Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for insulindependent diabetes mellitus as a side-effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy. A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti-PD-1 therapy.

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SUMMARYObjectives: Endothelial progenitor cells (EPCs) have been shown to participate in the process of vascular repair, thus playing a protective role against cardiovascular disease (CVD). It is known that atherosclerotic risk factors could affect EPC number and function. Advanced glycation end products (AGEs) contribute to the pathogenesis of atherosclerosis as well. However, as far as we know, there is no report to show the relationship between serum AGE levels and circulating EPCs in humans. Therefore, in this study, we investigated whether serum level of AGEs was associated with EPC number and functions in apparently healthy subjects, independent of traditional cardiovascular risk factors. Research Design and Methods: Apparently healthy volunteers (34.6 ± 6.9 years old, 40 males and 8 females) who were not on any medications underwent a complete history and physical examination, determination of blood chemistries, including AGEs, and number, differentiation and migratory activity of circulating EPCs. Results: Serum AGEs levels were 9.20 ± 1.85 U/mL. Multiple stepwise regression analysis revealed that serum levels of AGEs and smoking were independently correlated with reduced number of EPCs. Further, female, AGEs, and reduced HDL-cholesterol levels were independently associated with impaired migratory activity of circulating EPCs. Conclusions: This study demonstrated for the first time that the serum level of AGEs was one of the independent correlates of decreased cell number and impaired migratory activity of circulating EPCs in apparently healthy subjects. Our present observations suggest that even in young healthy subjects, serum level of AGEs may be a biomarker that could predict the progression of atherosclerosis and future cardiovascular events.

Forkhead box protein O1 (FoxO1) is a transcription factor and a critical regulator of angiogenesis. Various environmental stimuli, including growth factors, nutrients, shear stress, oxidative stress and hypoxia, affect FoxO1 subcellular localization and strongly influence its transcriptional activity; however, FoxO1-localization patterns in endothelial cells (ECs) during development have not been clarified in vivo. Here, we reported that FoxO1 expression was observed in three layers of angiogenic vessels in developing mouse retinas and that among these layers, the front layer showed high levels of FoxO1 expression in the nuclei of most tip ECs. Because tip ECs migrate toward the avascular hypoxic area, we focused on hypoxia as a major stimulus regulating FoxO1 subcellular localization in tip cells. In cultured ECs, FoxO1 accumulated into the nucleus under hypoxic conditions, with hypoxia also inducing expression of tip-cell-specific genes, including endothelial-specific molecule 1 (ESM1), which was suppressed by FoxO1 knockdown. Additionally, in murine models, EC-specific FoxO1 deletion resulted in reduced ESM1 expression and suppressed tip-cell migration during angiogenesis. These findings indicated roles for FoxO1 in tip-cell migration and that its transcriptional activity is regulated by hypoxia.

Diabetic micro- and macroangiopathies are leading causes of acquired blindness, end-stage renal failure and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Recent large landmark clinical studies have shown that intensive control of blood glucose or blood pressure (BP) reduces the risk for vascular complications in diabetes. However, the strict control of blood glucose or BP is often difficult to maintain, and current therapeutic options are far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target vascular complications in diabetes may be actually desired for most patients with diabetes. Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors with complex neurotrophic, neuroprotective, anti-angiogenic, anti-oxidative, and anti-inflammatory properties, any of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes. This article summarizes the pathophysiological role of PEDF for vascular complication in diabetes and its potential therapeutic implication in this devastating disorder.

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, stroke, blindness, and end‐stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Recent clinical studies have substantiated the concept of “hyperglycemic memory” in the pathogenesis of cardiovascular disease (CVD) in diabetes. Indeed, the Diabetes Control and Complications Trial‐Epidemiology of Diabetes Interventions and Complications (DCCT‐EDIC) Research, has revealed that intensive therapy during the DCCT reduces the risk of cardiovascular events by about 50% in type 1 diabetic patients 11 years after the end of the trial. Among various biochemical pathways activated under diabetic conditions, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory “hyperglycemic memory.” Further, there is a growing body of evidence that AGEs play an important role in CVD in diabetes. These observations suggest that the inhibition of AGEs formation may be a promising target for therapeutic intervention in diabetic vascular complications. Therefore, in this article, we review several agents with inhibitory effects on AGEs formation and their therapeutic implications in CVD in diabetes.

Diabetes is associated with a marked increase in the risk of atherosclerotic vascular disorders, including coronary, cerebrovascular and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. Conventional risk factors, including hyperlipidaemia, hypertension, smoking, obesity, lack of exercise and a positive family history, contribute similarly to macrovascular complications in type 2 diabetic patients and non-diabetic subjects. The levels of these factors in diabetic patients are certainly increased, but not enough to explain the exaggerated risk for macrovascular complications in diabetic population. Therefore, specific diabetes-related risk factors should be involved in the excess risk in diabetic patients. In this paper, we review the molecular mechanisms for accelerated atherosclerosis in diabetes, especially focusing on postprandial hyperglycaemia. We also discuss here the potential therapeutic strategy that specifically targets CVD in patients with diabetes.

Background: Ovarian cancer (OC) is a leading cause of cancer-related death in women, and thus an accurate diagnosis of the predisposition and its early detection is necessary. The aims of this study were to determine whether serum exosomal microRNA-34a (miR-34a) in ovarian cancer could be used as a potential biomarker. Methods: Exosomes from OC patients' serum were collected, and exosomal miRNAs were extracted. The relative expression of miR-34a was calculated from 58 OC samples by quantitative real-time polymerase chain reaction. Results: Serum exosomal miR-34a levels were significantly increased in early-stage OC patients compared with advanced-stage patients. Its levels were significantly lower in patients with lymph node metastasis than in those with no lymph node metastasis. Furthermore, its levels in the recurrence group were significantly lower than those in the recurrence-free group. Conclusions: Serum exosomal miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC.