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.