The response of glucose-excited neurones in the ventromedial hypothalamus to decreased glucose is enhanced in a murine model of type 2 diabetes mellitus.
Obesity and type 2 diabetes mellitus (T2DM) are associated with dysfunctional insulin signalling and impaired central glucose sensing. Glucose sensing neurones reside in key areas of the brain involved in glucose and energy homeostasis (e.g. ventromedial hypothalamus; VMH). We have recently shown that insulin attenuates the ability of glucose-excited (GE) neurones to sense decreased glucose. We hypothesise that this effect of insulin on VMH GE neurones is impaired during T2DM when insulin signalling is dysfunctional. To test our hypotheses, we used whole cell patch clamp recording techniques to evaluate the effects of insulin on VMH GE neurones in brain slices from wild-type and diabetic (db/db) mice. The effects of decreasing glucose from 2.5 to 0.1 mM on VMH GE neurones were similar in wild-type and db/db mice. However, decreasing glucose from 2.5 to 0.5 mM decreased the action potential frequency, membrane potential and input resistance of VMH GE neurones to a significantly greater extent in db/db versus wild-type mice. Furthermore, insulin (5 nM) blunted the effects of decreased glucose in wild-type, but not db/db mice. These differences in both glucose and insulin sensitivity between wild-type and db/db mice were completely ameliorated by the insulin sensitiser, Compound 2 (300 nM). These data are consistent with our hypothesis that impaired insulin signalling in T2DM sensitises VMH GE neurones to decreased glucose.
Cotero
V E
VE
Department of Pharmacology and Physiology, New Jersey Medical School (UMDNJ), Newark, NJ, USA.
Zhang
B B
BB
Routh
V H
VH
D000199:Actins / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology*
D000199:Actins; D007328:Insulin; D005947:Glucose