Implantable closed-loop glucose-sensing and insulin delivery: the future for insulin pump therapy.

Objective. —To determine whether implantable insulin pump (IIP) therapy and multiple daily insulin (MDI) injections could equally attain improved blood glucose control, and to compare the 2 treatments with respect to reducing daily blood glucose fluctuations, reducing serious hypoglycemic insulin reactions, and improving patients' quality of life. Design. —Randomized clinical trial. Setting. —Seven Veterans Affairs medical centers. Patients. —One hundred twenty-one male type II diabetic patients between the ages of 40 and 69 years, receiving at least 1 injection of insulin per day and having hemoglobin A1c(HbA1c) levels of 8% or above. Intervention. —Intensive therapy (IIP or MDI) for 1 year. Main Outcome Measures. —Hemoglobin A1cand blood glucose levels. Results. —Blood glucose levels declined to 7.96±1.08 mmol/L (143.4±19.5 mg/dL) and 8.30±1.52 mmol/L (149.6±27.4 mg/dL) (mean ± SD) for IIP and MDI, respectively (P=.57). Hemoglobin A1clevels improved in both groups (time effectP Conclusions. —Intensive insulin therapy with IIP and MDI is effective in controlling non—insulin-dependent diabetes mellitus. IIP has significant advantages in reducing glycemic variability, clinical hypoglycemia, and weight gain, while improving aspects of quality of life.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=jama&articleId=409934&pdfFileName=jama_276_16_031.pdf

Implantable Insulin Pump vs Multiple-Dose Insulin for Non—Insulin-Dependent Diabetes Mellitus: A Randomized Clinical Trial

There are several approaches of immunoprotection of pancreatic islets for the purpose of successful allo- or xenotransplantation in the absence of immunosuppressive medication. Extravascular approaches are either macroencapsulation (large numbers of islets together in one device) or microencapsulation. The latter approach is to envelop each individual islet in a semipermeable immunoprotective capsule. Quite promising results have been achieved with polylysine-alginate microencapsulated islet grafts in rodents, but clinical application is still restricted to a very small number of cases. Relevant considerations regard the following aspects. The biocompatibility of the microcapsules is influenced by the chemical composition of the materials applied and by mechanical factors related to the production process. With purified instead of crude alginates, the percentage of capsules with fibrotic overgrowth is reduced to approximately ten percent, and the remaining overgrowth is mainly explained by mechanical factors, i.e. inadequate encapsulation of individual islets. Even with purified alginates, however, the duration of encapsulated graft function is limited to a period of six to twenty weeks. Obviously, other factors than bioincompatibility play a role, which factors have to be identified. The limited duration of graft survival cannot be explained by rejection since, in rats, survival times of encapsulated isografts are similar, if not identical, to those of encapsulated allografts. An important factor is probably insufficient nutrition as a consequence of insufficient blood supply of the encapsulated and thus isolated islet. This also influences the functional performance of encapsulated islet grafts. Although normoglycemia can be readily obtained in streptozotocin diabetic rat recipients, glucose tolerance remains severely impaired, as a consequence of an insufficient increase of insulin levels in response to intravenous or oral glucose challenge. Important factors are the characteristics of the capsules applied in view of optimal diffusion kinetics, and the fact that an encapsulated islet graft can only be implanted in the peritoneal cavity because of its volume. Further studies should focus on finding a practically applicable method to reduce the barrier between encapsulated islets and the bloodstream, in order to improve both the functional performance and the survival of encapsulated islet grafts.

Factors influencing the properties and performance of microcapsules for immunoprotection of pancreatic islets.

Self-regulating insulin delivery systems: III. In vivo studies

Although single or multiple daily subcutaneous injections of insulin are the mainstay of insulin delivery techniques, several other methods of insulin delivery are now available or in development, including: (a) continuous subcutaneous insulin infusion by a wearable infusion pump; (b) total or segmental transplantation of a pancreas; (c) transplantation of isolated islet cells; (d) implantation of a programmable insulin pump; (e) oral, nasal, rectal and transdermal mechanisms of insulin delivery; (f) insulin analogues; (g) implantation of polymeric capsules which give continuous or time-pulsed release of insulin; and (h) implantation of a biohybrid artificial pancreas which uses encapsulated islets. Many of these methods of insulin delivery are aimed at achieving a more physiological means of delivery of the insulin, thus to improve glycaemic control and hopefully minimise the secondary complications of diabetes. Techniques of multiple insulin injections and continuous subcutaneous insulin infusion pumps are already in widespread use and are resulting in improved glycaemic control. With the recent increased use of pancreatic transplantation, the rule of establishing euglycaemia will be elucidated in the treatment and prevention of microvascular and macrovascular complications of diabetes mellitus. Despite these advances, the ideal delivery of insulin to patients has yet to be developed. Subcutaneous methods of insulin delivery do not precisely mimic physiological insulin needs and transplantation requires risky immunosuppression. However, the future does look bright as glucose sensors are developed and insulin analogues synthesised.

Recent developments in insulin delivery techniques. Current status and future potential.

This study examined the relationship between the delivery of insulin into the peritoneal space and its absorption into the peripheral circulation. Studies were performed in conscious dogs receiving somatostatin (5.0 μg/min) to suppress endogenous insulin secretion, and intravenous glucose (50 mg/min) to prevent hypoglycemia. The biologic effectiveness of the absorbed insulin was determined by its hypoglycemic effect. The possibility of direct absorption of insulin into the portal circulation from the peritoneal space in anesthetized, portal vein-catheterized dogs was examined with radiolabeled I125 insulin. Our results suggest that absorption of insulin from the peritoneal space is volume, concentration, and time-dependent. Maximal absorption of insulin was observed at 50 min when 1.92 U of insulin in a volume of 3 ml was infused intraperitoneally over 30 min. More rapid absorption was observed at 30 min when this quantity of insulin was given in a 1-min intraperitoneal bolus, compared to 30 min of intraperitoneal infusion. Least rapid absorption of insulin followed the delivery of 1.92 U of insulin in a volume of 15 ml. Intermediate absorption of insulin was observed at 40 min when the 1.92 U was delivered in a volume of 0.6 ml. Peripheral intravenous insulin delivery of 1.92 U reached a maximal plasma concentration at 20 min, which was more than three times the concentration observed with intraperitoneal insulin. Isotopic tracer studies, in which radioiodinated insulin was placed into the peritoneal space in anesthetized dogs, demonstrated greater radioactivity in the portal vein than in the aorta throughout a 30-min observation period. These studies demonstrate that intraperitoneal administration of insulin results in absorption of insulin which is volume, concentration, and time-dependent. Thus, the peritoneal space may be an appropriate site for insulin delivery through a transcutaneous catheter.

Ron Kubica

Papers

The kinetics of peritoneal insulin absorption