INDIRECT EVIDENCE FOR SHORT-LOOP NEGATIVE FEEDBACK OF INSULIN-SECRETION IN THE RAT

Feedback inhibition of glucose-mediated insulin release has repeatedly been demonstrated in isolated pancreatic islets and in the perfused pancreas. It was the aim of the present study to determine whether inhibition occurs through a long-loop (plasma concentration of insulin) or a short-loop (local concentration) action of insulin. The perfused rat pancreas was used, with different perfusion rates and different insulin concentrations in the medium. Increasing the flow rate from 1 to either 3 or 6 ml/min gradually decreased the insulin concentration in the effluent, at stimulatory concentrations of glucose (11.1 and 16.7 mmol/1). Under the same conditions, however, the integrated amount of insulin released over a period of 30 min was significantly enhanced. When exogenous insulin (2.7 and 5.4-mu-mol/1) was added to the perfusion medium, insulin secretion in the presence of 11.1 or 16.7 mmol glucose/1 at flow rates of 3 and 6 ml/min was diminished. This effect was most prominent with 11.1 mmol glucose/1 and 2.7-mu-mol exogenous insulin/1 at all flow rates (except 1 ml/min), as well as at the high perfusion flow rates with other glucose concentrations. Insulin secretion was not affected by 5.4-mu-mol exogenous insulin/1 at 1 ml/min or by 2.7-mu-mol exogenous insulin/1 at 3 ml/min. The data support a negative feedback inhibition of insulin secretion by secreted insulin, since insulin secretion was decreased by either adding exogenous insulin or by lowering endogenous insulin as the consequence of increased flow rates. They also suggest that the local extracellular concentration of insulin is of more importance than the plasma concentration, consistent with the concept of a short-loop feedback as already claimed for other hormones and/or neurotransmitters.