Insulin-producing Islet Cells Research Articles

Potential risk factors for diabetes mellitus type 1

Diabetes mellitus type 1 (T1D) develops as a result of the interaction of genetic and environmental factors. Genetic predisposition to T1D turns into clinical reality only in half of hereditary cases, which indirectly indicates the importance of external factors, the significance of which is periodically reviewed. Retrospective and prospective clinical foreign and national studies were included. PubMed, Medline and eLibrary were searched. Modern ideas about the possible impact of the main prenatal and postnatal environmental factors on the development of autoimmune response against insulin-producing islet cells and T1D were discussed. The risk of developing type 1 diabetes is determined by the complex interaction of environmental factors and genetic predisposition. The mechanisms of their influence remain rather unknown. Further research is needed to determine strategies of primary and secondary prevention of T1D.

Serum Activities of Ferritin Among Controlled and Uncontrolled Type 2 Diabetes Mellitus Patients.

BackgroundDiabetes mellitus (DM) is a metabolic disorder characterized by the cells' inefficient utilization of blood glucose. DM occurs in two types: type 1 DM (T1DM) and type 2 DM (T2DM). DM results in increased blood sugar levels attributed to the non-functioning of the insulin-producing islet cells of the pancreas (type 1 DM) and insulin resistance, among other causes. Despite the initiation of treatment, in some people, diabetes remains uncontrolled and, over some time, could cause damage to other organs of the body, including the eyes, heart, and kidneys, among others. Recently, it was observed that iron metabolism and increased activity of serum ferritin (hyperferritinemia) could influence the development of T2DM. This study aims to assess the activities of ferritin among controlled and uncontrolled T2DM patients and compare them with the control group who were non-diabetic.MethodsThe study included 30 controlled and uncontrolled T2DM patients and an equal number of controls. The study was conducted between September and October 2021, and all patients included were those attending the General Medicine outpatient department attached to the RVM Institute of Medical Sciences and Research Centre, Siddipet, Telangana, South India. Blood glucose activities were estimated by the glucose oxidase-peroxidase (GOD-POD) method using the Randox Daytona plus analyzer, and serum ferritin was measured by the chemiluminescence method using the Beckmann Coulter Access 2 instrument.ResultsThe mean age of the cases and the controls was 56.5 years and 46.7 years, respectively. Serum ferritin activities among people with controlled diabetes (73.3±56.6 ng/ml) (p=0.0003) and uncontrolled diabetes (269.8±347.1 ng/ml) (p=0.0006) varied significantly as compared to the controls (40.853±15.55). Glucose activities among controls (82.9±7.4 mg/dl), controlled T2DM patients (120.9±28.6 mg/dl), and uncontrolled T2DM patients (316.06±145.41 mg/dl) also showed significant differences.ConclusionHyperferritinemia is evident among uncontrolled T2DM patients. However, increased serum ferritin activities were also noted among controlled T2DM patients as compared to normal activities observed in the non-diabetic control group.

Environmental Factors and the Risk of Developing Type 1 Diabetes-Old Disease and New Data.

Simple SummaryDespite many studies, the risk factors of type 1 diabetes (T1DM) in children and adolescents are still not fully understood and remain a big challenge. Therefore, an extensive online search for scientific research on factors related to diabetes has been performed for the identification of new factors of unexplained etiology. A better understanding of the role of viral, bacterial, and yeast-like fungi infections related to the risk of T1DM in children and adolescents and the identification of new risk factors, especially those spread by the droplet route, is of great importance for people and families with diabetes.The incidence of type 1 diabetes (T1D) is increasing worldwide. The onset of T1D usually occurs in childhood and is caused by the selective destruction of insulin-producing pancreatic islet cells (β-cells) by autoreactive T cells, leading to insulin deficiency. Despite advanced research and enormous progress in medicine, the causes of T1D are still not fully understood. Therefore, an extensive online search for scientific research on environmental factors associated with diabetes and the identification of new factors of unexplained etiology has been carried out using the PubMed, Cochrane, and Embase databases. The search results were limited to the past 11 years of research and discovered 143 manuscripts published between 2011 and 2022. Additionally, 21 manuscripts from between 2000 and 2010 and 3 manuscripts from 1974 to 2000 were referenced for historical reference as the first studies showcasing a certain phenomenon or mechanism. More and more scientists are inclined to believe that environmental factors are responsible for the increased incidence of diabetes. Research results show that higher T1D incidence is associated with vitamin D deficiency, a colder climate, and pollution of the environment, as well as the influence of viral, bacterial, and yeast-like fungi infections. The key viral infections affecting the risk of developing T1DM are rubella virus, mumps virus, Coxsackie virus, cytomegalovirus, and enterovirus. Since 2020, i.e., from the beginning of the COVID-19 pandemic, more and more studies have been looking for a link between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and diabetes development. A better understanding of the role of viral, bacterial, and yeast-like fungi infections related to the risk of T1DM in children and adolescents and the identification of new risk factors, especially those spread by the droplet route, is of great importance for people and families with diabetes.

Characterization of Transplantable Insulinoma Cells.

This chapter describes the propagation and characterization of transplantable insulinoma cells as model of insulin-producing pancreatic islet cells in the rat. Here, the cells are propagated by transplantation into rats followed by harvesting after growth for approximately 1month. The cells are then purified by Percoll density gradient centrifugation and characterized by pulse-chase radiolabelling and immunoprecipitation of the insulin-related peptides. The results show that the transplantable insulinoma cells produce insulin in a manner similar to that found in normal pancreatic islets.

Technical Modifications to Improve Islet Yield from Chronic Pancreatitis Pancreas (CPP) for Islet Auto-Transplantation (IAT)

Surgical removal of the pancreas in patients with intractable chronic pancreatitis will potentially mitigate the long standing suffering of abdominal pain and improve the quality of life. Nonetheless, the induction of iatrogenic diabetes from surgery becomes irrevocable as the insulin producing islet cells are removed. This novel process of islet isolation (both auto- and allo-) involves specific procurement and packaging of the pancreas which is then transported to a specialized clean-room where islets are isolated. The isolation involves distending the pancreas with dissociation enzymes that help in digesting the extracellular matrix and freeing the islets. The cells are then collected as pellets and purified if necessary by density gradient and later packed in the transplant bag for intra-portal infusion back to the patient. The expectant metabolic outcome following the procedure is solely dependent on the total islet mass transplanted. Despite incorporating the most standardized isolation techniques, the overall islet yields available from the diseased pancreas are still very low. Factors such as donor characteristics, pancreatic fibrosis and cellular atrophy further reduce the yield highlighting the need for effective islet isolation techniques.

Advances in islet encapsulation technologies.

Type 1 diabetes is an autoimmune disorder in which the immune system attacks and destroys insulin-producing islet cells of the pancreas. Although islet transplantation has proved to be successful for some patients with type 1 diabetes, its widespread use is limited by islet donor shortage and the requirement for lifelong immunosuppression. An encapsulation strategy that can prevent the rejection of xenogeneic islets or of stem cell-derived allogeneic islets can potentially eliminate both of these barriers. Although encapsulation technology has met several challenges, the convergence of expertise in materials, nanotechnology, stem cell biology and immunology is allowing us to get closer to the goal of encapsulated islet cell therapy for humans.

Does Glycogen Accumulation in Pancreatic Islet Beta Cells Play a Minor or Major Role in the Physiology and Pathology of the Insulin Secretory Response to Glucose

The role of beta cell glycogen in the control of glucose homeostasis was recently questioned. This review aims at reminding that glycogen accumulation in insulin-producing pancreatic islet cells was previously proposed to play a role in the phenomenon of beta cell glucotoxicity. The findings recently reported in an article published in Diabetologia do not invalidate the concept mentioned above. J Endocrinol Metab. 2016;6(4):104-108 doi: http://dx.doi.org/10.14740/jem368w

Current Progress in Stem Cell Research and its Potential for Islet Cell Transplantation

Diabetes is characterized by insulin deficiency concomitant with hyperglycemia due to reduced islet cell mass and/or dysfunction. Currently, insulin replacement is the first-line treatment option for patients with type 1 and a severe form of type 2 diabetes. Treatment by insulin injection is generally effective but nonphysiological, and has the potential of producing chronic complications. On the other hand, islet transplantation can maintain normoglycemia without hypoglycemic side effects, potentially freeing diabetic patients of insulin dependence. In practice, islet transplantation remains hindered by the lack of organ donors and transplant rejection concerns. Recent advances in stem cell research and regenerative medicine, however, offer promise for the clinical application of islet cell transplantation. This review article offers a critical appraisal of current molecular induction approaches, such as directed differentiation, microenvironment induction, and genetic modification, which mimic islet cell development by inducing a variety of stem cells; they include embryonic stem cells, induced pluripotent stem cells, and various tissue-derived stem cells to become functional and transplantable insulin-producing islet cells. Despite good progress, several obstacles remain to be overcome before islet transplantation can be translated into a therapy for human patients, including, but are not limited to, immunogenicity and risk of tumorogenesis.

Current Progress in Stem Cell Research and its Potential for Islet Cell Transplantation

Diabetes is characterized by insulin deficiency concomitant with hyperglycemia due to reduced islet cell mass and/or dysfunction. Currently, insulin replacement is the first-line treatment option for patients with type 1 and a severe form of type 2diabetes. Treatment by insulin injection is generally effective but nonphysiological, and has the potential of producing chronic complications. On the other hand, islet transplantation can maintain normoglycemia without hypoglycemic side effects, potentially freeing diabetic patients of insulin dependence. In practice, islet transplantation remains hindered by the lack of organ donors and transplant rejection concerns. Recent advances in stem cell research and regenerative medicine, however, offer promise for the clinical application of islet cell transplantation. This review article offers a critical appraisal of current molecular induction approaches, such as directed differentiation, microenvironment induction, and genetic modification, which mimic islet cell development by inducing a variety of stem cells; they include embryonic stem cells, induced pluripotent stem cells, and various tissue-derived stem cells to become functional and transplantable insulin-producing islet cells. Despite good progress, several obstacles remain to be overcome before islet transplantation can be translated into a therapy for human patients, including, but are not limited to, immunogenicity and risk of tumorogenesis. Keywords: Diabetes mellitus, immunogenicity, in vivo regeneration, islet engineering, stem cell therapy, transplantation

Current Progress in Stem Cell Research and its Potential for Islet Cell Transplantation

Diabetes is characterized by insulin deficiency concomitant with hyperglycemia due to reduced islet cell mass and/or dysfunction. Currently, insulin replacement is the first-line treatment option for patients with type 1 and a severe form of type 2 diabetes. Treatment by insulin injection is generally effective but nonphysiological, and has the potential of producing chronic complications. On the other hand, islet transplantation can maintain normoglycemia without hypoglycemic side effects, potentially freeing diabetic patients of insulin dependence. In practice, islet transplantation remains hindered by the lack of organ donors and transplant rejection concerns. Recent advances in stem cell research and regenerative medicine, however, offer promise for the clinical application of islet cell transplantation. This review article offers a critical appraisal of current molecular induction approaches, such as directed differentiation, microenvironment induction, and genetic modification, which mimic islet cell development by inducing a variety of stem cells; they include embryonic stem cells, induced pluripotent stem cells, and various tissue-derived stem cells to become functional and transplantable insulin-producing islet cells. Despite good progress, several obstacles remain to be overcome before islet transplantation can be translated into a therapy for human patients, including, but are not limited to, immunogenicity and risk of tumorogenesis.

Improving the Pancreatic Islet Graft Structure and Function: Application of a Novel Bioengineered Composite Scaffold

Introduction: Transplantation of the insulin-producing islet cells of the pancreas has been a promising strategy for management of type 1 diabetes. However, shortage of islet donors, and poor survival of the islets after transplantation are some of the main challenges of this procedure. Enzymatic digestion of the pancreas in the process of islet isolation results in the loss of peri-insular extracellular matrix (ECM) and peri-vascular basement membrane of the islets that can significantly disrupt the ECM-mediated interactions and result in apoptosis. Naturally a collagen matrix provides for a viable environment in which both stromal and islet cells can survive. However this matrix is mainly biodegradable and subject to gradual disintegration and contraction after transplantation. We have previously shown that a fibroblast populated collagen matrix (FPCM) significantly improves islet cell viability and glucose responsiveness and reduces the marginal islet mass required for hyperglycemia reversal in diabetic mice. Fibroblasts were incorporated to provide a favorable support for islets by producing various growth and angiogenic factors, while maintaining the integrity of the collagen matrix. Although this composite was able to promote the islet graft survival and function, it was still prone to gradual biodegradation. For this reason, we designed a novel bioengineered crosslinked-interpenetrating network of glycosaminoglycan (GAG) and type I collagen (Collagen-GAG matrix, CGM). When populated with fibroblasts (FP-CGM), it would provide an optimal matrix biomimetic with reduced contraction and enhanced mechanical strength for the transplanted islets. Methods: Pancreatic islets and dermal fibroblasts were obtained from Balb/c mice. Islets (50 islets per well in 48-well plates) were cultured in medium (2D), acellular collagen matrix (CM), FPCM, acellular CGM and FP-CGM composites. In order to prepare the FPCM and FP-CGM composites, 200,000 fibroblasts per 100μl of the gel were used. The viability of the islets within composites was assessed by a Live/Dead assay kit on days 1, 15 and 30 post culture. Islets were retrieved on days 1, 15 and 30 post culture and paraffin-embedded sections were stained for insulin, glucagon, caspase-3 and Ki67 and the β-cell proliferation rate was calculated. Retrieved islets were evaluated for glucose-stimulated insulin secretion. Finally, the expression of the islet key specific genes including insulin, PDX1, GLUT2, Pax4, and Pax6 were examined before and after culture at different conditions using reverse transcriptase-PCR analysis. Results: Our preliminary findings have demonstrated that our matrix is non-toxic to both fibroblasts and islets and able to withstand contraction in vitro: Live and Dead assay showed that islets perfectly survive within the new composite matrix. Histology revealed reductions in graft contraction and fibroblast cellularity, increased insulin and glucagon production, and decreased apoptosis rate compared to naked islets in 2D system. Islet morphology remained intact within the composite FP-CGM. PCR analysis showed high expression of islets key genes when islets are embedded within the proposed matrix. Conclusions: We have identified that the use of a crosslinked collagen-GAG graft has the potential to improve graft survival, improving the post-surgical outcome of the transplanted islets.

Antidiabetic Effects of Rice Hull Smoke Extract on Glucose-Regulating Mechanism in Type 2 Diabetic Mice

The aim of this study is to determine the protective effect of a liquid rice hull smoke extract (RHSE) against type 2 diabetes (T2D) in mice induced by a high-fat diet. As compared to the control group of mice on a high-fat diet (HFD), feeding the HFD supplemented with 0.5% or 1% RHSE for 7 weeks resulted in significantly reduced blood glucose and triglyceride and cholesterol concentrations, higher serum insulin levels, and improved glucose tolerance, as assessed by an oral glucose tolerance assay. The hypoglycemic effect of RHSE was accompanied by changes in enzyme activities and cognate gene expression assessed using RT-PCR. Among the glucose metabolism regulating genes evaluated, hepatic glucokinase (GCK), the glucose transporters GLUT2 and GLUT4, and peroxisome proliferator-activated receptor-γ (PPAR-γ) were up-regulated, whereas glucose-6-phosphatase (G6 Pase) and phosphoenolpyruvate carboxykinase (PEPCK) were down-regulated in the liver of mice with RHSE-supplementation. These changes resulted in restoration of glucose-regulating activities to normal control levels. Histopathology showed that a high-fat diet intake also induced liver necrosis and damage of the islet of Langerhans in the pancreas, whereas RHSE supplementation restored necrotic damage to normal levels. Immunohistochemistry showed that RHSE supplementation can restore the reduced insulin-producing β-cell population in islet of Langerhans associated with a high-fat diet intake to nondiabetic normal control levels in a dose-dependent manner. RHSE-supplemented food could protect insulin-producing islet cells against damage triggered by oxidative stress and local inflammation associated with diabetes.

Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases

The spectrum of periodic fever syndromes (PFS)/autoinflammation diseases is continuously expanding. This review provides an overview of the primary research and an update on the main clinical developments in these disorders published in the past 12-18 months. IL-1β is pivotal to the pathogenesis of most of the PFS. In familial Mediterranean fever (FMF) MEFV mutations lead to gain of pyrin function, resulting in inappropriate IL-1β release that is dependent on ASC but not the NLRP3 inflammasome. Anti-IL-1 therapy is effective in tumour necrosis factor receptor-associated periodic syndrome (TRAPS), whilst both spontaneous and pathogen-associated molecular patterns (PAMPs) induced IL-1β release have been demonstrated in NLRP12-associated periodic syndrome (NAPS12). Somatic NLRP3/CIAS1 mosaicism is a significant cause of cryopyrin-associated periodic syndromes (CAPS). Close connections have also been established between metabolic and inflammatory pathways. In TRAPS increased reactive oxygen species (ROS) of mitochondrial origin leads to production of pro-inflammatory cytokines, whilst NLRP3 inflammasome activation in type 2 diabetes (T2D) is induced by oligomers of islet amyloid polypeptides (IAPP). Caspase 1 activation and IL-1β release is central to the pathogenesis of many autoinflammatory syndromes. This is supported by the effectiveness of anti-IL-1 biologics in treatment of these disorders.

Antidiabetic Effects of Rice Hull Smoke Extract in Alloxan-Induced Diabetic Mice

This study investigated the protective effect of a liquid rice hull smoke extract (RHSE) against diabetes in alloxan-induced diabetic mice. Antidiabetic effects of RHSE were evaluated in both the rat insulinoma-1 cell line (INS-1) and diabetic ICR mice induced by intraperitoneal (ip) injection of alloxan. Alloxan treatment (10 mM) increased cellular reactive oxygen species (ROS) levels in the INS-1 cells, which were inversely related to cell viabilities. RHSE inhibited alloxan-induced nitric oxide (NO) generation through inhibition of inducible nitric oxide synthase (iNOS) gene expression and suppressed the inflammatory reaction in INS-1 cells through inhibition of expression of pro-inflammatory genes, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Dietary administration of 0.5 or 1% RHSE to alloxan-induced diabetic mice caused a decrease in blood glucose and increases in both serum insulin and hepatic glycogen levels. RHSE induced decreases in glucose-6-phosphatase (G6 Pase) and phosphoenolpyruvate carboxykinase (PEPCK) levels and an increase in the glucokinase (GCK) level. These changes resulted in restoring glucose-regulating enzyme levels to control values. Histopathology showed that alloxan also induced damage of Langerhans islet cells of the pancreas and liver necrosis associated with diabetes. Oral administration of RHSE restored the islet and liver cells to normal levels. RHSE-supplemented functional food could protect insulin-producing islet cells against damage triggered by oxidative stress and local inflammation associated with diabetes.

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Type 1 diabetes is a chronic autoimmune disease in which genetic predispositions affect the immune system, leading to a loss of T cell tolerance to β cells and consequent T cell-mediated destruction of insulin-producing islet cells. Genetic studies have suggested that PRSS16 is linked to a diabetes susceptibility locus of the extended HLA class I region in humans. PRSS16 encodes what we believe to be a novel protease, thymus-specific serine protease (TSSP), which shows predominant expression in thymic epithelial cells and is suspected to have a restricted role in the class II presentation pathway. Consistently, Tssp is necessary for the intrathymic selection of few class II-restricted T cell receptor specificities in B6 mice. To directly assess the role of Tssp in autoimmune diabetes, we generated Tssp-deficient (Tssp°) NOD mice. While remaining immunocompetent, Tssp° NOD mice were protected from diabetes and severe insulitis. Diabetes resistance of Tssp° NOD mice was a property of the CD4 T cell compartment that is acquired during thymic selection and correlated with an impaired selection of CD4 T cells specific for islet antigens. Hence, in the NOD mouse, Tssp is a critical regulator of diabetes development through the selection of the autoreactive CD4 T cell repertoire.

The Promise and Therapeutic Potential of Human ES and iPS Cells

The Promise and Therapeutic Potential of Human ES and iPS Cells

Mathematical modelling of immune regulation of type 1 diabetes

Type 1 diabetes is a disease characterized by progressive loss of β cell function due to an autoimmune reaction affecting the islets of Langerhans. Two types of T cells are involved in diabetes: turncoat auto-reactive T cells, or T cells gone bad, that kill the insulin-producing cells, and regulatory T cells that are unable to control the auto-reactive T cells. We formulate a mathematical model that incorporates the role of cytotoxic T cells and regulatory T cells in type 1 diabetes. This study shows that onset of type 1 diabetes is due to a collective, dynamical instability, rather than being caused by a single etiological factor. It is also a numbers game between regulatory T cells and auto-reactive T cells. The problem in the onset of this disease is that there are not enough of the regulatory cells that suppress the immune response against the body's insulin-producing pancreatic islet cells.

Status of stem cell therapy in type-1 diabetics

For years, researchers have painstakingly studied type-1 diabetes, a complicated disease caused by the destruction of insulin-producing islet cells of the pancreas. Despite significant attempts to understand the contributing disease mechanisms for diabetes, there is still no solution for a cure. Investigators are continuously working on strategies for pancreatic transplantation and islet cell replacement. Adult stem cells that appear to be precursors to islet cells and embryonic stem cells that produce insulin seem to have caught the attention of researchers worldwide. However, the universal consensus is that until a therapeutically useful source of human islet cells is developed, a persistent search for a potential surrogate replacement needs to be pursued. The other challenge that needs to be overcome is autoimmunity. This is perhaps why type-1 diabetes still continues to exact its toll on humankind.

Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms.

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on celiac disease (CD), an autoimmune enteropathy, and type 1 diabetes (T1D), a hyperglycosaemia caused by a destructive autoimmune process targeting the insulin-producing pancreatic islet cells. Even if environmental factors and genetic susceptibility are clearly involved in the pathogenesis of autoimmunity, for most autoimmune disorders there is no or little knowledge about the causing agent or genetic makeup underlying the disease. In this respect, CD represents a unique autoimmune disorder because a close genetic association with HLA-DQ2 or HLA-DQ8 haplotypes and, more importantly, the environmental trigger (the gliadin fraction of gluten-containing grains wheat, barley, and rye) are known. Conversely, the trigger for autoimmune destruction of pancreatic ss cells in T1D is unclear. Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity. In this review, each of these components will be briefly reviewed.

Long term elimination of epitope-specific diabetogenic CD8+ T cells using toxin coupled tetramers in NOD mice (50.37)

Abstract Type 1 diabetes (T1D) is an autoimmune disease in which CD8+ T cells with help from CD4+ T cells and B cells kill the insulin-producing islet cells in the pancreas. Although islet transplants have been successful in treating T1D, the transplants may not persist because of the ongoing autoimmunity. Patients can be treated with immunosuppressants, however these drugs have serious side effects. Selective elimination of diabetogenic T cells should specifically eliminate islet autoimmunity. We previously showed MHC class I tetramers coupled to the toxin saporin could selectively kill transgenic virus specific T cells. We have now used saporin coupled NRP-V7 tetramers to target diabetogenic T cells in vitro and in vivo in non-obese diabetes-prone (NOD) mice. NRP-V7 is a high affinity mimotope that is recognized by the 8.3 T cell clone, a known diabetogenic T cell. Treatment with saporin coupled NRP-V7 tetramers acutely depleted NRP-V7+ CD8+ T cells expressing Vβ 13-3 and elimination appeared to be long term since very few NRP-V7+ T cells were detectable in the islets of toxic-NRP-V7 tetramer treated NOD mice up to 45 weeks later. Treatment with toxic NRP-V7 tetramers resulted in a delay of T1D with a mean onset of 24 weeks compared to 16 weeks for treatment with PBS. Toxic tetramers could potentially be used to treat T1D as well as other T cell mediated autoimmune disease. Supported by JDRF 5-2006-13 and 1-2008-24.