Diabetes, microvascular complications, and cardiovascular complications: What is it about glucose?

Glycemic control is the primary mediator of diabetic microvascular complications and also contributes to macrovascular complications. A new study (see related article beginning on page 1049) reveals a previously unrecognized association between oxidant activation of poly (ADP ribose) polymerase (PARP) and upregulation of known mediators of glycemic injury. Inhibitors of PARP may have potential therapeutic roles in the prevention of diabetic complications

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 impressiveimpact 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).

Diabetic complications and glucose

Glucose is the driving force in microvascular complications of diabetes, yet the action of glucose alone seems inadequate and unable to account for the excess atherosclerosis observed in subjects with diabetes. In type 2 diabetes, insulin resistance, and the metabolic syndrome, the vasculature is exposed to a frontal assault by hypertension, dyslipidemia (increased triglycerides, low HDL and high LDL cholesterol), inflammation, and impaired fibrinolysis (5, 6). This toxic metabolic environment increases atherosclerotic risk in persons with the metabolic syndrome. The heightened risk observed in the metabolic syndrome inevitably sets the stage for increased vascular disease in type 2 diabetics, but hyperglycemia adds additional risk.

Strong epidemiological evidence suggests a correlation among glucose, atherosclerotic plaque burden, cardiovascular events, and increased morbidity and mortality (15–17). In an autopsy study of 18- to 34–year-olds there was an increase in atherosclerotic plaque burden in subjects with elevated hemoglobin A1C (17). The Honolulu Heart Program demonstrated a predictive correlation between fasting plasma glucose levels (nondiabetic, impaired glucose tolerance, and diabetic ranges) and cardiovascular events and mortality (18). Large population studies from Northern Europe indicate a direct correlation between glycemic control (as measured by glycohemoglobin) and cardiovascular morbidity and mortality (16, 19). As will be discussed later, hyperglycemia has specific deleterious effects upon vascular endothelial function that could account for these epidemiological correlations between hyperglycemia and poor vascular outcomes. One would predict, based upon epidemiological data, that interventional studies targeting hyperglycemia would show improved cardiovascular outcomes. To date, no such compelling evidence has emerged. In fact, in the largest prospective glucose-lowering trial in type 2 diabetes patients, the United Kingdom Prospective Diabetes Study (4), there were no statistical improvements in cardiovascular outcomes when glucose was lowered using insulin or sulfonylureas. Only in the small metformin cohort (n = 342) were cardiovascular outcomes improved by optimal glycemic control. A few small studies have suggested a positive impact of glycemic control on cardiovascular events, but this point remains highly debated. The conclusions of a recent panel convened by the American Heart Association suggest that while glycemia contributes to cardiovascular risk, treatment of glycemia, exclusive of other potent cardiovascular risk factor intervention, is inadequate to reverse or reduce the complex atherosclerotic process (18).

Mechanisms of Glycotixicity

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).

Implications for therapy

It has been well established that diabetes leads to microvascular complications, and it has also been suggested that hyperglycemia plays an accelerating role in macrovascular disease. This excess disease burden is driven by glucose-related activation of PKC, accumulation of AGEs, excess polyol flux, and accumulation of glucosamine (20, 22–25). Interventions for each of these mechanisms have had great efficacy in animal models but disappointing outcomes in clinical trials (26). It was concluded that a cocktail of inhibitors might be necessary to effectively block these deleterious cellular responses in a complex human model of fluctuating hyperglycemia (20). The observation that these pathways reflect a single hyperglycemia-induced process, namely oxidative stress, suggested that antioxidants could serve as a single agent in the prevention of diabetes complications. To date, human studies with a lipoic acid suggest a therapeutic benefit (27, 28), but the use of conventional antioxidants has been disappointing in larger trials (29). Conventional antioxidants scavenge free radicals in an inefficient stoichiometric manner so that one molecule of the antioxidant would be needed to neutralize each free radical generated. Novel small molecular weight compounds that function as superoxide dismutase mimetics may offer more reliable benefits due to the catalytic properties that could permit enzymatic detoxification (30). The observation that PARP drives glucotoxicity through inhibition of GAPDH suggests PARP inhibitors as another therapeutic tool for complication prevention. In theory, these agents could have an effect equivalent to combination inhibitor therapy due to positive effects on AGE, PKC, and NF-kB. Indeed, the few reports employing PARP inhibitors in animal models of diabetes support the therapeutic potential of these agents (31, 32). With the incidence of diabetes and its complications on the rise, these results offer hope for new treatments in the foreseeable future.

Jane E.B. Reusch, J Clin Invest. 2003 October 1; 112 (7): 986-988

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


  1. Boyle, J.P. et al. (2001). Projection of diabetes burden through 2050: impact of changing demography and disease prevalence in the U.S. Diabetes Care. 24, 19361940 [PubMed][Full Text]
  2. Benjamin, S.M., Valdez, R., Geiss, L.S., Rolka, D.B., & Narayan, K.M. (2003). Estimated number of adults with prediabetes in the U.S. in 2000: opportunities for prevention. Diabetes Care. 26, 645649 [PubMed][Full Text]
  3. (1993). The Diabetes ControlComplications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977986 [PubMed][Full Text]
  4. (1998). UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 352, 837853 [PubMed][Full Text]
  5. Hanson, R.L., Imperatore, G., Bennett, P.H., & Knowler, W.C. (2002). Components of the “metabolic syndrome” and incidence of type 2 diabetes. Diabetes. 51, 31203127 [PubMed][Full Text]
  6. Abbasi, F., Brown, B.W., Jr., Lamendola, C., McLaughlin, T., & Reaven, G.M. (2002). Relationship between obesity, insulin resistance, and coronary heart disease risk. J. Am. Coll. Cardiol. 40, 937943 [PubMed][Full Text]
  7. Haffner, S.M. et al. (1999). Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch. Intern. Med. 159, 26612667 [PubMed][Full Text]
  8. Pyorala, K. et al. (1997). Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 20, 614620 [PubMed]
  9. Goldberg, R.B. et al. (1998). Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 98, 25132519 [PubMed][Free Full Text]
  10. (2003). Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 361, 20052016 [PubMed][Full Text]
  11. Pedersen, O. & Gaede, P. (2003). Intensified multifactorial intervention and cardiovascular outcome in type 2 diabetes: The Steno-2 study. Metabolism. 52, 1923
  12. Lindholm, L.H. et al. (2002). Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 359, 10041010 [PubMed][Full Text]
  13. (2000). Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 355, 253259 [PubMed][Full Text]
  14. Du, X. et al. (2003). Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J. Clin. Invest. 112, 10491057. doi:10.1172/JCI200318127 [ Free Full text in PMC]
  15. Tominaga, M. et al. (1999). Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 22, 920924 [PubMed][Free Full Text]
  16. Laakso, M. (1996). Glycemic control and the risk for coronary heart disease in patients with non-insulin-dependent diabetes mellitus. The Finnish studies. Ann. Intern. Med. 124, 127130 [PubMed]
  17. Ledru, F. et al. (2001). New diagnostic criteria for diabetes and coronary artery disease: insights from an angiographic study. J. Am. Coll. Cardiol. 37, 15431550 [PubMed][Full Text]
  18. Donahue, R.P., Abbott, R.D., Reed, D.M., & Yano, K. (1987). Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes. 36, 689692 [PubMed]
  19. Kuusisto, J., Mykkanen, L., Pyorala, K., & Laakso, M. (1994). NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes. 43, 960967 [PubMed]
  20. Sheetz, M.J. & King, G.L. (2002). Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA. 288, 25792588 [PubMed][Full Text]
  21. Nishikawa, T. et al. (2000). Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 404, 787790 [PubMed][Full Text]
  22. Schmidt, A.M. et al. (1995). Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J. Clin. Invest. 96, 13951403 [PubMed]
  23. Hart, G.W. (1997). Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu. Rev. Biochem. 66, 315335 [PubMed][Full Text]
  24. Greene, D.A., Arezzo, J.C., & Brown, M.B. (1999). Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology. 53, 580591 [PubMed][Full Text]
  25. Vlassara, H., Brownlee, M., Manogue, K.R., Dinarello, C.A., & Pasagian, A. (1988). Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science. 240, 15461548 [PubMed]
  26. Brownlee, M. (2001). Biochemistry and molecular cell biology of diabetic complications. Nature. 414, 813820 [PubMed][Full Text]
  27. Evans, J.L. & Goldfine, I.D. (2000). Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol. Ther. 2, 401413 [PubMed][Full Text]
  28. Ametov, A.S. et al. (2003). The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 26, 770776 [PubMed][Full Text]
  29. (2000). Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 355, 253259 [PubMed][Full Text]
  30. Ross, A.D. et al. (2002). Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species specificity. Free Radic. Biol. Med. 33, 16571669 [PubMed][Full Text]
  31. Pacher, P. et al. (2002). The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes. 51, 514521 [PubMed][Full Text]
  32. Soriano, F.G., Pacher, P., Mabley, J., Liaudet, L., & Szabo, C. (2001). Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ. Res. 89, 684691 [PubMed][Free Full Text]