TY - JOUR
T1 - Increased expression of GAD65 and GABA in pancreatic β-cells impairs first-phase insulin secretion
AU - Shi, Yuguang
AU - Kanaani, Jamil
AU - Menard-Rose, Virginie
AU - Ma, Yan Hui
AU - Chang, Pi Yun
AU - Hanahan, Douglas
AU - Tobin, Allan
AU - Grodsky, Gerold
AU - Baekkeskov, Steinunn
PY - 2000
Y1 - 2000
N2 - The functional role of glutamate decarboxylase (GAD) and its product GABA in pancreatic islets has remained elusive. Mouse β-cells express the larger isoform GAD67, whereas human islets express only the smaller isoform GAD65. We have generated two lines of transgenic mice expressing human GAD65 in pancreatic β-cells (RIP7-hGAD65, Lines 1 and 2) to study the effect that GABA generated by this isoform has on islet cell function. The ascending order of hGAD65 expression and/or activity in β-cells was Line 1 heterozygotes < Line 2 heterozygotes < Line 1 homozygotes. Line 1 heterozygotes have normal glucose tolerance, whereas Line 1 homozygotes and Line 2 heterozygotes exhibit impaired glucose tolerance and inhibition of insulin secretion in vivo in response to glucose. In addition, fasting levels of blood glucose are elevated and insulin is decreased in Line 1 homozygotes. Pancreas perfusion 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.
AB - The functional role of glutamate decarboxylase (GAD) and its product GABA in pancreatic islets has remained elusive. Mouse β-cells express the larger isoform GAD67, whereas human islets express only the smaller isoform GAD65. We have generated two lines of transgenic mice expressing human GAD65 in pancreatic β-cells (RIP7-hGAD65, Lines 1 and 2) to study the effect that GABA generated by this isoform has on islet cell function. The ascending order of hGAD65 expression and/or activity in β-cells was Line 1 heterozygotes < Line 2 heterozygotes < Line 1 homozygotes. Line 1 heterozygotes have normal glucose tolerance, whereas Line 1 homozygotes and Line 2 heterozygotes exhibit impaired glucose tolerance and inhibition of insulin secretion in vivo in response to glucose. In addition, fasting levels of blood glucose are elevated and insulin is decreased in Line 1 homozygotes. Pancreas perfusion 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.
KW - Glucose intolerance
KW - Neurotransmitter
KW - Pancreas perfusion
KW - Regulation of insulin secretion
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U2 - 10.1152/ajpendo.2000.279.3.e684
DO - 10.1152/ajpendo.2000.279.3.e684
M3 - Article
C2 - 10950838
AN - SCOPUS:0033834685
SN - 0193-1849
VL - 279
SP - E684-E694
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 3 42-3
ER -