Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes

Ali J. Chakera, Paul S. Hurst, Gill Spyer, Emmanuel O. Ogunnowo-Bada, William J. Marsh, Christine H. Riches, Chen-Yu Yueh, S.Pauliina Markkula, Jeffrey W. Dalley, Roger D. Cox, Ian A. Macdonald, Stephanie A. Amiel, Kenneth M. MacLeod, Lora K. Heisler, Andrew T. Hattersley, Mark L. Evans

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Abstract

Objective
Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses.

Methods
Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase.

Results
GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated β-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in β-cells. For epinephrine, we found increased responses in GCK-MODY patients, in β-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release.

Conclusions
Our data suggest that glucokinase in brain and other non β-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.
Original languageEnglish
Pages (from-to)17-27
Number of pages11
JournalMolecular Metabolism
Volume17
Early online date13 Aug 2018
DOIs
Publication statusPublished - Nov 2018

Keywords

  • Glucokinase
  • Hypoglycemia
  • Counter-regulation
  • Glucagon
  • Epinephrine
  • Insulin clamp
  • Maturity Onset Diabetes of Young (MODY)
  • β-cells
  • ARC
  • Arcuate nucleus
  • GE
  • Glucose excited
  • GI
  • Glucose inhibited
  • GCK
  • HOM
  • Homozygous
  • HET
  • Heterozygous
  • STZ
  • Streptozotocin
  • VMN
  • Ventromedial hypothalamus
  • WT
  • Wild type

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  • Cite this

    Chakera, A. J., Hurst, P. S., Spyer, G., Ogunnowo-Bada, E. O., Marsh, W. J., Riches, C. H., Yueh, C-Y., Markkula, S. P., Dalley, J. W., Cox, R. D., Macdonald, I. A., Amiel, S. A., MacLeod, K. M., Heisler, L. K., Hattersley, A. T., & Evans, M. L. (2018). Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes. Molecular Metabolism, 17, 17-27. https://doi.org/10.1016/j.molmet.2018.08.001