神戸大学 · 医学部附属病院 · 助教

研究キーワードdiabetic nephropathy・pancreatic beta-cell mass・type 1 diabetes・type 2 diabetes・DNA methylation・mTORC1 signaling・extracellular vesicle microRNA

研究分野代謝、内分泌学

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• High-Fat Diet-Fed Kcnq1 Mutant Mice Have Reduced Pancreatic β-Cell Mass via Gene-Environment Interaction.BACKGROUND: The potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene has recently received much attention as a candidate susceptibility gene for type 2 diabetes mellitus, especially in Asian populations. We previously reported that Kcnq1 mutant mice exhibit reduced insulin secretion and hyperglycemia due to a decrease in pancreatic β-cell mass. Through in vivo and in vitro analyses, we ascertained that this mechanism is the result of the downregulation of the non-coding RNA 'Kcnq1ot1,' which is expressed in the paternal allele of the Kcnq1 gene region, causing an increase in the expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1C (Cdkn1c). It was found that decreased Kcnq1ot1 expression resulted in pancreatic β-cell failure; however, the degree of pancreatic β-cell volume reduction was not severe. METHODS: We induced obesity in Kcnq1ot1 truncation mice by feeding them a high-fat diet and evaluated pancreatic β-cell mass. RESULTS: In the present study, we reveal that CCAAT/enhancer binding protein beta (C/EBPβ), which is expressed at higher levels in pancreatic β-cells in obese individuals, further increases the expression of Cdkn1c, which is upregulated by the Kcnq1 gene mutation. We found that simultaneous Cdkn1c hypomethylation and C/EBPβ overexpression in pancreatic β-cells causes a synergistic decrease in pancreatic β-cell mass. CONCLUSION: This finding suggests that the synergistic effect of genetic factors such as Kcnq1 gene mutations and environmental factors such as obesity and overeating, which lead to increased expression of C/EBPβ, contribute to the regulation of pancreatic β-cell mass. This study is the first to show that the Kcnq1 gene is related to pancreatic β-cell mass through genetic-environment interactions.
• 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. To do so, we used a pull-down assay to identify molecules that competitively inhibit the binding of the T1462 phosphorylation site of TSC2 to 14-3-3. l-asparaginase was identified. Although l-asparaginase is frequently used as an anticancer drug for acute lymphoblastic leukemia, little is known about endogenous l-asparaginase. l-Asparaginase, which is expressed downstream of GCN2, was found to bind 14-3-3 and thereby to inhibit its binding to the T1462 phosphorylation site of TSC2 and contribute to TSC2 activation and mTORC1 inactivation upon TSC2 dephosphorylation. Further investigation of the regulation of mTORC1 activity in pancreatic β-cells by l-asparaginase should help to elucidate the mechanism of diabetes and insulin secretion failure during anticancer drug use.
• 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. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors' protective effect on pancreatic β-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic β-cell protection.
• Association between diabetic nephropathy and left ventricular longitudinal myocardial function in type 1 diabetes mellitus patients with preserved ejection fraction.Left ventricular (LV) longitudinal myocardial dysfunction can be observed even in type 2 diabetes mellitus (DM) (T2DM) patients with preserved LV ejection fraction (LVEF), and is considered the earliest marker of DM-related cardiac dysfunction. Furthermore, diabetic nephropathy (DN), a common complication in DM, is strongly associated with LV longitudinal myocardial function in T2DM patients, but its association with type 1 DM (T1DM) has not been fully investigated. We studied 125 asymptomatic T1DM patients with preserved LVEF, and 75 age-, gender-, LVEF-matched non-diabetic healthy controls. Two-dimensional speckle-tracking strain LV was used to assess longitudinal myocardial function as global longitudinal strain (GLS). GLS of T1DM patients was significantly lower than that of normal controls (19.7 ± 3.6% vs. 20.6 ± 1.8%, P = 0.049). GLS of T1DM patients with DN was significantly lower that of T1DM patients without DN (17.3 ± 3.7% vs. 20.2 ± 3.5%, P

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