Best Practice & Research Clinical Endocrinology & Metabolism
12Link between obesity and type 2 diabetes
Section snippets
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)
- et al.
Obesity: epidemiology and possible prevention
Best Pract Res Clin Endocrinol Metab
(2002) - et al.
Type 2 diabetes: principles of pathogenesis and therapy
Lancet
(2005) - et al.
Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations
Metabolism
(1979) - et al.
Relationships between insulin resistance and lipoproteins in nondiabetic African Americans
Hispanics and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study. Metabolism
(1998) - et al.
Impaired glucose tolerance and diabetes in obesity: a 6-year follow-up study of glucose metabolism
Metabolism
(1990) - et al.
The glucose-fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus
Lancet
(1963) Pathogenesis of type 2 diabetes
Insulin resistance. Endocrinol Metab Clin North Am
(2001)- et al.
Metabolic factors in the insulin resistance in human obesity
Metabolism
(1987) - et al.
Correlations of glycogen synthase and phosphorylase activities with glycogen concentration in human muscle biopsies
Evidence for a double feed-back mechanism regulating glycogen synthesis and breakdown. Metabolism
(1993) - et al.
Fat and carbohydrate balances during adaptation to a high-fat
Am J Clin Nutr
(2000)