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© 2001 by the American Diabetes Association, Inc.
Physiological Increase in Plasma Leptin Markedly Inhibits Insulin Secretion In Vivo
From the Diabetes Research and Training Center and the Division of Endocrinology (J.A.C., I.G., X.H.M., X.M.Y., N.F., L.R., N.B.), Department of Medicine, and the Department of Molecular Pharmacology (T.M.), Albert Einstein College of Medicine, Bronx, New York.
Address correspondence and reprint requests to Nir Barzilai, MD, Division of Endocrinology, Department of Medicine, Belfer Bldg. #701, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: barzilai{at}aecom.yu.edu .
The demonstration of leptin receptors on the pancreatic ß-cells
suggests the possibility of direct actions of leptin on insulin secretion. In
vitro studies on islets or perfused pancreas and ß-cell lines produced
inconsistent results. We performed an in vivo study to distinctly examine
whether leptin has an effect on glucose-stimulated insulin secretion. Young
chronically catheterized Sprague-Dawley rats (n = 28) were subjected
to a 4-h hyperglycemic clamp study (
11 mmol/l). At minute 120 to 240,
rats were assigned to receive either saline or leptin (0.1, 0.5, and 5 µg
· kg-1 · min) infusion. Leptin decreased plasma
insulin levels abruptly, and an approximately twofold decrease in plasma
insulin levels compared with saline control was sustained over the 2 h of the
study (14.8 ± 5.8 vs. 34.8 ± 2.6 ng/ml with leptin and saline
infusion, respectively, P < 0.001). Moreover, a dose-dependent
decrease in plasma insulin levels was noted (r = -0.731, P
< 0.01). Since milrinone, an inhibitor of cAMP phosphodiesterase (PDE) 3,
did not reverse the effect of leptin on glucose-induced insulin secretion, its
action may be independent of PDE3. These findings suggest that acute
physiological increase in plasma leptin levels acutely and significantly
inhibits glucose-stimulated insulin secretion in vivo. The site of leptin
effects on insulin secretion remains to be determined.
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