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Crossing borders: the role of the endothelial glycocalyx and intravascular
haemostasis in vascular complications of diabetes mellitus
Lemkes, B.A.
Publication date
2011
Link to publication
Citation for published version (APA):
Lemkes, B. A. (2011). Crossing borders: the role of the endothelial glycocalyx and
intravascular haemostasis in vascular complications of diabetes mellitus.
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CHAPTER
1
Introduction
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‘Banting’s discovery of insulin only allowed patients with diabetes to live just long enough to develop blindness, renal failure, and coronary disease’
Michael Brownlee, Banting Lecture 20051.
While this statement about one of the most important medical discoveries of the past century may sound unduly harsh, its content unfortunately holds true. In an era with rapid advances in the treatment of hyperglycaemia, including new oral glucose-lowering drugs, biosynthetic insulin analogues and state-of-the-art insulin administration devices, patients with diabetes mellitus are still facing an uncertain fate. Damage to the small blood vessels of the retina will cause severe visual loss in 10% of patients and blindness in 2%2. Diabetic nephropathy will cause the death of 10-20%.2 Neuropathy will affect
one in two patients with diabetes and, together with impaired blood flow, increases the risk of foot ulcers and limb amputation2. Ultimately, 50% of patients with diabetes die of
cardiovascular disease2.
When Dr. Brownlee delivered his lecture, over half a century of research into the development of diabetic complications had passed. If anything, the current body of evidence suggests that the pathogenesis of complications in diabetes is multifactorial. This is especially true for the complex entity called type 2 diabetes mellitus, were hyperglycaemia is often accompanied by obesity, insulin resistance, hypertension and dyslipidaemia.
Although each of the diabetic complications has its own tissue-specific pathogenesis, they all share a (micro-or macro)vascular component. Traditionally, hyperglycaemia-induced vascular damage is believed to start with damage to the vascular endothelium, causing endothelial dysfunction. However, the vascular endothelium is lined with a protective border of proteoglycans and adhered glycosaminoglycans, the so-called glycocalyx, and damage to this border is likely to precede endothelial injury. In fact, recent studies by Nieuwdorp and colleagues have shown a direct damaging effect of both acute hyperglycaemia and type 1 diabetes on the glycocalyx3, 4. These findings have led
to the hypothesis that hyperglycaemia-induced glycocalyx damage is the first step in the development of vascular damage in diabetes and this suggests a new therapeutic target in the prevention of diabetic complications. In chapter 2 of this thesis an overview of the research into this protective layer is presented and its possible role in the development of vascular complications of diabetes is further explored.
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focus of research has been the development of atherosclerosis, diabetes has been labelled a ‘prothrombotic condition’, predisposing patients to thrombotic events5, 6. Current
evidence for the effects of diabetes and acute hyperglycaemia on the haemostatic system is reviewed in chapter 3.
As described in the chapters 2 and 3, the negative effects of hyperglycaemia on both the endothelial glycocalyx and the coagulation system have been well established. However, little is known about the exact nature of these effects. At which glucose level do these effects first occur? Are these on-off phenomena occurring at a certain glycaemic threshold, or continuous effects? Could these effects be mediated by oxidative stress, as Brownlee suggested in his lecture? These questions were the focus of the study described in chapter 4.
In chapter 5 the observations regarding damage to the endothelial glycocalyx in patients with type 1 diabetes are expanded to a population with type 2 diabetes and it is explored whether glycocalyx damage might be reversed by oral glycocalyx precursor treatment. This issue is further addressed in chapter 6, where we investigated the reversibility of hyperglycaemia-induced alterations in glycocalyx metabolism, coagulation and fibrinolysis following improved glycaemia through insulin treatment.
Finally, the glycocalyx has also been suggested to be of significance in patients with end stage renal disease, who are dependent on dialysis7. A suggested loss of glycocalyx
could contribute to the accelerated vascular disease seen in dialysis patients, even in the absence of diabetes, but could also be of importance in peritoneal dialysis by affecting peritoneal transport. However, these hypotheses were all based on experimental in vitro and animal studies and human research was lacking. In chapter 7 we investigated the state of the endothelial glycocalyx in patients on peritoneal or haemodialysis
The prothrombotic state that characterizes patients with type 2 diabetes is the consequence of coagulation activation and fibrinolytic impairment, but is also the result of hyper reactivity of blood platelets. In fact, the propensity of patients with type 2 diabetes towards cardiovascular events has made them likely candidates for primary prevention with an antiplatelet agent. In recent years, several large clinical trials have investigated whether these patients would benefit from low dose aspirin treatment to prevent first cardiovascular events. Surprisingly, these trials have not been able to show a benefit of aspirin 8-10. Several factors may play a role in the reduced efficacy of aspirin
as an antiplatelet drug in patients with diabetes. Of these, hyperglycaemia is thought to interfere with the mechanism of action of aspirin. Also, patients with diabetes may require higher doses of aspirin due to high baseline platelet reactivity. In chapter 8, the role of glycaemic control as well as aspirin dose on the anti-platelet efficacy of aspirin is examined in a cohort of patients with type 2 diabetes. However, this research into blood platelets is notoriously hampered by suboptimal testing conditions. For one, the
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fect of sulodexide on endothelial glycocalyx and vascular permeability
preservative used in the blood collection tubes may influence the test results through its own anticoagulant properties. Thus, in chapter 9 we describe the effects of various blood preservatives on the platelet function tests used to monitor the effect of aspirin.
This thesis explores two aspects of the development of vascular complications in diabetes that may have been somewhat underexposed before: the role of the endothelial glycocalyx and of haemostasis, each representing a different phase in the pathogenesis of vascular disease. A summary of the most important findings of this thesis and final considerations can be found in chapter 10.
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References
1. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54(6):1615-1625.
2. World health organisation. Fact sheet Nº 312. 2011.
3. Nieuwdorp M, van Haeften TW, Gouverneur MC et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 2006;55(2):480-486.
4. Nieuwdorp M, Mooij HL, Kroon J et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 2006;55(4):1127-1132.
5. Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001;15(1):44-54. 6. Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007;262(2):157-172. 7. Flessner MF. Endothelial glycocalyx and the peritoneal barrier. Perit Dial Int 2008;28(1):6-12. 8. Belch J, MacCuish A, Campbell I et al. The prevention of progression of arterial disease and diabetes
(POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337(oct16_2):a1840. 9. Ogawa H, Nakayama M, Morimoto T et al. Low-dose aspirin for primary prevention of
atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;300(18):2134-2141.
10. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003;26(12):3264-3272.
