Why Intraperitoneal Delivery of Insulin With Implantable Pumps in NIDDM?

Abstract

In the normal state, pancreatic secretion of insulin results in a portal/peripheral gradient with the highest concentrations of insulin in the liver. In diabetic patients with absent or insufficient pancreatic insulin secretion who require exogenous insulin, this normal gradient is lost, resulting in numerous abnormalities. This consideration led to interest in the intraperitoneal delivery of insulin, hoping to produce a therapeutic state more closely resembling normal physiology. The development of implantable insulin pumps, which can deliver insulin intraperitoneally, led to numerous studies on insulin-dependent diabetes mellitus (IDDM) patients, demonstrating that insulin delivered intraperitoneally is rapidly and predictably absorbed with most of it going into the portal system, resulting in hepatic delivery of insulin. Studies in IDDM patients have demonstrated that good glucose control can be achieved with intraperitoneal delivery of insulin from implantable pumps with lesser glycemic fluctuations and, therefore, fewer episodes of hypoglycemia. Furthermore, intraperitoneal insulin results in carbohydrate and particularly lipid metabolism that more closely mimics the normal physiological state than produced by injections of insulin. Thus, implantable insulin pumps are being studied for use in IDDM. Many non-insulin-dependent diabetes mellitus (NIDDM) patients have insufficient pancreatic secretion and require exogenous insulin. Because of alterations in hepatic sensitivity to insulin, increments in insulin delivery to the liver may be even more important in NIDDM than IDDM. Furthermore, insulin resistance, which is an integral part of NIDDM, results in higher physiological levels of insulin, which are required for glucose control, and thus significant peripheral hyperinsulinemia occurs in patients receiving exogenous insulin. Because of hepatic extraction, intraperitoneal administration of insulin in NIDDM could provide sufficient insulin to the liver to control hepatic metabolism and reduce peripheral insulin levels, the risk for atherosclerosis, and other adverse effects of hyperinsulinemia. Because of these considerations, a Veterans Affairs Cooperative Study examining the use of implantable insulin pumps delivering intraperitoneal insulin in NIDDM patients was initiated to determine whether this is a feasible approach to NIDDM patients' therapy and whether this results in beneficial effects on carbohydrate and lipid metabolism and peripheral insulin levels