THURSDAY, July 29 (HealthDay News) -- Leptin deficiency appears to lead to insulin resistance in uncontrolled, insulin-deficient diabetes mellitus (uDM), according to an animal study published in the July issue of Diabetes.

Jonathan P. German, of the University of Washington in Seattle, and colleagues evaluated adult male Wistar rats without diabetes and those injected with β-cell toxin (streptozotocin [STZ]) to induce uDM. The rats then underwent subcutaneous implantation of an osmotic minipump than contained vehicle or leptin at a dose (150 µg/kg/day) intended to replace leptin at nondiabetic plasma levels. In an effort to control for leptin effects on food intake, the researchers pair fed another group of STZ-injected animals to match the intake of those receiving leptin.

Unrelated to changes in food intake or body weight, the researchers found that physiologic leptin replacement prevented insulin resistance in uDM. This effect was linked to reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction through the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in adipose tissue or skeletal muscle. Leptin replacement completely normalized high plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes that characterize uDM rats, despite only slightly lowering blood glucose levels.

"We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM," the authors write. "Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency."

The study was funded in part by AstraZeneca.

Abstract
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