Discrete brain areas, including hypothalamic nuclei, have been implicated in glucose homeostasis. Some contain molecular machinery capable of detecting changes in blood glucose such as glucokinase (GK) , a low affinity hexokinase important for pancreatic beta cell glucose-sensing. A subset of arcuate nucleus AGRP neurons express GK. We created GKAGRP knockout (KO) mice by crossing AGRP Cre with GK floxed mice, hypothesizing that they would display impaired gluco-regulation. Despite established sex differences in metabolic neurocircuitry, female mice are not always studied. In pilots, we found impaired glucose handling in i.p. glucose tolerance tests in older GKAGRP KO females, but not younger female, nor male mice. Here, we perform detailed phenotyping, using sequential euglycemic (with stable glucose isotope tracers) and hyperglycemic clamp studies in conscious, free moving, 19-23 week old female mice with implanted carotid artery and jugular vein catheters. As shown below, we found that GKAGRP KO females were insulin resistant with a lower dextrose infusion rate and reduced suppression of hepatic glucose production during euglycemic clamps. They also displayed reduced insulin secretory responses during hyperglycemic clamps. Our data support a sexually-dimorphic central gluco-regulatory role for AGRP neurons which requires the presence of GK to facilitate normal insulin release and action.
M.Josipovic: Research Support; Novo Nordisk A/S. E.O.Staricoff: Research Support; Novo Nordisk A/S. C.H.Riches: Research Support; Novo Nordisk. L.Sheppard: None. M.Evans: Advisory Panel; Pila Pharma, Zucara Therapeutics, Other Relationship; Abbott Diabetes, Dexcom, Inc., Medtronic, Novo Nordisk, Research Support; AstraZeneca, Sanofi, Speaker’s Bureau; Lilly Diabetes.
European Union’s Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777460) also supported by EFPIA, T1D Exchange, JDRF, International Diabetes Federation (IDF) , The Leona M. and Harry B. Helmsley Charitable Trust, Wellcome Trust, Medical Research Council UK and Gates Cambridge Trust.