Comparison over Time of Adverse Drug Reactions in Diabetes Patients Treated with Sodium-Glucose Cotransporter 2 Inhibitors.

Backgrounds: The prescription of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been increasing due to their additional benefits, including weight loss, cardioprotection and renoprotection. Accordingly, there are concerns about the potential rise in severe adverse drug reactions (ADRs), such as urinary tract infections, diabetic ketoacidosis, volume depletion, and hypoglycemia. The Society has announced recommendations on the proper use of SGLT2 inhibitors.

Dapagliflozin administration to a mouse model of type 2 diabetes induces DNA methylation and gene expression changes in pancreatic islets.

Decreased pancreatic β-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic β-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes.

A High Fibrosis-4 Index is Associated with a Reduction in the Estimated Glomerular Filtration Rate in Non-obese Japanese Patients with Type 2 Diabetes Mellitus.

Liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD), and one of the most important risk factors for NAFLD is type 2 diabetes (T2DM). The Fibrosis-4 (FIB-4) index, a noninvasive liver fibrosis score, has been found to be useful for estimating liver fibrosis. Because individuals with non-obese NAFLD were recently reported to be metabolically unhealthy and have a higher risk of T2DM than individuals with obese NAFLD, we hypothesized that the clinical factors related to a high FIB-4 index would differ between non-obese and obese Japanese T2DM patients.

Dietary Intervention for Control of Clinical Symptom in Patients with Systemic Metal Allergy: A Single Center Randomized Controlled Clinical Study.

Patients with eczema with a systemic metal allergy, such as nickel (Ni), cobalt (Co), chromium (Cr), and tin (Sn), should pay attention to symptomatic exacerbation by excessive metal intake in food. However, dietary intervention for systemic metal allergy can be difficult. In this study, we evaluated the effect of dietary intervention by a registered dietitian on clinical symptoms in patients with a systemic metal allergy.

Cyb5r3 activation rescues secondary failure to sulfonylurea but not β-cell dedifferentiation.

Diabetes mellitus is characterized by insulin resistance and β-cell failure. The latter involves impaired insulin secretion and β-cell dedifferentiation. Sulfonylurea (SU) is used to improve insulin secretion in diabetes, but it suffers from secondary failure.

Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown.

Distinct hypoglycemic effect of different formulations of a fixed ratio of basal insulin plus glucagon-like peptide-1 receptor agonist in a patient with pancreatic diabetes.

Unlabelled: Fixed-ratio combination injection therapy (FRC) is a fixed-ratio mixture containing basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in a single injection for the treatment of patients with type 2 diabetes. The two types of FRC products contain different concentrations and mixing ratios of basal insulin and GLP-1 RA. Both products demonstrated satisfactory blood glucose control throughout the day, with less hypoglycemia and weight gain.

Chlorogenic Acid and Caffeine in Coffee Restore Insulin Signaling in Pancreatic Beta Cells.

The incidence of type 2 diabetes is reported to be lower in frequent coffee drinkers than in non-coffee drinkers. To elucidate the mechanism by which coffee prevents the onset of type 2 diabetes, we analyzed how caffeine and chlorogenic acid, which are components of coffee, alter insulin signaling in MIN6 cells, a mouse pancreatic Β cell line. The results showed that caffeine improved insulin signaling under endoplasmic reticulum stress, and chlorogenic acid protected pancreatic Β cells by enhancing the expression of insulin receptor substrate 2 via cAMP response element-binding protein and promoting insulin signaling downstream of insulin receptor substrate 2.

l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells.

Eif2ak4, a susceptibility gene for type 2 diabetes, encodes GCN2, a molecule activated by amino acid deficiency. Mutations or deletions in GCN2 in pancreatic β-cells increase mTORC1 activity by decreasing Sestrin2 expression in a TSC2-independent manner. In this study, we searched for molecules downstream of GCN2 that suppress mTORC1 activity in a TSC2-dependent manner.

Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes.

Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) down-regulation as a mechanism of secondary SU failure and successfully reverse it.

The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice.

Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis.

Roles of mTOR in the Regulation of Pancreatic β-Cell Mass and Insulin Secretion.

Pancreatic β-cells are the only type of cells that can control glycemic levels via insulin secretion. Thus, to explore the mechanisms underlying pancreatic β-cell failure, many reports have clarified the roles of important molecules, such as the mechanistic target of rapamycin (mTOR), which is a central regulator of metabolic and nutrient cues. Studies have uncovered the roles of mTOR in the function of β-cells and the progression of diabetes, and they suggest that mTOR has both positive and negative effects on pancreatic β-cells in the development of diabetes.

Regulation of Pancreatic β-Cell Mass by Gene-Environment Interaction.

The main pathogenic mechanism of diabetes consists of an increase in insulin resistance and a decrease in insulin secretion from pancreatic β-cells. The number of diabetic patients has been increasing dramatically worldwide, especially in Asian people whose capacity for insulin secretion is inherently lower than that of other ethnic populations. Causally, changes of environmental factors in addition to intrinsic genetic factors have been considered to have an influence on the increased prevalence of diabetes.

Oral administration of D-serine prevents the onset and progression of colitis in mice.

Background: L-amino acids are the predominant forms of organic molecules on the planet, but recent studies have revealed that various foods contain D-amino acids, the enantiomers of L-amino acids. Though diet plays important roles in both the development and progression of inflammatory bowel disease (IBD), to our best knowledge, there has been no report on any potential interactions between D-amino acids and IBD. In this report, we aim to assess the effects of D-serine in a murine model of IBD.

Patch-seq shows the heterogeneity of pancreatic islet cells.

In 2016, Patch-seq was established to analyze electrophysiology, gene expression and morphology in neuronal cells. Recently, Camunas-Soler et al. used Patch-seq to analyze the functions and gene expression profiles of individual cells in pancreatic islets.

Glutamate is an essential mediator in glutamine-amplified insulin secretion.

Aims/introduction: Glutamine is the most abundant amino acid in the circulation. In this study, we investigated cell signaling in the amplification of insulin secretion by glutamine.

Materials And Methods: Clonal pancreatic β-cells MIN6-K8, wild-type B6 mouse islets, glutamate dehydrogenase (GDH) knockout clonal β-cells (Glud1KOβCL), and glutamate-oxaloacetate transaminase 1 (GOT1) knockout clonal β-cells (Got1KOβCL) were studied.

Sex difference in the association of obesity with personal or social background among urban residents in Japan.

The development of obesity is influenced by genetic and environmental factors and is associated with a variety of health problems. To gain insight into environmental factors that contribute to obesity, we analyzed the relation of personal or social background to obesity in men and women separately with the use of data from a community-based questionnaire survey of 5425 residents aged 20 to 64 years of Kobe, a representative large city in Japan. Obesity and normal weight were defined as a body mass index (BMI) of ≥25 and of ≥ 18.

Histone deacetylase 6 regulates insulin signaling in pancreatic β cells.

The reduction of pancreatic β cell mass is one of the key factors for the onset of type 2 diabetes. Many reports have indicated that insulin signaling is important for type 2 diabetes, but the mechanism by which insulin signaling is altered in pancreatic β cells remains unclear. This study was designed to examine the role of histone deacetylases (HDACs) in the regulation of insulin signaling in pancreatic β cells.

GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels.

EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass.

En face slab optical coherence tomography imaging successfully monitors progressive degenerative changes in the innermost layer of the diabetic retina.

Objective: To evaluate the usefulness of en face slab optical coherence tomography (OCT) imaging for monitoring diabetic retinal neurodegeneration with supporting animal experimental data.

Research Design And Methods: We retrospectively examined 72 diabetic eyes over 3 years using Cirrus-HD OCT. Two-dimensional en face slab OCT images of the innermost retina were reconstructed and graded according to the ratio of dark area to total area, and relative red, green, and blue color area ratios were calculated and used as indexes for each en face slab OCT image.

Association between mean platelet volume in the pathogenesis of type 2 diabetes mellitus and diabetic macrovascular complications in Japanese patients.

Aims/introduction: Mean platelet volume (MPV) is a widely used biological marker of platelet function and activity. Increased MPV is associated with accelerated thrombopoiesis and an elevated risk of cardiovascular disease. However, it is not known whether higher MPV is related to the pathogenesis of type 2 diabetes and diabetic macrovascular complications in Japanese patients.

Neuronatin and glucose-induced stress in pancreatic β-cells.

Recently, reports have described the association between neuronatin (Nnat) and endoplasmic reticulum stress, and the promotion of insulin processing by Nnat, the expression of which is greatly induced by glucose stimulation. The roles of Nnat are worthy of note under both physiological and pathological conditions. In this Commentary, I discuss the association between Nnat and glucose-induced stress on the basis of recent knowledge.

Docosahexaenoic Acid Reduces Palmitic Acid-Induced Endoplasmic Reticulum Stress in Pancreatic Β Cells.

Endoplasmic reticulum (ER) stress leads to peripheral insulin resistance and the progression of pancreatic beta cell failure in type 2 diabetes. Although ER stress plays an important role in the pathogenesis of diabetes, it is indispensable for cellular activity. Therefore, when assessing the pathological significance of ER stress, it is important to monitor and quantify ER stress levels.

Early administration of dapagliflozin preserves pancreatic β-cell mass through a legacy effect in a mouse model of type 2 diabetes.

Aims/introduction: The preservation of pancreatic β-cell mass is an essential factor in the onset and development of type 2 diabetes mellitus. Recently, sodium-glucose cotransporter 2 inhibitors have been launched as antihyperglycemic agents, and their organ-protective effects are attracting attention. They are also reported to have favorable effects on the preservation of pancreatic β-cell mass, but the appropriate timing for the administration of sodium-glucose cotransporter 2 inhibitors is obscure.