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Link between obesity and type 2 diabetes

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The relationship between obesity and diabetes is of such interdependence that the term ‘diabesity’ has been coined. The passage from obesity to diabetes is made by a progressive defect in insulin secretion coupled with a progressive rise in insulin resistance.

Both insulin resistance and defective insulin secretion appear very prematurely in obese patients, and both worsen similarly towards diabetes. Thus, the classic ‘hyperbolic relationship’ between insulin resistance and insulin secretion and the ‘glucose allostasis concept’ remain prevailing concepts in this particular field of knowledge.

An increase in overall fatness, preferentially of visceral as well as ectopic fat depots, is specifically associated with insulin resistance. The accumulation of intramyocellular lipids may be due to reduced lipid oxidation capacity. The ability to lose weight is related to the capacity to oxidize fat. Thus, a relative defect in fat oxidation capacity is responsible for energy economy and hampered weight loss.

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The ‘diabesity’ epidemic

The World Health Organization has termed the increased prevalence of obesity and diabetes as a ‘21st Century epidemic’. Obesity is the most frequently encountered metabolic disease worldwide. Moreover, its incidence and prevalence are rising rapidly.1, 2, 3 More than half of the world's population is considered to be overweight.4 Being overweight constitutes a health risk as it is associated with several comorbidities including type 2 diabetes mellitus (T2DM), cardiovascular diseases,

Insulin deficiency or insulin resistance?

Both T2DM and impaired glucose tolerance (IGT) have been identified as clinical entities sharing a deficit in both insulin sensitivity and insulin secretion. Recently, Turner's hyperbolic law between insulin resistance and insulin secretion has been discussed by Stumvoll et al12 and Hockaday.13 A reduction in insulin action is accompanied by up-regulation of insulin secretion, and normoglycaemia is maintained by a compensatory increase in insulin secretion.14 Both Stumvoll et al12 and Hockaday13

Limits of methodology

At the methodological level, insulin sensitivity is measured by tests far more sophisticated than those for insulin secretion. Insulin sensitivity is usually measured by the clamp technique (the accepted gold standard22) and by other methods that basically estimate the insulin-mediated glucose disappearance from the plasma under specified conditions of different stimuli (i.e. insulin, glucose).23, 24 In addition, insulin sensitivity/resistance have been measured in a large population series.25,

A mathematical model for assessment of insulin secretion

A mathematical model of β-cell function has been proposed by Mari et al37 The model describes the characteristics of insulin secretion, such as the rate sensitivity parameter defined by the anticipated rise in insulin secretion. The direct dependence of insulin secretion on glucose concentration represented by the dose-response curve is defined as the β-cell glucose sensitivity. The time dependence of secretion for similar glucose concentrations with higher secretion at the end of the OGTT

Evolution from ngt to diabetes

Longitudinal studies, frequently gathering cross-sectional results, have illustrated the aggravation of the metabolic state in obese patients towards diabetes.

In a follow-up study, Jallut et al39 re-investigated 33 obese subjects and observed a fall of glucose storage (non-oxidative glucose uptake) during a 100-g OGTT after a 6-year period in relation to the increase in basal glucose levels (Figure 2a). The reverse observation after weight loss of 10 kg confirms the role of obesity in the

The cause of insulin resistance

The fact that T2DM is typically a disease of the elderly suggests that genetically determined insulin resistance is not a dominant cause for its development. More is known about lifestyle-related causes of insulin resistance. The most common causes are aging, obesity and physical inactivity. It is well known that insulin sensitivity decreases with advancing age and that it is perfectly correlated with the increase in body fat content.44 In addition, insulin resistance during pregnancy is

Role of FFAs on insulin sensitivity

Overall obesity, particularly increased visceral fat tissue and even ectopic fat tissue storage, is associated with insulin resistance.49, 50 FFAs play an important role, since they induce dual negative feedback on insulin secretion and action, and increase hepatic glucose production51, 52 in T2DM patients. FFAs are an important link between obesity and insulin resistance.53 FFAs are elevated in obesity, while acute elevation of plasma FFAs increases insulin resistance dose dependently in

Role of visceral fat

It has been clearly demonstrated that both an increase in fatness and preferential upper body fat accumulation are related to insulin resistance.65 Magnetic resonance imaging and computed tomography have shown that visceral fat accumulation is specifically associated with insulin resistance in both genders.66, 67, 68 Additionally, Gastaldelli et al showed that insulin resistance is proportional to visceral fat mass, independently of BMI.69 Many authors have suggested a role for visceral fat

Intramyocellular lipids and insulin action in muscle

It is now recognized that intramyocellular lipids (IMCLs) display a better correlation with insulin sensitivity than circulating plasma FFAs.73, 74 This is the case for both T2DM patients and insulin-resistant patients, particularly obese patients and the lean offspring of two parents with T2DM.75 Other studies using H1 nuclear magnetic resonance have shown that IMCL is a strong determinant of in vivo insulin resistance in humans.76, 77, 78 The role of IMCL-triglyceride content in mediating

References (94)

  • Formiguera X & Canton A. Obesity: epidemiology and clinical aspects. Best Pract Res Clin Gastroenterol 2004; 18,...
  • World Health Organization. Obesity and Overweight. Facts. Geneva: World Health Organization, 2004. Available at:...
  • A.E. Field et al.

    Impact of overweight on the risk of developing common chronic diseases during a 10-year period

    Arch Intern Med

    (2001)
  • T.L. Visscher et al.

    The public health impact of obesity

    Annu Rev Public Health

    (2001)
  • E.S. Ford et al.

    Weight change and diabetes incidence: findings from a national cohort of US adults

    Am J Epidemiol

    (1997)
  • H. King et al.

    Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections

    Diabetes Care

    (1998)
  • P. Zimmet et al.

    Global and societal implications of the diabetes epidemic

    Nature

    (2001)
  • Halpern A & Mancini MC. Diabesity: are weight loss medications effective? Treat Endocrinol 2005; 4:...
  • A.E. Field et al.

    Impact of overweight on the risk of developing common chronic diseases during a 10-year period

    Arch Int Med

    (2001)
  • M. Stumvoll et al.

    The hyperbolic law - a 25-year perspective

    Diabetologia

    (2005)
  • Hockaday TDR. Letter to the editor. Diabetologia 2005;...
  • M. Stumvoll et al.

    Glucose allostasis

    Diabetes

    (2003)
  • M. Stumvoll et al.

    The role of glucose allostasis in type 2 diabetes

    Rev Endocr Metab Disord

    (2004)
  • J.E. Gerich

    The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity

    Endocr Rev

    (1998)
  • J.H. Warram et al.

    Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents

    Ann Intern Med

    (1990)
  • G. Gulli et al.

    The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents

    Diabetes

    (1992)
  • J. Eriksson et al.

    Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus

    N Engl J Med

    (1989)
  • S. Lillioja et al.

    Spraul M, et al

    Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med

    (1993)
  • R.A. DeFronzo et al.

    Glucose clamp technique: a method for quantifying insulin secretion and resistance

    Am J Physiol

    (1979)
  • Ferrannini E & Mari A. How to measure insulin sensitivity. J Hypertens 1998; 16:...
  • R.N. Bergman et al.

    Assessment of insulin sensitivity in vivo

    Endocr Rev

    (1985)
  • E. Ferrannini et al.

    Insulin action and age

    European Group for the Study of Insulin Resistance (EGIR). Diabetes

    (1996)
  • S.M. Haffner et al.

    Insulin sensitivity and acute insulin response in African-Americans, non-Hispanic whites, and Hispanic with NIDDM: the insulin resistance atherosclerosis study

    Diabetes

    (1997)
  • J.O. Clausen et al.

    Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians

    J Clin Invest

    (1996)
  • S. Camastra et al.

    Effect of obesity and insulin resistance on resting and glucose-induced thermogenesis in man

    EGIR (European Group for the Study of Insulin Resistance). Int J Obes

    (1999)
  • S.E. Kahn

    The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes

    Diabetologia

    (2003)
  • N.H. McClenaghan et al.

    Physiological and pharmacological regulation of insulin release: insights offered through exploitation of insulin-secreting cell lines

    Diabetes Obes Metab

    (1999)
  • E. Ferrannini et al.

    Lalic N & Mingrone G

    Insulin resistance and hypersecretion in obesity. J Clin Invest

    (1997)
  • *.3.3. Ferrannini

    E & Mari A

    Beta cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia

    (2004)
  • S.M. Haffner et al.

    A prospective analysis of the HOMA model: the Mexico city diabetes study

    Diabetes Care

    (1996)
  • A. Golay et al.

    Metabolic bases of obesity and non insulin-dependent diabetes mellitus

    Diabetes Metab Rev

    (1988)
  • J.P. Felber et al.

    The metabolic consequences of long-term human obesity

    Int J Obes

    (1988)
  • A. Mari et al.

    Meal and oral glucose tests for assessment of beta-cell function: modelling analysis in normal subjects

    Am J Physiol Endocrinol Metab

    (2002)
  • A. Ferrannini et al.

    role of reduced beta-cell sensitivity to glucose over insulin resistance in impaired glucose tolerance

    Diabetologia

    (2003)
  • J.P. Golay et al.

    of weight loss on glucose disposal in obese and obese diabetic patients

    Int J Obes

    (1985)
  • R. Golay et al.

    defect of insulin action on glycogen synthase in obesity and diabetes

    Metabolism

    (2002)
  • A. Ferrannini et al.

    function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis

    J Clin Endocrinol Metab

    (2005)
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