Yg. Shi et al., Increased expression of GAD65 and GABA in pancreatic beta-cells impairs first-phase insulin secretion, AM J P-ENDO, 279(3), 2000, pp. E684-E694
Citations number
59
Categorie Soggetti
Endocrinology, Nutrition & Metabolism
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
The functional role of glutamate decarboxylase (GAD) and its product GABA i
n pancreatic islets has remained elusive. Mouse beta-cells express the larg
er isoform GAD67, whereas human islets express only the smaller isoform GAD
65. We have generated two lines of transgenic mice expressing human GAD65 i
n pancreatic beta-cells (RIP7-hGAD65, Lines 1 and 2) to study the effect th
at GABA generated by this isoform has on islet cell function. The ascending
order of hGAD65 expression and/or activity in beta-cells was Line 1 hetero
zygotes, Line 2 heterozygotes, Line 1 homozygotes. Line 1 heterozygotes hav
e normal glucose tolerance, whereas Line 1 homozygotes and Line 2 heterozyg
otes exhibit impaired glucose tolerance and inhibition of insulin secretion
in vivo in response to glucose. In addition, fasting levels of blood gluco
se are elevated and insulin is decreased in Line 1 homozygotes. Pancreas pe
rfusion experiments suggest that GABA generated by GAD65 may function as a
negative regulator of first-phase insulin secretion in response to glucose
by affecting a step proximal to or at the K-ATP(+) channel.