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Mitochondrial dysfunction in pancreatic β-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment’s effects on mQC in diabetic β-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic β-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db β-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db β-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced β-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving β-cell function and effective glycemic control in T2D.

In preparation for the metabolic demands of pregnancy, β cells in the maternal pancreatic islets increase both in number and in glucose-stimulated insulin secretion (GSIS) per cell. Mechanisms have been proposed for the increased β cell mass, but not for the increased GSIS. Because serotonin production increases dramatically during pregnancy, we tested whether flux through the ionotropic 5-HT3 receptor (Htr3) affects GSIS during pregnancy. Pregnant Htr3a ⁻/⁻ mice exhibited impaired glucose tolerance despite normally increased β cell mass, and their islets lacked the increase in GSIS seen in islets from pregnant wild-type mice. Electrophysiological studies showed that activation of Htr3 decreased the resting membrane potential in β cells, which increased Ca ²⁺ uptake and insulin exocytosis in response to glucose. Thus, our data indicate that serotonin, acting in a paracrine/autocrine manner through Htr3, lowers the β cell threshold for glucose and plays an essential role in the increased GSIS of pregnancy.

This study aims to clarify the effect of occupational stress and changes in the work environment on non-healthcare workers’ (HCWs) mental health during the third wave of the COVID-19 pandemic in Japan. A web-based, cross-sectional survey was conducted from 16 to 17 December 2020. Data from 807 non-HCWs were included. We evaluated occupational stress using the Generic Job Stress Questionnaire (GJSQ). Depressive and anxiety symptoms were assessed using the Japanese version of the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder 7-item scale, respectively. We collected demographic variables, work-related variables, and the variables associated with COVID-19. The adjusted odds ratios for depressive and anxiety groups were estimated using multivariate logistic regression analyses, adjusted for all the demographic variables, work-related variables, COVID-19-related variables, and the six subdivided GJSQ subscales. The results confirm a relationship between variance in workload, job future ambiguity, social support from coworkers, having contact with COVID-19 patients, and depressive and anxiety symptoms. Paying attention to job future ambiguity, the variance in workload at the workplace and individual perspectives, promoting contact and support among coworkers using online communication tools, and reducing contact with COVID-19 patients, will be useful for decreasing the depressive and anxiety symptoms among non-HCWs.

TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

The severity of major depressive disorder (MDD), which is related to the depressive symptoms, is a predictor of clinical outcomes and may be used to determine the appropriate treatment. However, there is a lack of systematic research on the relationship between early depressive symptoms and MDD severity. This study aimed to clarify the association between initial depressive symptoms and MDD severity in working patients. We assessed 118 patients aged over 20 years who visited the Neuropsychiatry Department of the Osaka City University Hospital following their first episode of MDD. Logistic regression analyses were performed to estimate the odds ratios (OR) with 95% confidence intervals (CI) for the associations between age, gender, marital status, working hours, and initial self-perceived depressive symptoms and MDD severity. Age and working hours were analyzed as continuous variables, and gender (man, woman), marital status (married, single) and severity (mild to moderate MDD, severe to very severe MDD) were analyzed as categorical variables. The most common initial self-perceived symptom was “depressed mood,” followed by “fatigue or loss of energy nearly every day.” The univariate analysis found no association between age, gender, marital status, or working hours and MDD severity. Initial self-perceived non-somatic symptoms were associated with increased odds of having severe MDD (odds ratio = 3.32, 95% confidence interval 1.46–7.58), and this association persisted in the adjusted model (odds ratio = 3.35, 95% confidence interval 1.47–7.60). Initial self-perceived non-somatic depressive symptoms are significantly associated with MDD severity at its first onset. Workplace support may lead to the early detection and treatment of working patients with non-somatic symptoms.

The coronavirus disease 2019 (COVID‐19) pandemic and government regulations have affected the daily lives and mental health of individuals worldwide. This study aimed to determine how much the change in time spent on exercise (exercise time), outdoor activities (“going‐out” time), and screen usage (screen time) before and after the COVID‐19 pandemic has affected mental health (depression, anxiety, and insomnia). In June 2021, during the third wave of the COVID‐19 pandemic, a web‐based, cross‐sectional survey was conducted in Japan through an online research company. A total of 824 workers participated in this study. Depression, anxiety, and insomnia were assessed using the Patient Health Questionnaire‐9, General Anxiety Disorder‐7, and Insomnia Severity Index, respectively. The symptoms of depression were associated with age and decreased exercise time. Symptoms of anxiety were associated with not decreased going‐out time. Symptoms of insomnia were associated with reduced exercise time. The results indicated that during the COVID‐19 pandemic, an increase in exercise time could have prevented depression and insomnia. Similarly, a decrease in going‐out time could have prevented anxiety. Furthermore, in the event of future outbreaks of unpredictable infections, such as COVID‐19, decreased going out and increased exercise may help maintain mental health. The study of 824 Japanese workers found reduced exercise tied to depression and insomnia during the COVID‐19 pandemic. Maintained outdoor activity was linked to anxiety. It suggests more exercise and less outdoor time can improve mental health in future pandemics.

In glucose-induced insulin secretion from pancreatic β-cells, a population of insulin granules fuses with the plasma membrane without the typical docking process (newcomer granule fusions), however, its mechanism is unclear. In this study, we investigated the PI3K signaling pathways involved in the upregulation of newcomer granule fusions. Acute treatment with the class IA-selective PI3K inhibitors, PIK-75 and PI-103, enhanced the glucose-induced insulin secretion. Total internal reflection fluorescent microscopy revealed that the PI3K inhibitors increased the fusion events from newcomer granules. We developed a new system for transfection into pancreatic islets and demonstrated the usefulness of this system in order for evaluating the effect of transfected genes on the glucose-induced secretion in primary cultured pancreatic islets. Using this transfection system together with a series of constitutive active mutants, we showed that the PI3K-3-phosphoinositide dependent kinase-1 (PDK1)-Akt pathway mediated the potentiation of insulin secretion. The Akt inhibitor also enhanced the glucose-induced insulin secretion in parallel with the upregulation of newcomer granule fusions, probably via increased motility of intracellular insulin granules. These data suggest that the PI3K-PDK1-Akt pathway plays a significant role in newcomer granule fusions, probably through an alteration of the dynamics of the intracellular insulin granules.

A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes and reduced insulin release in humans; however, the role of CDKAL1 in β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice. Total internal reflection fluorescence imaging of CDKAL1 KO β cells showed that the number of fusion events during first-phase insulin release was reduced. However, there was no significant difference in the number of fusion events during second-phase release or high K(+)-induced release between WT and KO cells. CDKAL1 deletion resulted in a delayed and slow increase in cytosolic free Ca(2+) concentration during high glucose stimulation. Patch-clamp experiments revealed that the responsiveness of ATP-sensitive K(+) (K(ATP)) channels to glucose was blunted in KO cells. In addition, glucose-induced ATP generation was impaired. Although CDKAL1 is homologous to cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1, there was no difference in the kinase activity of CDK5 between WT and CDKAL1 KO islets. We provide the first report describing the function of CDKAL1 in β cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in β cells by facilitating ATP generation, K(ATP) channel responsiveness and the subsequent activity of Ca(2+) channels through pathways other than CDK5-mediated regulation.

Aims/hypothesis Mitophagy, the selective autophagy of mitochondria, is essential for maintenance of mitochondrial function. Recent studies suggested that defective mitophagy in beta cells caused diabetes. However, because of technical difficulties, the development of a convenient and reliable method to evaluate mitophagy in beta cells in vivo is needed. The aim of this study was to establish beta cell-specific mitophagy reporter mice and elucidate the role of mitophagy in beta cell function under metabolically stressed conditions induced by a high-fat diet (HFD). Methods Mitophagy was assessed using newly generated conditional mitochondrial matrix targeting mitophagy reporter (CMMR) mice, in which mitophagy can be visualised specifically in beta cells in vivo using a fluorescent probe sensitive to lysosomal pH and degradation. Metabolic stress was induced in mice by exposure to the HFD for 20 weeks. The accumulation of dysfunctional mitochondria was examined by staining for functional/total mitochondria and reactive oxygen species (ROS) using specific fluorescent dyes and antibodies. To investigate the molecular mechanism underlying mitophagy in beta cells, overexpression and knockdown experiments were performed. HFD-fed mice were examined to determine whether chronic insulin treatment for 6 weeks could ameliorate mitophagy, mitochondrial function and impaired insulin secretion. Results Exposure to the HFD increased the number of enlarged (HFD-G) islets with markedly elevated mitophagy. Mechanistically, HFD feeding induced severe hypoxia in HFD-G islets, which upregulated mitophagy through the hypoxia-inducible factor 1-ɑ (Hif-1ɑ)/BCL2 interacting protein 3 (BNIP3) axis in beta cells. However, HFD-G islets unexpectedly showed the accumulation of dysfunctional mitochondria due to excessive ROS production, suggesting an insufficient capacity of mitophagy for the degradation of dysfunctional mitochondria. Chronic administration of insulin ameliorated hypoxia and reduced ROS production and dysfunctional mitochondria, leading to decreased mitophagy and restored insulin secretion. Conclusions/interpretation We demonstrated that CMMR mice enabled the evaluation of mitophagy in beta cells. Our results suggested that metabolic stress induced by the HFD caused the aberrant accumulation of dysfunctional mitochondria, which overwhelmed the mitophagic capacity and was associated with defective maintenance of mitochondrial function and impaired insulin secretion. Graphical abstract

Imaging Docking and Fusion of Insulin Granules Induced by Antidiabetes Agents Sulfonylurea and Glinide Drugs Preferentially Mediate the Fusion of Newcomer, but Not Previously Docked, Insulin Granules Shinya Nagamatsu , Mica Ohara-Imaizumi , Yoko Nakamichi , Toshiteru Kikuta and Chiyono Nishiwaki From the Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo, Japan Address correspondence and reprint requests to Shinya Nagamatsu, MD, Department of Biochemistry, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka, Tokyo 181-8611, Japan. E-mail: shinya{at}kyorin-u.ac.jp Abstract Sulfonylurea and glinide drugs, commonly used for antidiabetes therapies, are known to stimulate insulin release from pancreatic β-cells by closing ATP-sensitive K + channels. However, the specific actions of these drugs on insulin granule motion are largely unknown. Here, we used total internal reflection fluorescence (TIRF) microscopy to analyze the docking and fusion of single insulin granules in live β-cells exposed to either the sulfonylurea drug glibenclamide or the glinide drug mitiglinide. TIRF images showed that both agents caused rapid fusion of newcomer insulin granules with the cell membrane in both control and diabetic Goto-Kakizaki (GK) rat pancreatic β-cells. However, in the context of β-cells from sulfonylurea receptor 1 (SUR1) knockout mice, TIRF images showed that only mitiglinide, but not glibenclamide, caused fusion of newcomer insulin granules. Compositely, our data indicate that 1 ) the mechanism by which both sulfonylurea and glinide drugs promote insulin release entails the preferential fusion of newcomer, rather than previously docked, insulin granules, and that 2 ) mitiglinide can induce insulin release by a mechanism independent of mitiglinide binding to SUR1. KATP channel, ATP-sensitive K+ channel [Ca2+]i, intracellular Ca2+ concentration CCD, charge-coupled device GFP, green fluorescent protein KRB, Krebs-Ringer buffer SUR, sulfonylurea receptor TIRF, total internal reflection fluorescence Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 27, 2006. Received January 24, 2006. DIABETES