Short Communication

International Journal of Obesity (2004) 28, 1344–1348. doi:10.1038/sj.ijo.0802753 Published online 17 August 2004

Obesity, leptin resistance, and the effects of insulin reduction

R H Lustig1, S Sen2, J E Soberman3 and P A Velasquez-Mieyer4

  1. 1Department of Pediatrics, University of California, San Francisco, CA, USA
  2. 2Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
  3. 3Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
  4. 4Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA

Correspondence: Dr R Lustig, Department of Pediatrics, University of California San Francisco, Box 0434, 513 Parnassus Avenue, San Francisco, CA 94143-0434, USA. E-mail:

Received 4 January 2004; Revised 3 May 2004; Accepted 15 June 2004; Published online 17 August 2004.



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.


insulin, octreotide, leptin, leptin resistance, IRS/PI3K



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