Length of metabolic normalization after rat islet cell transplantation depends on endocrine cell composition of graft and on donor age

Abstract

Experimental diabetes mellitus in rodents can be corrected by different types of islet cell grafts which have been placed in different locations [1]. While numerous studies have demonstrated short-term benefits of islet transplantation, relatively few investigations have examined the conditions for longterm metabolic normalization. The latter is however a requisite for a preventive effect on chronic complications, the main objective for developing islet transplantation as a cure of diabetes. Several reports have described conditions under which metabolic control by islet transplants was progressively lost during a mid-or long-term follow-up [1][2][3][4][5][6][7][8]. It was often not clear whether this delayed failure was due to an insufficient graft, an inadequate implantation site or an immune reactivity [1][2][3][4][5][6][7][8]. We recently observed that the composition of the donor tissue can be responsible for a late loss of metabolic control in streptozotocin-diabetic rats which had been successfully treated by islet cell transplantation [9]. Number of beta cells, proportion of other endocrine and nonendocrine cells and particle size were found to be potentially influential variables. The present study was designed to assess whether the duration of metabolic normalization is reduced by a higher age of the beta-cell donor and by the absence of islet endocrine non-beta-cells in the implant. The rationale for investigating these two variables comes from in vitro experiments in which both factors were found to Diabetologia (1997Diabetologia ( ) 40: 1152Diabetologia ( -1158 Length of metabolic normalization after rat islet cell transplantation depends on endocrine cell composition of graft and on donor age Summary In vitro studies have demonstrated that beta-cell functions are negatively influenced by age and positively by the presence of glucagon producing alpha cells. This study examines whether the function of beta-cell grafts varies with the age of the donor and with the presence of other endocrine islet cells. Islet beta and endocrine non-beta-cells were purified from 10-to 30-week-old Lewis rats, and reaggregated into pure beta and mixed endocrine cell aggregates. Grafts consisted of 1.2 to 1.7 million beta cells with or without 0.6-0.7 million alpha cells. Their intraportal transplantation in 10-week-old streptozotocin-diabetic rats corrected hyperglycaemia in all experimental groups, with normal glucose tolerance curves at post-transplantation week (PT wk) 4. Recipients of mixed endocrine cell grafts from 10-week-old donors maintained a glucose tolerant state until PT wk 20, but turned glucose intolerant thereafter; only 1 of 12 animals was overtly diabetic at PT wk 64. Recipients of pure beta-cell grafts from 10-week-old donors became glucose-intolerant from PT wk 4 on, with 5 of 11 cases developing overt diabetes before PT wk 64. When grafts were prepared from 30-week-old donors, metabolic deterioration started earlier, again with a more rapid loss for pure beta-cell grafts; at PT wk 64, virtually all ...

Blockade of β1 Integrin–Laminin-5 Interaction Affects Spreading and Insulin Secretion of Rat β-Cells Attached on Extracellular Matrix

“…In this study we demonstrated that laminin-5 is expressed in rat and human islets, mainly in ␣-cells. This is in agreement with data showing that in some circumstances, ␣-cells may improve the function of ␤-cells (44), and this could be attributable to provision of a more appropriate extracellular matrix as well as possible paracrine effects of glucagon. Moreover, laminin-5 was also detected in islet culture media (data not shown), suggesting this molecule could be secreted by insular cells.…”

Suitability of human juvenile pancreatic islets for clinical use

“…Islet loss rate was not different from that of adult islet preparations [24,27]. Previous work [19] addressed donor age as a factor that affects islet performance; in rodent models of syngeneic and allogeneic islet transplantation it was demonstrated that donor age inversely correlates with the duration of glycaemia normalisation. The potential advantage offered by young donor pancreatic tissue had been addressed already in the 1970s [36].…”

“…The medical history of younger donors is usually uneventful and the incidence of chronic pathological conditions is extremely low, having, with the exception of type 1 diabetes, little or no effect on the functional status of the islets. Previous studies in rodent models have established an inverse correlation between duration of islet graft function and donor age [19]. In clinical transplantation, pancreases obtained from young donors showed good performance in adult recipients [20], providing an additional rationale to justify the efforts to improve the isolation of islets from young donors and overcome the technical limitations in their complete purifica- tion.…”

A Novel Method for the Assessment of Cellular Composition and Beta-Cell Viability in Human Islet Preparations

“…More conventional techniques such as immunohistochemical (23,24) and electron microscopic (EM) analysis rely on subjective interpretation of the results and scoring based on observation of samples by the operator(s). The LSC hardware and software provide objective analysis of substantially higher number of cells (e.g.…”