Deficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Nature communications - 9(2018), 1 vom: 22. Mai, Seite 2015 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xiao, Yao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.12.2018 Date Revised 22.05.2019 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-018-04352-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM284353884 |
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| 100 | 1 | |a Xiao, Yao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Deficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 11.12.2018 | ||
| 500 | |a Date Revised 22.05.2019 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Calcium Channels, L-Type |2 NLM | |
| 650 | 7 | |a Codon, Nonsense |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a DNA-Activated Protein Kinase |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a PRKDC protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Glucose |2 NLM | |
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| 650 | 7 | |a Calcium |2 NLM | |
| 650 | 7 | |a SY7Q814VUP |2 NLM | |
| 700 | 1 | |a Wang, Can |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jia-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Fujian |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jue |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Xiaomin |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Fanxin |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Dongwei |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xueting |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yuli |e verfasserin |4 aut | |
| 700 | 1 | |a Shang, Haibao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Wenzhen |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Chensheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yulin |e verfasserin |4 aut | |
| 700 | 1 | |a Ouyang, Kunfu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Liangyi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ju |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Rui-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chuan-Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiuqin |e verfasserin |4 aut | |
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