Diabetes Research and Clinical Practice
Impact of mitochondrial ROS production on diabetic vascular complications
Introduction
Diabetes is characterized by chronic hyperglycemia and the development of diabetic microvascular and macrovascular complications. The outcome of the Diabetes Control and Complication Trial [1], Kumamoto Study [2], [3], [4] and UK Prospective Diabetes Study [5] appears to have effectively resolved the long debate over whether chronic hyperglycemia is an important cause of diabetic vascular complications, but it is still unclear the mechanisms through which hyperglycemia acts as a crucial risk factor for vascular complications. Four seemingly independent mechanisms are involved in the pathogenesis of diabetic complications: glucose-induced activation of protein kinase C (PKC) isoforms [6], [7]; increased formation of glucose-derived advanced glycation end-products [8], [9], [10], [11]; increased polyol pathway [12]; and increased production of reactive oxygen species (ROS) [13]. There is no unifying hypothesis linking these four mechanisms together. However, we recently demonstrated that hyperglycemia could increase ROS production from mitochondrial electron transport chain, and we proposed that this mitochondrial ROS production could be a key event in the development of diabetic complications.
Here we demonstrate the mechanism of hyperglycemia-induced damage by mitochondrial ROS overproduction, and we also show the relationship between mitochondrial ROS production and diabetes complications in type 2 diabetes patients.
Section snippets
Role of mitochondrial electron transport chain in hyperglycemia-induced ROS production
Mitochondria are central in the traffic of cellular metabolism and transport. The most universal and critical mitochondrial function is oxidative phosphorylation. The overall system of oxidative phosphorylation includes five large multienzyme complexes, designated as complexes I, II, III, IV and ATP synthase (Fig. 1). This mitochondrial respiratory system is thought to be the major source of ROS under normal physiological condition. There are two main sites of superoxide generation in this
A single element linking hyperglycemia-induced damage
Three main hypotheses about how hyperglycemia causes diabetic complications have generated a large amount of data, as well as several clinical trials based on specific inhibitors of these mechanisms. Three hypotheses are: activation of PKC; increased AGE formation; and activation of polyol pathway. Until recently, there was no unifying hypothesis linking these four mechanisms. Therefore, we examined the effects of mitochondrial ROS inhibitor on these three independent biochemical pathways.
Mitochondrial ROS production in type 2 diabetic patients
It is still unclear whether mitochondrial ROS production associates with the progression of diabetic complications in type 2 diabetic patients. Therefore, to determine the role of mitochondrial ROS production in type 2 diabetic patients, the relationship between 8-hydroxydeoxyguanosine (8-OHdG) and the severity of diabetic complications were examined. 8-OHdG is a product of oxidative DNA damage following specific enzymatic cleavage after 8-hydroxylation of the guanine base (Fig. 4). As
Relationship between glycemic control and mitochondrial ROS production
Kumamoto Study was a randomized clinical trial designed to compare intensive insulin therapy (MIT) using multiple insulin injections with conventional insulin injection therapy (CIT) to evaluate the effects of glycemic control on the development and progression of microvascular complications in Japanese patients with type 2 diabetes. We have already reported that intensive glycemic control could delay the onset and progression of early stages of diabetic microvascular complications [2], [3], [4]
Conclusion
The main purpose of treatment in diabetes patients must be to prevent the onset and progression of chronic diabetic vascular complications, and hyperglycemia must be the primary initiating factor in the pathogenesis of diabetic complications. Here we demonstrated that hyperglycemia-induced mitochondrial ROS production could be a key event in the development of diabetic complications. The present study must provide a conceptual framework for future research and drug discovery, which targets
Acknowledgements
The authors thank Dr. M. Brownlee (Albert Einstein College of Medicine, Bronx, NY) for providing the rat UCP-1 and human MnSOD adenoviral vectors.
This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Japan (No. 18590995 to T.N.), and by grants from Takeda Science Foundation (to T.N.).
References (19)
- et al.
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study
Diabetes Res. Clin. Pract.
(1995) - et al.
Cost-effectiveness of intensive insulin therapy for type 2 diabetes: a 10-year follow-up of the Kumamoto study
Diabetes Res. Clin. Pract.
(2000) 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.
(1993)- et al.
Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients
Diabetes Care
(2000) 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
(1998)- et al.
Protein kinase C activation and the development of diabetic complications
Diabetes
(1998) - et al.
Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor
Science
(1996) - et al.
Antigenic heterogeneity of vascular endothelium
Am. J. Pathol.
(1992) - et al.
Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat
Diabetes
(1991)