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t FFA, cytokines



TG VLDL I Glu utilization t Glu output

Skeletal muscle

Glu disDosal t Glucose

Beta cells

I Insulin secretion t Glucose

FIGURE 11.1 The pathogenesis of glucose intolerance in obese subjects. FFA, free fatty acids; TG, triglycerides; glu, glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.

abdominal subcutaneous) fat is associated with insulin resistance. In contrast, insulin sensitivity correlates less well with stores of femoral and gluteal subcutaneous fat.

The mechanisms by which abdominal fat deposition induces insulin resistance and glucose intolerance have begun to emerge (Figure 11.1) [20-22]. In human adults and experimental animals, the accumulation of abdominal fat is accompanied by adipose tissue resistance to insulin action and heightened sensitivity to catechola-mines. Adipose tissue uptake of glucose and FFA is reduced, rates of lipolysis are increased, and triglyceride (TG) clearance is impaired because of down-regulation of lipoprotein lipase. The resistance to insulin appears to be mediated by changes in the expression of adipocyte cytokines. Tumor necrosis factor-a (TNF-a), inter-leukin-6 (IL-6), and resistin are overexpressed in adipose tissue of obese subjects, while adiponectin expression is reduced. TNF alpha and resistin inhibit insulinmediated glucose and FFA uptake and TG synthesis in fat and, like the catechola-mines, induce lipolysis and the release of FFA from adipose stores. The lipolytic effects are potentiated by IL-6, which inhibits lipoprotein lipase and TG deposition in adipose tissue. Interestingly, IL-6 and TNF alpha reduce expression of adiponectin in cultured preadipocytes, explaining, in part, the down-regulation of adiponectin in obesity. Plasma adiponectin concentrations are inversely related to BMI, waist circumference, and abdominal-fat mass and are higher in females than in males. Adiponectin levels correlate with insulin sensitivity in children as well as adults, and targeted deletion of adiponectin causes diet-dependent resistance to insulin action in skeletal muscle and liver.

Rates of FFA flux in patients with upper-body abdominal obesity exceed those in lower-body obese and lean subjects. FFA derived from visceral fat are transported through the portal vein directly to the liver and used for TG synthesis; portal flux of FFA increases in proportion to the mass of visceral fat. FFA from abdominal subcutaneous fat gain access to the liver via the systemic circulation and are taken up by nonhepatic tissues, including skeletal muscle, pancreatic beta cells, and the heart. Storage of surplus fuel in peripheral tissues is facilitated by a resistance to, or a relative deficiency of, leptin, which normally stimulates tissue fatty-acid oxidation and inhibits lipogenesis [22]. The accumulation of TG in liver (hepatic steatosis) may induce hepatic inflammation (steatohepatitis) and a rise in serum transaminases. In rare cases, children with steatohepatitis can develop progressive liver damage, including cirrhosis [23]. Hepatic TG deposition impedes insulin uptake and clearance, contributing to circulating hyperinsulinemia, and limits insulin action. Direct effects of TNF alpha, IL-6, and resistin, and reductions in plasma adiponection concentrations, may exacerbate hepatic insulin resistance. The resulting increase in hepatic glucose production, likely mediated by induction of gluconeogenesis, contributes to mild increases in fasting blood-glucose concentrations and stimulates pancreatic insulin secretion. Hepatic production of TG is also increased; this exacerbates the rise in circulating TG levels caused by adipose tissue insulin resistance. Exchange of very low density lipoprotein-triglyceride (VLDL-TG) for cholesterol esters in high-density lipoproteins (HDL) increases HDL clearance and thereby reduces plasma HDL levels. Enrichment of LDL particles with excess TG facilitates their hydrolysis (by hepatic lipase) to small, dense LDL. Small, dense LDL particles are highly atherogenic and predispose to coronary-artery disease in adults.

The elevations in plasma FFAs, TG, and circulating adipocytokines in the setting of leptin resistance have profound effects on insulin action in skeletal muscle. Analysis of muscle biopsies from insulin-resistant adults shows reductions in tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1, decreased IRS-1-associated PI-3 kinase activity, and impaired threonine- and serine-phosphorylation of protein kinase B (Akt). The defects in insulin signaling are thought to be induced by intramyocellular accumulation of TG or other lipid species, including long-chain fatty acyl-CoA, diacylglycerol, ceramide, or beta hydroxybutyrate [24]. The myocellular lipid accumulation may reflect in part an inherited defect in mitochondrial oxidative phosphorylation [21]; insulin resistance may, in some cases, be detected even in lean siblings of obese patients with insulin resistance or PCOS. Inhibition of Akt phosphorylation impairs skeletal muscle glucose uptake by reducing glucose transporter 4 (GLUT-4) expression, translocation, and activity [20-21]. The result is a progressive decrease in insulin-stimulated, nonoxidative glucose disposal.

Insulin resistance in an obese child or adult does not guarantee progression to frank glucose intolerance; indeed, most obese, insulin-resistant subjects never develop type 2 diabetes. The development of glucose intolerance requires beta-cell dysfunction and loss of glucose-dependent insulin secretion. Some evidence suggests that beta-cell dysfunction may be a familial or genetic trait that predisposes individuals to type 2 diabetes. Other findings suggest that FFA, cytokines, and glucose may promote beta-cell dysfunction in genetically predisposed subjects [20, 21]. Acute elevations of FFA increase P-cell insulin secretion, and the rise in FFA during fasting may sustain basal insulin production and preserve the normal insulin secretory response to glucose. Prolonged administration of FFA, on the other hand, impairs insulin secretion in rodents, but the response to chronic lipids in humans is more variable; in some studies, insulin secretion is maintained or even increased. However, long-term administration of lipids to obese, insulin-resistant adults reduces insulin secretion, though plasma insulin concentrations are increased because insulin clearance is impaired. The response to chronic lipid administration may be conditioned by genetic factors and the prevailing metabolic milieu: In insulin-resistant adult men and women with a strong family history of type 2 diabetes, a four-day infusion of TG emulsion reduced first- and second-phase insulin secretion and hepatic insulin clearance and increased hepatic glucose production. In contrast, chronic lipid administration increased insulin secretion and had no effect on insulin clearance or hepatic glucose production in normal age- and BMI-matched controls [25]. Thus, chronic elevations in FFA likely contribute to beta-cell failure in obese, insulin-resistant subjects predisposed to developing type 2 diabetes.

The mechanisms by which lipids induce toxic effects (lipotoxicity) on beta cells remain unclear. FFA and inflammatory cytokines, such as TNF alpha and IL-1 (possibly from macrophages within pancreatic islets), may enhance production of nitric oxide and reactive-oxygen species, which activate beta-cell apoptosis and inhibit glucose-stimulated insulin secretion [26]. Resistance to leptin action may contribute to lipotoxicity, because leptin reduces islet expression of nitric oxide synthetase and maintains expression of islet antiapoptotic genes, including Bcl-2 [22]. In concert with excess glucose, FFA may also impair glucose-stimulated insulin secretion by altering the mitochondrial metabolism of pyruvate. Moreover, hyper-glycemia, like hyperlipidemia, increases beta-cell production of reactive-oxygen species and the expression of IL-1 and uncoupling protein-2 [26]. Nutrient- and cytokine-dependent loss of beta-cell mass and function in an insulin-resistant subject lead inexorably to glucose intolerance and ultimately to type 2 diabetes.

The relative roles of visceral and subcutaneous fat in the pathogenesis of insulin resistance may vary along racial and ethnic lines. When matched for BMI and total body fat, African American children have less visceral fat than Caucasian children but have lower insulin sensitivity, higher insulin secretion, lower insulin clearance, and higher glucose-disposition index (the product of insulin sensitivity and firstphase insulin secretion) [27, 28]. Yet, the incidence of type 2 diabetes in African American children and adolescents greatly exceeds that in Caucasians. It is currently unclear if the differences in fat distribution and diabetes prevalence reflect genetic variations or environmental influences such as diet, physical activity, or stress [28].


A. Diet

The role of dietary macronutrients in the pathogenesis of obesity, insulin resistance, and type 2 diabetes is highly controversial. Diets high in saturated fat are typically caloric-rich; many, but not all, studies in adults and children demonstrate that such diets predispose to weight gain, insulin resistance, and hyperinsulinemia [28].

Conversely, intake of polyunsaturated and monounsaturated fat and long-chain omega-3 fatty acids is associated with improved insulin sensitivity or glucose tolerance. Diets low in saturated fats reduce total energy intake, improve insulin sensitivity, and, in combination with exercise, can reduce significantly the risks of type 2 diabetes and cardiovascular disease in adults with impaired glucose tolerance [29-32].

Yet, recent investigations have shown that obese men and women lost more weight and had more significant reductions in plasma TG concentrations on low-carbohydrate diets than on conventional low-fat diets [33, 34]. A review of adult studies [35] suggests that the efficacy of low-carbohydrate diets may be related to decreased caloric intake rather than to reduction in carbohydrate intake, per se. Moreover, the effect of a low-carbohydrate diet may diminish with time.

Limited evidence suggests that the nature or quality of ingested carbohydrate may modulate weight gain in childhood. The insulin secretory response to foods containing rapidly absorbed, concentrated carbohydrates (high glycemic index) exceeds the response to foods containing protein, fat, and fiber; the postprandial hyperinsulinemia may facilitate weight gain and reduce resting-energy expenditure. The rapid rise and subsequent fall in blood glucose following ingestion of sucrose may precipitate hunger [36], while fructose is lipogenic and delays the oxidation of fatty acids, facilitating fat storage [37].

Studies of the effects of glycemic index on weight gain in children are inconclusive. Still, a 19-month study [38] of Massachusetts school children found a positive correlation between BMI and the consumption of sugar-sweetened drinks, and a modified low-glycemic diet (45 percent to 50 percent carbohydrate, 30 percent to 35 percent fat) reduced BMI Z score and fat mass in a pilot study of seven obese adolescents [39]. Anecdotal evidence suggests that simple elimination of concentrated soft drinks from the diet can reduce caloric intake in some obese adolescents by as much as 500-1000 Kcal/d and thereby facilitate weight reduction.

Other macronutrients, vitamins, and trace elements may contribute to diabetes risk. For example, intake of fiber (particularly whole grains and cereal) correlates inversely with the risks of type 2 diabetes and cardiovascular disease [40]. Insoluble and soluble fiber may limit fat absorption and thereby improve glucose tolerance. The intake of magnesium (from whole grains, nuts, and green, leafy vegetables) and dairy products containing vitamin D and calcium may also correlate inversely with diabetes risk in young adults [41, 42].

B. Exercise

A sedentary lifestyle increases the risk of diabetes, while exercise, in combination with caloric and fat restriction, reduces the rate of progression to diabetes in adults with IGT [29-32]. The mechanisms by which exercise improves insulin sensitivity and glucose tolerance are complex, involving metabolic adaptations in adipose tissue, liver, and skeletal muscle (Figure 11.2) [43]. Exercise has beneficial effects on fat storage and distribution, with losses of visceral-fat depots exceeding those of subcutaneous fat stores. Lean body mass increases, thereby augmenting resting-energy expenditure. A reduction in abdominal-fat mass increases adipose-tissue sensitivity

Adipose Visceral fat Abdominal SQ fat


  • Glucose uptake + Glucose output
  • Glycogen synthesis

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