Critical islet mass for successful porcine islet autotrasplantation

Abstract

A major reason for the failure of clinical islet transplantations may be a limited islet mass. The aim of this study was to determine the critical islet mass necessary for normalization of glucose metabolism in a porcine model. Diabetes was induced by total pancreatectomy. The splenic lobe of the pancreas was intraductally distended with UW-solution containing 2.67-3.33 mg/ml collagenase, and the distended pancreas was digested in a continuous digestion filtration device. The islets were purified on a isoosmotic Ficoll-sodium-diatrizoate gradient. The survival period of the diabetic recipients in group 2 and 3 receiving, respectively, a low (2.14+/-0.39 microL/kg body weight) and a high (4.99+/-0.83 microL/kg body weight) islet mass was significantly prolonged compared to that of diabetic recipients in group 1 receiving no islet transplantation. However, the survival period of the recipients in group 2 was not significantly different to that in group 3. Three recipients of an islet mass of >5 microl/kg body weight became normoglycemic (fasting blood glucose <100 mg/dl) for more than two months. Furthermore, the glucose and insulin release reactions to the glucose challenge were comparable to that before pancreatectomy. Contrarily, another five diabetic recipients of an islet mass of <4 microL/kg body weight became a fasting blood glucose level of <200 mg/dl. The glucose and insulin release reactions to the glucose challenge were improved only, but not normalized compared to that before pancreatectomy. The data presented in this study demonstrate that metabolic normalization in pancreatectomized diabetic minipigs can be established by autotransplantation of an islet mass of >5 microl/kg body weight.

Intracellular Stress Signaling Pathways Activated During Human Islet Preparation and Following Acute Cytokine Exposure

“…These drawbacks indicated that transplantation of a sufficient number of islets, ϳ6,000 islet equivalents/kg body wt (1 islet equivalent ϭ 150-m diameter islet), is an essential condition for a successful graft (49). The high level of ␤-cell loss subsequent to isolation makes this number of islets difficult to obtain from one single pancreas, making until recently the use of "double-donor" transplants to provide for an adequate therapeutic islet mass a prerequisite to successful grafting (50). Better pancreas preservation before islet transplantation remains therefore one of the potential improvements to overcome islet shortage and to improve PNF (46,51).…”

Measurements of Insulin Secretory Capacity and Glucose Tolerance to Predict Pancreatic β-Cell Mass In Vivo in the Nicotinamide/Streptozotocin Göttingen Minipig, a Model of Moderate Insulin Deficiency and Diabetes

“…However, most likely, the different results obtained are, to some extent, explained by the relatively small number of observations in each study and the possibility that variability in ␤-cell function at very low values of ␤-cell mass seems to occur. Transplantation studies in both humans (16) and pigs (17) have shown a strong relation between islet mass and metabolic control. Since the ␤-cell mass (milligrams per kilogram body weight) in pigs is higher than in humans, this could affect the way in which functional tests can be used as a predictor of ␤-cell mass in each species.…”

“…In animals dosed with NIA plus STZ or STZ alone, pancreata were obtained 35 Ϯ 27 days (range 11-84) after the OGTT and 8 Ϯ 7 days (range 0 -27) after the insulin secretion test. In the normal control animals, pancreata were obtained 21 Ϯ 4 days (range [17][18][19][20][21][22][23][24][25][26] after the OGTT and 13 Ϯ 7 days (range 6 -23) after the insulin secretion test.…”

“…However, a greater than 80 -90% reduction of ␤-cell mass seems to be required before overt insulin-dependent diabetes develops in humans (2,3,6) and rats (15). In both humans (16) and pigs (17), there is a strong relation between islet mass used in transplantation studies and metabolic control, as evaluated by glucose levels and insulin secretion. Therefore, in patients with type 2 diabetes, the slight reduction of ␤-cell mass reported is unlikely to be the only factor responsible for development of hyperglycemia.…”

The c-Jun N-terminal kinase JNK participates in cytokine- and isolation stress-induced rat pancreatic islet apoptosis

“…Both effects, stress conditions during isolation and nonspecific inflammatory events following transplantation, then combine to strongly impair viability of islets. Consequently, a high number of islets from multiple donors are required to perform islet grafting [9], and therefore islet shortage and early loss of FIM are the main limitations to the expansion of islet transplantation as a curative therapy for type 1 diabetes mellitus [10].…”