Deficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders

Yao Xiao,Liangyi Chen,Yuli Liu,Kunfu Ouyang,Ju Chen,Yi Ding,Can Wang,Yulin Zhang,Wenzhen Zhu,Chensheng Han,Fanxin Zeng,Dongwei Ma,Chuan-Yun Li,Xueting Sun,Yan Zhang,Xiaomin Hu,Wen Zheng,Haibao Shang,Ning Hou,Fujian Lu,Jue Wang,Jiayu Chen ,Rui‐Ping Xiao ,Xiuqin Zhang

doi:10.1038/s41467-018-04352-z

Yao Xiao, Liangyi Chen + Show 22 more

Open Access

https://doi.org/10.1038/s41467-018-04352-z

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Abstract

Hyperinsulinemia is the earliest symptom of insulin resistance (IR), but a causal relationship between the two remains to be established. Here we show that a protein kinase D2 (PRKD2) nonsense mutation (K410X) in two rhesus monkeys with extreme hyperinsulinemia along with IR and metabolic defects by using extreme phenotype sampling and deep sequencing analyses. This mutation reduces PRKD2 at both the mRNA and the protein levels. Taking advantage of a PRKD2-KO mouse model, we demonstrate that PRKD2 deletion triggers hyperinsulinemia which precedes to IR and metabolic disorders in the PRKD2 ablation mice. PRKD2 deficiency promotes β-cell insulin secretion by increasing the expression and activity of L-type Ca2+ channels and subsequently augmenting high glucose- and membrane depolarization-induced Ca2+ influx. Altogether, these results indicate that down-regulation of PRKD2 is involved in the pathogenesis of hyperinsulinemia which, in turn, results in IR and metabolic disorders.

Highlights

Hyperinsulinemia is the earliest symptom of insulin resistance (IR), but a causal relationship between the two remains to be established
As a model species closely related to humans, the rhesus monkey presents a unique model to study complex metabolic diseases, due to its human-like genome, the controllability of environmental factors, as well as the feasibility of real-time monitoring of the metabolic phenotypes
Through the combination of primate-based extreme phenotype sampling and mice model-based verification, we reveal that mutation of protein kinase D2 (PRKD2) is involved in the pathogenesis of hyperinsulinemia which, in turn, results in IR and metabolic disorders

Summary

Introduction

Hyperinsulinemia is the earliest symptom of insulin resistance (IR), but a causal relationship between the two remains to be established. Nonsense mutation (K410X) in two rhesus monkeys with extreme hyperinsulinemia along with IR and metabolic defects by using extreme phenotype sampling and deep sequencing analyses. This mutation reduces PRKD2 at both the mRNA and the protein levels. PRKD2 deficiency promotes β-cell insulin secretion by increasing the expression and activity of L-type Ca2+ channels and subsequently augmenting high glucose- and membrane depolarization-induced Ca2+ influx. These results indicate that down-regulation of PRKD2 is involved in the pathogenesis of hyperinsulinemia which, in turn, results in IR and metabolic disorders. Identification and characterization of pathogenic factors and signaling pathways are needed urgently to cope with the increasingly prevalent cardiometabolic disease

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Conclusion