New therapeutic approaches for type 1 diabetes: Disease-modifying therapies

It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.     

Type 1 diabetes mellitus and its oral tolerance therapy

As a T cell-mediated autoimmune disease,type 1 diabetes mellitus(T1 DM) is marked by insulin defect resulting from the destruction of pancreatic β-cells.The understanding of various aspects of T1 DM,such as its epidemiology,pathobiology,pathogenesis,clinical manifestations,and complications,has been greatly promoted by valuable research performed during the past decades.However,these findings have not been translated into an effective treatment.The ideal treatment should safely repair the destroyed immune balance in a longlasting manner,preventing or stopping the destruction of β-cells.As a type of immune hypo-responsiveness to the orally administrated antigen,oral tolerance may be induced by enhancement of regulatory T cells(Tregs) or by anergy/deletion of T cells,depending on the dosage of orally administrated antigen.Acting as an antigen-specific immunotherapy,oral tolerance therapy for T1 DM has been mainly performed using animal models and some clinical trials have been completed or are still ongoing.Based on the review of the proposed mechanism of the development of T1 DM and oral tolerance,we give a current overview of oral tolerance therapy for T1 DM conducted in both animal models and clinical trials.     

Mechanism of immune attack in the progression of obesity-related type 2 diabetes

Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.     

Skeletal muscle as a therapeutic target for delaying type 1 diabetic complications

Type 1 diabetes mellitus(T1DM) is a chronic autoimmune disease targeting the pancreatic beta-cells and rendering the person hypoinsulinemic and hyperglycemic. Despite exogenous insulin therapy, individuals with T1 DM will invariably develop long-term complications such as blindness, kidney failure and cardiovascular disease. Though often overlooked, skeletal muscle isalso adversely affected in T1 DM, with both physical and metabolic derangements reported. As the largest metabolic organ in the body, impairments to skeletal muscle health in T1 DM would impact insulin sensitivity, glucose/lipid disposal and basal metabolic rate and thus affect the ability of persons with T1 DM to manage their disease. In this review, we discuss the impact of T1 DM on skeletal muscle health with a particular focus on the proposed mechanisms involved. We then identify and discuss established and potential adjuvant therapies which, in association with insulin therapy, would improve the health of skeletal muscle in those with T1 DM and thereby improve disease managementultimately delaying the onset and severity of other longterm diabetic complications.     

FOXO1 Mediates Vitamin D Deficiency–Induced Insulin Resistance in Skeletal Muscle

Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin‐resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency–induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. Although sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle‐specific vitamin D receptor (VDR)‐null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR‐null mice. Treatment of C2C12 muscle cells with 1,25‐dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3‐dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR‐dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR‐null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling‐deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2. © 2015 American Society for Bone and Mineral Research.     

Treatment of insulin-dependent diabetes by hematopoietic stem cell transplantation

Type 1 diabetes (T1D) is an autoimmune disease resulting from the demolition of β-cells that are responsible for producing insulin in the pancreas. Treatment with insulin (lifelong applying) and islet transplantation (in rare cases and severe diseases), are standards of care for T1D. Pancreas or islet transplantation have some limitations, such as lack of sufficient donors and longtime immune suppression for preventing allograft rejection. Recent studies demonstrate that autologous hematopoietic stem cells (HSC) can regenerate immune tolerance against auto-antigens. Taking advantage of this feature, autologous HSC transplantation (auto-HSCT) is likely the only treatment for T1D that is associated with lasting and complete remission. None of the other evaluated immunotherapies worldwide had the clinical efficacy of auto-HSCT. Therapy with auto-HSCT is insulin-independent rather than reducing insulin needs or delaying loss of insulin production. This review provided the latest findings in auto-HSCT for treatment of T1D.     

A comparative study of pancreas transplantation between type 1 and 2 diabetes mellitus

BackgroundPancreas transplantation remains the best long-term treatment option to achieve physiological euglycemia and insulin independence in patients with labile diabetes mellitus (DM). It is widely accepted as an optimal procedure for type 1 DM (T1DM), but its application in type 2 DM (T2DM) is not unanimously acknowledged.MethodsIn total, 146 diabetes patients undergoing pancreas transplantation were included in this study. Clinical data and outcomes were compared between the T1DM and T2DM groups.ResultsMajority (93%) of the pancreas transplantations in T2DM were for uremic recipients. Complications occurred in 106 (73%) patients, including 70 (48%) with early complications before discharge and 79 (54%) with late complications during follow-up period. Overall, rejection of pancreas graft occurred in 37 (25%) patients. Total rejection rate in T2DM recipients was significantly lower than that in T1DM. The short- and long-term outcomes for endocrine function in terms of fasting blood sugar and hemoglobin A1c levels and graft survival rates are comparable between the T2DM and T1DM groups.ConclusionsT2DM is not inferior to T1DM after pancreas transplantation in terms of surgical risks, immunological and endocrine outcomes, and graft survival rates. Therefore, pancreas transplantation could be an effective option to treat selected uremic T2DM patients without significant insulin resistance.     

Alterations of the female reproductive system in islet recipient receiving immunosuppression

Pancreatic islet allotransplantation is an option for patients with unstable type 1 diabetes mellitus (T1DM). Major improvements in islet isolation techniques and the implementation of steroid-free immunosuppressive regimens can maintain insulin independence in the majority of T1DM for at least 1 year after transplantation. Recent studies have emphasized the impact of sirolimus on female reproductive tract. In this communication we report on the alterations of the female reproductive tract in 18 chronically immunosuppressed patients with T1DM following allogenic islet transplantation. Previous research has shown development of ovarian cysts in islet transplant patients receiving sirolimus. We extensively reevaluated this and other possible side effects on the female reproductive system. These side effects have been underestimated, although they are significant, requiring surgical or intensive medical treatment. Pre- and posttransplant gynecological evaluation should be performed to address the development of complications secondary to sirolimus in order to intervene sooner with alternative therapies.     

Pharmacological control of blood sugar

Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving β-cell function. Moreover, the emergence of a new class of drugs such as the sodium–glucose transporter inhibitors for patients with T2DM holds much promise. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.     

Pharmacological control of blood sugar

Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving β-cell function. Moreover, the emergence of a new class of drugs such as the sodium–glucose transporter inhibitors for patients with T2DM holds much promise. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.     

β-cell dysfunction: Its critical role in prevention and management of type 2 diabetes

Type 2 diabetes(T2DM) is characterized by insulin resistance and β-cell dysfunction. Although, in contrast to type 1 diabetes, insulin resistance is assumed to be a major pathophysiological feature of T2 DM, T2 DM never develops unless β-cells fail to compensate insulin resistance. Recent studies have revealed that a deficit of β-cell functional mass is an essential component of the pathophysiology of T2 DM, implying that β-cell deficit is a common feature of both type 1 and type 2 diabetes. β-cell dysfunction is present at the diagnosis of T2 DM and progressively worsens with disease duration. β-cell dysfunction is associated with worseningof glycemic control and treatment failure; thus, it is important to preserve or recover β-cell functional mass in the management of T2 DM. Since β-cell regenerative capacity appears somewhat limited in humans, reducing β-cell workload appears to be the most effective way to preserve β-cell functional mass to date, underpinning the importance of lifestyle modification and weight loss for the treatment and prevention of T2 DM. This review summarizes the current knowledge on β-cell functional mass in T2 DM and discusses the treatment strategy for T2 DM.     

Update on cystic fibrosis-related diabetes

Diabetes mellitus has emerged as a common comorbidity in cystic fibrosis and is considered a clinical entity (cystic fibrosis-related diabetes, CFRD) distinct from that of type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The relevance of this diagnosis extends not only from its imposition of additional medical burden but its association with worse health outcomes in individuals with CF. This paper will review the 2010 U.S. and other international guidelines for screening and treating CFRD. It will highlight newer data regarding early glucose and insulin secretion defects, mechanisms linking CFRD to worse outcomes, and recent advances in T2DM that may provide insights for CFRD; insulin secretion will be reviewed as background for these recent developments.     

Coinhibitory T-cell signaling in islet allograft rejection and tolerance

Autoaggressive T cells directed against insulin secreting pancreatic beta-cells mediate the development of type 1 diabetes. Islet transplantation offers superior glycemic control over exogenous insulin, but chronic immunosuppression limits its broad application. Pathogenic T cells are also important in allograft rejection. Inducing and maintaining antigen-specific peripheral T-cell tolerance toward beta-cells is an attractive strategy to prevent autoimmune disease, and to facilitate treatment of diabetes with islet allografts without long-term immunosuppression. Recent efforts have focused on blocking costimulatory T-cell signals for tolerance induction. Although costimulatory blockade can prolong graft survival, true immunological tolerance remains elusive. Costimulatory signals may even be required for the maintenance of peripheral tolerance. The discovery of novel coinhibitory T-cell pathways, including CTLA-4, PD-1, and BTLA, offers an alternative approach. Stimulating negative T cell cosignals alone or in combination may help induce tolerance. The focus of this review is to summarize the strategies directed at turning off the immune response by exploiting these negative cosignaling pathways in tolerance induction in islet transplantation. Activating several coinhibitory pathways together may be synergistic in preventing pathogenic T-cell responses. Tolerance induction will likely rely on understanding the balance of positive and negative signals affecting the state of T-cell activation.     

Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes

Eliminating autoantigen-specific B cells is an attractive alternative to global B-cell depletion for autoimmune disease treatment. To identify the potential for targeting a key autoimmune B-cell specificity in type 1 diabetes, insulin-binding B cells were tracked within a polyclonal repertoire using heavy chain B-cell receptor (BCR) transgenic (VH125Tg) mice. Insulin-specific B cells are rare in the periphery of nonautoimmune VH125Tg/C57BL/6 mice and WT/NOD autoimmune mice, whereas they clearly populate 1% of mature B-cell subsets in VH125Tg/NOD mice. Autoantigen upregulates CD86 in anti-insulin B cells, suggesting they are competent to interact with T cells. Endogenous insulin occupies anti-insulin BCR beginning with antigen commitment in bone marrow parenchyma, as identified by a second anti-insulin monoclonal antibody. Administration of this monoclonal antibody selectively eliminates insulin-reactive B cells in vivo and prevents disease in WT/NOD mice. Unexpectedly, developing B cells are less amenable to depletion, despite increased BCR sensitivity. These findings exemplify how a critical type 1 diabetes B-cell specificity escapes immune tolerance checkpoints. Disease liability is corrected by eliminating this B-cell specificity, providing proof of concept for a novel therapeutic approach for autoimmune disease.     

IRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice

Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by progressive destruction of insulin-secreting pancreatic β-cells. Both T-cell–mediated adaptive responses as well as innate immune processes are involved in pathogenesis. Interleukin-1 receptor–associated kinase M (IRAK-M) can effectively inhibit the MyD88 downstream signals in Toll-like receptor pathways, while lack of IRAK-M is known to be associated with autoimmunity. Our study showed that IRAK-M–deficient (IRAK-M^−/−) nonobese diabetic (NOD) mice displayed early onset and rapid progression of T1DM with impaired glucose tolerance, more severe insulitis, and increased serum anti-insulin autoantibodies. Mechanistic studies showed that the enhanced activation and antigen-presenting function of IRAK-M^−/− antigen-presenting cells from IRAK-M^−/− mice were responsible for the rapid progression of disease. Moreover, IRAK-M^−/− dendritic cells induced enhanced activation of diabetogenic T cells in vitro and the rapid onset of T1DM in vivo in immunodeficient NOD mice when cotransferred with diabetogenic T cells. This study illustrates how the modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.     

Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes

Diabetes mellitus (DM) is still one of the most common diseases worldwide, and its prevalence is still increasing globally. According to the American and European recommendations, metformin is considered a first-line oral hypo-glycemic drug for controlling type 2 DM (T2DM) patients. Metformin is the ninth most often prescribed drug in the world, and at least 120 million diabetic people are estimated to receive the drug. In the last 20 years, there has been increasing evidence of vitamin B12 deficiency among metformin-treated diabetic patients. Many studies have reported that vitamin B12 deficiency is related to the ma-labsorption of vitamin B12 among metformin-treated T2DM patients. Vitamin B12 deficiency may have a very bad complication for the T2DM patient. In this review, we will focus on the effect of metformin on the absorption of vitamin B12 and on its proposed mechanisms in hindering vitamin B12 absorption. In addition, the review will describe the clinical outcomes of vitamin B12 deficiency in metformin-treated T2DM.     

Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes

Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.     

Pharmacological control of blood sugar

Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics and sodium glucose co-transporter 2 inhibitors have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving β-cell function with improved cardiovascular outcomes associated with some of these agents. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.     

Comparison of vitamin D levels in diabetes mellitus patients with and without diabetic foot ulcers: An analytical observational study in Jakarta,Indonesia

Diabetic foot ulcer (DFU) is a form of chronic wound which becomes a serious complication in diabetes mellitus (DM). Recently, the role of vitamin D on T cell-mediated immunity, pancreatic insulin secretion, and its mechanism on cell growth and healing processes have been reported. This study aims to compare the vitamin D level of DM patients with DFU and without DFU to assess the duration and severity of DFU and its correlation with vitamin D levels. The sociodemographic characteristics and DFU duration were documented. The severity was examined in accordance with PEDIS classification. 25-hydroxyvitamin D (25[OH]D) was analysed using in-vitro chemiluminescent immunoassay (CLIA). Statistical analysis was performed and the P-value <.05 was considered as statistically significant. The vitamin D levels in DM patients with and without DFU were 8.90 ng/mL (6.52–10.90) and 16.25 ng/mL (13–19.59), respectively, with P < .001. There was no correlation between the duration of DFU and DFU severity by PEDIS score with vitamin D levels. Vitamin D levels in DM patients with DFU are lower than those in patients without DFU. However, there was insufficient evidence to conclude that there is no correlation between the DFU duration and DFU severity by PEDIS score with vitamin D levels.     

Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping β-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.