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Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes.

ABSTRACT: Type 2 diabetes (T2D) is one of the most escalating global metabolic diseases, which is highly associated with insulin resistance (IR) and risk of combination with nonalcoholic fatty liver disease (NAFLD). Previous studies suggest that soluble klotho (sKL) could serve as a circulating hormone to mediate energy metabolism, but the detailed mechanism is poorly understood. In this study, we generated T2D models of wild-type (WT), sKL heterozygous (KL +/-), and sKL transgenic (TgKL) mice continuously fed a high-fat diet (HFD) and constructed L02 cell lines that stably overexpress sKL to investigate the effect of sKL on hepatic glucose and lipid metabolism. Surprisingly, we discovered that sKL deficiency resulted in exacerbated diabetic phenotypes and hepatic glucolipid metabolism disorders in HFD-fed KL +/- diabetic mice (KL +/- DM), whereas TgKL diabetic mice (TgKL DM) exhibited ameliorated diabetic phenotypes and decreased IR. Mechanistic studies in vitro and in vivo demonstrated that sKL could inhibit the PI3K/AKT/mTORC1 signaling to upregulate peroxisome proliferator-activated receptor ? (PPAR?) expression by directly interacting with type 1 insulin-like growth factor receptor (IGF1R) in HFD-fed T2D mice. Thus, sKL could improve hepatic glucolipid homeostasis to ameliorate diabetic phenotypes and lipid accumulation and may function as a potential therapeutic target for the treatment of T2D and reduce the risk of NAFLD.

SUBMITTER: Gu H

PROVIDER: S-EPMC7479259 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes.

Gu Huiying H Jiang Wei W You Nan N Huang Xiaobing X Li Yuming Y Peng Xuehui X Dong Rui R Wang Zheng Z Zhu Yinan Y Wu Ke K Li Jing J Zheng Lu L

Molecular therapy. Methods & clinical development 20200805

Type 2 diabetes (T2D) is one of the most escalating global metabolic diseases, which is highly associated with insulin resistance (IR) and risk of combination with nonalcoholic fatty liver disease (NAFLD). Previous studies suggest that soluble klotho (sKL) could serve as a circulating hormone to mediate energy metabolism, but the detailed mechanism is poorly understood. In this study, we generated T2D models of wild-type (WT), sKL heterozygous (KL +/-), and sKL tr ...[more]

PMID: 32953932

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Project description:Aims/hypothesisRecovering functional beta cell mass is a promising approach for future diabetes therapies. The aim of the present study is to investigate the effects of adjudin, a small molecule identified in a beta cell screen using zebrafish, on pancreatic beta cells and diabetes conditions in mice and human spheroids.MethodsIn zebrafish, insulin expression was examined by bioluminescence and quantitative real-time PCR (qPCR), glucose levels were examined by direct measurements and distribution using a fluorescent glucose analogue, and calcium activity in beta cells was analysed by in vivo live imaging. Pancreatic islets of wild-type postnatal day 0 (P0) and 3-month-old (adult) mice, as well as adult db/db mice (i.e. BKS(D)-Leprdb/JOrlRj), were cultured in vitro and analysed by qPCR, glucose stimulated insulin secretion and whole mount staining. RNA-seq was performed for islets of P0 and db/db mice. For in vivo assessment, db/db mice were treated with adjudin and subjected to analysis of metabolic variables and islet cells. Glucose consumption was examined in primary human hepatocyte spheroids.ResultsAdjudin treatment increased insulin expression and calcium response to glucose in beta cells and decreased glucose levels after beta cell ablation in zebrafish. Adjudin led to improved beta cell function, decreased beta cell proliferation and glucose responsive insulin secretion by decreasing basal insulin secretion in in vitro cultured newborn mouse islets. RNA-seq of P0 islets indicated that adjudin treatment resulted in increased glucose metabolism and mitochondrial function, as well as downstream signalling pathways involved in insulin secretion. In islets from db/db mice cultured in vitro, adjudin treatment strengthened beta cell identity and insulin secretion. RNA-seq of db/db islets indicated adjudin-upregulated genes associated with insulin secretion, membrane ion channel activity and exocytosis. Moreover, adjudin promoted glucose uptake in the liver of zebrafish in an insulin-independent manner, and similarly promoted glucose consumption in primary human hepatocyte spheroids with insulin resistance. In vivo studies using db/db mice revealed reduced nonfasting blood glucose, improved glucose tolerance and strengthened beta cell identity after adjudin treatment.Conclusions/interpretationAdjudin promoted functional maturation of immature islets, improved function of dysfunctional islets, stimulated glucose uptake in liver and improved glucose homeostasis in db/db mice. Thus, the multifunctional drug adjudin, previously studied in various contexts and conditions, also shows promise in the management of diabetic states.Data availabilityRaw and processed RNA-seq data for this study have been deposited in the Gene Expression Omnibus under accession number GSE235398 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235398 ).

Dataset Information

Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes.

Publications

Soluble Klotho Improves Hepatic Glucose and Lipid Homeostasis in Type 2 Diabetes.

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