Article

Insulin resistance, serum adiponectin, and proinflammatory markers in young subjects with the metabolic syndrome

Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Białystok, 15-276 Białystok, Poland.
Metabolism: clinical and experimental (Impact Factor: 3.61). 11/2008; 57(11):1539-44. DOI: 10.1016/j.metabol.2008.06.008
Source: PubMed

ABSTRACT Insulin resistance is the underlying metabolic abnormality in the metabolic syndrome. The low-grade chronic inflammation may be associated with metabolic risk factors and atherogenesis. The aim of our study was to establish the link between the metabolic syndrome, as defined by the National Cholesterol Education Program (NCEP) criteria, and insulin sensitivity, serum adiponectin, and parameters of chronic inflammation in young subjects. The group of 223 subjects (mean age, 25.86 +/- 5.49 years; body mass index, 28.04 +/- 6.91 kg/m2) was studied. Oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and estimation of serum adiponectin and proinflammatory factors were performed. The NCEP-defined metabolic syndrome was present in 49 subjects (21.97%). The higher the number of NCEP criteria fulfilled was, the bigger were the decrease in insulin sensitivity (P < .0001) and adiponectin (P < .0001) and the increase in fasting and postload insulin (both Ps < .0001), C-reactive protein (P < .0001), interleukin 18 (P < .0001), interleukin 6 (P < .0001), and soluble tumor necrosis factor-alpha receptors sTNFR1 (P < .0001) and sTNFR2 (P < .0001) observed. Multiple regression analysis revealed that adiponectin and inflammatory factors predicted NCEP score independent of insulin sensitivity (all adjusted beta values between .16 and .32, all Ps < .01). Young subjects with metabolic syndrome demonstrate an increased inflammatory response and lower adiponectin concentration.

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Observational and prospective studies have also shown the benefits of lifestyle intervention in reducing the incidence of diabetes in those judged to be at greater risk. People with a parental history of type 2 diabetes have an increased lifetime risk of diabetes and frequently display metabolic abnormalities which, despite persisting normoglycaemia, are evidence of a ‘pre-diabetic’ state and which may themselves carry increased morbidity and mortality. Observational studies suggest a greater difference in insulin sensitivity between active and sedentary offspring, compared to the difference between active and sedentary individuals with no diabetes family history. This is thought to represent an interaction between positive energy balance, a sedentary lifestyle and a ‘thrifty genotype’. 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Twenty eight Offspring subjects and thirty four matched Controls participated in a seven-week aerobic exercise intervention, training at 65-80 % of predicted maximal heart rate with incremental increases in training duration on a weekly basis. The previously described assessments were performed before and 15-24 hours after the intervention and in a subgroup of 19 Controls and 17 Offspring subjects, further assessments of insulin sensitivity, adipose tissue-derived hormone concentration, substrate utilisation and endothelial function were performed after a further three day period without exercise. In order to determine potential mediators of exercise-induced fat loss fifty five women participated in measurements of substrate utilisation, body composition, endothelial function, insulin sensitivity, cardiorespiratory fitness, dietary intake and habitual physical activity prior to, and after the seven week exercise intervention. The findings from these studies confirmed that sedentary women with a family history of type 2 diabetes displayed lower insulin sensitivity than those without a parental history of diabetes. In addition, insulin resistance in this group appears to be related to a greater sensitivity to the influence of adipose tissue, particularly circulating non-esterified fatty acids and adipose tissue-derived inflammatory cytokines. In Offspring alone, baseline insulin sensitivity was associated with plasma adiponectin concentration and negatively associated with circulating non-esterified fatty acid concentration. These associations may represent physiological attempts to compensate for developing insulin resistance. Offspring also displayed an augmented metabolic response to the exercise intervention in comparison to Controls. This study showed a 23% increase in post-intervention insulin sensitivity in Offspring with no significant increase in insulin sensitivity in Controls despite a similar improvement in cardiorespiratory fitness and adherence to the exercise regime. Improved post-intervention insulin sensitivity was accompanied by reduced circulating leptin, increased fat and decreased carbohydrate oxidation in both fasting and post-glucose states. No change in diet was observed but Offspring appeared to increase their level of habitual physical activity. The magnitude of change in insulin sensitivity was associated with a parental history of diabetes, but stronger associations were observed between baseline insulin resistance and an ability to reduce circulating leptin in response to exercise. Wide individual variation in fat mass change was observed in the response to exercise, and as expected the strongest predictor of exercise-mediated fat mass reduction was the net energy cost of the intervention. However, a change in fasting respiratory exchange ratio (RER), suggesting an increase in fat oxidation was also independently associated with reduced fat mass. The combined findings of this thesis suggest that sedentary pre-menopausal daughters of people with type 2 diabetes are more insulin resistant and that this state is, in part, a consequence of heightened sensitivity to fatty acid and inflammatory cytokine release from adipose tissue. However, it would also appear that they represent a high-risk group who are susceptible to the insulin-sensitising effects of exercise and that this may be mediated by a metabolic pathway which involves reductions in circulating leptin concentrations. Finally, the ability to lose fat mass in response to exercise is related to the energy deficit incurred by the activity but also by an individual’s ability to shift fasting substrate utilisation towards fat oxidation. 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