Advertisement

The Obese Patient with Diabetes Mellitus: From Research Targets to Treatment Options

  • Arya M. Sharma
    Correspondence
    Address correspondence to Arya M. Sharma, MD, PhD, Department of Medicine, McMaster University, Hamilton General Hospital, 237 Barton Street East, Ontario L8L 2X2, Canada.
    Affiliations
    Michael G. deGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
    Search for articles by this author

      Abstract

      Abdominal obesity is a recognized risk factor for both type 2 diabetes mellitus and cardiovascular disease. The metabolic consequences of obesity, such as insulin resistance and impaired glucose tolerance, are primarily attributable to visceral, rather than to subcutaneous, adipose tissue. As a result, liposuction, which mainly removes subcutaneous fat, has no significant effect on insulin sensitivity; by contrast, weight loss resulting from bariatric surgical procedures is associated with resolution of type 2 diabetes in almost 80% of patients. Even modest weight loss in overweight or obese individuals is associated with significant reductions in the risk of diabetes and increased survival. Recent studies have suggested that the renin-angiotensin system (RAS) functions in the regulation of adipogenesis. Activation of this system is increased in obese individuals and angiotensin II, acting via angiotensin type 1 receptors, inhibits the differentiation of preadipocytes into mature adipocytes. This might be expected to result in ectopic storage of fat in tissues such as skeletal muscle and liver, thereby decreasing insulin sensitivity. Evidence from animal studies suggests that angiotensin-receptor blockers can promote redistribution of excess fat from these ectopic sites to mature adipocytes, resulting in improved insulin sensitivity. Clinical trials with telmisartan are currently investigating the effects of RAS blockade on insulin sensitivity in humans.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Deitel M.
        Overweight and obesity worldwide now estimated to involve 1.7 billion people.
        Obes Surg. 2003; 13: 329-330
        • Chan J.M.
        • Stampfer M.J.
        • Rimm E.B.
        • Willett W.C.
        • Colditz G.A.
        Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men.
        Diabetes Care. 1994; 17: 961-969
        • Colditz G.A.
        • Willet W.C.
        • Rotnitzky A.
        • Manson J.E.
        Weight gain as a risk factor for clinical diabetes mellitus in women.
        Ann Intern Med. 1995; 122: 481-486
        • Kissebah A.H.
        • Vydelingum N.
        • Murray R.
        • et al.
        Relation of body fat distribution to metabolic complications of obesity.
        J Clin Endocrinol Metab. 1982; 54: 254-260
        • Iacobellis G.
        • Corradi D.
        • Sharma A.M.
        Epicardial adipose tissue.
        Nat Clin Pract Cardiovasc Med. 2005; 2: 536-543
        • Yusuf S.
        • Hawken S.
        • Ôunpuu S.
        • et al.
        Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study).
        Lancet. 2004; 364: 937-952
        • Yusuf S.
        • Hawken S.
        • Ôunpuu S.
        • et al.
        Obesity and the risk of myocardial infarction.
        Lancet. 2005; 366: 1640-1649
        • lberti K.G.
        • Zimmet P.Z.
        Definition, diagnosis, and classification of diabetes mellitus and its complications. Part 1.
        Diabet Med. 1998; 15: 539-553
        • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
        Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
        Circulation. 2002; 106: 3143-3421
        • Sharma A.M.
        Adipose tissue.
        Int J Obes Relat Metab Disord. 2002; 26: S5-S7
        • Abate N.
        • Garg A.
        • Peshock R.M.
        • et al.
        Relationships of generalized and regional adiposity to insulin sensitivity in men.
        J Clin Invest. 1995; 96: 88-98
        • Klein S.
        • Fontana L.
        • Young V.L.
        • et al.
        Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease.
        N Engl J Med. 2004; 350: 2549-2557
        • Buchwald H.
        • Avidor Y.
        • Braunwald E.
        • et al.
        Bariatric surgery.
        JAMA. 2004; 292: 1724-1737
        • Diabetes Prevention Program Research Group
        Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
        N Engl J Med. 2002; 346: 393-403
        • Pan X.R.
        • Li G.W.
        • Hu Y.H.
        • et al.
        Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance.
        Diabetes Care. 1997; 20: 537-544
        • Tuomilehto J.
        • Lindstrom J.
        • Eriksson J.G.
        • et al.
        Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.
        N Engl J Med. 2001; 344: 1343-1350
        • Lean M.E.J.
        • Powrie J.K.
        • Anderson A.S.
        • et al.
        Obesity, weight loss, and prognosis in type 2 diabetes.
        Diabet Med. 1990; 7: 228-233
        • UK Prospective Diabetes Study Group
        Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
        Lancet. 1998; 352: 854-865
        • UK Prospective Diabetes Study (UKPDS) Group
        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. 1998; 352 ([published correction appears in Lancet. 1999;354:60]): 837-853
        • Scheen A.J.
        VALUE.
        Lancet. 2004; 362 ([letter]): 932-933
        • The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
        Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker or diuretic.
        JAMA. 2002; 288: 2981-2997
        • Hansson L.
        • Lindholm L.H.
        • Niskanen L.
        • et al.
        Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension.
        Lancet. 1999; 353: 611-616
        • The Heart Outcomes Prevention Evaluation Study Investigators
        Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
        N Engl J Med. 2000; 342: 145-153
        • Dahlöf B.
        • Devereux R.B.
        • Kjeldsen S.E.
        • et al.
        Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE).
        Lancet. 2002; 359: 995-1003
        • Lithell H.
        • Hansson L.
        • Skoog I.
        • et al.
        The Study on Cognition and Prognosis in the Elderly (SCOPE).
        J Hypertens. 2003; 21: 875-886
        • Hansson L.
        • Lindholm L.
        • Ekbom T.
        • et al.
        Randomised trial of old and new antihypertensive drugs in elderly patients.
        Lancet. 1999; 354: 1751-1756
        • Julius S.
        • Kjeldsen S.E.
        • Weber M.
        • et al.
        Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine.
        Lancet. 2004; 363: 2022-2031
        • Engeli S.
        • Böhnke J.
        • Gorzelniak K.
        • et al.
        Weight loss and the renin-angiotensin-aldosterone system.
        Hypertension. 2005; 45: 356-362
        • Ahima R.S.
        • Flier J.S.
        Adipose tissue as an endocrine organ.
        Trends Endocrinol Metab. 2000; 11: 327-332
        • Nisoli E.
        • Clementi E.
        • Tonello C.
        • et al.
        Effects of nitric oxide on proliferation and differentiation of rat brown adipocytes in primary cultures.
        Br J Pharmacol. 1998; 125: 888-894
        • Aubert J.
        • Saint-Marc P.
        • Belmonte N.
        • Dani C.
        • Negrel R.
        • Ailhaud J.
        Prostacyclin IP receptor up-regulates the early expression of C/EBP-beta and C/EBP-delta in preadipose cells.
        Mol Cell Endocrinol. 2000; 160: 149-156
        • Hauner H.
        • Petruschke T.
        • Gries F.A.
        Endothelin-1 inhibits the adipose differentiation of cultured human adipocyte precursor cells.
        Metabolism. 1994; 43: 227-232
        • Ailhaud G.
        • Fukamizu A.
        • Massiera F.
        • et al.
        Angiotensinogen, angiotensin II, and adipose tissue development.
        Int J Obes Relat Metab Disord. 2000; 24: S33-S35
        • Janke J.
        • Engeli S.
        • Gorzelniak K.
        • Luft F.C.
        • Sharma A.M.
        Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors.
        Diabetes. 2002; 51: 1699-1707
        • Sharma A.M.
        • Janke J.
        • Gorzelniak K.
        • et al.
        Angiotensin blockade prevents type 2 diabetes by formation of fat cells.
        Hypertension. 2002; 40: 609-611
        • Gavrilova O.
        • Mareus-Samuels B.
        • Graham D.
        • et al.
        Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice.
        J Clin Invest. 2000; 105: 271-278
        • McGarry J.D.
        • Dobbins R.L.
        Fatty acids, lipotoxicity, and insulin secretion.
        Diabetologia. 1999; 42: 128-138
        • Weber M.
        The telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) Programme.
        J Hypertens. 2003; 21: S37-S46
      1. Sharma AM. Study of Micardis on overweight/obese type 2 diabetics with hypertension (SMOOTH): rationale and design. Presented at the 7th International Forum for the Evaluation of Cardiovascular Care; January 2004; Monte Carlo, Monaco.