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Obesity, leptin resistance, and the effects of insulin reduction


Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>−3 kg/m2) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively with the change in REE:Leptin. These results suggest that the REE:Leptin ratio, while derivative, may serve as a useful clinical indicator of changes in leptin sensitivity within obese subjects. They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.

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The funding for this study was provided in part by Novartis Pharmaceuticals Corporation and the University of Tennessee General Clinical Research Center (5M01RR 00211). This work was presented in part at The Endocrine Society 85th Annual Meeting, Philadelphia, PA, USA, June 2003.

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Correspondence to R H Lustig.

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Lustig, R., Sen, S., Soberman, J. et al. Obesity, leptin resistance, and the effects of insulin reduction. Int J Obes 28, 1344–1348 (2004).

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  • insulin
  • octreotide
  • leptin
  • leptin resistance
  • IRS/PI3K

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