Background. Blood flow is impaired in islet transplants, but there is conflicting evidence on improving the outcome by promoting vascularization. We previously reported that islet endothelial cells (EC) possess significant angiogenic capacity. Methods. To further address this issue, we studied human islets in culture under hypoxic conditions. Moreover, we used a transgene mouse model with human vascular endothelial growth factor (VEGF) production in β-cells under the control of the rat insulin promoter (RIP) to stimulate islet EC proliferation. Results. Subsequent to a hypoxic stimulus, islets responded with specific expression patterns of VEGF and fibroblast growth factor; however, this was not sufficient to prevent the decay of islet EC. VEGF release of RIP-VEGF transgenic islets was controlled by glucose and resulted in the formation of sprouts. When transplanted to the kidney capsule of diabetic mice, RIP-VEGF islets significantly enhanced microvascular density and functional blood flow to the graft compared with controls. Conclusions. Optimized angiogenesis of islet transplants resulted in greater availability of insulin caused by β-cell proliferation and a significantly higher percentage (90% versus 20%) of mice cured from diabetes.

Transplantation of pancreatic islets reconstitutes glucose homeostasis in diabetes mellitus. Before transplantation, islets are disrupted from the surrounding blood vessels by the isolation procedure, with the grafted tissue being subject to ischemic damage. The survival of transplanted islets is assumed to depend on effective revascularization. Perfusion studies suggest that newly formed microvessels supplying the graft with nutrients are exclusively rebuilt by the host. It is generally not known whether isolated islets contain endothelial cells (EC), which potentially participate in the revascularization process. Therefore, we tried to detect immature EC in isolated islets by transformation with polyoma middle T antigen. Endothelioma cells were generated, implicating the presence of de‐differentiated EC within isolated islets. When embedded in a fibrin gel, the islets developed cellular cords consisting of EC, whereas FGF‐2 and VEGF stimulated the formation of cord‐like structures. Furthermore, we studied the presence of donor EC in islet grafts by using transgenic mice with an EC lineage‐specific promotor‐LacZ reporter construct (Tie‐2LacZ). Following islet transplantation, Tie‐2LacZ‐positive EC of both donor and recipient were identified in the vicinity of or within the graft up to 3 wk after transplantation. In conclusion, EC and/or their progenitors with angiogenic capacity reside within isolated islets of different species, and their proliferative potential can be stimulated by various inducers. These graft‐related endothelia persist after islet transplantation and are integrated within newly formed microvessels.

Summary: β-cell replacement is the only way to restore euglycaemia in patients with type-1 diabetes. Pancreatic tissue, processed for subsequent clinical islet transplantation, is exposed to ischaemia causing injury and death in a large number of islets before and after transplantation. In this review we summarize what is known on the sources of environmental stress for pancreatic islets, such as insufficient oxygen supply during pancreas procurement and in culture prior to intraportal transplantation, nutritional and oxygen deprivation during the isolation process, and the consequences of hyperglycaemia. An increasingly recognized role in the modulation of β-cell function and these environmental stress factors plays the vascular network of the pancreatic islets. Islet revascularization by angiogenesis is relevant for the survival of the graft subsequent to transplantation. Potential strategies offered by therapeutic induction of revascularization to ameliorate the detrimental impact of these factors on the quality of islet transplants are discussed.

Diabetes-induced hyperglycemia has previously been shown to impact on male sub-/infertility, however, still little is known about the underlying mechanisms. In the present study we have addressed three major biochemical pathways implicated in the pathogenesis of hyperglycemia induced organ damage (the advanced glycation end product (AGE) formation pathway, the diacylglycerol-protein kinase C pathway (PKC), and the polyol pathway) in both testis and epididymis of the Ins2^Akita mouse model of Type 1 diabetes (T1DM). Hyperglycemia activated both the PKC and the polyol pathway in a significant and progressive manner within the testis, but not within the epididymis. While the AGE receptor was ubiquitiously expressed in the testis, concentrations of precursor methylglyoxal and AGE carboxymethyllysine were increased in both epididymis and testis in diabetic mice. However, AGEs did not activate intracellular pathways of ERK1, ERK2, Rela, Nrf-2, IkBkB, NFkB except CDC42, Akt1. In conclusion, two of the major pathways of hyperglycemia-induced organ damage were clearly activated within the testis of T1DM mice. This provides therapeutical opportunities in the treatment of diabetic male reproductive dysfunction.

Low glycemic index diets are supposed to achieve a more beneficial effect on blood glucose control in people with diabetes mellitus and may also provide metabolic benefits for the general population. A prototype of a low-glycemic index carbohydrate is the natural occurring disaccharide isomaltulose that can be commercially produced from sucrose (beet sugar) to industrial scale. It is currently used in various food and drink applications as well as special and clinical nutrition feeds and formula diet as a food ingredient and alternative sugar. Here we provide an overview on clinical trials with isomaltulose including an analysis of its effects on glycemia and fat oxidation as compared to high glycemic index sugars and carbohydrates. In addition, we discuss recent reports on beneficial effects in weight-loss maintenance and pregnancy.