Cargando…

Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes

The 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 increa...

Descripción completa

Detalles Bibliográficos
Autores principales: Rabbani, Naila, Xue, Mingzhan, Thornalley, Paul J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877341/
https://www.ncbi.nlm.nih.gov/pubmed/35216280
http://dx.doi.org/10.3390/ijms23042165
_version_ 1784658397570793472
author Rabbani, Naila
Xue, Mingzhan
Thornalley, Paul J.
author_facet Rabbani, Naila
Xue, Mingzhan
Thornalley, Paul J.
author_sort Rabbani, Naila
collection PubMed
description The 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—trans-resveratrol 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 tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes.
format Online
Article
Text
id pubmed-8877341
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-88773412022-02-26 Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes Rabbani, Naila Xue, Mingzhan Thornalley, Paul J. Int J Mol Sci Review The 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—trans-resveratrol 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 tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes. MDPI 2022-02-16 /pmc/articles/PMC8877341/ /pubmed/35216280 http://dx.doi.org/10.3390/ijms23042165 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Rabbani, Naila
Xue, Mingzhan
Thornalley, Paul J.
Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes
title Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes
title_full Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes
title_fullStr Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes
title_full_unstemmed Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes
title_short Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes
title_sort hexokinase-2-linked glycolytic overload and unscheduled glycolysis—driver of insulin resistance and development of vascular complications of diabetes
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877341/
https://www.ncbi.nlm.nih.gov/pubmed/35216280
http://dx.doi.org/10.3390/ijms23042165
work_keys_str_mv AT rabbaninaila hexokinase2linkedglycolyticoverloadandunscheduledglycolysisdriverofinsulinresistanceanddevelopmentofvascularcomplicationsofdiabetes
AT xuemingzhan hexokinase2linkedglycolyticoverloadandunscheduledglycolysisdriverofinsulinresistanceanddevelopmentofvascularcomplicationsofdiabetes
AT thornalleypaulj hexokinase2linkedglycolyticoverloadandunscheduledglycolysisdriverofinsulinresistanceanddevelopmentofvascularcomplicationsofdiabetes