Premium
Muscarinic agonist carbachol restores insulin secretion and abolishes type 2 diabetes‐like condition in Wolframin1 deficient mice in glucose tolerance test
Author(s) -
Loomets Maarja,
Reimets Riin,
Plaas Mario,
Vasar Eero
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.734.7
Subject(s) - endocrinology , medicine , carbachol , muscarinic acetylcholine receptor , muscarinic agonist , diabetes mellitus , insulin , type 2 diabetes , agonist , impaired glucose tolerance , chemistry , biology , receptor
Mutations in WFS1 gene cause autosomal recessive disorder Wolfram syndrome (WS). One of the first hallmarks of WS is diabetes mellitus. Impairment of glucose metabolism is also present in Wfs1‐deficient mice. While homozygous mutations in Wfs1 cause WS, GWAS studies have shown that heterozygous Wfs1 mutation carriers have increased risk for development of type 2 diabetes. Therefore, in this study, first and second phase insulin secretion was investigated, using glucose tolerance test, muscarinic receptor agonist carbachol and ELISA. Intracellular calcium measurements in single beta‐cells were performed, using cell permeant calcium indicator Fluo‐4 AM. Results of study show that impaired insulin secretion can be managed by evoking insulin release via muscarinic pathway, using carbachol. Although there seems not to be notable differences in the second phase insulin secretion between wild‐type and heterozygous littermates, first phase secretion in heterozygous animals is delayed and this deficit is possibly related to the delayed calcium response in beta‐cells. Altogether, these results show that Wfs1 mutations cause impairment of insulin release in heterozygous animals, the first definite hallmark of type 2 diabetes.