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

Naila Rabbani,Paul J Thornalley,Mingzhan Xue

doi:10.3390/ijms23042165

Abstract

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.

Highlights

Human Hexokinase-2—Overview of Molecular Characteristics and Subcellular and Tissue ExpressionHexokinase-2 (HK2; EC:2.7.1.1) is one of four isozymes of hexokinase in mammalian metabolism that catalyze the first step of glucose metabolism, the conversion of glucose to glucose-6-phosphate (G6P): Glucose + MgATP → G6P + MgADP
In studies of metabolic dysfunction supporting dicarbonyl stress induced by high glucose concentrations in human aortic endothelial cells and human periodontal ligament fibroblasts in primary culture, we discovered that the increased glucose metabolism driving metabolic dysfunction in model hyperglycemia was mediated by glucose-induced stabilization of HK2 to proteolysis, producing HK2-linked glycolytic overload [13,17]
This was corrected by off-target effects of glyoxalase 1 (Glo1) inducer, trans-resveratrol, and hesperetin in combination [13,17]. We describe this and evidence that the hypothesis of HK2-linked glycolytic overload and unscheduled glycolysis are likely key initiators of metabolic dysfunction, contributing to the development of vascular complications of diabetes, diabetic embryopathy, and insulin resistance

Summary

Introduction

Human Hexokinase-2—Overview of Molecular Characteristics and Subcellular and Tissue Expression. HK2 is the major isozyme of hexokinase in skeletal muscle and adipose tissue. HK2 has high expression levels in many types of human tumor, together with increased expressions of phosphofructokinase (PFK), other glycolytic enzymes, and glucose-6-phosphate dehydrogenase (G6PD). This supports increased flux through glycolysis for tumor growth without an increase in the intermediates of earlystage glycolysis [9,10]. The promoter of HK2 in tumors is often hypomethylated, which is associated with the dysregulation of transcription—including the direct binding of glucose to increase expression [11,12]. A novel genetic polymorphism of HK2 was found in Pima Indians—a Native American tribe with a high prevalence of T2DM—but it displayed no significant association with risk of T2DM [16]

Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis

Evidence of Hexokinase-2 Linked Glycolytic Overload Occurring at Sites of

Abnormal glycogen deposition in proximal and renal tubules