Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.
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Authors
Chakera, Ali J
Hurst, Paul S
Spyer, Gill
Ogunnowo-Bada, Emmanuel O
Marsh, William J
Riches, Christine H
Yueh, Chen-Yu
Markkula, S Pauliina
Dalley, Jeffrey W
Cox, Roger D
Macdonald, Ian A
Amiel, Stephanie A
MacLeod, Kenneth M
Heisler, Lora K
Hattersley, Andrew T
Evans, Mark L
Publication Date
2018-11Journal Title
Mol Metab
ISSN
2212-8778
Publisher
Elsevier BV
Volume
17
Pages
17-27
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Chakera, A. J., Hurst, P. S., Spyer, G., Ogunnowo-Bada, E. O., Marsh, W. J., Riches, C. H., Yueh, C., et al. (2018). Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.. Mol Metab, 17 17-27. https://doi.org/10.1016/j.molmet.2018.08.001
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.
Keywords
Animals, Mice, Inbred BALB C, Humans, Mice, Diabetes Mellitus, Hyperinsulinism, Hypoglycemia, Disease Models, Animal, Epinephrine, Glucagon, Insulin, Glucokinase, Glucose, Blood Glucose, Hypoglycemic Agents, Glucose Clamp Technique, Adult, Middle Aged, Female, Male, Insulin-Secreting Cells
Sponsorship
Yousef Jameel Fund
Sir Jukes Thorn Trust
Elmore Fund
Chang Gung University College of Medicine
Funder references
Sir Jules Thorn Charitable Trust (unknown)
Diabetes Research & Wellness Foundation (DRWF) (DRWF/MO/STUDENTSHIP/2005)
Juvenile Diabetes Research Foundation Ltd (JDRF) (1-2006-29)
Diabetes UK (BDA:RD05/0003059)
Wellcome Trust (100574/Z/12/Z)
Diabetes UK (None)
Wellcome Trust (089942/Z/09/A)
Medical Research Council (G1000183)
Wellcome Trust (093875/Z/10/Z)
Wellcome Trust (098012/Z/11/Z)
Identifiers
External DOI: https://doi.org/10.1016/j.molmet.2018.08.001
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279641
Rights
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/
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