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Concept: Diabetes mellitus type 1

203

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

178

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

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

174

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

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

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

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

149

Background In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. Methods In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. Results A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). Conclusions Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).

Concepts: Insulin, Diabetes mellitus, Diabetes mellitus type 1, Diabetes, Blood sugar, Hypoglycemia, Hyperglycemia, Diabetic ketoacidosis

145

Sodium-glucose linked transporter 2 inhibition recently emerged as a promising therapy for reducing the risk of heart failure (HF) in patients with type 2 diabetes mellitus (T2DM). However, there is a lack of data endorsing its role in symptomatic HF patients. We sought to evaluate the short-term effects of empagliflozin on maximal exercise capacity in these patients.

Concepts: Hypertension, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Diabetes mellitus type 1, Obesity, Insulin resistance, Sulfonylurea

138

To compare steady state pharmacodynamic and pharmacokinetic profiles of insulin glargine 300U/mL (Gla-300) with insulin degludec 100U/mL (Deg-100) in people with type 1 diabetes.

Concepts: Diabetes mellitus type 2, Diabetes mellitus type 1, Pharmacokinetics, Pharmacodynamics