Long-term leptin treatment of ob/ob mice improves glucose-induced insulin secretion.
OBJECTIVE
Previous studies have demonstrated that leptin inhibits glucose-stimulated insulin secretion from isolated islets, although a lack of leptin effect on insulin secretion has also been reported. The effect of long term in vivo leptin treatment of insulin secretion has, however, not been established. Therefore, in the present study, we have evaluated the effect of long term in vivo treatment of leptin on glucose-induced insulin secretion in ob/ob mice.


METHODS
After 7 days' treatment of leptin (100 microg daily s.c.), insulin release was measured in isolated islets by batch incubation followed by radioimmunoassay. Glucose utilization and oxidation were measured by measuring the formation of (3)H(2)O and (14)CO(2) from [5-(3)H] and [U-(14)C] glucose, respectively. Glucose-6-phosphatase activity was measured by measuring the conversion of (14)C-glucose-6-P to (14)C-glucose. In addition, immunohistochemistry of pancreatic specimens was undertaken for study of expression of insulin, GLUT-2 and hormone-sensitive lipase (HSL).


RESULTS
Leptin treatment significantly improved insulin secretion both at 5.5 mM (by 15%; P<0.05) and 16.7 mM (by 85%; P<0.001) glucose, compared to vehicle-treated controls. Furthermore, whereas leptin treatment did not affect islet insulin or DNA contents, a significant decrease in islet triglyceride content and glucose-6-phosphatase activity was observed. Moreover, the immunocytochemical data revealed an increased immunostaining for insulin, GLUT-2 and hormone-sensitive lipase (HSL) in islets from leptin-treated ob/ob mice.


CONCLUSIONS
The results suggest that long-term leptin treatment of ob/ob mice improves glucose-stimulated insulin secretion in parallel with reduced glucose-6-phosphatase activity, increased HSL and decreased triglyceride levels in islets. These perturbations may explain the improvement of glucose-stimulated insulin secretion induced by leptin.
Khan
A
A
Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute, S-171 76 Stockholm, Sweden. akhtar.khan@molmed.ki.se
Narangoda
S
S
Ahren
B
B
Holm
C
C
Sundler
F
F
Efendic
S
S
D000818:Animals; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D002787:Sterol Esterase
D007328:Insulin; D020738:Leptin; D002787:Sterol Esterase; D005952:Glucose-6-Phosphatase; D005947:Glucose