Effect of Hypoxia on Insulin Secretion by Isolated Rat and Canine Islets of Langerhans

Abstract

The effect of pO2s reduced below physiological levels on GSIR by isolated islets of Langerhans was investigated with a microperifusion apparatus that provided control of pO2 and rapid dynamic response. Second-phase insulin secretion was reduced substantially by hypoxia. The response to lower pO2 was rapid and reversible. Although the steady, normoxic (pO2 = 142 mmHg) second-phase secretion rate varied widely from one islet preparation to another, the ratio of Sx to S142 for each preparation could be represented by a single curve that exhibited a continuous reduction with decreasing pO2. For rat islets perifused 1 day after isolation, the secretion rate was nearly 100% of the normoxic value at a pO2 of 60 mmHg, 50% at 27 mmHg (P50, the pO2 at which the S142 is reduced by 50%), and approximately 2% at 5 mmHg. Oxygen sensitivity of second-phase secretion rate declined after 1 wk of in vitro culture: P50 was 13 mmHg after 1 wk and remained at 10 mmHg after 2-5 wk of culture. Canine islets exhibited a P50 of 16 mmHg after 1 wk of culture. The reduction in insulin secretion is thought to be associated with the existence of pO2 gradients outside and inside the isolated islets, resulting in exposure of islet cells to low pO2 levels that decrease radially from the periphery to the core. We hypothesize that the effect of low pO2 on S is manifested through depletion of the energy stores of the beta-cells. The effect of hypoxia on S may be an important factor in some in vitro secretion studies and may play a critical role in the effectiveness of transplanted islets before their revascularization and of immunoisolated islet implantation devices.

Different susceptibility of rat pancreatic alpha and beta cells to hypoxia

“…Low beta cell survival and abnormal insulin release from pancreatic beta cells exposed to hypoxia have been extensively studied and found in different mammalian species (Dionne et al 1993;Moritz et al 2002;Lai et al 2009). Fig.…”

“…Currently, clinical trials show that long-term outcomes of islet transplantation are hampered by rejection, which lead to a gradual decrease in islet function usually taking place over the first years after transplantation (Shapiro et al 2006). One of the major factors of beta cell destruction after islet transplantation is the markedly decreased oxygen tension in the implantation sites and the high susceptibility of beta cells to hypoxia (Carlsson et al 2001;Dionne et al 1993). Recently, it was also shown that alteration of islet cell organization and impaired glucose sensing mechanisms may be induced by activation of hypoxia inducible factor-1a by deletion of the Vhlh gene codes for the von Hippel-Lindau protein that is a key player in the cellular response to oxygen sensing (Puri et al 2009;Cantley et al 2009).…”

Biocompatibility of alginate–poly-l-lysine microcapsules for cell therapy

“…We now understand that to ensure a better nutrient and oxygen supply to encapsulated islets, the distance between islets and the vasculature should be kept to a minimum. In vascularised tissue, the maximum distance for an effective diffusion of oxygen and nutrients from capillary to cells is 200 mm [47][48][49][50]. Because there is no convection movement within a capsule, the only driving force for the transfer of nutrients to islet cells is the concentration gradient.…”

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

“…In addition, activation of HIF-1a reduces glucose uptake and changes aerobic glucose metabolism to anaerobic glycolysis. During isolation and early post-transplantation, providing oxygen solely by gradient-driven passive diffusion results in decreasing oxygen pressure in islets radially from the periphery to the core (131). Different strategies suggested to overcome the hypoxia challenge include hyperbaric oxygen (HBO) therapy (132), design of gas permeable devices (133), oxygen carrier agents (134) and in situ oxygen generators (135).…”