Glutamate decarboxylase and GABA in pancreatic islets: lessons from knock-out mice.
The GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) is expressed in pancreatic beta-cells and GABA has been suggested to play a role in islet cell development and function. Mouse beta-cells predominantly express the larger isoform of the enzyme, GAD67, and very low levels of the second isoform, GAD65. Yet GAD65 has been shown to be a target of very early autoimmune T-cell responses associated with beta-cell destruction in the non-obese diabetic (NOD) mouse model of Type 1 diabetes. Mice deficient in GAD67, GAD65 or both were used to assess whether GABA is important for islet cell development, and whether GAD65 is required for initiation of insulitis and progression to Type 1 diabetes in the mouse. Lack of either GAD65 or GAD67 did not effect the development of islet cells and the general morphology of islets. When GAD65-/-(129/Sv) mice were backcrossed into the NOD strain for four generations, GAD65-deficient mice developed insulitis similar to GAD65+/+ mice. Furthermore, at the low penetrance of diabetes in this backcross, GAD65-deficient mice developed disease at the same rate and incidence as wildtype mice. The results suggest that GABA generated by either GAD65 or GAD67 is not critically involved in islet formation and that GAD65 expression is not an absolute requirement for development of autoimmune diabetes in the NOD mouse.
Kash
S F
SF
Department of Medicine, and Hormone Research Institute, University of California San Francisco, 94143-0534, USA.
Condie
B G
BG
Baekkeskov
S
S
D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D007527:Isoenzymes; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase