Anatomy of the endocrine pancreas in actinopterygian fishes and its phylogenetic implications.

The anatomy and organisation of the endocrine pancreas in ray-finned fishes vary widely. The two main morphoanatomical character states are diffuse versus compact pancreatic tissue. The latter are called Brockmann Bodies (BBs), or principal islets. The present study is the first comprehensive survey on the anatomy of the endocrine pancreas (diffuse versus compact) across 322 actinopterygian species in 39 orders and 135 families based on literature, specimen dissections, and Magnetic Resonance Imaging (MRI). The data obtained show that large endocrine pancreatic islets (BB) have appeared several times in teleost evolution: in some ostariophysian clades and within the Salmoniformes and Neoteleostei. Acanthomorpha (spiny-rayed fishes) is the largest clade of the Neoteleostei. Within this clade, an absence of BBs is only observed in flying fishes (Exocoetidae), parrotfishes (Scarinae), and some of the scarine relatives, the Labridae. The presence of BBs in examined jellynose fish species from the Ateleopodiformes indicates support for its sister-group relationship to the Ctenosquamata (Myctophiformes + Acanthomorpha). More investigations are still needed to corroborate the presence or absence of BBs as a putative synapomorphy for a clade comprising Ateleopodiformes and Ctenosquamata.

Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice.

The pancreatic islet vasculature is of fundamental importance to the ß-cell response to obesity-associated insulin resistance. To explore islet vascular alterations in the pathogenesis of type 2 diabetes, we evaluated two insulin resistance models: ob/ob mice, which sustain large ß-cell mass and hyperinsulinemia, and db/db mice, which progress to diabetes due to secondary ß-cell compensation failure for insulin secretion. Time-dependent changes in islet vasculature and blood flow were investigated using tomato lectin staining and in vivo live imaging. Marked islet capillary dilation was observed in ob/ob mice, but this adaptive change was blunted in db/db mice. Islet blood flow volume was augmented in ob/ob mice, whereas it was reduced in db/db mice. The protein concentrations of total and phosphorylated endothelial nitric oxide synthase (eNOS) at Ser1177 were increased in ob/ob islets, while they were diminished in db/db mice, indicating decreased eNOS activity. This was accompanied by an increased retention of advanced glycation end-products in db/db blood vessels. Amelioration of diabetes by Elovl6 deficiency involved a restoration of capillary dilation, blood flow, and eNOS phosphorylation in db/db islets. Our findings suggest that the disability of islet capillary dilation due to endothelial dysfunction impairs local islet blood flow, which may play a role in the loss of ß-cell function and further exacerbate type 2 diabetes.

Beneficial impact of Ac3IV, an AVP analogue acting specifically at V1a and V1b receptors, on diabetes islet morphology and transdifferentiation of alpha- and beta-cells.

Ac3IV (Ac-CYIQNCPRG-NH2) is an enzymatically stable vasopressin analogue that selectively activates Avpr1a (V1a) and Avpr1b (V1b) receptors. In the current study we have employed streptozotocin (STZ) diabetic transgenic Ins1Cre/+;Rosa26-eYFP and GluCreERT2;Rosa26-eYFP mice, to evaluate the impact of sustained Ac3IV treatment on pancreatic islet cell morphology and transdifferentiation. Twice-daily administration of Ac3IV (25 nmol/kg bw) to STZ-diabetic Ins1Cre/+;Rosa26-eYFP mice for 12 days increased pancreatic insulin (p<0.01) and significantly reversed the detrimental effects of STZ on pancreatic islet morphology. Such benefits were coupled with increased (p<0.01) beta-cell proliferation and decreased (p<0.05) beta-cell apoptosis. In terms of islet cell lineage tracing, induction of diabetes increased (p<0.001) beta- to alpha-cell differentiation in Ins1Cre/+;Rosa26-eYFP mice, with Ac3IV partially reversing (p<0.05) such transition events. Comparable benefits of Ac3IV on pancreatic islet architecture were observed in STZ-diabetic GluCreERT2;ROSA26-eYFP transgenic mice. In this model, Ac3IV provoked improvements in islet morphology which were linked to increased (p<0.05-p<0.01) transition of alpha- to beta-cells. Ac3IV also increased (p<0.05-p<0.01) CK-19 co-expression with insulin in pancreatic ductal and islet cells. Blood glucose levels were unchanged by Ac3IV in both models, reflecting the severity of diabetes induced. Taken together these data indicate that activation of islet receptors for V1a and V1b positively modulates alpha- and beta-cell turnover and endocrine cell lineage transition events to preserve beta-cell identity and islet architecture.

Probing ß-Cell Biology in Space and Time.

ß-Cells in the islet of Langerhans have a central role in maintaining energy homeostasis. Understanding the physiology of ß-cells and other islet cells requires a deep understanding of their structural and functional organization, their interaction with vessels and nerves, the layout of paracrine interactions, and the relationship between subcellular compartments and protein complexes inside each cell. These elements are not static; they are dynamic and exert their biological actions at different scales of time. Therefore, scientists must be able to investigate (and visualize) short- and long-lived events within the pancreas and ß-cells. Current technological advances in microscopy are able to bridge multiple spatiotemporal scales in biology to reveal the complexity and heterogeneity of ß-cell biology. Here, I briefly discuss the historical discoveries that leveraged microscopes to establish the basis of ß-cell anatomy and structure, the current imaging platforms that allow the study of islet and ß-cell biology at multiple scales of resolution, and their challenges and implications. Lastly, I outline how the remarkable longevity of structural elements at different scales in biology, from molecules to cells to multicellular structures, could represent a previously unrecognized organizational pattern in developing and adult ß-cells and pancreas biology.

Architecture of the Pancreatic Islets and Endocrine Cell Arrangement in the Embryonic Pancreas of the Grass Snake (Natrix natrix L.). Immunocytochemical Studies and 3D Reconstructions.

During the early developmental stages of grass snakes, within the differentiating pancreas, cords of endocrine cells are formed. They differentiate into agglomerates of large islets flanked throughout subsequent developmental stages by small groups of endocrine cells forming islets. The islets are located within the cephalic part of the dorsal pancreas. At the end of the embryonic period, the pancreatic islet agglomerates branch off, and as a result of their remodeling, surround the splenic "bulb". The stage of pancreatic endocrine ring formation is the first step in formation of intrasplenic islets characteristics for the adult specimens of the grass snake. The arrangement of endocrine cells within islets changes during pancreas differentiation. Initially, the core of islets formed from B and D cells is surrounded by a cluster of A cells. Subsequently, A, B, and D endocrine cells are mixed throughout the islets. Before grass snake hatching, A and B endocrine cells are intermingled within the islets, but D cells are arranged centrally. Moreover, the pancreatic polypeptide (PP) cells are not found within the embryonic pancreas of the grass snake. Variation in the proportions of different cell types, depending on the part of the pancreas, may affect the islet function-a higher proportion of glucagon cells is beneficial for insulin secretion.

Alpha cell regulation of beta cell function.

The islet of Langerhans is a complex endocrine micro-organ consisting of a multitude of endocrine and non-endocrine cell types. The two most abundant and prominent endocrine cell types, the beta and the alpha cells, are essential for the maintenance of blood glucose homeostasis. While the beta cell produces insulin, the only blood glucose-lowering hormone of the body, the alpha cell releases glucagon, which elevates blood glucose. Under physiological conditions, these two cell types affect each other in a paracrine manner. While the release products of the beta cell inhibit alpha cell function, the alpha cell releases factors that are stimulatory for beta cell function and increase glucose-stimulated insulin secretion. The aim of this review is to provide a comprehensive overview of recent research into the regulation of beta cell function by alpha cells, focusing on the effect of alpha cell-secreted factors, such as glucagon and acetylcholine. The consequences of differences in islet architecture between species on the interplay between alpha and beta cells is also discussed. Finally, we give a perspective on the possibility of using an in vivo imaging approach to study the interactions between human alpha and beta cells under in vivo conditions. Graphical abstract.

Morphogenesis of the ventral pancreas anlagen is influenced by the SMA branching pattern.

Developmentally, the uncinate process of the pancreas is derived from the ventral pancreatic anlagen, supplied by the superior mesenteric artery (SMA), and contains pancreatic polypeptide (PP)-rich islets of Langerhans. In contrast, the other parts of the pancreas originate from the dorsal anlagen supplied by the celiac system and contain PP-poor islets. This study was performed to investigate whether morphogenesis of the ventral pancreas anlagen is associated with the pattern of SMA branching. SMA branches to the pancreatic body were dissected in 44 cadavers. The cadavers were divided into two groups: the SMA group in which the SMA gave off branches to the pancreatic body and the General group in which it did not. In the SMA group, the ratio of the diameter of the SMA branch supplying the pancreatic body (SMA branch) to that of the SMA itself was calculated. After dissection was completed, tissues were collected from all pancreatic specimens for HE staining and for immunohistochemistry with PP and insulin antibodies. There were 25 cadavers in the General group and 19 in the SMA group. In 10/19 cadavers from the SMA group, PP-rich islets were confirmed in the pancreatic body. The SMA branch diameter ratio was significantly smaller in the SMA group cadavers with PP-poor islets (n = 9) than in cadavers with PP-rich islets (n = 10) (P < 0.001). These findings suggest a relation between the SMA branching pattern and the distribution of PP cells.

Microscopic study of the rat pancreas after denervation

The aim of this study is to demonstrate that the denervation of the pancreas may affect the enteric neuronal plexus, which controls both the endocrine and exocrine parts of the pancreas. By using the light microscope, the histological changes of the islets of Langerhans and the pancreatic acini in the rat pancreas were studied two and three weeks after sympathectomy and truncal vagotomy. More-over, measurements of the changes infasting blood glucose levels and glucose tolerance tests in the control and experimental animals were recorded. Atrophic changes and degeneration of the pancreatic acinar cells and islets of Langerhans cells were observed after both sympathectomy and vagotomy. Biochemical measurements of fasting blood, and the glucose tolerance tests after sympathectomy and vagotomy were increased significantly, which is consistent with the histological results. The results of this study explain that the exocrine and endocrine parts of the pancreas are dependent on both sympathetic and parasympathetic innervation via the enteric plexuses of the rat pancreas. These results establish a firm correlation between the autonomic innervation and the enteric plexus, which controls the function of the endocrine and exocrine parts of the pancreas

No disponible

Immunohistochemical distribution of insulin-, glucagon- and somatostatin-containing cells in the pancreas of Lake Van fish (Alburnus tarichi Güldenstädt, 1814) (Cyprinidae).

The Lake Van fish (Alburnus tarichi) is a species that is endemic to Turkey's Lake Van basin. In this study, the regional distribution, volume density, and relative frequency of some pancreatic endocrine cells in Lake Van fish were investigated via immunohistochemistry using specific mammalian antibodies. The pancreatic tissue was observed to be surrounded by adipose tissue, which was adjacent to the gall bladder or extrahepatic bile duct, or dispersed in the adipose tissue ranked among coils of post-esophageal swelling and intestine. The pancreatic endocrine cells were examined, including the islets, exocrine pancreas, and pancreatic ducts. According to the modified aldehyde fuchsin staining and immunohistochemistry, insulin-secreting beta cells were observed to localize throughout the islets. Glucagon immune-reactive (IR) cells were observed to be situated moderately on the islet periphery, and were rarely determined in the islet central region. A small number of somatostatin-IR cells were observed in the islet centers and peripheries. Similar distributions of those 3 endocrine cells were also determined in the secondary islets. Additionally, the endocrine cell percentages did not differ between the primary and secondary islets; insulin-, glucagon- and somatostatin-IR cells comprised approximately 54%, 29%, and 11% of the endocrine cells in the principal islets, whereas they comprised 52%, 27%, and 14% in the secondary islets, respectively. Insulin-, glucagon- and somatostatin-IR cells were also determined among the epithelium and subepithelial connective tissue in the pancreatic ducts or exocrine areas of the pancreas. With this study, the existence, regional distribution, and relative frequency of the insulin-, glucagon- and somatostatin-IR cells were first investigated in the pancreatic tissue of Lake Van fish and the results were discussed.

Litter Size Reduction Induces Metabolic and Histological Adjustments in Dams throughout Lactation with Early Effects on Offspring.

In the present study we analyzed morphological and metabolic alterations in dams nursing small litters and their consequences to offspring throughout lactation. Offspring sizes were adjusted to Small Litter (SL, 3 pups/ dam) and Normal Litter (NL, 9 pups/ dam). Body weight, food intake, white adipose tissue (WAT) content, histological analysis of the pancreas, mammary gland (MG) and brown adipose tissue (BAT) as well as, plasma parameters and milk composition were measured in dams and pups on the 7th, 14th and 21st days of lactation. In general, SL-dams presented higher body weight and retroperitoneal fat content, elevated fat infiltration in BAT, reduced islets size and hyperglycemia throughout lactation in relation to NL-dams (p<0.05). Moreover, MG from SL-dams had reduced alveoli development and high adipocytes content, resulting in milk with elevated energetic value and fat content in relation to NL-dams (p<0.05). Maternal states influenced offspring anthropometric conditions during lactation, offspring-SL displayed higher body weight and growth, hyperglycemia, augmented lipid deposition in BAT and elevated islet. Thus, maternal histological and metabolic changes are due to modifications to nursing small litters and reinforce the importance of preserving maternal health during lactation avoiding early programming effects on offspring preventing metabolic consequences later in life.

The Flaws and Future of Islet Volume Measurements.

When working with isolated islet preparations, measuring the volume of tissue is not a trivial matter. Islets come in a large range of sizes and are often contaminated with exocrine tissue. Many factors complicate the procedure, and yet knowledge of the islet volume is essential for predicting the success of an islet transplant or comparing experimental groups in the laboratory. In 1990, Ricordi presented the islet equivalency (IEQ), defined as one IEQ equaling a single spherical islet of 150 µm in diameter. The method for estimating IEQ was developed by visualizing islets in a microscope, estimating their diameter in 50 µm categories and calculating a total volume for the preparation. Shortly after its introduction, the IEQ was adopted as the standard method for islet volume measurements. It has helped to advance research in the field by providing a useful tool improving the reproducibility of islet research and eventually the success of clinical islet transplants. However, the accuracy of the IEQ method has been questioned for years and many alternatives have been proposed, but none have been able to replace the widespread use of the IEQ. This article reviews the history of the IEQ, and discusses the benefits and failings of the measurement. A thorough evaluation of alternatives for estimating islet volume is provided along with the steps needed to uniformly move to an improved method of islet volume estimation. The lessons learned from islet researchers may serve as a guide for other fields of regenerative medicine as cell clusters become a more attractive therapeutic option.

In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo.

Widespread use of pancreatic islet transplantation for treatment of type 1 diabetes (T1D) is currently limited by requirements for long-term immunosuppression, limited donor supply, and poor long-term engraftment and function. Upon isolation from their native microenvironment, islets undergo rapid apoptosis, which is further exacerbated by poor oxygen and nutrient supply following infusion into the portal vein. Identifying alternative strategies to restore critical microenvironmental cues, while maximizing islet health and function, is needed to advance this cellular therapy. We hypothesized that biophysical properties provided through type I oligomeric collagen macroencapsulation are important considerations when designing strategies to improve islet survival, phenotype, and function. Mouse islets were encapsulated at various Oligomer concentrations (0.5 -3.0 mg/ml) or suspended in media and cultured for 14 days, after which viability, protein expression, and function were assessed. Oligomer-encapsulated islets showed a density-dependent improvement in in vitro viability, cytoarchitecture, and insulin secretion, with 3 mg/ml yielding values comparable to freshly isolated islets. For transplantation into streptozotocin-induced diabetic mice, 500 islets were mixed in Oligomer and injected subcutaneously, where rapid in situ macroencapsulation occurred, or injected with saline. Mice treated with Oligomer-encapsulated islets exhibited rapid (within 24 h) diabetes reversal and maintenance of normoglycemia for 14 (immunocompromised), 90 (syngeneic), and 40 days (allogeneic). Histological analysis showed Oligomer-islet engraftment with maintenance of islet cytoarchitecture, revascularization, and no foreign body response. Oligomer-islet macroencapsulation may provide a useful strategy for prolonging the health and function of cultured islets and has potential as a subcutaneous injectable islet transplantation strategy for treatment of T1D.

[Effect of Electroacupuncture at "Weiwanxiashu" (EX-B 3) on Islet Morphology and the Expression of Pancreatic Glucagon-like Peptide-1 Receptor in Type 2 Diabetes Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on pancreatic glucagon-like peptide-1 receptor (GLP-1 R), pancreatic and duodenal homeobox 1 (PDX-1) protein expression and blood glucose in type 2 diabetes rats, so as to explore the underlying mechanism of EA treatment in improving type 2 diabetes. METHODS: Sprague-Dawley rats were randomly divided into blank control group, model group, "Weiwanxiashu" (EX-B 3) group, "Xinshu" (BL 15) group, and "Shenshu" (BL 23) group, 12 rats in each group. Diabetes model was established by feeding the rat with high fat and high sugar diet combined with intraperitoneal injection of streptozotocin (35 mg/kg). All the EA groups received 2 Hz, 2 mA continuous wave treatment for 20 min everyday, 6 times per week lasting for 4 weeks. Fasting blood glucose was measured by Roche glucometer before and after treatment. Hematoxylin and eosin (HE) staining and Masson staining were used to detect pancreas morphology. GLP-1 R and PDX-1 protein expressions in the pancreas were detected by Western blot. RESULTS: Compared to the blank control group, fasting blood glucose was significantly increased in the model group(P<0.01), accompanied with shrunken islet area, reduced nucleus counts of islet ß cells, and compensatorily enlarged ß cell nucleus. Compared to the model group, EA intervention significantly reduced fasting blood glucose level only in the EX-B 3 group (P<0.05), partly restored pancreas morphology and nucleus counts of islet ß cells in the EX-B 3, BL 15, and BL 23 groups. Compared to the blank control group, GLP-1 R and PDX-1 expressions were decreased in the model group (P<0.01), while EA treatment could obviously increase GLP-1 R expression in the EX-B 3(P<0.01), BL 15 (P<0.01) and BL 23 (P<0.05) groups compared with the model group. The expression of GLP-1 R in the BL 15 group was the highest among the three EA groups (P<0.05,P<0.01), and that in the EX-B 3 group was higher than in the BL 23 group (P<0.05).There were no signifincant differences in the expression of PDX-1 protein among the three EA groups (P>0.05). CONCLUSIONS: EA treatment at EX-B 3 can reduce blood glucose via regulating pancreas function, increasing pancreatic GLP-1 R expression, and partly restoring the morphology of pancreas.

A novel toolbox to investigate tissue spatial organization applied to the study of the islets of Langerhans.

Thanks to the development of new 3D Imaging techniques, volumetric data of thick samples, especially tissues, are commonly available. Several algorithms were proposed to analyze cells or nuclei in tissues, however these tools are limited to two dimensions. Within any given tissue, cells are not likely to be organized randomly and as such have specific patterns of cell-cell interaction forming complex communication networks. In this paper, we propose a new set of tools as an approach to segment and analyze tissues in 3D with single cell resolution. This new tool box can identify and compute the geographical location of single cells and analyze the potential physical interactions between different cell types and in 3D. As a proof-of-principle, we applied our methodology to investigation of the cyto-architecture of the islets of Langerhans in mice and monkeys. The results obtained here are a significant improvement in current methodologies and provides new insight into the organization of alpha cells and their cellular interactions within the islet's cellular framework.

Influence of feeding habits in the endocrine pancreas of insectivore bat Pteronotus personatus and nectarivore bat Anoura geoffroyi: A comparative stereological and immunohistochemical study.

Pteronotus personatus as an insectivore bat and has a diet that consists of a high protein diet, whereas the diet of Anoura geoffroyi, a predominantly nectarivore bat, is rich in simple sugars like sucrose, glucose and fructose. Considering that diet influences the activation of different pathways, which may influence morphological adaptations in the gastrointestinal system, the aim of this study was to compare the morphology of the endocrine pancreas in P. personatus and A. geoffroyi. For this, histological, stereological and immunohistochemical methods were used. In P. personatus, the average diameter of the pancreatic islet was 40.47µm±13.94, while in A. geoffroyi was 88.16µm±36.40. The total number of pancreatic islets in P. personatus was 26150±2346 and in A. geoffroyi was 15970±1666. In P. personatus, the volume density of the pancreatic islets was 3.4%± 2.6, whereas in A. geoffroyi the volume density was 6.1%±3.7. In addition, the immunodensity of the α, ß and δ cells, in P. personatus was 25.8%±11.9, 35.5%±13.5, 3.9%±0.7, respectively, and in A. geoffroyi was 33.10%±12.7, 55.08%±7.4, 6.2%±4.6, respectively. In conclusion, the results of this study indicate differences in the pancreatic weight/body, weight ratio, diameter and volume density of pancreatic islets and in immunodensity of the ß and α cells between both species, which have different dietary habits.

Histological and Metabolic State of Dams Suckling Small Litter or MSG-Treated Pups.

Lactation is an important function that is dependent on changes in the maternal homeostasis and sustained by histological maternal adjustments. We evaluated how offspring manipulations during the lactational phase can modulate maternal morphologic aspects in the mammary gland, adipose tissue, and pancreatic islets of lactating dams. Two different models of litter-manipulation-during-lactation were used: litter sizes, small litters (SL) or normal litters (NL) and subcutaneous injections in the puppies of monosodium glutamate (MSG), or saline (CON). SL Dams and MSG Dams presented an increase in WAT content and higher plasma levels of glucose, triglycerides, and insulin, in relation to NL Dams and CON Dams, respectively. The MG of SL Dams and MSG Dams presented a high adipocyte content and reduced alveoli development and the milk of the SL Dams presented a higher calorie and triglyceride content, compared to that of the NL Dams. SL Dams presented a reduction in islet size and greater lipid droplet accumulation in BAT, in relation to NL Dams. SL Dams and MSG Dams present similar responses to offspring manipulation during lactation, resulting in changes in metabolic parameters. These alterations were associated with higher fat accumulation in BAT and changes in milk composition only in SL Dams.

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for ß-cell mass assessments.

Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in ß-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total ß-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Alternative methods are therefore warranted to cross-validate ß-cell imaging using radiotracers. In this study, we introduce multimodal SPECT - optical projection tomography (OPT) imaging as an accurate approach to cross-validate radionuclide-based imaging of ß-cells. Uptake of a promising radiotracer for ß-cell imaging by SPECT, (111)In-exendin-3, was measured by ex vivo-SPECT and cross evaluated by 3D quantitative OPT imaging as well as with histology within healthy and alloxan-treated Brown Norway rat pancreata. SPECT signal was in excellent linear correlation with OPT data as compared to histology. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of (111)In-exendin-3 and insulin positive ß-cell volumes between different pancreatic lobes, both visually and quantitatively. We propose ex vivo SPECT-OPT multimodal imaging as a highly accurate strategy for validating the performance of ß-cell radiotracers.

The role of endothelial cells on islet function and revascularization after islet transplantation.

Islet transplantation has become a widely accepted therapeutic option for selected patients with type 1 diabetes mellitus. However, in order to achieve insulin independence a great number of islets are often pooled from 2 to 4 pancreata donors. Mostly, it is due to the massive loss of islets immediately after transplant. The endothelium plays a key role in the function of native islets and during the revascularization process after islet transplantation. However, if a delayed revascularization occurs, even the remaining islets will also undergo to cell death and late graft dysfunction. Therefore, it is essential to understand how the signals are released from endothelial cells, which might regulate both differentiation of pancreatic progenitors and thereby maintenance of the graft function. New strategies to facilitate islet engraftment and a prompt revascularization could be designed to intervene and might lead to improve future results of islet transplantation.