Abstract
The hypothesis that the adipocyte hormone leptin has modulatory effects on the secretion of insulin in the presence of glucose by the islets of Langerhans of normal male rats, and which was postulated to be inhibitory, was investigated. Evidence obtained indicated that the modulatory effect was mediated through the possible combination of neural and endocrine parameters. A previously unreported humoral connection between the intestine and the pancreas was demonstrated, by which incretins could potentially mediate their effects on the production of insulin and other endocrine functions. In the study, an ex vivo perfusion of the pancreas was used, in a purposely designed perfusion system with a surgery platform, and an artificial perfusion medium (KRBB medium) with combinations of concentrations of 4, 8, 12 & 16mM glucose and leptin at 0, 5, 10, 15 & 20ng/ml, in the aim of developing an index for the modulatory effect of leptin on insulin secretion. Insulin output was measured by radioimmunoassay and the results were statistically assessed and analyzed. It was confirmed that insulin secretion from the ex-vivo perfused pancreas in response to glucose stimulation follows a bi-phasic secretion pattern. Leptin reduced insulin secretion at 8 and 12 mmol/L stimulatory concentrations of glucose but either stimulated or had no effect at 4 and 16 mmol/L glucose. A U-shaped dose-response relationship was observed when the range of leptin and glucose concentrations of 5, 10, 15 and 20 ng/ml and 4, 8, 12 and 16 mmol/L respectively were examined, where minimal suppressions were observed at low and high concentrations of both leptin and glucose. In addition, leptin showed distinct suppressive effects on phase one and phase two concentrations depending on the glucose concentration used. This suggested the presence of two or more interdependent intracellular cascades responsible for the secretion and synthesis of insulin in the B-cells of the pancreas, through which leptin exerts its effects on both phases. The presence of various potential incretins together with the newly reported humoral connection between the duodenum and the pancreas implicates other factors controlling insulin secretion and the manner by which leptin modulates insulin secretion. It was concluded that leptin possesses both an inhibitory and a stimulatory effect on insulin secretion and synthesis in a dose-dependent manner and in the presence of different glucose concentrations. This modulatory effect may depend on the presence of certain incretins, possibly including Glucagon Like Peptide (GLP-1), where the common intracellular pathways present potential common sites of action for the inhibitory cascade of leptin.