ER Stress Response Failure and Steatohepatitis Comorbid with Diabetes

Dynamic metabolic changes occur in the liver during the transition between fasting and eating, which is mainly mediated by insulin, a hormone to promote anabolism and suppress catabolism. In obesity and diabetes, insulin resistance is induced via various mechanisms, and among them is endoplasmic reticulum (ER) stress. We recently reported that eating induces transient ER stress and consequent ER stress response in the liver. During eating, expression of Sdf2l1, an ER-resident molecule involved in ER stress-associated degradation, is induced as a part of ER stress response. XBP-1s regulates expression of Sdf2l1 at the transcription level, and Sdf2l1 terminates eating-induced ER stress in the liver, consequently regulating glucose and lipid metabolism. In obesity and diabetes, however, ER stress response is impaired, partly because insulin-mediated translocation of XBP-1s to the nucleus is suppressed, which results in further excessive ER stress. Induction of Sdf2l1 by XBP-1s is highly down-regulated, but restoration of Sdf2l1 ameliorates glucose intolerance and fatty liver. In diabetic patients, hepatic insulin resistance induces enhanced ER stress and ER stress response failure in the liver, which in turn promote hepatic fibrosis and contribute to the development of steatohepatitis comorbid with diabetes

Intensified Multifactorial Intervention in Patients with Type 2 Diabetes Mellitus

In the management of diabetes mellitus, one of the most important goals is to prevent its micro- and macrovascular complications, and to that end, multifactorial intervention is widely recommended. Intensified multifactorial intervention with pharmacotherapy for associated risk factors, alongside lifestyle modification, was first shown to be efficacious in patients with microalbuminuria (Steno-2 study), then in those with less advanced microvascular complications (the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care [ADDITION]-Europe and the Japan Diabetes Optimal Treatment study for 3 major risk factors of cardiovascular diseases [J-DOIT3]), and in those with advanced microvascular complications (the Nephropathy In Diabetes-Type 2 [NID-2] study and Diabetic Nephropathy Remission and Regression Team Trial in Japan [DNETT-Japan]). Thus far, multifactorial intervention led to a reduction in cardiovascular and renal events, albeit not necessarily significant. It should be noted that not only baseline characteristics but also the control status of the risk factors and event rates during intervention among the patients widely varied from one trial to the next. Further evidence is needed for the efficacy of multifactorial intervention in a longer duration and in younger or elderly patients. Moreover, now that new classes of antidiabetic drugs are available, it should be addressed whether strict and safe glycemic control, alongside control of other risk factors, could lead to further risk reductions in micro- and macrovascular complications, thereby decreasing all-cause mortality in patients with type 2 diabetes mellitus

Changes in the quality of diabetes care in Japan between 2007 and 2015: A repeated cross-sectional study using claims data

AimTo assess the temporal changes in the quality indicators pertaining to the process measures of diabetes care during a recent decade in Japan.MethodsA five-fold repeated cross-sectional study was conducted using health insurance claims data provided by the Japan Medical Data Center between April 2006 and March 2016. We identified 46,631 outpatients with antidiabetic medication who regularly visited hospitals or clinics at least every three months. We evaluated the quality indicators pertaining to glycemic control monitoring, lipid profile monitoring, retinopathy screening, nephropathy screening, and appropriate medication choice. The proportions of patients who received appropriate examinations/prescriptions, by observation period and either the type of antidiabetic medication or facility type were estimated using generalized estimating equation (GEE) models with multiple covariate adjustments.ResultsThe quality indicator values for appropriate medication choice and nephropathy screening improved between 2007 and 2015, whereas those for glycemic control monitoring and retinopathy screening remained suboptimal. Patients prescribed medications in larger hospitals were likelier to undergo the recommended examinations (e.g. retinopathy screening: 36.1% (95% CI: 35.4–36.7%) for clinic, 40.6% (95% CI: 39.1–42.2%) for smaller hospital, and 46.0% (95% CI: 44.8–47.2%) for larger hospital in 2015).ConclusionsSeveral process measures of diabetes care remained suboptimal in Japan

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA–KIDNEY

Background: EMPA–KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. Methods: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20  Results: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64–0.82; P  Conclusions: Empagliflozin safely reduced the risk of “kidney disease progression or cardiovascular death” in patients with CKD, with consistent effects in participants from Japan

Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms

SummaryType 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca2+ influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes

Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity

M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity

HbA1c and telemedicine during COVID-19

Aims/Introduction: To investigate whether the COVID-19 pandemic affected behavioral changes and glycemic control in patients with diabetes and to conduct a survey of telemedicine during the pandemic. Materials and Methods: In this retrospective study, a total of 2,348 patients were included from 15 medical facilities. Patients were surveyed about their lifestyle changes and attitudes toward telemedicine. Hemoglobin A1c (HbA1c) levels were compared among before (from June 1 to August 31, 2019) and in the first (from June 1 to August 31, 2020) and in the second (from June 1 to August 31, 2021) year of the pandemic. A survey of physician attitudes toward telemedicine was also conducted. Results: The HbA1c levels were comparable between 2019 (7.27 ± 0.97%), 2020 (7.28 ± 0.92%), and 2021 (7.25 ± 0.94%) without statistical difference between each of those 3 years. Prescriptions for diabetes medications increased during the period. The frequency of eating out was drastically reduced (51.7% in 2019; 30.1% in 2020), and physical activity decreased during the pandemic (48.1% in 2019; 41.4% in 2020; 43.3% in 2021). Both patients and physicians cited increased convenience and reduced risk of infection as their expectations for telemedicine, while the lack of physician–patient interaction and the impossibility of consultation and examination were cited as sources of concern. Conclusions: Our data suggest that glycemic control did not deteriorate during the COVID-19 pandemic with appropriate intensification of diabetes treatment in patients with diabetes who continued to attend specialized diabetes care facilities, and that patients and physicians shared the same expectations and concerns about telemedicine

CD206+ M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors

Adipose tissue resident macrophages have important roles in the maintenance of tissue homeostasis and regulate insulin sensitivity for example by secreting pro-inflammatory or anti-inflammatory cytokines. Here, we show that M2-like macrophages in adipose tissue regulate systemic glucose homeostasis by inhibiting adipocyte progenitor proliferation via the CD206/TGFβ signaling pathway. We show that adipose tissue CD206+ cells are primarily M2-like macrophages, and ablation of CD206+ M2-like macrophages improves systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. Mice genetically engineered to have reduced numbers of CD206+ M2-like macrophages show a down-regulation of TGFβ signaling in adipose tissue, together with up-regulated proliferation and differentiation of adipocyte progenitors. Our findings indicate that CD206+ M2-like macrophages in adipose tissues create a microenvironment that inhibits growth and differentiation of adipocyte progenitors and, thereby, control adiposity and systemic insulin sensitivity

Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation

Identification of regulatory elements within the genome is crucial for understanding the mechanisms that govern cell type–specific gene expression. We generated genome-wide maps of open chromatin sites in 3T3-L1 adipocytes (on day 0 and day 8 of differentiation) and NIH-3T3 fibroblasts using formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). FAIRE peaks at the promoter were associated with active transcription and histone modifications of H3K4me3 and H3K27ac. Non-promoter FAIRE peaks were characterized by H3K4me1+/me3-, the signature of enhancers, and were largely located in distal regions. The non-promoter FAIRE peaks showed dynamic change during differentiation, while the promoter FAIRE peaks were relatively constant. Functionally, the adipocyte- and preadipocyte-specific non-promoter FAIRE peaks were, respectively, associated with genes up-regulated and down-regulated by differentiation. Genes highly up-regulated during differentiation were associated with multiple clustered adipocyte-specific FAIRE peaks. Among the adipocyte-specific FAIRE peaks, 45.3% and 11.7% overlapped binding sites for, respectively, PPARγ and C/EBPα, the master regulators of adipocyte differentiation. Computational motif analyses of the adipocyte-specific FAIRE peaks revealed enrichment of a binding motif for nuclear family I (NFI) transcription factors. Indeed, ChIP assay showed that NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes. Overexpression of NFIA in 3T3-L1 cells resulted in robust induction of these genes and lipid droplet formation without differentiation stimulus. Overexpression of dominant-negative NFIA or siRNA–mediated knockdown of NFIA or NFIB significantly suppressed both induction of genes and lipid accumulation during differentiation, suggesting a physiological function of these factors in the adipogenic program. Together, our study demonstrates the utility of FAIRE-seq in providing a global view of cell type–specific regulatory elements in the genome and in identifying transcriptional regulators of adipocyte differentiation