Pulsatile intravenous insulin therapy: the best practice to reverse diabetes complications?

In the basal state and after oral ingestion of carbohydrate, the normal pancreas secretes insulin into the portal vein in a pulsatile manner. The end organ of the portal vein is the liver, where approximately 80% of pancreatic insulin is extracted during first pass. In Type 1 diabetes, pancreatic insulin secretion is nearly or completely absent whilst in Type 2 diabetes the normal pattern is absent, abnormal, or blunted. Exogenous subcutaneous insulin treatment results in plasma insulin concentrations that are not pulsatile and a fraction of normal portal vein levels. Oral hypoglycemic agents also do not result in normal pulsatile response to a glucose load. Due to hypoglycemia risk, intensive treatment is not recommended after serious complications develop. Consequently, no conventional therapy has proved effective in treating advanced diabetes complications. Beta-cell replacement using whole pancreas or islet transplantation has been utilized to treat certain problems in Type 1 diabetic patients, but still unavailable for all diabetics. Pulsatile intravenous insulin therapy (PIVIT) is an insulin therapy, which mimics the periodicity and amplitude of normal pancreatic function. Numerous studies show PIVIT effective in preventing, reversing, and reducing the severity and progression of diabetes complications, however, the mechanisms involved with the improvement are not clearly understood. Here, we review the cellular basis of normal and abnormal insulin secretion, current treatments available to treat diabetes, the physiologic basis of PIVIT and possible mechanisms of action.

Compaction of islets is detrimental to transplant outcome in mice.

BACKGROUND: Despite recent progress in clinical islet transplantation, the cumulative world experience remains small. Optimizing protection of islets throughout the isolation, purification, and peritransplant period remains critical to outcome. We herein investigate the potential detrimental impact of maintaining islets in a pelleted state for periods preceding implantation. We hypothesize that periods of islet compaction lead to impairment if islet function in vivo. METHODS: In this study, 250-islet marginal mass transplants were conducted in the BALB/c syngeneic mouse model using islets either preincubated as an islet pellet or suspended in culture during the 30 min immediately preceding transplant. Nonfasting blood glucose, intraperitoneal glucose tolerance test, graft histology, and graft insulin content were all used to monitor graft function up to four weeks posttransplant. RESULTS: Maintaining islets in a compact pellet for 30 min prior to transplantation significantly reduces the proportion of transplant recipients that achieve normoglycemia (from 100% to 38%, P=0.026) and increases the proportion of apoptotic beta-cells. CONCLUSION: Our findings confirm that damage induced by sustained islet compaction results in poor graft outcome in mice. These findings raise concerns relating to potential damage to human islets prior to clinical transplantation, and this will be explored in further studies.