Effects on pancreas alpha and beta cell composition and glutamate decarboxylase expression due to lack of functional GABAB receptors

CRIVELLO M; BONAVENTURA MM; BETTLER B; LIBERTUN C; LUX LANTOS V

Boston

Congreso; ENDO 2011; 2011

The Endocrine Society

Effects on pancreas alpha and beta cell composition and glutamate decarboxylase expression due to lack of functional GABAB receptors   Martín Crivello(1), María Marta Bonaventura(1), Bernhard Bettler (2), Carlos Libertun(1,3) and Victoria Lux-Lantos(1). (1)Neuroendocrinology Laboratory, IBYME-CONICET. (2)University of Basel, Basel, Switzerland. (3)School of Medicine, University of Buenos Aires, Argentina.     crivello@dna.uba.ar   We have previously shown that GABA participates, through GABAB receptors (GABABRs), in the regulation of glucose homeostasis. Mice with a deletion of GABABRs (GABAB1KO), present a prediabetic condition, with insulin resistance and high islet insulin content (1). Since GABABRs have been demonstrated to regulate cell proliferation in the central nervous system (2), here we studied islet cell composition (alpha and beta cells) in GABAB1KO and wild-type (WT) adult mice by immunohistochemistry. In addition, we have shown that the absence of functional GABABRs induced an increased expression of the GABA synthesis rate limiting enzyme in the hypothalamus, glutamate decarboxylase (GAD) (3). Here we determined GAD expression by immunohistochemistry in pancreas of adult WT and GABAB1KO mice of both sexes. Islet number per pancreas area did not differ between sexes or genotypes (ANOVA: ns). Islet area was significantly larger in males (M) than in females (F), without differences due to genotype [islet area (um2): WT M: 8632.9±1422.1, GABAB1KO M: 6889.4±1209.7, WT F: 5354.3±681.3, GABAB1KO F: 4532.5±574.3; two-way ANOVA: interaction: ns, sex: p<0.01, genotype: ns]. Average alpha cell area per islet area was significantly decreased in GABAB1KO mice with regards to WTs and was larger in females than in males [alpha area / islet area (%): WT M: 19.0±1.6, GABAB1KO M: 15.9±0.8, WT F: 25.6±3.3, GABAB1KO F: 18.7±0.9; two-way ANOVA: interaction: ns, sex: p<0.02, genotype: p<0.02]. Average beta cell area per islet increased in GABAB1KO and was larger in males with regard to females [beta area / islet area (%): WT M: 81.05±1.6, GABAB1KO M: 84.13±0.8, WT F: 74.35±3.3, GABAB1KO F: 81.24±0.9; two-way ANOVA: interaction: ns, sex: p<0.02, genotype: p<0.02]. GAD positive area per islet was increased in GABAB1KO islets in relation to WT, and was larger in males than in females [GAD area/islet (%): WT M: 35.6±2.2, GABAB1KO M: 39.0±1.2, WT F: 29.3±2.5, GABAB1KO F: 35.0±1.5; two-way ANOVA: interaction: ns, genotype: p<0.04, sex: p<0.02]. We conclude that the absence of functional GABABRs alters the islet?s cell composition, with an increase of beta cell area at the expense of alpha cell area in GABAB1KO mice. In addition, an increase in GAD expression was observed in GABAB1KO mice, in agreement with what was observed previously in the hypothalamus of these mice. These changes may contribute to the alterations in glucose homeostasis regulation observed in GABAB1KO mice.   Supported by grants from CONICET (PIP 363 2010); ANPCyT (BID PICT 2006 Nº00200 and BID PICT 2007 Nº 01050) and Universidad de Buenos Aires (ME 038).   References      1.   Bonaventura MM, Catalano PN, Chamson-Reig A, Arany E, Hill D, Bettler B, Saravia F, Libertun C, Lux-Lantos VA 2008 GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice. Am J Physiol Endocrinol Metab 294:E157-E167    2.   Magnaghi V, Ballabio M, Cavarretta IT, Froestl W, Lambert JJ, Zucchi I, Melcangi RC 2004 GABAB receptors in Schwann cells influence proliferation and myelin protein expression. Eur J Neurosci 19:2641-2649    3.   Catalano PN, Di Giorgio N, Bonaventura MM, Bettler B, Libertun C, Lux-Lantos VA 2010 Lack of functional GABA(B) receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain. Am J Physiol Endocrinol Metab 298:E683-E696