Destruction Of Islet Beta Cells Research Articles

Long-term TNF-alpha therapy for preserving beta cell function in new onset type 1 diabetes: a case report

BackgroundType 1 diabetes mellitus (T1D) is an autoimmune disease caused by destruction of pancreatic islet beta-cells. There is significant residual beta-cell function, measured through circulating C-peptide, present at the time of T1D diagnosis but this subsequently decreases with time. Higher residual beta-cell function at diagnosis associates with better glycaemic control and less glucose variability, and later in the disease course with less hypoglycaemia, lower glucose variability and fewer microvascular complications. There is therefore value in preserving residual beta cell function in new onset T1D Immunotherapeutic agents can protect residual beta-cell function in type 1 diabetes. However, clinical trials of such agents, whilst demonstrating C-peptide preservation in short term studies, have yet to be taken forward into routine clinical care due to concerns around safety and long-term efficacy. Here we report the case of a gentleman with newly diagnosed T1D whose glycaemic control and insulin requirement improved whilst on a five year infusion programme of infliximab, a monoclonal antibody against TNF-alpha, for colitis.Case presentationA 52-year-old White Caucasian man was diagnosed with T1D in August 2018. Glucose was 25.6 mmol/L, HbA1c was 98mmol/mol and GAD antibodies were strongly positive. HbA1c marginally improved to 91mmol/mol following initiation of insulin detemir 5 units at night and 1:10 g of insulin aspart (November 2018). In June 2019, he developed rectal bleeding and abdominal pain. Following colonoscopy, he was diagnosed with “indeterminate colitis” and commenced on 6-weekly infusions of 400-450 mg infliximab. Thus far, he has received 32 doses and achieved colitis remission. Following infliximab initiation there was increased frequency of mild-moderate hypoglycaemia and he was gradually weaned off and discontinued detemir in June 2020. Since then, HbA1c improved from 57mmol/mol in August 2019 to 52mmol/mol in April 2022, remaining stable at 51mmol/mol. His most recent HbA1c is 54mmol/mol in February 2024. His c-peptide was 550pmol/L in October 2022 and 442pmol/L in February 2024, suggesting well-preserved beta-cell function almost 6 years post-diagnosis.ConclusionsOur patient’s improvement in glycaemic control can be explained by immunomodulation and C peptide preservation from infliximab. With the growing focus on type 1 diabetes disease modulation and working towards an ‘insulin free T1D’, our findings strengthen the evidence base for the repurposing of and long-term treatment with anti-TNF-α agents to preserve beta-cell function in new onset T1D.

Enrichment of Bioactive Lipids in Urinary Extracellular Vesicles and Evidence of Apoptosis in Kidneys of Hypertensive Diabetic Cathepsin B Knockout Mice after Streptozotocin Treatment.

Cathepsin B (CtsB) is a ubiquitously expressed cysteine protease that plays important roles in health and disease. Urinary extracellular vesicles (uEVs) are released from cells associated with urinary organs. The antibiotic streptozotocin (STZ) is known to induce pancreatic islet beta cell destruction, diabetic nephropathy, and hypertension. We hypothesized that streptozotocin-induced diabetic kidney disease and hypertension result in the release of bioactive lipids from kidney cells that induce oxidative stress and renal cell death. Lipidomics was performed on uEVs isolated from CtsB knockout mice treated with or without STZ, and their kidneys were used to investigate changes in proteins associated with cell death. Lysophosphatidylethanolamine (LPE) (18:1), lysophosphatidylserine (LPS) (22:6), and lysophosphatidylglycerol (LPG) (22:5) were among the bioactive lipids enriched in uEVs from CtsB knockout mice treated with STZ compared to untreated CtsB mice (n = 3 uEV preparations per group). Anti-oxidant programming was activated in the kidneys of the CtsB knockout mice treated with STZ, as indicated by increased expression of glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter SLC7A11 (XCT) (n = 4 mice per group), which was supported by a higher reactivity to 4-hydroxy-2-nonenal (4-HNE), a marker for oxidative stress (n = 3 mice per group). Apoptosis but not ferroptosis was the ongoing form of cell death in these kidneys as cleaved caspase-3 levels were significantly elevated in the STZ-treated CtsB knockout mice (n = 4 mice per group). There were no appreciable differences in the pro-ferroptosis enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) or the inflammatory marker CD93 in the kidneys (n = 3 mice per group), which further supports apoptosis as the prevalent mechanism of pathology. These data suggest that STZ treatment leads to oxidative stress, inducing apoptotic injury in the kidneys during the development of diabetic kidney disease and hypertension.

Decellularized Wharton’s jelly scaffold enhances differentiation of mesenchymal stem cells to insulin-secreting cells

Diabetes is caused by the destruction of beta-cells in the pancreatic islets. This study was designed to fabricate a favorable bio-scaffold to improve the differentiation of Wharton’s jelly (WJ) mesenchymal stem cells (WMJSCs) to the insulin-secreted cells (ISCs). In this study, a decellularized-WJ scaffold (DWJS) was established and characterized by histological assessments, scanning electron microscopy, determination of residual DNA, and examination of the mechanical tensile property. The WJMSCs were seeded on DWJS and exposed to ISC-differentiation media. The functional maturity of ISCs was examined using Ditizone (DTZ) staining, insulin and C-Peptide secretion, and mRNA expression of insulin-related genes. The main components of the WJ such as collagens, proteoglycans, and glycosaminoglycans remained after decellularization. Very low residual DNA, good mechanical behavior, and appropriate porosity of the DWJS provided an ideal extracellular microenvironment for the ISCs. The insulin secretion of DWJS-seeded ISCs in response to glucose stimulation was significantly more than that in the 2D-culture system. DWJS significantly increased the number of DTZ-positive cells compared to the 2D-culture system. In addition, it enhanced the expression of the PDX-1, GLUT-2, and INS genes in the ISCs. These results collectively provided solid evidence that DWJS is a suitable scaffold for stabilizing the artificial pancreatic island.

Tolerance induction by liposomes targeting a single CD8 epitope IGRP206-214 in a model of type 1 diabetes is impeded by co-targeting a CD4+ islet epitope.

The autoimmune disease type 1 diabetes is predominantly mediated by CD8+ cytotoxic T-cell destruction of islet beta cells, of which islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206-214 is a dominant target antigen specificity. Previously, we found that a liposome-based antigen-specific immunotherapy encapsulating the CD4+ T-cell islet epitope 2.5mim together with the nuclear factor-κB inhibitor calcitriol induced regulatory T cells and protected from diabetes in NOD mice. Here we investigated whether the same system delivering IGRP206-214 could induce antigen-specific CD8+ T-cell-targeted immune regulation and delay diabetes. Subcutaneous administration of IGRP206-214 /calcitriol liposomes transiently activated and expanded IGRP-specific T-cell receptor transgenic 8.3 CD8+ T cells. Liposomal co-delivery of calcitriol was required to optimally suppress endogenous IGRP-specific CD8+ T-cell interferon-γ production and cytotoxicity. Concordantly, a short course of IGRP206-214 /calcitriol liposomes delayed diabetes progression and reduced insulitis. However, when IGRP206-214 /calcitriol liposomes were delivered together with 2.5mim /calcitriol liposomes, disease protection was not observed and the regulatory effect of 2.5mim /calcitriol liposomes was abrogated. Thus, tolerogenic liposomes that target either a dominant CD8+ or a CD4+ T-cell islet epitope can delay diabetes progression but combining multiple epitopes does not enhance protection.

Safety and Efficacy of Teplizumab for Treatment of Type One Diabetes Mellitus: A Systematic Review and Meta-Analysis

Type one diabetes mellitus (T1DM) is an autoimmune disease characterized by gradual destruction of beta cells in islets of Langerhans. Teplizumab is a humanized anti- CD3 monoclonal antibody, which may have beneficial effects for T1DM patients. The aim of the study was to assess the safety and efficacy of teplizumab in T1DM patients. We searched electronic databases using related keywords for randomized clinical trials assessing the safety and efficacy of teplizumab. We evaluated the retrieved citations for eligibility, and we extracted the data and then analyzed it using Review Manager Software. We included eight randomized clinical trials with 866 patients. Teplizumab was associated with lower insulin use than placebo at 6 months (MD = -0.17, 95% CI [-0.24, -0.09], P < 0.001), 12 months (MD = -0.12, 95% CI [-0.18, -0.06], P < 0.001), 18 months (MD = -0.22, 95% CI [-0.32, -0.11], P < 0.001) and 24 months (MD = -0.17, 95% CI [-0.28, -0.06], P = 0.003). The area under the curve of C-peptide was significantly increased in teplizumab group at 12 months (MD = 0.08, 95% CI [0.01, 0.15], P = 0.03), 18 months (MD = 0.13, 95% CI [0.01, 0.25], P = 0.03) and 24 months (MD = 0.13, 95% CI [0.01, 0.24], P = 0.03). No significant effect of teplizumab on HbA1c levels was observed at any time point. Teplizumab was found to be associated with some side effects such as lymphopenia, skin and subcutaneous tissue disorders. Teplizumab is associated with lower insulin use and higher AUC of C-peptide in type 1 diabetic patients with no significant effect on Hb1c levels. Besides, teplizumab has shown some adverse effects.

Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice

CD8+ T cells play a central role in beta-cell destruction in type 1 diabetes. CD8+ T cells use two main effector pathways to kill target cells, perforin plus granzymes and FAS ligand (FASL). We and others have established that in non-obese diabetic (NOD) mice, perforin is the dominant effector molecule by which autoreactive CD8+ T cells kill beta cells. However, blocking FASL pharmacologically was shown to protect NOD mice from diabetes, indicating that FASL may have some role. FASL can engage with its receptor FAS on target cells either as membrane bound or soluble FASL. It has been shown that membrane-bound FASL is required to stimulate FAS-induced apoptosis in target cells, whereas excessive soluble FASL can induce NF-κB-dependent gene expression and inflammation. Because islet inflammation is a feature of autoimmune diabetes, we tested whether soluble FASL could be important in disease pathogenesis independent of its cell death function. We generated NOD mice deficient in soluble FASL, while maintaining expression of membrane-bound FASL due to a mutation in the FASL sequence required for cleavage by metalloproteinase. NOD mice lacking soluble FASL had normal numbers of lymphocytes in their spleen and thymus. Soluble FASL deficient NOD mice had similar islet inflammation as wild-type NOD mice and were not protected from diabetes. Our data indicate that soluble FASL is not required in development of autoimmune diabetes.

LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.

Cellular models for beta-cell function and diabetes gene therapy.

Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, invitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

Umbilical cord blood pluripotent stem cell immune education treatment for juvenile type 1 diabetes

Type 1 diabetes is a autoimmune disease that occurs under the influence of both genetic predisposition and environmental factors, mediated mainly by T lymphocytes with various kinds of other involved immune cells. The autoimmune attacks eventually lead to the islet beta cell destruction and insulin insufficiency. Multiple fundamental studies and clinical trials have revealed that umbilical cord blood pluripotent stem cells have the potential to help restore immune balance, induce immune tolerance, stop the autoimmune attacks against beta cells, and promote beta cell regeneration in type 1 diabetes mellitus (T1DM), by means of cell to cell contact and soluble cytokine secretion. For the past few years, the National Clinical Research Center for Metabolic Diseases of Second Xiangya Hospital has been leading the research on stem cell education therapy and has performed the therapy for 35 juvenile type 1 diabetes patients from China and foreign countries, introducing a novel treatment for T1DM. Key words: Fetal blood; Multipotent stem cells; Immunotherapy; Education; Diabetes mellitus, type 1/IM/TH

Type 1 diabetes pathogenesis - Prevention???

Pathogenesis of type 1 diabetes is multi-faceted, including, autoimmunity, genetics and environment. Autoimmunity directed against pancreatic islet cells results in slowly progressive selective beta-cell destruction (“Primary autoimmune insulitis”), culminating over years in clinically manifested insulin-dependent diabetes mellitus (IDDM). Circulating serum autoantibodies directed against the endocrine cells of the islets of Langerhans (Islet cell autoantibodies - ICAb) are an important hallmark of this disease. Assays for islet cell autoantibodies have facilitated the investigation and understanding of several facets in the pathogenesis of autoimmune diabetes. Their applications have extended into clinical practice and have opened new avenues for early preclinical prediction and preventive prophylaxis in IDDM/type 1 DM. Recently, surprisingly, differences in insulin content between T1DM islets, as well as, ‘patchy’ or ‘lobular’ destruction of islets have been described. These unique pathobiological phenomena, suggest that beta cell destruction may not always be inexorable and inevitably complete/total, and thus raise hopes for possible therapeutic interruption of beta cell autoimmunity – destruction and cure of type 1 diabetes. “Recurrent or secondary autoimmune insulitis” refers to the rapid reappearance of islet cell autoantibodies post pancreas transplant, and selective islet beta cell destruction in the grafted pancreas [never forgetting or “anamnestic” beta cell destructive memory], in the absence of any graft pancreas rejection [monozygotic twin to twin transplantation]. The one definite environmental factor is congenital rubella, because of which a subset of children subsequently develop type 1 diabetes. The putative predisposing factors are viruses, gluten and cow's milk. The putative protective factors include gut flora, helminths, viral infections, and Vitamin D. Prevention of T1DM can include: Primary prevention strategies before the development of autoantibodies and Secondary prevention regimens after autoantibody development. Once islet cell autoantibodies have developed, the goal is to establish a therapeutic regimen to preserve at least 90% of the beta cells, and prevent the development of hyperglycaemia. The targets for T1DM reversal should include autoimmunity, beta cell regeneration and protection of beta cell mass. Anti-CD3 teplizumab and anti-CD3 otelixizumab have been shown to provide C-peptide preservation. The unanswered questions in diabetes research include elimination of autoimmune memory responses, reestablishment of immune self-tolerance, and mechanisms of disease initiation.

Use of genetically-engineered pig donors in islet transplantation.

Type 1 diabetes (T1D) is an autoimmune disease wherein the pancreas does not produce enough insulin due to islet beta cell destruction. Despite improvements in delivering exogenous insulin to T1D patients, pancreas or islet transplantation remains the best way to regulate their glycaemia. Results from experimental islet transplantation have improved dramatically in the last 15 years, to the point where it can be comparable to pancreas transplantation, but without the accompanying morbidity associated with this procedure. As with other transplants, the limiting factor in islet allotransplantation is the relatively small number of organs made available by deceased human donors throughout the world. A strong case can be made for islet xenotransplantation to fill the gap between supply and demand; however, transplantation across species presents challenges that are unique to that setting. In the search for the most suitable animal for human xenotransplantation, the pig has many advantages that make it the likely animal of choice. Potentially one of the most beneficial advantages is the ability to genetically engineer porcine donors to be more compatible with human recipients. Several genetic manipulations have already proven useful in relation to hyperacute rejection and inflammation (instant blood mediated inflammatory reaction), with the potential of even further advancement in the near future.

Rotavirus Infection Induces Transient Pancreatic Involution and Hyperglycemia in Weanling Mice

Rotavirus is a ubiquitous double-stranded RNA virus responsible for most cases of infantile gastroenteritis. It infects pancreatic islets in vitro and is implicated as a trigger of autoimmune destruction of islet beta cells leading to type 1 diabetes, but pancreatic pathology secondary to rotavirus infection in vivo has not been documented. To address this issue, we inoculated 3 week-old C57Bl/6 mice at weaning with rhesus rotavirus, which is closely related to human rotaviruses and known to infect mouse islets in vitro. Virus was quantified in tissues by culture-isolation and enzyme-linked immunosorbent assay. A requirement for viral double stranded RNA was investigated in toll-like receptor 3 (TLR3)-deficient mice. Cell proliferation and apoptosis, and insulin expression, were analyzed by immunohistochemistry. Following rotavirus inoculation by gavage, two phases of mild, transient hyperglycemia were observed beginning after 2 and 8 days. In the first phase, widespread apoptosis of pancreatic cells was associated with a decrease in pancreas mass and insulin production, without detectable virus in the pancreas. These effects were mimicked by injection of the double-stranded RNA mimic, polyinosinic-polycytidylic acid, and were TLR3-dependent. By the second phase, the pancreas had regenerated but islets were smaller than normal and viral antigen was then detected in the pancreas for several days. These findings directly demonstrate pathogenic effects of rotavirus infection on the pancreas in vivo, mediated initially by the interaction of rotavirus double-stranded RNA with TLR3.

Imbalance of rare CCR10+ CD8+ and CD4+ memory T cells in children at onset of type 1 diabetes

Type 1 diabetes is a chronic autoimmune disease characterised by the presence of memory autoreactive CD4+ and CD8+ T cells that mediate islet beta cell destruction. We asked whether there are changes in the distributions of major and rare memory T cell subsets in the children with type 1 diabetes. Peripheral blood samples from 47 children at diabetes onset, aged 7 – 11 years, and from 47 age-matched autoantibody negative control children were processed for multi-parameter FACS analysis for markers of memory lymphocytes and the surface markers CD25, CCR7, CXCR5, CCR4, CCR10, CRTH2, CCR6 and CXCR3. Boolean gating was used to quantify major and rare phenotypes. The distribution of CD4+ central memory and effector memory, and CD8+ effector memory and TEMRA cells did not differ between patients and controls. However, several rare populations of CD8+ memory and CD4+ memory were altered in patients. These included increases in a novel CCR10+ CRTH2- Tc22 cell population in both the CD8+ effector memory and TEMRA cells (p < 0.001). This subpopulation of cells yields IL-22 and IL-17 enhanced responses. In contrast, the corresponding CD4+ CCR10+ CRTH2- effector memory phenotype cells were reduced in the blood of patients with type 1 diabetes (p = 0.01), and the resulting CD8/CD4 ratio for this subtype was >three-fold higher in patients (p < 0.001). We suggest that these findings may be explained by an acute expansion of effector CD8+ T cells and recruitment of effector CD4+ T cells to the pancreas around diabetes onset.

Accelerated progression from islet autoimmunity to diabetes is causing the escalating incidence of type 1 diabetes in young children

The incidence of type 1 diabetes is rising worldwide, particularly in young children. Since type 1 diabetes is preceded by autoimmunity to islet antigens, there must be a consequent increase in the incidence of islet autoimmunity in young children or a more rapid rate of progression to diabetes once islet autoimmunity initiates. This study was to determine whether the incidence of islet autoimmunity or the rate of progression from autoimmunity to diabetes onset has changed over a 20-year period in children genetically predisposed to type 1 diabetes. Between 1989 and 2010, children who were first-degree relatives of patients with type 1 diabetes and who were born in Germany were prospectively followed from birth without intervention. A total of 324 children (BABYDIAB study) born between 1989 and 2000 and 216 children (TEDDY study) born between 2004 and 2010 with matched HLA genotypes were recruited before age 3 months and included for analysis. Children were followed for the development of autoantibodies to insulin, GAD, and IA-2, and for progression to diabetes. The cumulative frequency of diabetes by age 4 years was 2.5% (95% CI 0.8–4.2%) in BABYDIAB children and 6.2% (95% CI 2.3–10.1%) in TEDDY children ( p = 0.03). The cumulative frequency of islet autoantibodies by age 4 years was similar in the children from both studies (11.3% vs 13.9%). Progression to diabetes from the development of islet autoantibodies was markedly increased in autoantibody-positive children from the more recently recruited TEDDY cohort (50% progression within 85.2 months for BABYDIAB children vs 9.6 months for TEDDY children; p = 0.009), also if children were further selected on the basis of high-risk HLA genotypes or the development of autoantibodies to multiple islet antigens ( p = 0.01). The findings suggest that recent increasing incidence of type 1 diabetes in young children could be due to weakening of mechanisms that normally regulate autoimmune destruction of islet beta cells.

Exenatide: A new promising antidiabetic agent

Exenatide is a unique agent which can effectively control blood glucose levels in type 2 diabetes mellitus without producing dangerous adverse effects. In addition, it can lower body weight which is very essential for the treatment of obese type 2 diabetes mellitus patients. Since it can delay the destruction of islet beta-cells, type 2 diabetes mellitus patients are not rapidly converted to type 1 diabetes mellitus and ultimately appearance of complications of the disease is halted or delayed. Its long-acting-release formula, which would be used once per week, simultaneously retaining all the properties of twice-daily subcutaneous administration, is undergoing clinical trial. This drug is considered as an adjunct to metformin/sulfonylureas/insulin.

Acquired pMHC I Complexes Greatly Enhance CD4+ Th Cell's Stimulatory Effect on CD8+ T Cell-Mediated Diabetes in Transgenic RIP-mOVA Mice

CD4(+) helper T (Th) cells play pivotal roles in induction of CD8(+) CTL immunity. However, the mechanism of CD4(+) T cell help delivery to CD8(+) T cells in vivo is still elusive. In this study, we used ovalbumin (OVA)-pulsed dendritic cells (DC(OVA)) to activate OT-II mouse CD4(+) T cells, and then studied the help effect of these CD4(+) T cells on CD8(+) cytotoxic T lymphocyte (CTL) responses. We also examined CTL mediated islet beta cell destruction which led to diabetes in wild-type C57BL/6 mice and transgenic rat insulin promoter (RIP)-mOVA mice expressing beta cell antigen OVA with self OVA-specific tolerance, respectively. In adoptive transfer experiments, we demonstrated that help, in the form of peptide/major histocompatibility complex (pMHC) I acquired from DC(OVA) by DC(OVA) activation, was required for induction of OVA-specific CTL responses in C57BL/6 mice. However, in combination with TCR transgenic OT-I mouse CD8(+) T cells, the tolerogenic dosage of CD4(+) Th cells with acquired pMHC I, but not CD4(+) K(b-/-) Th cells without acquired pMHC I were able to cause diabetes in 8/10 (80%) RIP-mOVA mice. This study thus expands the current knowledge in T cell-mediated autoimmunity and provides insight into the nature of CD4(+) T cell-mediated help in CD8(+) CTL induction.

Mesenchymal stem cell therapy for diabetes through paracrine mechanisms

Type 1 diabetes is a chronic disorder characterized by the destruction of pancreatic islet beta-cells through autoimmune assault. Insulin replacement is the current main therapeutic approach. In recent years, several studies have showed that mesenchymal stem cells (MSCs) transplantation can improve the metabolic profiles of diabetic animal models. However the exact mechanisms of reversing hyperglycemia remain to be elusive. Trans-differentiation of MSCs into insulin-producing cells (IPCs) has ever been regarded as the main mechanism. But other reports have contradicted these findings and it is difficult to explain the timing and extent of improvement by only the effect through trans-differentiation. Researches have found that MSCs naturally produce a variety of cytokines and growth factors, promoting the survival of surrounding cells, called as paracrine mechanisms. Paracrine effects have been proved to play an important role in tissue regeneration and repair in recent researches. Therefore we speculate that MSCs transplantation into diabetic animals may prevent apoptosis of injured pancreatic beta cells and enhance regeneration of endogenous progenitor cells through paracrine actions such as angiogenic, cytoprotective, anti-inflammatory, mitogenic and anti-apoptotic effects. This hypothesis, if proved to be valid, may represent an important breakthrough in developing effective molecular or genetic therapeutics for diabetes.

Genetics of autoimmune diabetes mellitus

Autoimmune diabetes mellitus, called type 1 diabetes mellitus (T1DM), is caused by autoimmune destruction of islet beta cells in the pancreas. T1DM susceptibility loci mapped by different genome screening are IDDM1-IDDM18. It has been estimated that HLA (IDDM1) provides up to 40-50 % of the familial clustering of T1DM (LOD score of 65.8). Many studies have verified that DQB1*0302 is a strong susceptibility gene and that the heterozygous combination of DQA1*0301-DQB1*0302 on the HLA-DR4 haplotype and DQA1*0501-DQB1*0201 on the HLA-DR3 haplotype results in a synergistically increased risk of T1DM. The presence of predisposing genes in autoimmune diabetes decreases with age, probably due to increasing influence of environmental factors. Autoimmune diabetes with manifestation in adults may have partly different immunogenetic etiopathogenesis than autoimmune diabetes with manifestation in childhood. Compared to fast progressing adult-onset T1DM, slowly progressing adult-onset type 1 diabetes (LADA) might involve genes leading to a slow progressive beta-cells destruction.

Calcium Homeostasis in Type I Diabetes: Effects of Ionizing Radiation

PURPOSE: Enhanced oxidative stress is implicated in various forms of tissue injury ranging from radiation-induced cell damage to autoimmune destruction of islet beta cells. Diabetes mellitus is associated with disorders in calcium homeostasis and bone turnover resulting in the development of osteopenia. Moreover, ionizing radiation has been documented to affect the regulation of calcium metabolism. Thus, there is potential interest in the possibility that ionizing irradiation can aggravate abnormalities of calcium homeostasis in diabetics. METHODS: Diabetes was developed by subcutaneous injection of alloxan (80 mg/kg bw) and was manifested by hyperglycemia and insulonopenia. Diabetic and normal rats were irradiated at dose of 100 cGy (Cs-137, 0.45 Gy/min). Oxidative stress and calcium metabolism were evaluated in 3, 10 and 30 days after radiation exposure. RESULTS: Oxidative stress measured as TBARS level was significantly intensified in alloxan-treated and irradiated groups. Ionizing radiation reduced considerably serum calcium and phosphate in diabetic rats. Despite low alkaline phosphatase isoenzymes activity in irradiated rats, hyperphosphatasia was observed in diabetics exposed to radiation. Calcium-regulating hormones, both calcitonin and parathyroid hormone, were significantly elevated in irradiated animals with diabetes compared to control. CONCLUSION: Ionizing radiation showed synergistic effect on alterations in calcium homeostasis of diabetic rats and thus may contribute to the bone complication of diabetes through increased oxidative stress.

Roles of cytokines in the pathogenesis and therapy of type 1 diabetes

Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans by autoreactive T helper 1 (Th1) cells characterized by their cytokine secretory products, interleukin-2 (IL-2) and interferon gamma (IFNgamma). Th1-type cytokines (IL-2 and IFNgamma) correlate with T1D, whereas Th2 (IL-4 and IL-10), Th3 (transforming growth factor beta [TGFbeta]), and T regulatory cell-type cytokines (IL-10 and TGFbeta) correlate with protection from T1D. Paradoxically, however, administrations of Th1-type cytokines (IL-2 and IFNgamma) and immunotherapies that induce Th1-type cytokine responses actually prevent T1D, at least in animal models. Therefore, immunotherapies that inhibit IL-2 production/action will block Th1 cell/cytokine-driven effector mechanisms of pancreatic islet beta-cell destruction; however, anti-IL-2 therapy will not allow immune tolerance to be established. In contrast, immunotherapies that increase IL-2 production/action may correct an immunodeficiency in IL-2 production that appears to underlie the autoimmunity of T1D, thereby restoring immune tolerance to islet beta-cells and prevention of T1D.