rev. Nutr. 35, 321–348 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Bar-Peled, L. & Sabatini, D.M. Regulation of mTORC1 by amino acids. Trends Cell Biol. 24, 400–406 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Beck-Nielsen, H. The role of glycogen synthase in the development of hyperglycemia in type 2 diabetes: 'To store or not to store glucose, that's the question'. Diabetes Metab. Res. Rev. 28, 635–644 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Beck-Nielsen, H., Henriksen, J.E., Vaag, A. & Hother-Nielsen, O. Pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Res. Clin. Pract. 28 (Suppl. ), S13–S25 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Nolan, C.J., Ruderman, N.B., Kahn, S.E., Pedersen, O. & Prentki, M. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. Diabetes 64, 673–686 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Corkey, B.E. Diabetes: have we got it all wrong? Insulin hypersecretion and food additives: cause of obesity and diabetes? Diabetes Care 35, 2432–2437 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Erion, K.A., Berdan, C.A., Burritt, N.E., Corkey, B.E. & Deeney, J.T. Chronic exposure to excess nutrients left-shifts the concentration dependence of glucose-stimulated insulin secretion in pancreatic β-cells. J. Biol. Chem. 290, 16191–16201 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, M.K., Reaven, G.M., Chen, Y.D., Kim, E. & Kim, S.H. Hyperinsulinemia in individuals with obesity: Role of insulin clearance. Obesity (Silver Spring) 23, 2430–2434 (2015).

    Article  CAS  Google Scholar 

  44. Kobayashi, M. & Olefsky, J.M. Effect of experimental hyperinsulinemia on insulin binding and glucose transport in isolated rat adipocytes. Am. J. Physiol. 235, E53–E62 (1978).

    CAS  PubMed  Google Scholar 

  45. Soop, M. et al. Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans. Am. J. Physiol. Endocrinol. Metab. 282, E1276–E1285 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Siklova-Vitkova, M. et al. Effect of hyperinsulinemia and very-low-calorie diet on interstitial cytokine levels in subcutaneous adipose tissue of obese women. Am. J. Physiol. Endocrinol. Metab. 297, E1154–E1161 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Murdolo, G. et al. Monocyte chemoattractant protein-1 in subcutaneous abdominal adipose tissue: characterization of interstitial concentration and regulation of gene expression by insulin. J. Clin. Endocrinol. Metab. 92, 2688–2695 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Westerbacka, J. et al. Acute in vivo effects of insulin on gene expression in adipose tissue in insulin-resistant and insulin-sensitive subjects. Diabetologia 49, 132–140 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Westerbacka, J. et al. Insulin regulation of MCP-1 in human adipose tissue of obese and lean women. Am. J. Physiol. Endocrinol. Metab. 294, E841–E845 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Krogh-Madsen, R., Plomgaard, P., Keller, P., Keller, C. & Pedersen, B.K. Insulin stimulates interleukin-6 and tumor necrosis factor-alpha gene expression in human subcutaneous adipose tissue. Am. J. Physiol. Endocrinol. Metab. 286, E234–E238 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Jansen, H.J. et al. Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue. Diabetologia 56, 2573–2581 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Lackey, D.E. & Olefsky, J.M. Regulation of metabolism by the innate immune system. Nat. Rev. Endocrinol. 12, 15–28 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Tsiotra, P.C., Boutati, E., Dimitriadis, G. & Raptis, S.A. High insulin and leptin increase resistin and inflammatory cytokine production from human mononuclear cells. BioMed Res. Int. 2013, 487081 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Pedersen, D.J. et al. A major role of insulin in promoting obesity-associated adipose tissue inflammation. Mol. Metab. 4, 507–518 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Roth Flach, R.J. et al. Protein kinase mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) promotes obesity-induced hyperinsulinemia. J. Biol. Chem. 291, 16221–16230 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Boden, G., Chen, X., Rosner, J. & Barton, M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes 44, 1239–1242 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Stein, D.T. et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J. Clin. Invest. 97, 2728–2735 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Deeney, J.T. et al. Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin-secreting cells (HIT T-15 and NMRI beta-cells). J. Biol. Chem. 275, 9363–9368 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Templeman, N.M., Clee, S.M. & Johnson, J.D. Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity. Diabetologia 58, 2392–2402 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mehran, A.E. et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16, 723–737 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. D'souza, A.M., Johnson, J.D., Clee, S.M. & Kieffer, T.J. Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lep(ob/ob) mice. Mol. Metab. 5, 1103–1112 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nedergaard, J. & Cannon, B. The browning of white adipose tissue: some burning issues. Cell Metab. 20, 396–407 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Liu, D. et al. Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning. J. Clin. Invest. 126, 1704–1716 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Marban, S.L.R.J. Transgenic Hyperinsulinemia: A Mouse Model of Insulin Resistance and Glucose Intolerance without Obesity (Shafrir E, Boston, Birkhauser, 1996).

  65. Pontiroli, A.E., Alberetto, M., Capra, F. & Pozza, G. The glucose clamp technique for the study of patients with hypoglycemia: insulin resistance as a feature of insulinoma. J. Endocrinol. Invest. 13, 241–245 (1990).

    Article  CAS  PubMed  Google Scholar 

  66. Manousaki, D. et al. Toward precision medicine: TBC1D4 disruption is common among the inuit and leads to underdiagnosis of type 2 diabetes. Diabetes Care 39, 1889–1895 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Chen, D.L. et al. Phenotypic characterization of insulin-resistant and insulin-sensitive obesity. J. Clin. Endocrinol. Metab. 100, 4082–4091 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Waise, T.M. et al. One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice. Biochem. Biophys. Res. Commun. 464, 1157–1162 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Turner, N. et al. Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia 56, 1638–1648 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Scherer, T. et al. Short term voluntary overfeeding disrupts brain insulin control of adipose tissue lipolysis. J. Biol. Chem. 287, 33061–33069 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Paglialunga, S., Ludzki, A., Root-McCaig, J. & Holloway, G.P. In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice. Diabetologia 58, 1071–1080 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Barzel, B. et al. Short term fat feeding rapidly increases plasma insulin but does not result in dyslipidaemia. Front. Physiol. 5, 469 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Ji, Y. et al. Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4. J. Biol. Chem. 287, 24378–24386 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee, Y.S. et al. Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes 60, 2474–2483 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ben-Shlomo, S. et al. Perinephric and epididymal fat affect hepatic metabolism in rats. Obesity (Silver Spring) 20, 151–156 (2012).

    Article  CAS  Google Scholar 

  76. Commerford, S.R. et al. Diets enriched in sucrose or fat increase gluconeogenesis and G-6-Pase but not basal glucose production in rats. Am. J. Physiol. Endocrinol. Metab. 283, E545–E555 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Boden, G. et al. Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men. Sci. Transl. Med. 7, 304re7 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Brøns, C. et al. Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J. Physiol. (Lond.) 587, 2387–2397 (2009).

    Article  CAS  Google Scholar 

  79. Lagerpusch, M., Bosy-Westphal, A., Kehden, B., Peters, A. & Müller, M.J. Effects of brief perturbations in energy balance on indices of glucose homeostasis in healthy lean men. Int. J. Obes. 36, 1094–1101 (2012).

    Article  CAS  Google Scholar 

  80. Olefsky, J., Crapo, P.A., Ginsberg, H. & Reaven, G.M. Metabolic effects of increased caloric intake in man. Metabolism 24, 495–503 (1975).

    Article  CAS  PubMed  Google Scholar 

  81. Wadden, D. et al. Serum acylated ghrelin concentrations in response to short-term overfeeding in normal weight, overweight, and obese men. PLoS One 7, e45748 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cahill, F., Shea, J.L., Randell, E., Vasdev, S. & Sun, G. Serum peptide YY in response to short-term overfeeding in young men. Am. J. Clin. Nutr. 93, 741–747 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Numao, S. et al. Effects of a single bout of aerobic exercise on short-term low-carbohydrate/high-fat intake-induced postprandial glucose metabolism during an oral glucose tolerance test. Metabolism 62, 1406–1415 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Drucker, D.J. Deciphering metabolic messages from the gut drives therapeutic innovation: the 2014 Banting Lecture. Diabetes 64, 317–326 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Perry, R.J. et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lo, J.C. et al. Adipsin is an adipokine that improves β cell function in diabetes. Cell 158, 41–53 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kraegen, E.W. et al. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 40, 1397–1403 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Abdul-Ghani, M.A., Jenkinson, C.P., Richardson, D.K., Tripathy, D. & DeFronzo, R.A. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 55, 1430–1435 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Samuel, V.T. & Shulman, G.I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J. Clin. Invest. 126, 12–22 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Copps, K.D. & White, M.F. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55, 2565–2582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Petersen, M.C. et al. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J. Clin. Invest. 126, 4361–4371 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Chaurasia, B. & Summers, S.A. Ceramides – Lipotoxic Inducers of Metabolic Disorders. Trends Endocrinol. Metab. 26, 538–550 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Zhang, C. et al. Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol. J. Biol. Chem. 290, 3519–3528 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Guilherme, A., Virbasius, J.V., Puri, V. & Czech, M.P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kang, S., Tsai, L.T. & Rosen, E.D. Nuclear mechanisms of insulin resistance. Trends Cell Biol. 26, 341–351 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kusminski, C.M., Bickel, P.E. & Scherer, P.E. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat. Rev. Drug Discov. 15, 639–660 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. Newgard, C.B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sabio, G. & Davis, R.J. cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance. Trends Biochem. Sci. 35, 490–496 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hoehn, K.L. et al. IRS1-independent defects define major nodes of insulin resistance. Cell Metab. 7, 421–433 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mîinea, C.P. et al. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J. 391, 87–93 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sun, K. et al. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat. Commun. 5, 3485 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Barrett, E.J., Wang, H., Upchurch, C.T. & Liu, Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am. J. Physiol. Endocrinol. Metab. 301, E252–E263 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lee, W.L. & Klip, A. Endothelial transcytosis of insulin: does it contribute to insulin resistance? Physiology (Bethesda) 31, 336–345 (2016).

    CAS  Google Scholar 

  104. Williams, A.S., Kang, L. & Wasserman, D.H. The extracellular matrix and insulin resistance. Trends Endocrinol. Metab. 26, 357–366 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Williams, A.S. et al. Integrin α1-null mice exhibit improved fatty liver when fed a high fat diet despite severe hepatic insulin resistance. J. Biol. Chem. 290, 6546–6557 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kang, L. et al. Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin α2β1 in mice. Diabetes 60, 416–426 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kang, L. et al. Integrin-linked kinase in muscle is necessary for the development of insulin resistance in diet-induced obese mice. Diabetes 65, 1590–1600 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Abdennour, M. et al. Association of adipose tissue and liver fibrosis with tissue stiffness in morbid obesity: links with diabetes and BMI loss after gastric bypass. J. Clin. Endocrinol. Metab. 99, 898–907 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Corvera, S. & Gealekman, O. Adipose tissue angiogenesis: impact on obesity and type-2 diabetes. Biochim. Biophys. Acta 1842, 463–472 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Gealekman, O. et al. Control of adipose tissue expandability in response to high fat diet by the insulin-like growth factor-binding protein-4. J. Biol. Chem. 289, 18327–18338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Furler, S.M., Jenkins, A.B., Storlien, L.H. & Kraegen, E.W. In vivo location of the rate-limiting step of hexose uptake in muscle and brain tissue of rats. Am. J. Physiol. 261, E337–E347 (1991).

    CAS  PubMed  Google Scholar 

  112. Zierath, J.R., Krook, A. & Wallberg-Henriksson, H. Insulin action in skeletal muscle from patients with NIDDM. Mol. Cell. Biochem. 182, 153–160 (1998).

    Article  CAS  PubMed  Google Scholar 

  113. Turner, N., Cooney, G.J., Kraegen, E.W. & Bruce, C.R. Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J. Endocrinol. 220, T61–T79 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Bonadonna, R.C. et al. Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM. Diabetes 45, 915–925 (1996).

    Article  PubMed  Google Scholar 

  115. Cline, G.W. et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N. Engl. J. Med. 341, 240–246 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Petersen, K.F. & Shulman, G.I. Cellular mechanism of insulin resistance in skeletal muscle. J. R. Soc. Med. 95 (Suppl. 42), 8–13 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Kelley, D.E. et al. The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. J. Clin. Invest. 97, 2705–2713 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Williams, K.V., Price, J.C. & Kelley, D.E. Interactions of impaired glucose transport and phosphorylation in skeletal muscle insulin resistance: a dose-response assessment using positron emission tomography. Diabetes 50, 2069–2079 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Perry, R.J., Zhang, D., Zhang, X.M., Boyer, J.L. & Shulman, G.I. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347, 1253–1256 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Montgomery, M.K. & Turner, N. Mitochondrial dysfunction and insulin resistance: an update. Endocr. Connect. 4, R1–R15 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Patti, M.E. & Corvera, S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr. Rev. 31, 364–395 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Czech, M.P. Cellular basis of insulin insensitivity in large rat adipocytes. J. Clin. Invest. 57, 1523–1532 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kahn, B.B. Lilly lecture 1995. Glucose transport: pivotal step in insulin action. Diabetes 45, 1644–1654 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Gonzalez, E., Flier, E., Molle, D., Accili, D. & McGraw, T.E. Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor. Proc. Natl. Acad. Sci. USA 108, 10162–10167 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tan, S.X. et al. Amplification and demultiplexing in insulin-regulated Akt protein kinase pathway in adipocytes. J. Biol. Chem. 287, 6128–6138 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Tan, S.X. et al. Selective insulin resistance in adipocytes. J. Biol. Chem. 290, 11337–11348 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Morley, T.S., Xia, J.Y. & Scherer, P.E. Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements. Nat. Commun. 6, 7906 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Thomson, M.J., Williams, M.G. & Frost, S.C. Development of insulin resistance in 3T3-L1 adipocytes. J. Biol. Chem. 272, 7759–7764 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Richardson, D.K. & Czech, M.P. Primary role of decreased fatty acid synthesis in insulin resistance of large rat adipocytes. Am. J. Physiol. 234, E182–E189 (1978).

    CAS  PubMed  Google Scholar 

  131. Czech, M.P., Tencerova, M., Pedersen, D.J. & Aouadi, M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56, 949–964 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Herman, M.A. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tang, Y. et al. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat. Commun. 7, 11365 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Solinas, G., Borén, J. & Dulloo, A.G. De novo lipogenesis in metabolic homeostasis: More friend than foe? Mol. Metab. 4, 367–377 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Baraille, F., Planchais, J., Dentin, R., Guilmeau, S. & Postic, C. Integration of ChREBP-mediated glucose sensing into whole body metabolism. Physiology (Bethesda) 30, 428–437 (2015).

    CAS  Google Scholar 

  136. Lodhi, I.J. et al. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity. Cell Metab. 16, 189–201 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yore, M.M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Smith, U. & Kahn, B.B. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J. Intern. Med. 280, 465–475 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Guilherme, A. et al. Adipocyte lipid synthesis coupled to neuronal control of thermogenic programming. Mol. Metab. (in the press).

  140. Dutta, A., Abmayr, S.M. & Workman, J.L. Diverse activities of histone acylations connect metabolism to chromatin function. Mol. Cell 63, 547–552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wellen, K.E. & Thompson, C.B. A two-way street: reciprocal regulation of metabolism and signalling. Nat. Rev. Mol. Cell Biol. 13, 270–276 (2012).

    Article  CAS  PubMed  Google Scholar 

  142. Londoño Gentile, T. et al. DNMT1 is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation. Mol. Cell. Biol. 33, 3864–3878 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wellen, K.E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. McDonnell, E. et al. Lipids reprogram metabolism to become a major carbon source for histone acetylation. Cell Rep. 17, 1463–1472 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lefterova, M.I., Haakonsson, A.K., Lazar, M.A. & Mandrup, S. PPARγ and the global map of adipogenesis and beyond. Trends Endocrinol. Metab. 25, 293–302 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sugii, S. & Evans, R.M. Epigenetic codes of PPARγ in metabolic disease. FEBS Lett. 585, 2121–2128 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wilson-Fritch, L. et al. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J. Clin. Invest. 114, 1281–1289 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Choi, J.H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 466, 451–456 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Soccio, R.E. et al. Genetic variation determines PPARγ function and anti-diabetic drug response in vivo. Cell 162, 33–44 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Soccio, R.E. et al. Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice. J. Clin. Invest. 127, 1451–1462 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Kienesberger, P.C. et al. Adipose triglyceride lipase deficiency causes tissue-specific changes in insulin signaling. J. Biol. Chem. 284, 30218–30229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zechner, R. FAT FLUX: enzymes, regulators, and pathophysiology of intracellular lipolysis. EMBO Mol. Med. 7, 359–362 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kory, N., Farese, R.V. Jr. & Walther, T.C. Targeting fat: mechanisms of protein localization to lipid droplets. Trends Cell Biol. 26, 535–546 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Krahmer, N., Farese, R.V. Jr. & Walther, T.C. Balancing the fat: lipid droplets and human disease. EMBO Mol. Med. 5, 973–983 (2013).

    Article  CAS  PubMed  Google Scholar 

  155. Degerman, E. et al. Phosphorylation and activation of hormone-sensitive adipocyte phosphodiesterase type 3B. Methods 14, 43–53 (1998).

    Article  CAS  PubMed  Google Scholar 

  156. Choi, Y.H. et al. Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice. J. Clin. Invest. 116, 3240–3251 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kitamura, T. et al. Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol. Cell. Biol. 19, 6286–6296 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Choi, S.M. et al. Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol. Cell. Biol. 30, 5009–5020 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Koren, S. et al. The role of mouse Akt2 in insulin-dependent suppression of adipocyte lipolysis in vivo. Diabetologia 58, 1063–1070 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. DiPilato, L.M. et al. The role of PDE3B phosphorylation in the inhibition of lipolysis by insulin. Mol. Cell. Biol. 35, 2752–2760 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Shin, A.C. et al. Insulin receptor signaling in POMC, but not AgRP, neurons controls adipose tissue insulin action. Diabetes 66, 1560–1571 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Vigneri, R., Goldfine, I.D. & Frittitta, L. Insulin, insulin receptors, and cancer. J. Endocrinol. Invest. 39, 1365–1376 (2016).

    Article  CAS  PubMed  Google Scholar 

  163. Zierler, K.A. et al. Functional cardiac lipolysis in mice critically depends on comparative gene identification-58. J. Biol. Chem. 288, 9892–9904 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Whiteman, E.L., Cho, H. & Birnbaum, M.J. Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab. 13, 444–451 (2002).

    Article  CAS  PubMed  Google Scholar 

  165. Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292, 1728–1731 (2001).

    Article  CAS  PubMed  Google Scholar 

  166. Jiang, Z.Y. et al. Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc. Natl. Acad. Sci. USA 100, 7569–7574 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Leavens, K.F., Easton, R.M., Shulman, G.I., Previs, S.F. & Birnbaum, M.J. Akt2 is required for hepatic lipid accumulation in models of insulin resistance. Cell Metab. 10, 405–418 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank M. Birnbaum (Pfizer), S. O'Rahilly (University of Cambridge), and S. Corvera, J. Virbasius, A. Guilherme and D. Pedersen (University of Massachusetts Medical School) for their critical reading of the manuscript and their helpful comments. I also thank our laboratory group members for stimulating discussions on these topics, and L. Smith (University of Massachusetts Medical School) for her contributions to the formatting and editing of the manuscript. The work cited from our laboratory was funded by US National Institutes of Health (NIH) grants DK 103047 and DK 030898, and the Isadore and Fannie Foxman endowed professorship in medical science.

Author information

Authors and Affiliations

  1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Michael P Czech

Authors
  1. Michael P Czech
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael P Czech.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Czech, M. Insulin action and resistance in obesity and type 2 diabetes. Nat Med 23, 804–814 (2017). https://doi.org/10.1038/nm.4350

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4350

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing