1. Zinc-induced activation of GPR39 regulates glucose homeostasis through glucose-dependent insulinotropic polypeptide secretion from enteroendocrine K-cells
- Author
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Aine McKillop, Peter R. Flatt, Brian M Moran, Yasser Abdel-Wahab, and Michael G Miskelly
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Chemistry ,Insulin ,medicine.medical_treatment ,Clinical Biochemistry ,Incretin ,030209 endocrinology & metabolism ,Enteroendocrine cell ,medicine.disease ,Biochemistry ,Glucagon ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Knockout mouse ,medicine ,Glucose homeostasis ,Receptor ,Molecular Biology - Abstract
The role of Zn2+-sensing receptor GPR39 on glucose homeostasis and incretin regulation was assessed in enteroendocrine L- and K-cells. Anti-hyperglycaemic, insulinotropic and incretin secreting properties of Zn2+ were explored in normal, diabetic and incretin receptor knockout mice. Compared to intraperitoneal injection, oral administration of Zn2+ (50 μmol/kg body weight) with glucose (18 mmol/kg) in lean mice reduced the glycaemic excursion by 25–34% (p p p p 2+ lowered glucose by 24–31% (p p 2+ reduced glucose by 15–28% (p p p 2+ had no effect on responses of glucose-dependent insulinotropic polypeptide (GIP) receptor knockout mice. Consistent with this, Zn2+ had no effect on circulating total GLP-1 whereas GIP release was stimulated by 26% (p 2+ had a direct effect on GIP secretion from pGIPneo STC-1 cells, increasing GIP secretion by 1.3-fold. GPR39 is expressed on intestinal L- and K-cells, and stimulated GIP secretion plays an integral role in mediating enhanced insulin secretion and glucose tolerance following oral administration of Zn2+. This suggests development of potent and selective GPR39 agonists as a therapeutic approach for diabetes.
- Published
- 2019
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