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

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.

Methylglyoxal and glyoxalase 1—a metabolic stress pathway-linking hyperglycemia to the unfolded protein response and vascular complications of diabetes

“…This revealed that the increased concentration of triosephosphates and formation of MG is not produced by inhibition of glyceraldehyde-3-phosphate dehydrogenase, as was proposed earlier [ 1 ], but rather by increased dysregulated or ‘unscheduled’ early-stage glycolysis arising from increased accumulation and activity of hexokinase-2 (HK2) without similar change in activity of other glycolytic enzymes [ 18 , 20 ]. This produces a wave of increased glycolytic intermediates, accounting for increased formation of MG and also activation of protein kinase C and hexosamine pathways [ 41 ]— Figure 1 . The cause of the increased HK2 activity was stabilization of HK2 to proteolysis by increased binding of glucose to the C-terminal active site during increased cytosolic hyperglycemia, masking a degradation motif linked to chaperone-mediated autophagy [ 18 ].…”

“…In HK2-linked unscheduled glycolysis in hyperglycemia, increased formation of ROS is a consequence rather than a cause of metabolic dysfunction and is one of multiple dysfunctional pathways. This may explain why clinical evaluation of antioxidants for therapy of diabetic complications has been disappointing [ 41 ]. A better approach emerged when it was found that tRES-HESP corrected increased HK2 protein and activity by off-target effects mediated by Nrf2-mediated increased expression of glucose-6-phosphate dehydrogenase, decreasing cellular concentration of G6P, transcriptional signaling by Mondo A/Mlx/G6P and expression of HK2.…”

Emerging Glycation-Based Therapeutics—Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors

“…tRES induces increased activity of NAD-dependent deacetylase, Sirtuin-1, and may thereby promote the removal of an inhibitory acetylation of Nrf2 to increase transcriptional activity [ 43 , 76 ]. The mechanism of activation of Nrf2 by tRES-HESP has been discussed elsewhere in this Special Series [ 77 ]. HESP is a partial agonist which is likely due to inhibitory nuclear acetylation of Nrf2 blocking a high E max .…”

“…An increase in expression of G6PD was implicated in a decrease in transcriptional activity of G6P/mlx/Mondo A complex regulating genes with a functional carbohydrate response element (ChRE)—including HK2, TXNIP, and other glycolytic and lipogenic genes. This corrected multiple pathways of metabolic dysfunction in model hyperglycemia in HAECs and PDLFs in vitro [ 7 , 28 ] and was implicated in the development of insulin resistance, vascular complications of diabetes, diabetic embryopathy, and ischemia-reperfusion injury in vivo [ 77 , 81 ]. Functional genomic studies with tissue-selective activation of Nrf2 by partial knockdown of Keap1 in the obesogenic HFD-fed mouse model of insulin resistance indicated that selective activation of Nrf2 in skeletal muscle and the liver corrected insulin resistance and dysglycemia, respectively [ 82 ].…”

“…Further investigation is also required to fully understand the mechanism of action by which tRES and HESP activate Nrf2. Plausible receptors have been proposed [ 45 , 77 ].…”