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Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan.

ABSTRACT: Context:Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects. Purpose:The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations. Methods:We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m2) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin ?15 µU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia. Results:The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11). Conclusions:To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia.

SUBMITTER: Fujita S

PROVIDER: S-EPMC5686598 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan.

Fujita Shingo S Kuroda Yohei Y Fukui Kenji K Iwamoto Ryuya R Kozawa Junji J Watanabe Takehiko T Yamada Yuya Y Imagawa Akihisa A Iwahashi Hiromi H Shimomura Iichiro I

Journal of the Endocrine Society 20171012 11

<h4>Context</h4>Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyper ...[more]

PMID: 29264459

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Project description:BackgroundDysfunctional adipose tissue plays an important role in the etiology of the metabolic syndrome, type 2 diabetes, and dyslipidemia. However, the molecular mechanisms underlying adipocyte dysfunction are incompletely understood.AimThe aim of the study was to identify differentially regulated pathways in sc adipocytes of dyslipidemic subjects.MethodsWhole-genome expression profiling was conducted on sc adipocytes from a discovery group of nine marginally overweight subjects with familial combined hyperlipidemia (FCHL) and nine controls of comparable body sizes as well as two independent confirmation groups. In this study, FCHL served as a model of familial insulin resistance and dyslipidemia, in the absence of frank obesity.ResultsFunctional analyses and gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes or a custom pathway database identified the complement system and complement regulators as one of the top up-regulated pathways in FCHL [false discovery rate (FDR) < 1E-30]. Higher adipocyte complement expression in FCHL was confirmed in the appropriate confirmation group. Higher complement gene expression was associated with lower adipocyte insulin receptor substrate-1 expression as marker of adipocyte insulin resistance, independent of age, sex, or disease status, and this association was corroborated in the two confirmation groups. Additionally, complement gene expression was associated with triglycerides in the discovery set and with triglycerides and/or waist circumference in the confirmation groups. Complement pathway up-regulation did not appear to be driven by hypertriglyceridemia because a 40% pharmacological reduction in triglycerides did not affect complement expression.ConclusionsThese findings point to an up-regulation of a complement-related transcriptome in sc adipocytes under metabolically stressed conditions, even in the absence of overt obesity. Such up-regulation may subsequently influence downstream processes, including macrophage infiltration into adipose tissue and adipocyte insulin resistance.

Dataset Information

Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan.

Publications

Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan.

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