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AuthorRabbani, Naila
AuthorXue, Mingzhan
AuthorThornalley, Paul J.
Available date2023-10-11T09:28:39Z
Publication Date2022-02-16
Publication NameInternational Journal of Molecular Sciences
Identifierhttp://dx.doi.org/10.3390/ijms23042165
CitationRabbani, N., Xue, M., & Thornalley, P. J. (2022). Hexokinase-2-linked glycolytic overload and unscheduled glycolysis—Driver of insulin resistance and development of vascular complications of diabetes. International Journal of Molecular Sciences, 23(4), 2165.
ISSN1661-6596
URIhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85124607139&origin=inward
URIhttp://hdl.handle.net/10576/48444
AbstractThe recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose metabolism without a change in the expression and activity of glycolytic enzymes produces a wave of increased glycolytic intermediates driving mitochondrial dysfunction and increased reactive oxygen species (ROS) formation, the activation of hexosamine and protein kinase C pathways, the increased formation of methylglyoxal-producing dicarbonyl stress, and the activation of the unfolded protein response. This is called HK2-linked glycolytic overload and unscheduled glycolysis. The conditions required to sustain this are GLUT1 and/or GLUT3 glucose uptake and the expression of HK2. A metabolic biomarker of its occurrence is the abnormally increased deposition of glycogen, which is produced by metabolic channeling when HK2 becomes detached from mitochondria. These conditions and metabolic consequences are found in the vasculature, kidneys, retina, peripheral nerves, and early-stage embryo development in diabetes and likely sustain the development of diabetic vascular complications and embryopathy. In insulin resistance, HK2-linked unscheduled glycolysis may also be established in skeletal muscle and adipose tissue. This may explain the increased glucose disposal by skeletal uptake in the fasting phase in patients with type 2 diabetes mellitus, compared to healthy controls, and the presence of insulin resistance in patients with type 1 diabetes mellitus. Importantly, glyoxalase 1 inducer—transresveratrol and hesperetin in combination (tRES-HESP)—corrected HK2-linked glycolytic overload and unscheduled glycolysis and reversed insulin resistance and improved vascular inflammation in overweight and obese subjects in clinical trial. Further studies are now required to evaluate tRESHESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes.
SponsorThis research was funded by the Qatar Foundation, grant number QB14 (PJT) and Qatar University, grant number QU ERG-CMED-2020-1 (NR).
Languageen
PublisherMultidisciplinary Digital Publishing Institute (MDPI)
SubjectDiabetes
Diabetic complications
Glycolysis
Glyoxalase 1
Hexokinase-2
Hyperglycemia
Insulin resistance
Methylglyoxal
TitleHexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes
TypeArticle
Issue Number4
Volume Number23
ESSN1422-0067
dc.accessType Open Access


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