Effects of GABAB receptor agonists and antagonists on glycemia regulation in mice.
γ-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic β-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2-hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2-hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose-induced insulin secretion and this effect was reversed by coincubation with 1.10(-5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs.
Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
María M
MM
Bonaventura
Martín
M
Crivello
María Laura
ML
Ferreira
Martín
M
Repetto
Cora
C
Cymeryng
Carlos
C
Libertun
Victoria A
VA
Lux-Lantos
D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001481:Basal Metabolism / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D001786:Blood Glucose; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D007328:Insulin; D021122:Protein Subunits; D012333:RNA, Messenger; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; C057491:2-hydroxysaclofen