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Published on: November 11, 2022
Cisapride induced hypoglycemia via the KCNH6 potassium channel
Jing Lu1, Ting-Ting Shi1, Sha-Sha Yuan1,2
1Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Abstract:
Mutations in KCNH6 has been proved to cause hypoinsulinemia and diabetes in human and mice. Cisapride is a stomach-intestinal motility drug used to treat gastrointestinal dysfunction. Cisapride has been reported to be a potential inhibitor of the KCNH family, but it remained unclear whether cisapride inhibited KCNH6. Here, we discovered the role of cisapride on glucose metabolism, focusing on the KCNH6 potassium channel protein. Cisapride reduced blood glucose level and increased serum insulin secretion in wild-type (WT) mice fed standard normal chow/a high-fat diet or in db/db mice, especially when combined with tolbutamide. This effect was much stronger after 4 weeks of intraperitoneal injection. Whole-cell patch-clamp showed that cisapride inhibited KCNH6 currents in transfected HEK293 cells in a concentration-dependent manner. Cisapride induced an increased insulin secretion through the disruption of intracellular calcium homeostasis in a rat pancreatic β-cell line, INS-1E. Further experiments revealed that cisapride did not decrease blood glucose or increase serum insulin in KCNH6 β-cell knockout (Kcnh6-β-KO) mice when compared with WT mice. Cisapride also ameliorated glucose-stimulated insulin secretion (GSIS) in response to high glucose in WT but not Kcnh6-β-KO mice. Thus, our data reveal a novel way for the effect of KCNH6 in cisapride-induced hypoglycemia.
Insights
Cisapride, a motility drug, lowers blood glucose and boosts insulin by inhibiting the KCNH6 channel, particularly in KCNH6-expressing cells. This reveals KCNH6
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Mutations in KCNH6 are linked to hypoinsulinemia and diabetes.
- Cisapride, a gastrointestinal drug, may inhibit KCNH family channels, but its effect on KCNH6 was unknown.
Purpose of the Study:
- To investigate the role of cisapride on glucose metabolism via the KCNH6 potassium channel.
- To determine if cisapride affects KCNH6 channel activity and insulin secretion.
Main Methods:
- Whole-cell patch-clamp electrophysiology in HEK293 cells expressing KCNH6.
- In vivo studies using wild-type (WT), db/db, and KCNH6 β-cell knockout (Kcnh6-β-KO) mice.
- Insulin secretion assays in INS-1E rat pancreatic β-cell line.
Main Results:
- Cisapride reduced blood glucose and increased serum insulin in WT and db/db mice, an effect potentiated by tolbutamide and prolonged administration.
- Cisapride inhibited KCNH6 currents concentration-dependently in vitro.
- Cisapride-induced insulin secretion and improved glucose-stimulated insulin secretion (GSIS) were dependent on KCNH6 expression in pancreatic β-cells, as these effects were absent in Kcnh6-β-KO mice.
Conclusions:
- Cisapride's glucose-lowering and insulin-stimulating effects are mediated through the inhibition of the KCNH6 potassium channel.
- KCNH6 plays a crucial role in regulating insulin secretion and glucose homeostasis in response to cisapride.
- These findings identify a novel mechanism for cisapride's action in glucose metabolism, highlighting KCNH6 as a potential therapeutic target.
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