Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats

摘要

Objective-impaired glucose counterregulation during hypo-glycemia is well documented in patients with type 1 diabetes; however, the molecular mechanisms underlying this defect remain uncertain. We reported that the inhibitory neurotransmit-ter γ-aminobutyric acid (gaba), in a crucial glucose-sensing region within the brain, the ventromedial hypothalamus (vmh), plays an important role in modulating the magnitude of the glu-cagon and epinephrine responses to hypoglycemia and investigated whether vmh gabaergic tone is altered in diabetes and therefore might contribute to defective counterregulatory responses. Research design and methods-we used immuno-blots to measure gad_(65) protein (a rate-limiting enzyme in gaba synthesis) and microdialysis to measure extracellular gaba levels in the vmh of two diabetic rat models, the diabetic bb rat and the streptozotocin (stz)-induced diabetic rat, and compared them with nondiabetic controls. Results-both diabetic rat models exhibited an -50% increase in gad_(65) protein as well as a twofold increase in vmh gaba levels compared with controls under baseline conditions. Moreover, during hypoglycemia, vmh gaba levels did not change in the diabetic animals, whereas they significantly declined in non-diabetic animals. As expected, glucagon responses were absent and epinephrine responses were attenuated in diabetic rats compared with their nondiabetic control counterparts. The defective counterregulatory response in stz-diabetic animals was restored to normal with either local blockade of gaba_a receptors or knockdown of gad_(65) in the vmh. Conclusions-these data suggest that increased vmh gabaergic inhibition is an important contributor to the absent glucagon response to hypoglycemia and the development of counterregulatory failure in type 1 diabetes. Diabetes 60:1582-1589, 2011