UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Insulin Resistance and Obesity in Children

Insulin is integral to normal energy balance. Most obese children are hyperinsulinemic. Two separate and mechanistically disparate, yet overlapping, disorders of insulin dynamics contribute to the development of hyperinsulinemia. These two disorders may have different implications for the pathogenesis of obesity, racial disparities in obesity and risk for cardiovascular (CV) morbidity, and treatment.

The first and most common insulin abnormality is hepatic/muscle insulin resistance, which leads to compensatory fasting hyperinsulinemia. Since the adipocyte retains relative insulin sensitivity, the excess insulin promotes lipogenesis and obesity, especially in visceral fat. Insulin resistance correlates with sympathetic modulation, CV reactivity, and the development of the Metabolic Syndrome. This is probably the disorder associated with the highest CV morbidity. We have shown that improvement of hepatic/muscle insulin sensitivity using the drug metformin leads to reductions in insulinemia, glycemia, and BMI in patients with insulin resistance. However, despite having severe insulin resistance, African-Americans respond poorly to metformin monotherapy.

The second, less common insulin abnormality is glucose-stimulated insulin hypersecretion due to ß-cell dysfunction. These individuals have less visceral but more subcutaneous and gluteal fat. This form of hyperinsulinemia is correlated with increased vagal modulation. Insulin hypersecretion occurs in a subset of obese children who suffer cranial insult, so-called “hypothalamic obesity”. We have shown in two studies (one pilot, and one double-blind placebo-controlled) that suppression of ß-cell insulin secretion using the somatostatin agonist octreotide promotes weight loss in this syndrome. Yet glucose tolerance is maintained. We have also shown in two studies (one pilot, and one double-blind placebo-controlled) that a subset of normal obese adults (approx. 15%) manifest insulin hypersecretion and respond to octreotide with weight loss. Again, however, African-Americans, despite have marked insulin hypersecretion, respond poorly to octreotide therapy.

There is no doubt that these two disorders of insulin are to some extent reciprocally related; worsening resistance leads to excessive secretion. In an attempt to sort out the primary role of these two processes, we evaluated the insulin response to an oral GTT in 119 obese children. We plotted an index of insulin secretion (Corrected Insulin Response, or CIR) against an index of insulin resistance (Composite Insulin Sensitivity Index, or CISI). We found that Caucasians invariably had no insulin abnormality, children with hypothalamic obesity manifested insulin hypersecretion, and African-American subjects manifested both phenomena. Multiple linear regression analysis (when controlling for age, puberty, and BMI SDS) demonstrated that African-Americans have 10% more severe insulin resistance than Caucasians, which was not significant, but 70% greater insulin hypersecretion which was highly significant. These data show that insulin hypersecretion and resistance are separate entities and have racial, etiopathogenic, and treatment implications. We have also shown that insulin sensitivity at baseline predicts the response of weight loss to lifestyle changes. Insulin resistance at baseline predicts weight loss response to insulin sensitization using the drug metformin. Insulin hypersecretion at baseline predicts weight loss response to insulin suppression using the drug octreotide.

Finally, we have demonstrated that insulin suppression improves leptin resistance, as leptin decreases, but resting energy expenditure increases. It appears that hyperinsulinemia is the proximate cause of leptin resistance. This has implications for the pharmacologic treatment of obesity.

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