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The Influence of Obesity on the Development of Non-Insulin-Dependent Diabetes Mellitus

  • Chapter
Obesity: Pathology and Therapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 149))

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Abstract

The majority of patients diagnosed with NIDDM or type 2 diabetes have been obese for many years and are obese at the time of diagnosis. Moreover, quite commonly, weight gain continues throughout the years of living with the disease and, unquestionably, contributes through different pathogenetic mechanisms to the development of the numerous co-morbid conditions which add to the complexity of the management, health care costs, and worsening of disease outcomes. In contrast, weight loss is often associated with significant improvement of the metabolic control and, on occasion, even leads to a complete reversal of the diabetic state. This review will summarize some of the mechanisms involved in the development of type 2 diabetes in obese and overweight individuals. A broad scheme highlighting the pathophysiology of this process is shown in Fig. 1.

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References

  • Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM (1995) Relationship of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest 96:88–98

    Article  PubMed  CAS  Google Scholar 

  • Ahmad F, Considine RV, Goldstein BJ (1995) Increased abundance of the receptortype protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects. J Clin Invest 95:2806–2812

    Article  PubMed  CAS  Google Scholar 

  • Ahmad F, Azevedo JL, Cortright R, Dohm GL, Goldstein BJ (1997) Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulinresistant human obesity and diabetes. J Clin Invest 100:449–458

    Article  PubMed  CAS  Google Scholar 

  • Ahmad F, Considine RV, Bauer TL, Ohannesian JP, Marco CC, Goldstein BJ (1997a) Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue. Metabolism 46:1140–1145

    Article  PubMed  CAS  Google Scholar 

  • Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL (1991) Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 88:1282–1290

    Article  Google Scholar 

  • Backer JM, Schroeder GG, Kahn CR, Myers MG, Wilden PA, Cahill DA, White MF (1992) Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. J Biol Chem 267:1367–1374

    PubMed  CAS  Google Scholar 

  • Baltzan MA, Andres R, Cader G, Zierler KL (1962) Heterogeneity of forearm metabolism with special reference to free fatty acids. J Clin Invest 41:116–125

    Article  PubMed  CAS  Google Scholar 

  • Baron AD, Zhu J, Weldon H, Maianu L, Garvey WT (1995) Glucosamine induces insulin resistance in vivo by affecting GLUT4 translocation in skeletal muscle. J Clin Invest 96:2792–2801

    Article  PubMed  CAS  Google Scholar 

  • Bennett PH (1990) Epidemiology of diabetes mellitus. In: RifkIn H, Porte D Jr (eds) Ellenberg and Rifkin’s diabetes mellitus. New York, Elsevier, 363–77

    Google Scholar 

  • Beylot M, Sautot G, Laville M, Cohen R (1988) Metabolic studies on lipoatrophic diabetes: mechanism of hyperglycemia and evidence of resistance to insulin of lipid metabolism. Diabetes Metab 14:20–24

    CAS  Google Scholar 

  • Bjorntorp P (1990)“Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 10:4903–496

    Google Scholar 

  • Boden G (1996) Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 45:3–10

    Article  Google Scholar 

  • Boden G, Chen X (1995a) Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest 96:1261–1268

    Article  PubMed  CAS  Google Scholar 

  • Boden G, Chen X (1999) Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes. Diabetes 48:577–583

    Article  PubMed  CAS  Google Scholar 

  • Boden G, Jadali F (1991) Effects of lipid on basal carbohydrate metabolism in normal men. Diabetes 40:686–692

    Article  PubMed  CAS  Google Scholar 

  • Boden G, Jadali F, White J, Liang Y, Mozoli M, Chen X, Coleman E, Smith C (1991) Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest 88:960–966

    Article  PubMed  CAS  Google Scholar 

  • Boden G, Chen X, Ruiz J, White JV, Rossetti L (1994) Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93:2438–2446

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Boden G, Chen X, Mozzoli M, Ryan I (1996) Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 81:3424–3427

    Article  Google Scholar 

  • Boden G, Chen X, Iqbal N (1998) Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects. Diabetes 47:1609–1612

    Article  PubMed  CAS  Google Scholar 

  • Bonadonna RC, Zych K, Boni C, Ferrannini E, DeFronzo RA (1989) Time dependence of the interaction between lipid and glucose in humans. Am J Physiol 257:E49–E56

    PubMed  CAS  Google Scholar 

  • Bonora E, Del Prato S, Bonadonna RC, Gulli G, Solini A, Shank ML, Ghiatas AA, Lancaster JL, Kilcoyne RF, Alyassin AM, De Fronzo R (1992) Total body fatcontent and fat topography are associated differently with in vivo glucose metabolism in nonobese and obese nondiabetic women. Diabetes 41:1151–1159

    Article  PubMed  CAS  Google Scholar 

  • Bouchard C, Tremblay A, Despres JP, Nadeau A, Lupien PJ, Therriault G, Dussault J, Moorjani S, Pinault S, Fournier G (1990) The response to long-term overfeeding in identical twins N Engl J Med 322:1477–1482

    CAS  Google Scholar 

  • Burchfied CM, Sharp DS, Curb JD, Rodriguez BL, Hwang LJ, Marcus EB, Yano K (1995) Physical activity and incidence of diabetes: the Honolulu Heart Program. Am J Epidemiol 141:360–368

    Article  Google Scholar 

  • Burstein R, Polychronakos C,Toews CJ, MacDougal JD, Guyda HJ, Posner BI (1985) Acute reversal of the enhanced insulin action in trained athletes. Association with insulin receptor changes. Diabetes 34:756–760

    CAS  Google Scholar 

  • Burstein R, Epstein Y, Shapiro Y, Charuzi I, Karnieli E (1990) Effect of an acute bout of exercise on glucose disposal in human obesity. J Appl Physiol 69:299–304

    PubMed  CAS  Google Scholar 

  • Cao GY, Considine RV, Lynn RB (1997) Leptin receptors in the adrenal medulla of the rat. Am J Physiol 273(2 Pt 1):E448–E4452

    PubMed  CAS  Google Scholar 

  • Caro JF, Ittoop O, Pories WJ, Meelheim D, Flickinger EG, Thomas F, Jenquin M, Silverman JF, Khazanie PG, Sinha MK (1986): Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest 78:249–258

    Article  PubMed  CAS  Google Scholar 

  • Caro JF, Dohm GL, Pories WJ, Sinha MK (1989) Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes-Metab Revs 5:665–689

    Article  CAS  Google Scholar 

  • Castillo C, Bogartus C, Bergman R,Thuillez P, Lillioja S (1994) Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men. J Clin Invest 93:10–16

    Article  PubMed  CAS  Google Scholar 

  • Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC (1994) Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17:961–969

    Article  PubMed  CAS  Google Scholar 

  • Clore JN, Glickman PS, Nestler JE, Blackard WG (1991) In vivo evidence for hepatic autoregulation during FFA-stimulated gluconeogenesis in normal humans. Am J Physiol 261:E425–E429

    PubMed  CAS  Google Scholar 

  • Cohen N, Halberstam M, Shlimovich P, Chang CJ, Shamoon H, Rossetti L (1995) Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 95:2501–2509

    Article  PubMed  CAS  Google Scholar 

  • Colberg SR, Simoneau J-A, Thaete FL, DE Kelley (1995) Skeletal muscle utilization of free fatty acids in women with visceral obesity. J Clin Invest 95:1846–1853

    Article  PubMed  CAS  Google Scholar 

  • Colditz GA, Willett WC, Rotnitzky A, Manson JE (1995) Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 122:481–486

    PubMed  CAS  Google Scholar 

  • Dagenais GR, Tancredi RG, Zierler KL (1976) Free fatty acid oxidation by forearm muscle at rest, and evidence for an intramuscular lipid pool in the human forearm. J Clin Invest 58:421–431

    Article  PubMed  CAS  Google Scholar 

  • DeFronzo RA (1998) Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Revs 5:177–269

    Google Scholar 

  • Devlin JT, Hirshman M, Horton ED, Horton ES (1987) Enhanced peripheral and splanchnic insulin sensitivity in NIDDM men after single bout of exercise. Diabetes 36:434–439

    Article  PubMed  CAS  Google Scholar 

  • Egan BM, Stepniakowski K (1994) Compensatory hyperinsulinemia and the forearm vasodilator response during an oral glucose tolerance test in obese hypertensives. J Hypertens 12:1061–1067

    Article  PubMed  CAS  Google Scholar 

  • Felber JP, Meyer HU, Curchod B, Iselin HU, Rousselle J, Maeder E, Pahud P, Jequier E (1981) Glucose storage and oxidation in different degrees of obesity measured by continuous indirect calorimetry. Diabetologia 20:39–44

    Article  PubMed  CAS  Google Scholar 

  • Felber JP, Ferrannini E, Golay A, Meyer HU, Theibaud D, Curchod B, Maeder E, Jequier E, DeFronzo RA (1987) Role of lipid oxidation in the pathogenesis of insulin resistance of obesity and type II diabetes. Diabetes 36:1341–1350

    Article  PubMed  CAS  Google Scholar 

  • Felber JP, Golay A, Jequier E, Curchod B,Temler E, DeFronzo RA, Ferranini E (1988) The metabolic consequences of long-term human obesity. Int J Obesity 12:377–389

    CAS  Google Scholar 

  • Flatt JP (1995) McCollum Award Lecture, 1995: Diet, lifestyle, and weight maintenance. Am J Clin Nutr 62:820–836

    PubMed  CAS  Google Scholar 

  • Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM (1995) 15-deoxyA12,14 prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ-7. Cell 83:803–812

    Article  PubMed  CAS  Google Scholar 

  • Freidenberg GR, Henry RR, Klein HH, Reichart DR, and Olefsky JM (1987) Decreased kinase activity of insulin receptors from adipocytes of non-insulindependent diabetic subjects. J Clin Invest 79:240–250

    Article  PubMed  CAS  Google Scholar 

  • Freidenberg GR, Reichart D, Olefsky JM, Henry RR (1988) Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Effect of weight loss. J Clin Invest 82:1398–1406

    CAS  Google Scholar 

  • Friedman JE, Dohm GL, Leggettfrazier N, Elton CW, Tapscott EB, Pories WP, Caro JF (1992) Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss - effect on muscle glucose transport and glucose transporter GLUT4. J Clin Invest 89:701–705

    Article  PubMed  CAS  Google Scholar 

  • Garvey WT, Maianu L, Huecksteadt TP, Birnbaum MJ, Molina JM, Ciaraldi TP (1991) Pretranslational suppression of a glucose transporter protein causes insulin resistance in adipocytes from patients with non-insulin-dependent diabetes mellitus and obesity. J Clin Invest 87:1072–1081

    Article  PubMed  CAS  Google Scholar 

  • Garvey WT, Maianu L, Hancock JA, Golichowski AM, Baron A (1992) Gene expression and GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes 41:465–475

    Article  CAS  Google Scholar 

  • Giacchetti G, Faloia E, Taccaliti A, Morosini PP, Arnaldi G, Mantero F, Accili D, De Pirro, R (1994) Decreased expression of insulin-sensitive glucose transporter mRNA (GLUT-4) in adipose tissue of non-insulin-dependent diabetic and obese patients: evaluation by a simplified quantitative PCR assay. J Endocrinol Invest 17:709–715

    PubMed  CAS  Google Scholar 

  • Golay A, Swislowski ALM, Chen YDI, Jaspan JB, Reaven GM (1986) Effect of obesity on ambient plasma glucose, free fatty acid, insulin, growth hormone, and glucagon concentrations. J Clin Endocrinol Metab 63:481–484

    Article  PubMed  CAS  Google Scholar 

  • Golay A, Felber JP, Jequier E, DeFronzo RA, Ferrannini E (1988) Metabolic basis of obesity and non-insulin dependent diabetes mellitus. Diabetes Metab Rev 4:727–747

    Article  PubMed  CAS  Google Scholar 

  • Goldfine AB, Simonson DC, Folli F, Patti ME, Kahn CR (1995) Metabolic effects of sodium metavanadate in humans with insulin- dependent and noninsulindependent diabetes mellitus in vivo and in vitro studies. J Clin Endo Metab 80: 3311–3320

    Article  CAS  Google Scholar 

  • Goldstein BJ (1996) Protein-tyrosine phosphatases and the regulation of insulin action. In: Diabetes Mellitus: A Fundamental and Clinical Text, edited by D. LeRoith, J.M. Olefsky, and S.I. Taylor, Philadelphia: Lippincott, pp 174–186

    Google Scholar 

  • Goldstein BJ, Li PM, Ding W, Ahmad F, Zhang WR (1998) Regulation of insulin action by protein-tyrosine phosphatases. Vitamins and Hormones, vol 54, pp 67–96

    Article  PubMed  CAS  Google Scholar 

  • Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL (1995) Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95:2195–2204

    Article  PubMed  CAS  Google Scholar 

  • Groop LC, Saloranta C, Shank M, Bonadonna RC, Ferrannini E, De Fronzo RA (1991) The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and non-insulin-dependent diabetes mellitus. J Clin Endocrin Metab 72:96–107

    Article  CAS  Google Scholar 

  • Groop LC, Bonnadonna RC, Simonson DC, Petrides AS, Shank M, DeFronzo RA (1992) Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity. Am J Physiol 263 (Endocrinol Metab. 26):E79–E84

    PubMed  CAS  Google Scholar 

  • Gurwitz JH, Field TS, Glynn RJ, Manson JE, Avorn J, Taylor JO, Hennekens CH (1994) Risk factors for non-insulin-dependent diabetes mellitus requiring treatment in the elderly. J Am Geriatric Soc 42:1235–1240

    CAS  Google Scholar 

  • Hallakou S, Doare L, Foufelle F, Kergoat M, Guerre-Millo M, Berthault MF, Dugail I, Morin J, Auwerx J, Ferre P (1997) Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 46:1393–1399

    Article  PubMed  CAS  Google Scholar 

  • Hawkins S, Barzilai N, Liu R, Chen W, Rosetti L (1996) Increased FFA and hyperglycemia result in a similar increase in carbon flux into the glucosamine pathway and peripheral insulin resistance. Diabetes 45[Suppl 2]:11 A

    Google Scholar 

  • Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS Jr (1991) Physical activity and reduced occurrence of non-insulin dependent diabetes mellitus. N Engl J Med 325:147–152

    Article  PubMed  CAS  Google Scholar 

  • Henrion D, Laher L (1994) Insulin potentiates norepinephrine-induced vascular tone by activation of protein kinase C and tyrosine kinase. Can J Physiol Pharmacol 72:849–854

    Article  PubMed  CAS  Google Scholar 

  • Hofmann C, Lorentz K, Braithwaite SS, Colca JR, Palazuk BJJR, Hotamisligil GS, Spiegelman BM (1994) Altered gene expression for tumor necrosis factor-a and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 134:264–270

    Article  PubMed  CAS  Google Scholar 

  • Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha; direct role in obesity-linked insulin resistance. Science 259:87–91

    Article  PubMed  CAS  Google Scholar 

  • Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose expression of tumor necrosis factor-a in human obesity and insulin resistance. J Clin Invest 95:2409–2415

    Article  PubMed  CAS  Google Scholar 

  • Hotamisligil GH, Peraldi P, Budavari A, Ellis R, White MF, Spiegielman BM (1996) IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-a and obesity-induced insulin resistance. Science 271:665–670

    Article  PubMed  CAS  Google Scholar 

  • Hurrell DG, Pedersen O, Kahn CR (1989) Alterations in the hepatic insulin receptor kinase in genetic and acquired obesity in rats. Clin Exp Pharmacol Physiol 125: 2454–2462

    CAS  Google Scholar 

  • Jequier E (1996) A metabolic perspective on the interaction between obesity and diabetes. Current Concepts in Endocrinology and Diabetes 3:10–15.

    Article  CAS  Google Scholar 

  • Kahn BB, Pedersen O (1992) Tissue-specific regulation of glucose transporters in different forms of obesity. Proc Soc Exp Biol Med 200:214–217

    PubMed  CAS  Google Scholar 

  • Kahn BB (1998) Type 2 diabetes - when insulin secretion fails to compensate for insulin resistance. Cell 92:593–596

    Article  PubMed  CAS  Google Scholar 

  • Karam JH, Grodsky GM, Forsham PH (1963) Excessive insulin response to glucose in obese subjects as measured by immunochemical assay. Diabetes 12:197–204

    PubMed  CAS  Google Scholar 

  • Karlsson C, Lindell K, Svensson E, Bergh C, Lind P, Billig H, Carlsson LM, Carlsson B (1997) Expression of functional leptin receptors in human ovary. J Clin Endocrinol Metab 82:4144–4148

    Article  PubMed  CAS  Google Scholar 

  • Kelly DE, Simoneau JA (1994) Impaired free fatty acid utilization by skeletal muscle in non-insulin dependent diabetes mellitus. J Clin Invest 94:2349–2356

    Article  Google Scholar 

  • Kelly DE, Mokan M, Simoneau JA, Mandarino LJ (1993) Interaction between glucose and fatty acid metabolism in human skeletal muscle. J Clin Invest 92:91–98

    Article  Google Scholar 

  • Kelly KL, Ruderman NB, Chen KS (1992) Phosphatidylinositol-3-kinase in isolated rat adipocytes - Activation by insulin and subcellular distribution. J Biol Chem 267: 3423–3428

    PubMed  CAS  Google Scholar 

  • Kenny SJ, Aubert RE, Geiss LS (1995) Prevalence and incidence of non-insulin dependent diabetes mellitus. In: Diabetes In America. Harris MI (ed) Washington DC: US Government Printing Office, pp 37–46

    Google Scholar 

  • Kern PA, Saghizadeg M, Ong JM, Bosch RJ, Deem R, Simsolo RB (1995) The expression of tumor necrosis factor in adipose tissue: regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95:2111–2119

    Article  PubMed  CAS  Google Scholar 

  • King GL, Johnson SM (1985) Receptor-mediated transport of insulin across endothelial cells. Science 227:1583–1586

    Article  PubMed  CAS  Google Scholar 

  • Kirwan JP, Hickner RC, Yarasheski KE, Kohrt WM, Wiethop BV, Holloszy JO (1992) Eccentric exercise induces transient insulin resistance in healthy individuals. J Appl Physiol 72:2197–2202

    Article  PubMed  CAS  Google Scholar 

  • Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kallhoff RK, Adams PW (1982) Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 54:254–260

    Article  PubMed  CAS  Google Scholar 

  • Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM (1995) A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83:813–819

    Article  PubMed  CAS  Google Scholar 

  • Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisley GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, Lehmann JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 94:4318–4323

    Article  PubMed  CAS  Google Scholar 

  • Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF (1996) Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes 45: 1511–1515

    Article  PubMed  CAS  Google Scholar 

  • Kolaczynski JW, Ohannesian J, Considine RV, Marco C, Caro JF (1996) Response of leptin to short-term and prolonged overfeeding in humans. J Clin Endo Metab 81:4162–4165

    Article  CAS  Google Scholar 

  • Kriketos AD, Pan DA, Lillioja S, Cooney GJ, Baur LA, Milner MR, Sutton JR, Jenkins AB, Bogartus C, Storlien LH (1996) Interrelationships between muscle morphology, insulin action and adiposity. Am J Physiol 270(6 Pt 2):R1332–R1339

    PubMed  CAS  Google Scholar 

  • Krotkiewski M, Bjorntorp P, Sjostrom L, Smoth U (1983) Impact of obesity on metabolism in men and women: importance of regional adipose tissue distribution. J Clin Invest 72:1150–1162

    Article  PubMed  CAS  Google Scholar 

  • Krotkiewski M, Seidell JC, Bjorntorp P (1990) Glucose tolerance and hyperinsulinemia in obese women: role of adipose tissue distribution, muscle fibre characteristics and androgens. J Intern Med 228:385–392

    Article  PubMed  CAS  Google Scholar 

  • Kruszynska YT, Olefsky JM (1996) Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. J Invest Med 44:413–428

    CAS  Google Scholar 

  • Kulkarni RN, Wang ZL, Wang RM, Hurley JD, Smith DM, Ghatei MA, Withers DJ, Gardiner JV, Bailey CJ, Bloom SR (1997) Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. J Clin Invest 100:2729–2736

    Article  PubMed  CAS  Google Scholar 

  • Kusari J, Kenner KA, Suh KI, Hill DE, Henry RR (1994) Skeletal muscle protein tyrosine phosphatase activity and tyrosine phosphatase IB protein content are associated with insulin action and resistance. J Clin Invest 93:1156–1162

    Article  PubMed  CAS  Google Scholar 

  • Kutoh E, Boss O, Levasseur F, Giacobino JP (1998) Quantification of the full length leptin receptor (OB-Rb) in human brown and white adipose tissue. Life Sci 62:445–451.

    Article  PubMed  CAS  Google Scholar 

  • Laakso M, Edelman SV, Brechtel G, Baron AD (1990) Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men. J Clin Invest 85:1844–1852

    Article  PubMed  CAS  Google Scholar 

  • Laakso M, Edelman SV, Brechtel G, Baron AD (1992) Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 41:1076–83

    Article  PubMed  CAS  Google Scholar 

  • Le Stunff C, Bougneres P (1994) Early changes in postprandial insulin secretion, not in insulin sensitivity, characterize juvenile obesity. Diabetes 43:696–702

    Article  PubMed  Google Scholar 

  • Lee HU, Le HK, Koh CS, Min HK (1990) Artificial induction of intravascular lipolysis by lipid-heparin infusions leads to insulin resistance in man. Diabetologia 31:285–290

    CAS  Google Scholar 

  • Lillioja S, Young AA, Cutler CL, Ivy JL, Abbott WG, Zawadzki JK, Yki-Jarvinen H, Chriostin L, Secomb TW, Bogartus C (1987) Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest 80:415–24.

    Article  PubMed  CAS  Google Scholar 

  • Long SD, Pekala PH (1996) Lipid mediators of insulin resistance: ceramide signalling downregulates GLUT4 gene transcription in 3T3-L1 adipocytes. Biochemical Journal. 319:179–84

    PubMed  CAS  Google Scholar 

  • Manson JE, Rimm EB, Stampfer MJ, Willett WC, Hennekens CH (1991) Physical activity and incidence of non-insulin dependent diabetes mellitus in women Lancet 338:774–778

    Article  PubMed  CAS  Google Scholar 

  • Manson JE, Nathan DM, Krolewski AS, Stampfer MJ, Willett WC, Hennekens CH (1992) A prospective study of exercise and incidence of diabetes among US male physicians. JAMA 268:63–67

    Article  PubMed  CAS  Google Scholar 

  • Marco CC, Ohannesian JP, Najm PS, Caro JF, Kolaczynski JW (1998) Small weight gain is not associated with development of insulin resistance in healthy young individuals. Diabetes 47 [Suppl 1]:A80, (Abstract)

    Google Scholar 

  • Marin P, Andersson B, Krotkiewski M, Bjontorp P (1994) Muscle fiber composition and capillary density in women and men with NIDDM. Diabetes Care 17:382–386

    Article  PubMed  CAS  Google Scholar 

  • Marshall S, Bacote V,Traxinger RR (1991) Discovery of a metabolic pathway mediating glucose-induced desensitization of glucose transport system: role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem 266:4706–4712

    PubMed  CAS  Google Scholar 

  • McGuire MC, Fields RM, Nyomba BL, Raz I, Bogardus C, Tonks NK, Sommercorn J (1991) Abnormal regulation of protein tyrosine phosphatase activities in skeletal muscle of insulin-resistant humans. Diabetes 40:939–942

    Article  PubMed  CAS  Google Scholar 

  • Meyerovitch J, Rothenberg PL, ShechterY, Bonner-Weir S, Kahn CR (1991) Vanadate normalizes hyperglycemia in two mouse models of non-insulin dependent diabetes mellitus. J Clin Invest 87:1286–1294

    Article  PubMed  CAS  Google Scholar 

  • Muoio DM, Dohn GL, Fiedorek FT Jr, Tapscott EB, Coleman RA (1997) Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 46:1360–1363

    Article  PubMed  CAS  Google Scholar 

  • NguyenTT, Mijares AH, Johnson CM, Jensen MD (1996) Postprandial leg and splanchnic fatty acid metabolism in nonobese men and women. Am J Physiol 271(6 Pt 1):E965–E972

    PubMed  CAS  Google Scholar 

  • Nolan JJ, Freidenberg GR, Henry R, Reichart D, Olefsky JM (1994) Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity. J Clin Endocrinol Metab 78: 471–477

    Article  PubMed  CAS  Google Scholar 

  • Nolan J J, Ludvik B, Baloga J, Reichart D, Olefsky JM (1997) Mechanisms of the kinetic defect in insulin action in obesity and NIDDM. Diabetes 46:994–1000

    Article  PubMed  CAS  Google Scholar 

  • Nurjhan N, Campbell PJ, Kennedy FP, Miles JM, Gerich JE (1986) Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes 35:1326–30

    Article  PubMed  CAS  Google Scholar 

  • Nuutila P, Raitakari M, Laine H (1996) Role of blood flow in regulating insulinstimulated glucose uptake in humans. J Clin Invest 97:1741–1747

    Article  PubMed  CAS  Google Scholar 

  • Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R (1996) Effects of an engineered human anti-TNF-cc antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881–885

    Article  PubMed  Google Scholar 

  • Ohlson LO, Larsson B, Svardsudd K, Welin L, Eriksson H, Wilhelmsen L, Bjontorp P, Tibbin G (1985) The influence of body fat distribution on the incidence of diabetes mellitus. 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes 34:1055–1058

    Article  PubMed  CAS  Google Scholar 

  • Olefsky JM, Nolan JJ (1995) Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms. Am J Clin Nutr 61:S980–S986

    Google Scholar 

  • Oshida Y, Yamanouchi K, Hayamizu S, Sato Y (1989) Long-term mild jogging increases insulin action despite no influence on body mass index or V 0 2 m a x. J Appl Physiol66:2206–2210

    Article  PubMed  CAS  Google Scholar 

  • Ostman J, Arner P, Engfeldt P, Kager L (1979) Regional differences in the control of lipolysis in human adipose tissue. Metabolism Clin and Exp 28:1198–1205

    Article  CAS  Google Scholar 

  • Owen OE, Reichard GA Jr, Boden G, Schuman C (1974) Comparative measurements of glucose, beta-hydroxybutyrate, acetoacetate, and insulin in blood and cerebrospinal fluid during starvation. Metabolism 23:714–718

    Article  Google Scholar 

  • Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogartus C, Jenkins AB, Storlien LH (1997) Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46:983–988

    Article  PubMed  CAS  Google Scholar 

  • Paolisso G, Gambardella A, Amato L, Tortoriello R, D’Amore A, Varricchio M, D’Onoforio F (1995) Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects. Diabetologia 38:1295–1299

    Article  PubMed  CAS  Google Scholar 

  • Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F (1995) Effect of the obese gene product on body weight regulation in ob/ob mice. Science 269:540–543

    Article  PubMed  CAS  Google Scholar 

  • Perley M, Kipnis DM (1966) Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and non-diabetic subjects. Diabetes 15:867–874

    PubMed  CAS  Google Scholar 

  • Perry IJ, Wannamethee SG, Walker MK, Thompson AG, Whincup PH, Shaper AG (1995) Prospective study of risk factors for development of non-insulin dependent diabetes in middle-aged British men. BMJ 3:560–564

    Google Scholar 

  • Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, Rothman DL, Shulman G (1997) Increased glucose transport phosphorylation and muscle glycogen synthesis after exercise training in insulin resistant subjects. N Engl J Med 335:1357–1362

    Article  Google Scholar 

  • Petersen KF, Hendler R, Price T, Perseghin G, Rothman DL, Held N, Amatruda JM, Shulman GI (1998) C-13/P-31 NMR studies on the mechanism of insulin resistance in obesity. Diabetes 47:381–386

    Article  PubMed  CAS  Google Scholar 

  • Phillips DI, Caddy S, Ilic V, Fielding BA, Frayn KN, Borthwick AC, Taylor R (1996) Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. Metabol Clin & Exp 45:947–950

    Article  CAS  Google Scholar 

  • Pi-Sunyer FX (1985) Effects of exercise on food intake. In: Hirsch J, Van Itallie TB (eds) Recent Advances in Obesity Research IV, pp 368–373. London, John Libbey

    Google Scholar 

  • Pollare T, Vessby B, Lithell H (1991) Lipoprotein lipase activity in skeletal muscle is related to insulin sensitivity. Arterioscler Thromb 11:1192–1203

    Article  PubMed  CAS  Google Scholar 

  • Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillil H, Beebe C, Galloway JA, Frank BH, Karrison T, Van Cauter E (1988) Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest 81:435–441

    Article  PubMed  CAS  Google Scholar 

  • Posner BI, Faure R, Burgess JW, Bevan AP, Lachance D, Zhangsun G, Fantus IG, Ng JB, Hall DA, Lum BS, Shaver A (1994) Peroxovanadium compounds - A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. J Biol Chem 269:4596–4604

    PubMed  CAS  Google Scholar 

  • Prentki M, Corkey BE (1995) Are the beta cell signalling molecules malonyl-CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 44:863–870

    Article  Google Scholar 

  • Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle: its role in insulin sensitivity and metabolic disturbances of diabetes mellitus. Lancet 1:785–789

    Article  PubMed  CAS  Google Scholar 

  • Reaven GM, Lithell H, Landsberg L (1996) Hypertension and associated metabolic abnormalities - the role of insulin resistance and sympathoadrenal system. N Engl J Med 334:374–381

    Article  PubMed  CAS  Google Scholar 

  • Rebrin K, Steil GM, Getty L, Bergman RN (1995) Free fatty acids as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 44:1038–1045

    Article  PubMed  CAS  Google Scholar 

  • Rebuffe-Scrive M, Andersson B, Olbe L, Bjorntorp P (1989) Metabolism of adipose tissue in intraabdominal depots of non-obese men and women. Metabolism 38:453–458

    Article  PubMed  CAS  Google Scholar 

  • Richelsen B, Pedersen SB, Moller-Pedersen T, Schmit O, Moller N, Borglum JD (1993) Lipoprotein lipase activity in muscle tissue influenced by fatness, fat distribution and insulin in obese females. Eur J Clin Invest 23:226–233

    Article  PubMed  CAS  Google Scholar 

  • Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH, Smith U (1997) Insulin receptor substrate (IRS)-l is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulindependent diabetes mellitus. Proc Natl Acad Sci USA 94(8)4171–4175

    Article  PubMed  CAS  Google Scholar 

  • Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA (1996) The expression of TNF-a by human muscle; relationship to insulin resistance. J Clin Invest 97:1111–1116

    Article  PubMed  CAS  Google Scholar 

  • Segal KR, Edano A, Abalos A, Albu J, Blando L, Tomas MB, Pi-Sunyer FX (1991) Effect of exercise training on insulin sensitivity and glucose metabolism in lean, obese and diabetic men. J Appl Physiol 71:2402–2411

    PubMed  CAS  Google Scholar 

  • Shechter Y (1990) Insulin-mimetic effects of vanadate: possible implications for future treatment of diabetes. Diabetes 39:1–5

    Article  PubMed  CAS  Google Scholar 

  • Scherrer U, Vollenweider P, Randlin D, Jequier E, Nicod P, Tappy L (1993) Suppression of insulin induced sympathetic activation and vasodilation by dexamethasone in humans. Circulation 88:388–394

    PubMed  CAS  Google Scholar 

  • Scherrer U, Randin D, Vollenweider P, Lollenweider L, Nicod P (1994) Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest 94:2511–2515

    Article  PubMed  CAS  Google Scholar 

  • Shisheva A, Ikonomov O, Shechter Y (1994) The protein tyrosine phosphatase inhibitor, pervanadate, is a powerful antidiabetic agent in streptozotocin-treated diabetic rats. Clin Exp Pharm Physiol 134:507–510

    CAS  Google Scholar 

  • Sims EA, Danforth E, Horton ES, Bray GA, Glennon JA, Salans LB (1973) Endocrine and metabolic effects of experimental obesity in men. Recent Prog Horm Res 29:457–496

    PubMed  CAS  Google Scholar 

  • Sinha MK, Pories WJ, Flickinger EG, Meelheim D, Caro JF (1987) Insulin-receptor kinase activity of adipose tissue from morbidly obese humans with and without NIDDM. Diabetes 36:620–625

    Article  PubMed  CAS  Google Scholar 

  • Spiegelman BM (1998) PPAR’/adipogenic regulator and thazolidinedione receptor. Diabetes 47:507–514

    Article  PubMed  CAS  Google Scholar 

  • Spraul M, Ravussin E, Fontvieille AM, Rising R, Larson DE, Anderson EA (1993) Reduced sympathetic nerve activity: a potential mechanism predisposing to body weight gain. J Clin Invest 92:1730–1735

    Article  PubMed  CAS  Google Scholar 

  • Spraul M, Ravussin E, Baron AD (1996) Lack of relationship between muscle sympathetic nerve activity and skeletal muscle vasodilation in response to insulin infusion. Diabetologia 39:91–96

    PubMed  CAS  Google Scholar 

  • Steinberg HO, Brechtel G, Johnson A, Baron AD (1994) Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 94:1172–1179

    Article  PubMed  CAS  Google Scholar 

  • Takayama S, Kahn CR, Kubo K, Foley JE (1988) Alterations in insulin receptor autophosphorylation in insulin resistance: Correlation with altered sensitivity to glucose transport and anti-lipolysis to insulin. J Clin Endo Metab 66:992–990

    Article  CAS  Google Scholar 

  • Tartaglia LA (1997) The leptin receptor. J Biol Chem 272:6093–6096

    PubMed  CAS  Google Scholar 

  • Thies RS, Molina JM, Ciaraldi TP, Freidenberg GR, Olefsky JM (1990) Insulinreceptor autophosphorylation and endogenous substrate phosphorylation in human adipocytes from control, obese, and NIDDM subjects. Diabetes 39(2) 250–259

    Article  PubMed  CAS  Google Scholar 

  • Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA (1996) Vitamin C improves endothelium-dependent vasodilation in patients with non-insulindependent diabetes mellitus. Journal of Clinical Investigation 97:22–28

    Article  PubMed  CAS  Google Scholar 

  • Tontonoz P, Hu E, Graves RA, Budavari AB, Spiegelman BM (1994) mPPAR-/2: tissuespecific regulator of an adipocyte enhancer. Genes Dev 8:1224–1234

    Article  PubMed  CAS  Google Scholar 

  • Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR-/2, a lipid-activated transcription factor. Cell 79:1147–1156

    Article  PubMed  CAS  Google Scholar 

  • Tounian P, Schneiter P, Henry S, Tappy L (1996) Effects of infused glucose on glycogen metabolism in healthy humans. Clin Physiol 16:403–416

    Article  PubMed  CAS  Google Scholar 

  • Tuominen JA, Ebeling P, Bourney R, Koranyi L, Lamminen A, Rapola J, Sane T, Vuorinen-Markkola H, Koivisto VA (1996) Postmarathon paradox: insulin resistance in the face of glycogen depletion. Am J Physiol 270:E336–E343

    PubMed  CAS  Google Scholar 

  • Tuominen JA, Ebeling P, Laquier FW, Heiman ML, Stephens T, Koivisto VA (1997) Serum leptin levels and fuel homeostasis in healthy man. Europ J Clin Invest 27:206–211

    Article  PubMed  CAS  Google Scholar 

  • Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical implications. Diabetes 44:863–870

    Article  PubMed  CAS  Google Scholar 

  • Vague J (1956) The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculus disease. Am J Clin Nutr 4:20–34

    PubMed  CAS  Google Scholar 

  • Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, Caro JF, Flier JS (1997) Peroxisome-proliferator-activated receptor gene expression in human tissue: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 99:2416–2422

    Article  PubMed  CAS  Google Scholar 

  • Vollenweider P, Randlin D, Tappy L (1994) Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. J Clin Invest 93:2365–2371

    Article  PubMed  CAS  Google Scholar 

  • White MF, Kahn CR (1994) The insulin signalling system. J Biol Chem 269:1–4

    PubMed  CAS  Google Scholar 

  • Williamson JR, Kreisberg RA, Felts PW (1966) Mechanism for the stimulation of gluconeogenesis of fatty acids in perfused rat liver. Proc Natl Acad Sci USA 56:247–254

    Article  PubMed  CAS  Google Scholar 

  • Wolfe B, Klein MS, Peters EJ, Schmidt BF, Wolfe RR (1989) Effect of elevated free fatty acids on glucose oxidation in normal humans. Metab Clin Exp 37:323–329

    Article  Google Scholar 

  • Woo R, Garrow JS, Pi-Sunyer FX (1982) Effect of exercise on spontaneous calorie intake in obesity. Am J Clin Nutr 36:470

    PubMed  CAS  Google Scholar 

  • Woo R, Pi-Sunyer FX (1985) Effect of increased physical activity on voluntary intake in lean women. Metabolism 34:836

    Article  PubMed  CAS  Google Scholar 

  • Worm D, Vinten J, Staehr P, Henriksen JE, Handberg A, Beck-Nielsen H (1996) Altered basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle fractions from NIDDM patients compared with control subjects. Diabetologia 39:1208–1214

    Article  PubMed  CAS  Google Scholar 

  • Zeman RJ, Ludemann R, Easton TG, Etlinger JD (1988) Slow to fast alterations in skeletal muscle fibers caused by clenbuterol, a pi-receptor agonist. Am J Physiol 254:E726–E732

    PubMed  CAS  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 377:527–529

    Google Scholar 

  • Zurlo F, Lillioja S, Espositio-Del Puente A, Nyomba BL, Raz I, Saad MF, Swinburn BA, Knowler WC, Bogardus C, Ravussin E (1990) Low ratio of fat to carbohydrate oxidation as a predictor of weight gain: study of 24-h RQ. Am J Physiol 259:E650–E657

    PubMed  CAS  Google Scholar 

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  1. J. W. Kolaczynski
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  2. B. J. Goldstein
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Kolaczynski, J.W., Goldstein, B.J. (2000). The Influence of Obesity on the Development of Non-Insulin-Dependent Diabetes Mellitus. In: Lockwood, D.H., Heffner, T.C. (eds) Obesity: Pathology and Therapy. Handbook of Experimental Pharmacology, vol 149. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59651-3_4

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