From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

Yang, Jin-Kui; Lü, Jing; Yuan, Sha-Sha; Asan,; Cao, Xi; Qiu, Haiyan; Shi, Tingting; Yang, Fengying; Li, Qian; Liu, Cuiping; Wu, Qian; Wang, Yuhui; Huang, Haixia; Kayoumu, Abudurexiti; Feng, Jiafu; Xie, Ri-hua; Zhu, Xiaozhong; Liu, Chang; Gao, Yang; Zhang, Ming‐Rong; Xie, Conghua; Chen, Chen; Zhang, Bo; Liu, George; Zhang, Xiuqing; Xu, Aimin

doi:10.1016/j.celrep.2018.12.005

Cited by 40 publications

(69 citation statements)

References 44 publications

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“…12 We also found that Kcnh6 knockout (KO) or Kcnh6 p. P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. 12 These data imply that KCNH6 may play an important role in insulin secretion and glucose homeostasis. So, we used the whole-body Kcnh6 knockout model in this study.…”

Section: Discussionmentioning

confidence: 94%

KCNH6 protects pancreatic β‐cells from endoplasmic reticulum stress and apoptosis

Lü

Han

et al. 2020

The FASEB Journal

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Adult patients with dysfunction in human ether-ago go 2 (hERG2) protein, encoded by KCNH6, present with hypoinsulinemia and hyperglycemia. However, the mechanism of KCNH6 action in glucose disorders has not been clearly defined. Previous studies identified that sustained endoplasmic reticulum (ER) stress-mediated apoptosis of pancreatic β-cells and directly contributed to diabetes. In the present study, we showed that Kcnh6 knockout (KO) mice had impaired glucose tolerance mediated by high ER stress levels, and showed increased apoptosis and elevated intracellular calcium levels in pancreatic β-cells. In contrast, KCNH6 overexpression in islets isolated from C57BL/6J mice attenuated ER stress induced by thapsigargin or palmitic acid. This effect contributed to better preservation of β-cells, as reflected in increased β cell survival and enhanced glucose-stimulated insulin secretion. These results were further corroborated by studies evaluating KCNH6 overexpression in KO islets. Similarly, induction of Kcnh6 in KO mice by lentivirus injection improved glucose tolerance by reducing pancreatic ER stress and apoptosis. Our data provide new insights into how Kcnh6 deficiency causes ER calcium depletion and β cell dysfunction.

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Section: Discussionmentioning

confidence: 94%

KCNH6 protects pancreatic β‐cells from endoplasmic reticulum stress and apoptosis

Lü

Han

et al. 2020

The FASEB Journal

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“…Metabolism of glucose depends on a series of electrogenic events including intracellular Ca 2 + influx through the voltage-dependent Ca 2 + channels. In a previous study, we found that intracellular Ca 2 + influx was higher in the Kcnh6 KO mice [17]. Thus, sustained increased cytosolic Ca 2 + induced by the Kcnh6 knockout may be responsible for the ER stress.…”

Section: Discussionmentioning

confidence: 76%

“…Wild-type (Wt) and Kcnh6 knockout mice (KO) were maintained on a C57/BL6 background (Charles River Laboratories China, Beijing, China). Mice with a targeted deletion of Kcnh6 using Transcription activator-like effector nucleases (TALEN) have been previously described [17]. The mice with chow diet were raised in an environment with 45-65 % humidity and 20-24 °C temperature, a 12-hour light/dark cycle, and access to food and water ad libitum.…”

Section: Animals and Treatmentmentioning

confidence: 99%

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Effect of KCNH6 on Hepatic Endoplasmic Reticulum Stress and Glucose Metabolism

Lü

Han

et al. 2020

Horm Metab Res

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Adult patients with a dysfunctional ether-a-go-go 2 (hERG2) protein, which is encoded by the KCNH6 gene, present with hyperinsulinemia and hyperglycemia. However, the mechanism of KCNH6 in glucose metabolism disorders has not been clearly defined. It has been proposed that sustained endoplasmic reticulum (ER) stress is closely concerned with hepatic insulin resistance and inflammation. Here, we demonstrate that Kcnh6 knockout (KO) mice had impaired glucose tolerance and increased levels of hepatic apoptosis, in addition to displaying an increased insulin resistance that was mediated by high ER stress levels. By contrast, overexpression of KCNH6 in primary hepatocytes led to a decrease in ER stress and apoptosis induced by thapsigargin. Similarly, induction of Kcnh6 by tail vein injection into KO mice improved glucose tolerance by reducing ER stress and apoptosis. Furthermore, we show that KCNH6 alleviated hepatic ER stress, apoptosis, and inflammation via the NFκB-IκB kinase (IKK) pathway both in vitro and in vivo. In summary, our study provides new insights into the causes of ER stress and subsequent induction of primary hepatocytes apoptosis.

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“…Furthermore, loss-of-function mutants of the voltage-dependent K+ (Kv) channel KCNH6 plays a role in the modulation of insulin secretion. In a loss-of-function KCNH6 mutant in humans and mice, hyper–insulin secretion was observed initially, followed by subsequent hypo–insulin secretion as a result of overstimulation of insulin secretion; in the long-term, endoplasmic reticulum stress, apoptosis, loss of β-cell mass, and subsequent decreased insulin secretion were observed ( 52 ). These reports suggest that the overstimulation of insulin secretion causes β-cell failure in the long-term, which is in agreement with our results.…”

Section: Discussionmentioning

confidence: 99%

VMAT2 Safeguards β-Cells Against Dopamine Cytotoxicity Under High-Fat Diet–Induced Stress

et al. 2020

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Vesicular monoamine transporter 2 (VMAT2) uptakes cytoplasmic monoamines into vesicles for storage. VMAT2 plays a role in modulating insulin release by regulating dopamine levels in the pancreas, although the exact mechanism remains elusive. We found that VMAT2 expression in β-cells specifically increases under high blood glucose conditions. The islets isolated from β-cell–specific Vmat2 knockout (βVmat2KO) mice show elevated insulin secretion levels in response to glucose stimulation. Under prolonged high-fat diet feedings, the βVmat2KO mice exhibit impaired glucose and insulin tolerance and progressive β-cell dysfunction. Here we demonstrate VMAT2 uptake of dopamine to protect dopamine from degradation by monoamine oxidase, thereby safeguarding β-cells from excess reactive oxygen species (ROS) exposure. In the context of high demand for insulin secretion, the absence of VMAT2 leads to elevated ROS in β-cells, which accelerates β-cell dedifferentiation and β-cell loss. Therefore, VMAT2 controls the amount of dopamine in β-cells, thereby protecting pancreatic β-cells from excessive oxidative stress.

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From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

Cited by 40 publications

References 44 publications

KCNH6 protects pancreatic β‐cells from endoplasmic reticulum stress and apoptosis

KCNH6 protects pancreatic β‐cells from endoplasmic reticulum stress and apoptosis

Effect of KCNH6 on Hepatic Endoplasmic Reticulum Stress and Glucose Metabolism

VMAT2 Safeguards β-Cells Against Dopamine Cytotoxicity Under High-Fat Diet–Induced Stress

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