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Obesity pp 1-32 | Cite as

Obesity and Type 2 Diabetes

Living reference work entry
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Part of the Endocrinology book series (ENDOCR)

Abstract

This chapter separately describes the pathophysiology of type 2 diabetes and that of obesity, and identifies the relationship between these states. The important concept of long-term reversibility of type 2 diabetes is discussed along with the beta-cell dedifferentiation, which explains the insulin secretory defect.

Obesity brings about distinct pathophysiological changes as a consequence of individuals’ pattern of food intake and levels of activity. The practical issue of clinical management is considered with particular reference to the weight management goals for type 2 diabetes.

Following therapeutic weight loss in both conditions, long-term avoidance of weight regain is vital and is optimally achieved by a combination of ongoing food energy restriction and daily physical activity.

Keywords

Type 2 Diabetes Pathophysiology Twin Cycle Hypothesis De novo lipogenesis Obesity Whitehall II study Hepatic insulin resistance Long term reversibility of type 2 Diabetes Counterpoint study Counterbalance study Beta-Cell Dedifferentiation Beta-Cell reduction Impairment of insulin secretion Beta-Cell exhaustion Desensitization of Beta-Cell Endoplasmic reticulum (ER) stress Deposition of amyloid Muscle insulin resistance Liver insulin resistance Intracellular insulin action Elevation of non-esterified-fatty-acids (NEFA) Insulin resistance and mitochondrial function IRS-2 phosphorylation Physical inactivity Visceral fat Ectopic fat Subcutaneous adipose tissue Personal fat threshold (PFT) hypothesis Management of body weight Diabetes in Remission Clinical Trial (DiRECT) Type 2 Diabetes dietary management Dietary management for weight loss United Kingdom Prospective Diabetes Study (UKPDS) The Look AHEAD study (Action for Health in Diabetes Study) Avoidance of weight regain approaches Exercise Bariatric Surgery 
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References

  1. Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357(8):753–61.PubMedCrossRefGoogle Scholar
  2. Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49(4):755–65.PubMedCrossRefGoogle Scholar
  3. Ahlqvist E, Ahluwalia TS, Groop L. Genetics of Type 2 diabetes. Clin Chem. 2011;57(2):241–54.PubMedCrossRefGoogle Scholar
  4. Al-Mrabeh A, Hollingsworth KG, Steven S, Tiniakos D, Taylor R. Quantification of intrapancreatic fat in type 2 diabetes. PLoS One. 2017;12:e0174660.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bajaj M, Suraamornkul S, Pratipanawatr T, Hardies LJ, Pratipanawatr W, Glass L, et al. Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with Type 2 diabetes. Diabetes. 2003;52(6):1364–70.PubMedCrossRefGoogle Scholar
  6. Basu R, Chandramouli V, Dicke B, Landau B, Rizza R. Obesity and Type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis. Diabetes. 2005;54(7):1942–8.PubMedCrossRefGoogle Scholar
  7. Bazzano LA, Hu T, Reynolds K, Yao L, Bunol C, Liu Y, et al. Effects of low-carbohydrate and low-fat diets: a randomized trial. Ann Intern Med. 2014;161(5):309–18.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005;42(1):44–52.PubMedCrossRefGoogle Scholar
  9. Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes. 2005;54(6):1640–8.PubMedCrossRefGoogle Scholar
  10. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–307.PubMedCrossRefGoogle Scholar
  11. Bogardus C. Missing heritability and GWAS utility. Obesity (Silver Spring). 2009;17(2):209–10.CrossRefGoogle Scholar
  12. Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven GM. Relationships between degree of obesity and in vivo insulin action in man. Am J Physiol. 1985;248:E286–E91.PubMedGoogle Scholar
  13. Brady MJ, Nairn AC, Saltiel AR. The regulation of glycogen synthase by protein phosphatase 1 in 3T3-L1 adipocytes. Evidence for a potential role for DARPP-32 in insulin action. J Biol Chem. 1997;272(47):29698–703.PubMedCrossRefGoogle Scholar
  14. Brehm A, Krssak M, Schmid AI, Nowotny P, Waldhausl W, Roden M. Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes. 2006;55(1):136–40.PubMedCrossRefGoogle Scholar
  15. Brereton MF, Iberl M, Shimomura K, Zhang Q, Adriaenssens AE, Proks P, et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat Commun. 2014;5:4639.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Brown AW, Bohan Brown MM, Allison DB. Belief beyond the evidence: using the proposed effect of breakfast on obesity to show 2 practices that distort scientific evidence. Am J Clin Nutr. 2013;98(5):1298–308.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387–95.PubMedCrossRefGoogle Scholar
  18. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2(5):559–69.PubMedCrossRefGoogle Scholar
  19. Buchwald H, Estok R, Fahrbach K, Banel D, Jensen MD, Pories WJ, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122(3):248–56.e5.PubMedCrossRefGoogle Scholar
  20. Butler AE, Janson J, Soeller WC, Butler PC. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes. 2003;52(9):2304–14.PubMedCrossRefGoogle Scholar
  21. Carter S, Clifton PM, Keogh JB. The effects of intermittent compared to continuous energy restriction on glycaemic control in Type 2 diabetes; a pragmatic pilot trial. Diabetes Res Clin Pract. 2016;122:106–12.PubMedCrossRefGoogle Scholar
  22. Clayton DJ, Stensel DJ, James LJ. Effect of breakfast omission on subjective appetite, metabolism, acylated ghrelin and GLP-17-36 during rest and exercise. Nutrition. 2016;32(2):179–85.PubMedCrossRefGoogle Scholar
  23. Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in Type 2 diabetes. N Engl J Med. 1999;341(4):240–6.PubMedCrossRefGoogle Scholar
  24. Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med. 2012;18(1):59–68.PubMedCrossRefGoogle Scholar
  25. Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB. Purification and characterization of a peptide from amyloid-rich pancreases of Type 2 diabetic patients. Proc Natl Acad Sci U S A. 1987;84(23):8628–32.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Davis CS, Clarke RE, Coulter SN, Rounsefell KN, Walker RE, Rauch CE, et al. Intermittent energy restriction and weight loss: a systematic review. Eur J Clin Nutr. 2016;70(3):292–9.PubMedCrossRefGoogle Scholar
  27. de Koning EJ, Bodkin NL, Hansen BC, Clark A. Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population. Diabetologia. 1993;36(5):378–84.PubMedCrossRefGoogle Scholar
  28. de Souza RJ, Bray GA, Carey VJ, Hall KD, LeBoff MS, Loria CM, et al. Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral adipose tissue, and hepatic fat: results from the POUNDS LOST trial. Am J Clin Nutr. 2012;95(3):614–25.PubMedPubMedCentralCrossRefGoogle Scholar
  29. DeFronzo RA. Insulin resistance, lipotoxicity, Type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard lecture 2009. Diabetologia. 2010;53(7):1270–87.PubMedPubMedCentralCrossRefGoogle Scholar
  30. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981;30(12):1000–7.PubMedCrossRefGoogle Scholar
  31. DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (Type II) diabetes mellitus. J Clin Invest. 1985;76(1):149–55.PubMedPubMedCentralCrossRefGoogle Scholar
  32. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care. 1992;15(3):318–68.PubMedCrossRefGoogle Scholar
  33. Dent P, Lavoinne A, Nakielny S, Caudwell FB, Watt P, Cohen P. The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature. 1990;348(6299):302–8.PubMedCrossRefGoogle Scholar
  34. Dixon JB, O'Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, et al. Adjustable gastric banding and conventional therapy for Type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316–23.PubMedCrossRefGoogle Scholar
  35. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103(2):253–9.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Dyson PA, Kelly T, Deakin T, Duncan A, Frost G, Harrison Z, et al. Diabetes UK evidence-based nutrition guidelines for the prevention and management of diabetes. Diabet Med. 2011;28(11):1282–8.PubMedCrossRefGoogle Scholar
  37. Efanova IB, Zaitsev SV, Zhivotovsky B, Kohler M, Efendic S, Orrenius S, et al. Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem. 1998;273(50):33501–7.PubMedCrossRefGoogle Scholar
  38. Elks ML. Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release. Endocrinology. 1993;133(1):208–14.PubMedCrossRefGoogle Scholar
  39. Esposito K, Maiorino MI, Petrizzo M, Bellastella G, Giugliano D. The effects of a Mediterranean diet on the need for diabetes drugs and remission of newly diagnosed type 2 diabetes: follow-up of a randomized trial. Diabetes Care. 2014;37(7):1824–30.PubMedCrossRefGoogle Scholar
  40. Estruch R, Martinez-Gonzalez MA, Corella D, Salas-Salvado J, Fito M, Chiva-Blanch G, et al. Effect of a high-fat Mediterranean diet on bodyweight and waist circumference: a prespecified secondary outcomes analysis of the PREDIMED randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(8):666–76.PubMedCrossRefGoogle Scholar
  41. Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman EC, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015;31(1):1–13.PubMedCrossRefGoogle Scholar
  42. Ferrannini E, Galvan AQ, Gastaldelli A, Camastra S, Sironi AM, Toschi E, et al. Insulin: new roles for an ancient hormone. Eur J Clin Investig. 1999;29(10):842–52.CrossRefGoogle Scholar
  43. Finlayson G, Bryant E, Blundell JE, King NA. Acute compensatory eating following exercise is associated with implicit hedonic wanting for food. Physiol Behav. 2009;97(1):62–7.PubMedCrossRefGoogle Scholar
  44. Firth RG, Bell PM, Marsh HM, Hansen I, Rizza RA. Postprandial hyperglycaemia in patients with non-insulin dependent diabetes mellitus. J Clin Investig. 1986;77:1525–32.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007;116(1):39–48.PubMedCrossRefGoogle Scholar
  46. Gaborit B, Kober F, Jacquier A, Moro PJ, Cuisset T, Boullu S, et al. Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: relationship to metabolic profile, cardiac function and visceral fat. Int J Obes. 2012;36(3):422–30.CrossRefGoogle Scholar
  47. Garcia-Fernandez E, Rico-Cabanas L, Rosgaard N, Estruch R, Bach-Faig A. Mediterranean diet and cardiodiabesity: a review. Forum Nutr. 2014;6(9):3474–500.Google Scholar
  48. Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, et al. Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes. 2002;51(1):144–51.PubMedCrossRefGoogle Scholar
  49. Gregg EW, Cheng YJ, Narayan KM, Thompson TJ, Williamson DF. The relative contributions of different levels of overweight and obesity to the increased prevalence of diabetes in the United States: 1976–2004. Prev Med. 2007;45(5):348–52.PubMedCrossRefGoogle Scholar
  50. Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, Bantle J, et al. Association of an intensive lifestyle intervention with remission of Type 2 diabetes. JAMA. 2012;308(23):2489–96.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999;48(6):1270–4.PubMedCrossRefGoogle Scholar
  52. Groop L, Lyssenko V. Genes and Type 2 diabetes mellitus. Curr Diab Rep. 2008;8(3):192–7.PubMedCrossRefGoogle Scholar
  53. Guidone C, Manco M, Valera-Mora E, Iaconelli A, Gniuli D, Mari A, et al. Mechanisms of recovery from Type 2 diabetes after malabsorptive bariatric surgery. Diabetes. 2006;55(7):2025–31.PubMedCrossRefGoogle Scholar
  54. Harvie MN, Howell T. Could intermittent energy restriction and intermittent fasting reduce rates of cancer in obese, overweight, and normal-weight subjects? A summary of evidence. Adv Nutr. 2016;7(4):690–705.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Harvie M, Wright C, Pegington M, McMullan D, Mitchell E, Martin B, et al. The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr. 2013;110(8):1534–47.PubMedCrossRefGoogle Scholar
  56. Hayes MG, Pluzhnikov A, Miyake K, Sun Y, Ng MC, Roe CA, et al. Identification of Type 2 diabetes genes in Mexican Americans through genome-wide association studies. Diabetes. 2007;56(12):3033–44.PubMedCrossRefGoogle Scholar
  57. Henry RR, Scheaffer L, Olefsky JM. Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1985;61(5):917–25.PubMedCrossRefGoogle Scholar
  58. Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mechanisms of hyperglycaemia in obese non-insulin dependent diabetes mellitus. Diabetes. 1986;35:990–8.PubMedCrossRefGoogle Scholar
  59. Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism. 2006;55(5 Suppl 1):S2–5.PubMedCrossRefGoogle Scholar
  60. Hopkins M, Blundell JE, King NA. Individual variability in compensatory eating following acute exercise in overweight and obese women. Br J Sports Med. 2014;48(20):1472–6.PubMedCrossRefGoogle Scholar
  61. Howard CF Jr. Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia. 1986;29(5):301–6.PubMedCrossRefGoogle Scholar
  62. Howard CF Jr, Van Bueren A. Changes in islet cell composition during development of diabetes in Macaca nigra. Diabetes. 1986;35(2):165–71.PubMedCrossRefGoogle Scholar
  63. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, et al. Diet, lifestyle, and the risk of Type 2 diabetes mellitus in women. N Engl J Med. 2001;345(11):790–7.PubMedCrossRefGoogle Scholar
  64. Isbell JM, Tamboli RA, Hansen EN, Saliba J, Dunn JP, Phillips SE, et al. The importance of caloric restriction in the early improvements in insulin sensitivity after roux-en-Y gastric bypass surgery. Diabetes Care. 2010a;33(7):1438–42.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Isbell J, Tamboli R, Hansen E, Saliba J, Dunn J, Phillips S, et al. The importance of caloric restriction in the early improvement in insulin sensitivity after Roux-en-Y gastric bypass surgery. Diabetes Care. 2010b;33:1438–42.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes. 1999;48(3):491–8.PubMedCrossRefGoogle Scholar
  67. Jarrett RJ, Keen H, Fuller JH, McCartney M. Worsening to diabetes in men with impaired glucose tolerance (“borderline diabetes”). Diabetologia. 1979;16(1):25–30.PubMedCrossRefGoogle Scholar
  68. Jeffery RW, Hellerstedt WL, French SA, Baxter JE. A randomized trial of counseling for fat restriction versus calorie restriction in the treatment of obesity. Int J Obes Relat Metab Disord. 1995;19(2):132–7.PubMedGoogle Scholar
  69. Jimenez A, Casamitjana R, Viaplana-Masclans J, Lacy A, Vidal J. GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. Diabetes Care. 2013;36(7):2062–9.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Johnson KH, O'Brien TD, Jordan K, Westermark P. Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAPP) immunoreactivity in pancreatic beta cells. Am J Pathol. 1989;135(2):245–50.PubMedPubMedCentralGoogle Scholar
  71. Johnson AB, Argyraki M, Thow JC, Cooper BG, Fulcher G, Taylor R. Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man. Clin Sci. 1992;82:219–26.PubMedCrossRefGoogle Scholar
  72. Jorgensen NB, Jacobsen SH, Dirksen C, Bojsen-Moller KN, Naver L, Hvolris L, et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance. Am J Physiol Endocrinol Metab. 2012;303(1):E122–31.PubMedCrossRefGoogle Scholar
  73. Kahn CR. Banting lecture. Insulin action, diabetogenes, and the cause of Type II diabetes. Diabetes. 1994;43(8):1066–84.PubMedCrossRefGoogle Scholar
  74. Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86(9):4047–58.PubMedGoogle Scholar
  75. Kahn CR. Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes. Exp Diabesity Res. 2003;4(3):169–82.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Kahn SE, D'Alessio DA, Schwartz MW, Fujimoto WY, Ensinck JW, Taborsky GJ Jr, et al. Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells. Diabetes. 1990;39(5):634–8.PubMedCrossRefGoogle Scholar
  77. Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid: a long-recognized but underappreciated pathological feature of Type 2 diabetes. Diabetes. 1999;48(2):241–53.PubMedCrossRefGoogle Scholar
  78. Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop Type 2 diabetes. Diabetes. 2003;52(10):2461–74.PubMedCrossRefGoogle Scholar
  79. Kashyap SR, Belfort R, Berria R, Suraamornkul S, Pratipranawatr T, Finlayson J, et al. Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes. Am J Physiol Endocrinol Metab. 2004;287(3):E537–46.PubMedCrossRefGoogle Scholar
  80. Kayman S, Bruvold W, Stern JS. Maintenance and relapse after weight loss in women: behavioral aspects. Am J Clin Nutr. 1990;52(5):800–7.PubMedGoogle Scholar
  81. Kealey T. Breakfast is a dangerous meal. London: 4th Estate; 2016.Google Scholar
  82. Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Phys. 1999;277(6 Pt 1):E1130–41.Google Scholar
  83. Keys A. Atherosclerosis: a problem in newer public health. J Mt Sinai Hosp N Y. 1953;20(2):118–39.PubMedGoogle Scholar
  84. King NA, Horner K, Hills AP, Byrne NM, Wood RE, Bryant E, et al. Exercise, appetite and weight management: understanding the compensatory responses in eating behaviour and how they contribute to variability in exercise-induced weight loss. Br J Sports Med. 2012;46(5):315–22.PubMedCrossRefGoogle Scholar
  85. Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz PU. Islet pathology and the pathogenesis of Type 1 and Type 2 diabetes mellitus revisited. Surv Synth Pathol Res. 1985;4(2):110–25.PubMedGoogle Scholar
  86. Laferrere B, Heshka S, Wang K, Khan Y, McGinty J, Teixeira J, et al. Incretin levels and effect are markedly enhanced 1 month after Roux-en-Y gastric bypass surgery in obese patients with Type 2 diabetes. Diabetes Care. 2007;30(7):1709–16.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Lalloyer F, Vandewalle B, Percevault F, Torpier G, Kerr-Conte J, Oosterveer M, et al. Peroxisome proliferator-activated receptor alpha improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets. Diabetes. 2006;55(6):1605–13.PubMedCrossRefGoogle Scholar
  88. Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in Type 2 diabetes. Diabetologia. 2007;50(4):752–63.PubMedCrossRefGoogle Scholar
  89. Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A. 1994;91(23):10878–82.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Leslie RDG, Pyke DA. Genetics of diabetes. In: Alberti KGMM, Krall LP, editors. Diabetes Annual. Amsterdam: Elsevier; 1985. p. 53–66.Google Scholar
  91. Leslie WS, Ford I, Sattar N, Hollingsworth KG, Adamson A, Sniehotta FF, et al. The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial. BMC Fam Pract. 2016;17:20.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in Type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med. 1998;15(4):290–6.PubMedCrossRefGoogle Scholar
  93. Lim EL, Hollingsworth KG, Thelwall PE, Taylor R. Measuring the acute effect of insulin infusion on ATP turnover rate in human skeletal muscle using phosphorus-31 magnetic resonance saturation transfer spectroscopy. NMR Biomed. 2010;23(8):952–7.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of Type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011a;54:2506–14.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Lim EL, Hollingsworth KG, Smith FE, Thelwall PE, Taylor R. Inhibition of lipolysis in Type 2 diabetes normalizes glucose disposal without change in muscle glycogen synthesis rates. Clin Sci (Lond). 2011b;121(4):169–77.CrossRefGoogle Scholar
  96. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011c;54(10):2506–14.PubMedPubMedCentralCrossRefGoogle Scholar
  97. Lingvay I, Guth E, Islam A, Livingston E. Rapid improvement in diabetes after gastric bypass surgery: is it the diet or surgery? Diabetes Care. 2013;36(9):2741–7.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Logue J, Walker JJ, Leese G, Lindsay R, McKnight J, Morris A, et al. Association between BMI measured within a year after diagnosis of type 2 diabetes and mortality. Diabetes Care. 2013;36(4):887–93.PubMedPubMedCentralCrossRefGoogle Scholar
  99. LookAhead. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity. 2014;22(1):5–13.CrossRefGoogle Scholar
  100. Lorenzo A, Razzaboni B, Weir GC, Yankner BA. Pancreatic islet cell toxicity of amylin associated with Type-2 diabetes mellitus. Nature. 1994;368(6473):756–60.PubMedCrossRefGoogle Scholar
  101. Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, et al. The endoplasmic reticulum in pancreatic beta cells of Type 2 diabetes patients. Diabetologia. 2007;50(12):2486–94.PubMedCrossRefGoogle Scholar
  102. Marin P, Rebuffe-Scrive M, Smith U, Bjorntorp P. Glucose uptake in human adipose tissue. Metab Clin Exp. 1987;36(12):1154–60.PubMedCrossRefGoogle Scholar
  103. Marroqui L, Masini M, Merino B, Grieco FA, Millard I, Dubois C, et al. Pancreatic α cells are resistant to metabolic stress-induced apoptosis in Type 2 diabetes. EBioMedicine. 2015;2(5):378–85.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Martinez-Gonzalez MA, Martin-Calvo N. Mediterranean diet and life expectancy; beyond olive oil, fruits, and vegetables. Curr Opin Clin Nutr Metab Care. 2016;19(6):401–7.PubMedCrossRefGoogle Scholar
  105. Mathieu P, Pibarot P, Larose E, Poirier P, Marette A, Despres JP. Visceral obesity and the heart. Int J Biochem Cell Biol. 2008;40(5):821–36.PubMedCrossRefGoogle Scholar
  106. Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with Type 2 diabetes. Diabetes. 2002;51(3):797–802.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in Type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87(6):2784–91.PubMedCrossRefGoogle Scholar
  108. Ohlson LO, Larsson B, Bjorntorp P, Eriksson H, Svardsudd K, Welin L, et al. Risk factors for Type 2 (non-insulin-dependent) diabetes mellitus. Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913. Diabetologia. 1988;31(11):798–805.PubMedCrossRefGoogle Scholar
  109. Opie EL. The relation Oe diabetes mellitus to lesions of the pancreas. Hyaline degeneration of the islands Oe Langerhans. J Exp Med. 1901;5(5):527–40.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Paisey RB, Frost J, Harvey P, Paisey A, Bower L, Paisey RM, et al. Five year results of a prospective very low calorie diet or conventional weight loss programme in type 2 diabetes. J Hum Nutr Diet. 2002;15(2):121–7.PubMedCrossRefGoogle Scholar
  111. Palleja A, Kashani A, Allin KH, Nielsen T, Zhang C, Li Y, et al. Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota. Genome Med. 2016;8(1):67.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Pascale RW, Wing RR, Butler BA, Mullen M, Bononi P. Effects of a behavioral weight loss program stressing calorie restriction versus calorie plus fat restriction in obese individuals with NIDDM or a family history of diabetes. Diabetes Care. 1995;18(9):1241–8.PubMedCrossRefGoogle Scholar
  113. Perseghin G, Bonfanti R, Magni S, Lattuada G, De Cobelli F, Canu T, et al. Insulin resistance and whole body energy homeostasis in obese adolescents with fatty liver disease. Am J Physiol Endocrinol Metab. 2006;291(4):E697–703.PubMedCrossRefGoogle Scholar
  114. Perseghin G, Lattuada G, De Cobelli F, Ragogna F, Ntali G, Esposito A, et al. Habitual physical activity is associated with intrahepatic fat content in humans. Diabetes Care. 2007;30(3):683–8.PubMedCrossRefGoogle Scholar
  115. Peters C, Steven S, Taylor R. Reversal of type 2 diabetes by weight loss despite presence of macro-and micro-vascular complications. In: Draznin B, editor. Diabetes case studies: real problems, practical solutions. Alexandria: American Diabetes Association; 2015.Google Scholar
  116. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350(7):664–71.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54(3):603–8.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104(31):12587–94.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Petersen KF, Dufour S, Morino K, Yoo PS, Cline GW, Shulman GI. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with Type 2 diabetes. Proc Natl Acad Sci U S A. 2012;109(21):8236–40.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Pinnick K, Neville M, Clark A, Fielding B. Reversibility of metabolic and morphological changes associated with chronic exposure of pancreatic islet beta-cells to fatty acids. J Cell Biochem. 2010;109(4):683–92.PubMedGoogle Scholar
  121. Poitout V, Amyot J, Semache M, Zarrouki B, Hagman D, Fontés G. Glucolipotoxicity of the pancreatic beta cell. Biochim Biophys Acta. 2010;1801(3):289–98.PubMedCrossRefGoogle Scholar
  122. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339–50. discussion 50–2PubMedPubMedCentralCrossRefGoogle Scholar
  123. Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology. 2012;153(8):3613–9.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Pronk NP, Wing RR. Physical activity and long-term maintenance of weight loss. Obes Res. 1994;2(6):587–99.PubMedCrossRefGoogle Scholar
  125. Rabol R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A. 2011;108:13705–9.PubMedPubMedCentralCrossRefGoogle Scholar
  126. Rampersaud E, Damcott CM, Fu M, Shen H, McArdle P, Shi X, et al. Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes. 2007;56(12):3053–62.PubMedCrossRefGoogle Scholar
  127. Ravikumar B, Gerrard J, Dalla Man C, Firbank MJ, Lane A, English PT, et al. Pioglitazone decreases fasting and postprandial endogenous glucose production in proportion to decrease in hepatic triglyceride content. Diabetes. 2008;57:2288–95.PubMedPubMedCentralCrossRefGoogle Scholar
  128. Reitman ML, Arioglu E, Gavrilova O, Taylor SI. Lipoatrophy revisited. Trends Endocrinol Metab. 2000;11(10):410–6.PubMedCrossRefGoogle Scholar
  129. Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, 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(11):10290–7.PubMedCrossRefGoogle Scholar
  130. Ritchie SA, Connell JM. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr Metab Cardiovasc Dis. 2007;17(4):319–26.PubMedCrossRefGoogle Scholar
  131. Robertson RP, Olson LK, Zhang HJ. Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes. 1994;43(9):1085–9.PubMedCrossRefGoogle Scholar
  132. Rocken C, Linke RP, Saeger W. Immunohistology of islet amyloid polypeptide in diabetes mellitus: semi-quantitative studies in a post-mortem series. Virchows Arch A Pathol Anat Histopathol. 1992;421(4):339–44.PubMedCrossRefGoogle Scholar
  133. Rosenbaum S, Skinner RK, Knight IB, Garrow JS. A survey of heights and weights of adults in Great Britain, 1980. Ann Hum Biol. 1985;12(2):115–27.PubMedCrossRefGoogle Scholar
  134. Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KG, Zimmet PZ, et al. Metabolic surgery in the treatment algorithm for Type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care. 2016;39(6):861–77.PubMedCrossRefGoogle Scholar
  135. Ruderman NB, Kapeller R, White MF, Cantley LC. Activation of phosphatidylinositol 3-kinase by insulin. Proc Natl Acad Sci U S A. 1990;87(4):1411–5.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Saito K, Yaginuma N, Takahashi T. Differential volumetry of A, B and D cells in the pancreatic islets of diabetic and nondiabetic subjects. Tohoku J Exp Med. 1979;129(3):273–83.PubMedCrossRefGoogle Scholar
  137. Salas-Salvado J, Bullo M, Babio N, Martinez-Gonzalez MA, Ibarrola-Jurado N, Basora J, et al. Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial. Diabetes Care. 2011;34(1):14–9.PubMedCrossRefGoogle Scholar
  138. Salmela PI, Sotaniemi EA, Niemi M, Maentausta O. Liver function tests in diabetic patients. Diabetes Care. 1984;7(3):248–54.PubMedCrossRefGoogle Scholar
  139. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010;375(9733):2267–77.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Sattar N, McConnachie A, Ford I, Gaw A, Cleland SJ, Forouhi NG, et al. Serial metabolic measurements and conversion to Type 2 diabetes in the west of Scotland coronary prevention study: specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor. Diabetes. 2007;56(4):984–91.PubMedCrossRefGoogle Scholar
  141. Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE, McGuire AC, et al. A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. PLoS Med. 2008;5(1):e27.PubMedPubMedCentralCrossRefGoogle Scholar
  142. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–76.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. N Engl J Med. 2014;370(21):2002–13.PubMedPubMedCentralCrossRefGoogle Scholar
  144. Schlundt DG, Hill JO, Pope-Cordle J, Arnold D, Virts KL, Katahn M. Randomized evaluation of a low fat ad libitum carbohydrate diet for weight reduction. Int J Obes Relat Metab Disord. 1993;17(11):623–9.PubMedGoogle Scholar
  145. Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Jeneson JA, Backes WH, van Echteld CJ, et al. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia. 2007;50(1):113–20.PubMedCrossRefGoogle Scholar
  146. Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77(1):43–50.PubMedGoogle Scholar
  147. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–93.PubMedCrossRefGoogle Scholar
  148. Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Silander K, et al. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J of Clin Nut. 2012;96:427–34.CrossRefGoogle Scholar
  149. Shibata M, Kihara Y, Taguchi M, Tashiro M, Otsuki M. Nonalcoholic fatty liver disease is a risk factor for Type 2 diabetes in middle-aged Japanese men. Diabetes Care. 2007;30(11):2940–4.PubMedCrossRefGoogle Scholar
  150. Shimabukuro M, Zhou YT, Levi M, Unger RH. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A. 1998;95(5):2498–502.PubMedPubMedCentralCrossRefGoogle Scholar
  151. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care. 2004;27(10):2518–39.PubMedCrossRefGoogle Scholar
  152. Singhal P, Caumo A, Carey PE, Cobelli C, Taylor R. Regulation of endogenous glucose production after a mixed meal in Type 2 diabetes. Am J Physiol Endocrinol Metab. 2002;283(2):E275–E83.PubMedCrossRefGoogle Scholar
  153. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351(26):2683–93.PubMedCrossRefGoogle Scholar
  154. Spijker HS, Song H, Ellenbroek JH, Roefs MM, Engelse MA, Bos E, et al. Loss of beta-cell identity occurs in Type 2 diabetes and is associated with islet amyloid deposits. Diabetes. 2015;64(8):2928–38.PubMedCrossRefGoogle Scholar
  155. Spiro A, Stanner S. The National Obesity Forum report is an opinion piece not a scientific review. Nutr Bull. 2016;41(3):257–69.CrossRefGoogle Scholar
  156. Steven S, Taylor R. Restoring normoglycaemia by use of a very low calorie diet in long versus short duration type 2 diabetes. Diabet Med. 2015;32:47–53.PubMedCrossRefGoogle Scholar
  157. Steven S, Lim E, Taylor R. Population response to information on reversibility of type 2 diabetes. Diabet Med. 2013;30(4):e135–8.PubMedCrossRefGoogle Scholar
  158. Steven S, Carey PE, Small PK, Taylor R. Reversal of Type 2 diabetes after bariatric surgery is determined by the degree of achieved weight loss in both short- and long-duration diabetes. Diabet Med. 2015;32(1):47–53.PubMedCrossRefGoogle Scholar
  159. Steven S, Hollingsworth KG, Small P, Woodcock S, Pucci A, Aribisala BS, et al. Weight loss decreases excess pancreatic triacylglycerol specifically in Type 2 diabetes. Diabetes Care. 2016a;39:158–65.PubMedCrossRefGoogle Scholar
  160. Steven S, Hollingsworth KG, Al-Mrabeh A, Avery L, Aribisala BS, Caslake M, et al. Very low calorie diet and 6 months of weight stability in Type 2 diabetes: pathophysiological changes in responders and nonresponders. Diabetes Care. 2016b;39:158–65.PubMedCrossRefGoogle Scholar
  161. Steven S, Hollingsworth KG, Small PK, Woodcock SA, Pucci A, Aribasala B, et al. Calorie restriction and not glucagon-like peptide-1 explains the acute improvement in glucose control after gastric bypass in Type 2 diabetes. Diabet Med. 2016c;33(12):1723–31.PubMedCrossRefGoogle Scholar
  162. Storgaard H, Jensen CB, Vaag AA, Volund A, Madsbad S. Insulin secretion after short- and long-term low-grade free fatty acid infusion in men with increased risk of developing type 2 diabetes. Metab Clin Exp. 2003;52(7):885–94.PubMedCrossRefGoogle Scholar
  163. Sun XJ, Miralpeix M, Myers MG Jr, Glasheen EM, Backer JM, Kahn CR, et al. Expression and function of IRS-1 in insulin signal transmission. J Biol Chem. 1992;267(31):22662–72.PubMedGoogle Scholar
  164. Tabak AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimaki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of Type 2 diabetes: an analysis from the Whitehall II study. Lancet. 2009;373(9682):2215–21.PubMedPubMedCentralCrossRefGoogle Scholar
  165. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012;150(6):1223–34.PubMedPubMedCentralCrossRefGoogle Scholar
  166. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7(2):85–96.PubMedCrossRefGoogle Scholar
  167. Taylor R. Aetiology of non-insulin dependent diabetes. Br Med Bull. 1989;45:73–91.PubMedCrossRefGoogle Scholar
  168. Taylor R. Pathogenesis of Type 2 diabetes: tracing the reverse route from cure to cause. Diabetologia. 2008;51:1781–9.PubMedCrossRefGoogle Scholar
  169. Taylor R. Insulin resistance and type 2 diabetes. Diabetes. 2012;61(4):778–9.PubMedPubMedCentralCrossRefGoogle Scholar
  170. Taylor R. Type 2 diabetes: etiology and reversibility. Diabetes Care. 2013;36(4):1047–55.PubMedPubMedCentralCrossRefGoogle Scholar
  171. Taylor R, Barnes A. From new understanding of type 2 diabetes to practical management. Diabetologia 2017 (in press).Google Scholar
  172. Taylor R, Holman R. Normal weight individuals who develop Type 2 diabetes: the personal fat threshold. Clin Sci. 2015;128:405–10.PubMedCrossRefGoogle Scholar
  173. Taylor R, Price TB, Katz LD, Shulman RG, Shulman GI. Direct measurement of change in muscle glycogen concentration after a mixed meal in normal subjects. Am J Physiol. 1993;265:E224–E9.PubMedGoogle Scholar
  174. Taylor R, Magnussen I, Rothman DL, Cline GW, Caumo A, Cobelli C, et al. Direct assessment of liver glycogen storage by 13C-nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J Clin Investig. 1996a;97:126–32.PubMedPubMedCentralCrossRefGoogle Scholar
  175. Taylor R, Magnusson I, Rothman DL, Cline GW, Caumo A, Cobelli C, et al. Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J Clin Investig. 1996b;97(1):126–32.PubMedPubMedCentralCrossRefGoogle Scholar
  176. Tsujinaka S, Konishi F, Kawamura YJ, Saito M, Tajima N, Tanaka O, et al. Visceral obesity predicts surgical outcomes after laparoscopic colectomy for sigmoid colon cancer. Dis Colon Rectum. 2008;51(12):1757–65. discussion 65–7PubMedCrossRefGoogle Scholar
  177. Tsunehara CH, Leonetti DL, Fujimoto WY. Diet of second-generation Japanese-American men with and without non-insulin-dependent diabetes. Am J Clin Nutr. 1990;52(4):731–8.PubMedGoogle Scholar
  178. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of Type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343–50.PubMedCrossRefGoogle Scholar
  179. UK Prospective Diabetes Study (UKPDS). UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia. 1991;34(12):877–90.CrossRefGoogle Scholar
  180. UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with Type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65.CrossRefGoogle Scholar
  181. UKPDS. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33). Lancet. 1999;352:837–53.Google Scholar
  182. UKPDS Group. UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients, UKPDS Group. Metabolism. 1990;39(9):905–12.CrossRefGoogle Scholar
  183. Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes. 1995;44(8):863–70.PubMedCrossRefGoogle Scholar
  184. Unger RH. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol Metab. 2003;14(9):398–403.PubMedCrossRefGoogle Scholar
  185. Vaag A. On the pathophysiology of late onset non-insulin dependent diabetes mellitus. Current controversies and new insights. Dan Med Bull. 1999;46(3):197–234.PubMedGoogle Scholar
  186. Wang F, Hull RL, Vidal J, Cnop M, Kahn SE. Islet amyloid develops diffusely throughout the pancreas before becoming severe and replacing endocrine cells. Diabetes. 2001;50(11):2514–20.PubMedCrossRefGoogle Scholar
  187. Wang Z, York NW, Nichols CG, Remedi MS. Pancreatic beta cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 2014;19(5):872–82.PubMedPubMedCentralCrossRefGoogle Scholar
  188. Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with Type 2 diabetes. Ann Intern Med. 2000;132(8):605–11.PubMedCrossRefGoogle Scholar
  189. Weir GC, Aguayo-Mazzucato C, Bonner-Weir S. β-cell dedifferentiation in diabetes is important, but what is it? Islets. 2013;5(5):233–7.PubMedPubMedCentralCrossRefGoogle Scholar
  190. Westermark P, Wilander E. The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus. Diabetologia. 1978;15(5):417–21.PubMedCrossRefGoogle Scholar
  191. Westermark P, Wernstedt C, Wilander E, Hayden DW, O'Brien TD, Johnson KH. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci U S A. 1987;84(11):3881–5.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 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(6):787–94.PubMedPubMedCentralCrossRefGoogle Scholar
  193. White MF, Livingston JN, Backer JM, Lauris V, Dull TJ, Ullrich A, et al. Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell. 1988;54(5):641–9.PubMedCrossRefGoogle Scholar
  194. White MG, Marshall HL, Rigby R, Huang GC, Amer A, Booth T, et al. Expression of mesenchymal and alpha-cell phenotypic markers in islet beta-cells in recently diagnosed diabetes. Diabetes Care. 2013;36(11):3818–20.PubMedPubMedCentralCrossRefGoogle Scholar
  195. White MG, Shaw JAM, Taylor R. Type 2 diabetes: the pathologic basis of reversible beta-cell dysfunction. Diabetes Care. 2016;39:2080–8.PubMedCrossRefGoogle Scholar
  196. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124–31.PubMedCrossRefGoogle Scholar
  197. Wing RR. Behavioral strategies for weight reduction in obese type II diabetic patients. Diabetes Care. 1989;12(2):139–44.PubMedCrossRefGoogle Scholar
  198. Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr. 2001;21:323–41.PubMedCrossRefGoogle Scholar
  199. Wing RR, Phelan S. Long-term weight loss maintenance. Am J Clin Nutr. 2005;82(1 Suppl):222S–5S.PubMedGoogle Scholar
  200. Wojtaszewski JF, Higaki Y, Hirshman MF, Michael MD, Dufresne SD, Kahn CR, et al. Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. J Clin Invest. 1999;104(9):1257–64.PubMedPubMedCentralCrossRefGoogle Scholar
  201. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med. 1991;325(7):461–6.PubMedCrossRefGoogle Scholar
  202. Yki-Jarvinen H. Glucose toxicity. Endocr Rev. 1992;13(3):415–31.PubMedGoogle Scholar
  203. Yki-Jarvinen H, Mott D, Young AA, Stone K, Bogardus C. Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle. J Clin Invest. 1987;80(1):95–100.PubMedPubMedCentralCrossRefGoogle Scholar
  204. Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106(7):2365–70.PubMedPubMedCentralCrossRefGoogle Scholar
  205. Zhou YP, Grill VE. 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 Investig. 1994;93(2):870–6.PubMedPubMedCentralCrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Newcastle Magnetic Resonance CentreCampus for Ageing and Vitality, Newcastle UniversityNewcastle upon TyneUK

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