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Concept: Diabetes mellitus type 1

202

APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.

Concepts: Interferon, Somatic hypermutation, Immunology, Cytokine, Diabetes mellitus type 1, Protein, Antibody, Immune system

179

Diabetes is a major global health issue and the number of individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) increases annually across multiple populations. Research to develop a cure must overcome multiple immune dysfunctions and the shortage of pancreatic islet β cells, but these challenges have proven intractable despite intensive research effort more than the past decades. Stem Cell Educator (SCE) therapy-which uses only autologous blood immune cells that are externally exposed to cord blood stem cells adhering to the SCE device, has previously been proven safe and effective in Chinese and Spanish subjects for the improvement of T1D, T2D, and other autoimmune diseases. Here, 4-year follow-up studies demonstrated the long-term safety and clinical efficacy of SCE therapy for the treatment of T1D and T2D. Mechanistic studies found that the nature of platelets was modulated in diabetic subjects after receiving SCE therapy. Platelets and their released mitochondria display immune tolerance-associated markers that can modulate the proliferation and function of immune cells. Notably, platelets also expressed embryonic stem cell- and pancreatic islet β-cell-associated markers that are encoded by mitochondrial DNA. Using freshly-isolated human pancreatic islets, ex vivo studies established that platelet-releasing mitochondria can migrate to pancreatic islets and be taken up by islet β cells, leading to the proliferation and enhancement of islet β-cell functions. These findings reveal new mechanisms underlying SCE therapy and open up new avenues to improve the treatment of diabetes in clinics. Stem Cells Translational Medicine 2017.

Concepts: Mitochondrion, Embryonic stem cell, Islets of Langerhans, Diabetes mellitus type 2, Diabetes mellitus, Diabetes mellitus type 1, Stem cell, Insulin

176

Type 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control.

Concepts: Insulin resistance, Diabetes mellitus type 2, Diabetes mellitus type 1, Diabetes mellitus, Atherosclerosis, Endothelial progenitor cell, Diabetes, Blood vessel

175

Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.

Concepts: Diabetes mellitus, Insulin, Diabetes mellitus type 1, Actuarial science, Risk, Randomized controlled trial, The Canon of Medicine, Epidemiology

171

Hypoglycemia is a common complication of insulin treatment in type 1 diabetes mellitus and can occur in any patient with diabetes when glucose consumption exceeds supply. Many studies have been done to elucidate those factors that predict severe hypoglycemia: younger age, longer duration of diabetes, lower HgbA1c, higher insulin dose, lower Body Mass Index, male gender, Caucasian race, underinsurance or low socioeconomic status, and the presence of psychiatric disorders. Hypoglycemia can affect patients' relationships, occupation, and daily activities such as driving. However, one of the greatest impacts is patients' fear of severe hypoglycemic events, which is a limiting factor in the optimization of glycemic control. Therefore, the importance of clinicians' ability to identify those patients at greatest risk for hypoglycemic events is two-fold: 1) Patients at greatest risk may be counseled as such and offered newer therapies and monitoring technologies to prevent hypoglycemic events. 2) Patients at lower risk may be reassured and encouraged to improve their glycemic control. Since the risk of long-term complications with poor blood glucose control outweighs the risks of hypoglycemia with good blood glucose control, patients should be encouraged to aim for glucose concentrations in the physiologic range pre- and post-prandially. Advancements in care, including multiple daily injection therapy with analog insulin, continuous subcutaneous insulin infusion, and continuous glucose monitoring, have each subsequently improved glycemic control and decreased the risk of severe hypoglycemia.

Concepts: Glucagon, Obesity, Diabetes mellitus type 1, Diabetes, Hypoglycemia, Blood sugar, Insulin, Diabetes mellitus

167

The purpose of this study was to evaluate the efficacy of vildagliptin 50 mg once daily in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m(2)) and longstanding type 2 diabetes not adequately controlled with insulin therapy, which is a difficult-to-treat population, with limited therapeutic options and a high susceptibility to hypoglycemia.

Concepts: Dialysis, Renal function, Diabetes mellitus type 1, Diabetes mellitus type 2, Diabetes mellitus, Nephrology, Insulin, Renal failure

153

Diet plays a crucial role for maintaining normal growth and development while optimizing glycemic control in children with diabetes. Dietary restrictions, in a diabetic child’s diet may lead to micronutrient deficiencies.

Concepts: Insulin resistance, Obesity, Insulin, Diabetes mellitus type 1, Diabetes mellitus, Diabetes, Diabetic diet, Nutrition

129

Published evaluations of sensor glucose monitoring use in insulin treated type 2 diabetes are limited. The aim of this study was to assess the impact of flash glucose-sensing technology as a replacement for self-monitoring of blood glucose (SMBG) over a 12-month period in participants with type 2 diabetes who were on intensive insulin therapy.

Concepts: Obesity, Blood glucose monitoring, Diabetes, Insulin therapies, Diabetes mellitus type 1, Diabetes mellitus type 2, Diabetes mellitus, Insulin

120

Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end-organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the scarcity of organ donors and life-long need for often-toxic antirejection drugs. Coadministering islets with bone marrow-derived mesenchymal stem cells (MSCs) that exert robust immune-modulating, anti-inflammatory, anti-apoptotic, and angiogenic actions, improves intrahepatic islet survival and function. Encapsulation of insulin-producing cells to prevent immune destruction has shown both promise and failures. Recently, stem cell-derived insulin secreting β-like cells induced euglycemia in diabetic animals, although their clinical use would still require encapsulation or anti-rejection drugs. Instead of focusing on further improvements in islet transplantation, we demonstrate here that the intraperitoneal administration of islet-sized “Neo-Islets” (NIs), generated by in vitro coaggregation of allogeneic, culture-expanded islet cells with high numbers of immuno-protective and cyto-protective MSCs, resulted in their omental engraftment in immune-competent, spontaneously diabetic nonobese diabetic (NOD) mice. This achieved long-term glycemic control without immunosuppression and without hypoglycemia. In preparation for an Food and Drug Administration-approved clinical trial in dogs with T1DM, we show that treatment of streptozotocin-diabetic NOD/severe combined immunodeficiency mice with identically formed canine NIs produced durable euglycemia, exclusively mediated by dog-specific insulin. We conclude that this novel technology has significant translational relevance for canine and potentially clinical T1DM as it effectively addresses both the organ donor scarcity (>80 therapeutic NI doses/donor pancreas can be generated) and completely eliminates the need for immunosuppression. Stem Cells Translational Medicine 2017.

Concepts: Pancreas, Glucagon, Diabetes mellitus type 1, Organ transplant, Islets of Langerhans, Diabetes, Diabetes mellitus, Insulin

109

The artificial pancreas (closed-loop system) addresses the unmet clinical need for improved glucose control whilst reducing the burden of diabetes self-care in type 1 diabetes. Glucose-responsive insulin delivery above and below a preset insulin amount informed by sensor glucose readings differentiates closed-loop systems from conventional, threshold-suspend and predictive-suspend insulin pump therapy. Insulin requirements in type 1 diabetes can vary between one-third-threefold on a daily basis. Closed-loop systems accommodate these variations and mitigate the risk of hypoglycaemia associated with tight glucose control. In this review we focus on the progress being made in the development and evaluation of closed-loop systems in outpatient settings. Randomised transitional studies have shown feasibility and efficacy of closed-loop systems under supervision or remote monitoring. Closed-loop application during free-living, unsupervised conditions by children, adolescents and adults compared with sensor-augmented pumps have shown improved glucose outcomes, reduced hypoglycaemia and positive user acceptance. Innovative approaches to enhance closed-loop performance are discussed and we also present the outlook and strategies used to ease clinical adoption of closed-loop systems.

Concepts: Closed loop, Control theory, Diabetes, Glucagon, Diabetes mellitus type 1, Insulin pump, Diabetes mellitus, Insulin