Michelle Davenport

Expression of the Functional Leptin Receptor mRNA in Pancreatic Islets and Direct Inhibitory Action of Leptin on Insulin Secretion

Leptin, encoded for by the mouse ob gene, regulates feeding behavior and energy metabolism. Its receptor (Ob-R) is encoded by the mouse diabetic (db) gene and is mutated in the db/db mouse so that it lacks the cytoplasmic domain. We show that the full-length leptin receptor (Ob-Rb), which is believed to transmit the leptin signal, is expressed in pancreatic islets of ob/ob and wild-type mice, as well as in hypothalamus, liver, kidney, spleen, and heart. Recombinant leptin inhibited basal insulin release in the perfused pancreas preparation from ob/ob mice but not in that from Zucker fa/fa rats. Leptin (1–100 nmol/l) also produced a dose-dependent inhibition of glucose-stimulated insulin secretion by isolated islets from ob/ob mice. In contrast, leptin at maximum effective concentration (100 nmol/l) did not inhibit glucose-stimulated insulin secretion by islets from db/db mice. These results provide evidence that a functional leptin receptor is present in pancreatic islets and suggest that leptin overproduction, particularly from abdominal adipose tissue, may modify directly both basal and glucose-stimulated insulin secretion.

Plasma B-cell tropin (ACTH22-39) concentrations in lean and obese (ob/ob) mice and lean and obese (fa/fa) zucker rats

A method has been developed for the measurement of plasma concentrations of Beta-cell tropin (BCT), which is a potent insulinotropic and lipogenic peptide secreted by the pituitary. The method was employed to compare plasma Beta-cell tropin concentrations between lean and genetically obese (ob/ob) mice and between lean and genetically obese (fa/fa) Zucker rats. The plasma concentration in lean mice was 0.17 +/- 0.02 (5)nmole/l (mean +/- SEM, n = 5), while that in obese (ob/ob) mice was significantly higher, being 2.88 +/- 1.13 (5)nmole/l. The plasma BCT concentration in Zucker rats was 0.14 +/- 0.02 (15)nmole/l, while that in obese Zucker (fa/fa) rats was significantly higher, being 1.69 +/- 0.72 (16)nmole/l. These results explain previously observed differences in the Beta-cell tropin-like biological activity in plasma from lean and obese animals, and support the hypothesis that the peptide has a role in the development of hyperinsulinaemia and obesity.

Elevated plasma concentrations of β-cell tropin (ACTH22-39) in diet-treated type II diabetic patients

β-Cell tropin, the pituitary peptide ACTH22–39, is a potent insulin secretagogue and stimulates lipogenesis in adipose tissue in rodents. Plasma β-cell tropin was measured fasting and after glucose infusion (5 mg · kg glucose ideal body weight−1 · min−1 for 90 min) in 10 mild diet-treated non-insulin-dependent (type II) diabetic subjects and 10 control subjects (body mass index) (BMI): 26.4 ± 3.2 and 24.1 ± 2.0 kg/m−2, NS, fasting plasma glucose 7.8 ± 2.7 mM and 4.7 ± 0.3 mM, respectively). The diabetic subjects had raised fasting plasma β-cell tropin compared with the normal subjects (geometric mean (1 SD range): 0.49 (0.25–0.96) nM and 0.17 (0.10–0.28) nM, respectively, P = 0.007). In response to the glucose infusion, plasma glucose rose higher in the diabetic subjects (mean ± 1 SD: 13.7 ± 3.1 and 9.6 ± 0.9 mM, P = 0.007) and plasma insulin was impaired in the diabetic compared with the nondiabetic subjects (geometric mean (1 SD range): 14 (8–26) and 34 (18–63), P <0.01). β-Cell tropin concentrations in the diabetic subjects rose to 1.31 (0.74–2.30) nM (P = 0.007), whereas β-cell tropin did not change in the normal subjects at 0.19 (0.11–0.91) nM. There was no overlap between glucose-stimulated plasma β-cell tropin in the two groups (P = 0.0002). Pituitary-adrenal function, as assessed by plasma cortisol, did not differ between the two groups when fasting and did not change after the glucose infusion. Though its physiological role is unclear, abnormal plasma β-cell tropin may be a feature of type II diabetes.

The effects of insulin and the pituitary peptide Beta-cell tropin on the incorporation of D-3-3H-glucose into lipid in brown adipocytes from lactating and non-lactating rats

Lactating and non-lactating rat brown adipocytes were used to study the dose-dependent stimulation of lipogenesis by Beta-cell tropin (BCT) and insulin. In non-lactating animals BCT increased lipogenesis approximately 2-fold compared to a 3-fold stimulation with insulin; however BCT was effective at a substantially lower molar concentration than insulin. In lactating animals resistance was observed to both BCT and insulin action.