Advertisement
Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose?
Jane E.B. Reusch
Veterans Affairs Medical Center and Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
Address correspondence to: Jane E.B. Reusch, Section of Endocrinology (111H), Veterans Affairs Medical Center, 1055 Clermont Street, Denver, Colorado 80220, USA. Phone: (303) 399-8020 ext. 2775; Fax: (303) 393-5271; E-mail: jane.reusch@uchsc.edu.
Find articles by Reusch, J. in: JCI | PubMed | Google Scholar
Published October 1, 2003 - More info
J Clin Invest. 2003;112(7):986–988. https://doi.org/10.1172/JCI19902.
© 2003 The American Society for Clinical Investigation
The prevalence of obesity, diabetes, and the metabolic syndrome is increasing in the US and worldwide at astonishing rates (1, 2). Diabetes is the leading cause of blindness, renal failure, and amputation in the United States. These conditions can be slowed or prevented with optimal glycemic control (3, 4). Accompanying the diabetes epidemic is a concomitant two- to four-fold excess risk for cardiovascular disease (5, 6). Modification of traditional cardiovascular risk factors has an impressive impact on morbidity and mortality in subjects with diabetes and insulin resistance as reported in various studies, including the Scandinavian Simvastatin Survival Study (7, 8), the Cholesterol and Recurrent Events (CARE) study (9), the MRC/BHF Heart Protection Study (10), the Steno-2 study (11), the Losartan Intervention For Endpoint reduction in hypertension study (12; known as LIFE), and the Heart Outcomes Prevention Evaluation study (13; known as HOPE). Even with these effective interventions, people with diabetes still have increased morbidity and mortality when compared to the nondiabetic population. The question remains, what is it about diabetes (defined by high blood glucose levels) that leads to excess vascular risk? In this issue of the JCI, Du and colleagues present a new molecular target — poly(ADP ribose) polymerase (PARP) — dysregulated by hyperglycemic injury, which may have implications for prevention of both microvascular disease and macrovascular disease because this enzyme affects critical targets in the endothelial cell (14).
-
Mechanism of glucotoxicity
The negative impact of hyperglycemia on endothelial function and pathological changes observed in diabetes is supported in the literature (reviewed in refs. 20, 21). Endothelial cells in vitro are exquisitely sensitive to high glucose (25mM). Nishikawa et al. (21) and others have carefully characterized four major molecular signaling mechanisms activated by hyperglycemia in endothelial cells and other cell types vulnerable to hyperglycemic injury. These include activation of PKC (via diacylglycerol), increased hexosamine pathway flux, increased advanced glycation end product (AGE) formation, and increased polyol pathway flux. Nishikawa et al. recently proposed the existence of a unifying mechanism that integrates the above pathways: increased production of reactive oxygen species (ROS) (specifically superoxide) by the mitochondrial electron transport chain (21). In their original report, numerous theoretical constructs were outlined for the impact of altered redox state upon formation of polyols, AGEs, and PKC. What remained unclear were the downstream targets of oxidant stress. In the paper by Du et al. (14) in this issue of the JCI, this group takes their seminal observation one step further and defines one consequence of increased ROS, namely activation of PARP. PARP activation leads to ribosylation and inactivation of GAPDH. Inhibition of GAPDH increases delivery of glycolytic intermediates to the mitochondria. This change in turn would be expected to increase mitochondrial superoxide production and also to increase flux through the AGE and PKC glucotoxic pathways (Figure 1).
Figure 1High glucose flux through constitutive glucose transporters on endothelial cells overwhelms the mitochondrial electron transport system. Excess mitochondrial substrate flux results in the generation of reactive oxygen species that cause DNA strand breaks and activation of PARP. PARP ribosylates and inactivates GAPDH, thereby disrupting normal glucose metabolism. Inactivation of GAPDH effectively shunts glucose into the polyol pathway and leads to activation of PKC and accumulation of AGEs and glucosamine. DAG, diacylglycerol.
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)