Physiological increase in plasma leptin markedly inhibits insulin secretion in vivo.
The demonstration of leptin receptors on the pancreatic beta-cells suggests the possibility of direct actions of leptin on insulin secretion. In vitro studies on islets or perfused pancreas and beta-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 (approximately 11 mmol/l). At minute 120 to 240, rats were assigned to receive either saline or leptin (0.1, 0.5, and 5 microg x kg(-1) x 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.
Diabetes Research and Training Center and the Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J A
JA
Cases
I
I
Gabriely
X H
XH
Ma
X M
XM
Yang
T
T
Michaeli
N
N
Fleischer
L
L
Rossetti
N
N
Barzilai
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D020738:Leptin / Q000097:blood*; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D020738:Leptin; D010726:Phosphodiesterase Inhibitors; D020105:Milrinone