Review 10.1586/1744666X.2.3.403 © 2006 Future Drugs Ltd ISSN 1744-666X 403 www.future-drugs.com Growth factors in diabetic complications Sally E Thomson, Susan V McLennan and Stephen M Twigg † † Author for correspondence Discipline of Medicine, Department of Endocrinology, Royal Prince Alfred Hospital, Blackburn Building, DO6, University of Sydney, NSW 2006, Australia Tel.: +61 295 156 150 Fax: +61 295 161 273 stwigg@med.usyd.edu.au KEYWORDS: complications, connective tissue growth factor, diabetes, diabetic nephropathy, epidermal growth factor, fibroblast growth factor, insulin-like growth factor, platelet-derived growth factor, transforming growth factor-β, vascular endothelial growth factor, wound healing Diabetes mellitus is characterized by a lack of insulin, causing elevated blood glucose, often with associated insulin resistance. Over time, especially in genetically susceptible individuals, such chronic hyperglycemia can cause tissue injury. Dysregulation of growth factors in diabetes occurs through biochemical and hemodynamic pathways. In some tissues affected by diabetes, growth factors are induced to an excess, while in other sites a relative deficit of growth factors occurs. There is evidence that these growth factor changes contribute to the tissue pathology in diabetes, whether it be fibrosis, persistent inflammation or a combination of the two. This review focuses on the role of growth factors in diabetic nephropathy and wound healing in diabetes. Growth factor therapy in diabetic foot ulcers is already a clinical reality. As methods to finely regulate growth factors in a tissue- and time-specific manner are further developed and tested, downregulation of growth factors in vivo may well become a therapy to prevent and treat diabetic nephropathy. Expert Rev. Clin. Immunol. 2(3), 403–418 (2006) Diabetes & the common pathway to complications Diabetes is essentially a metabolic insult which leads to a clinical syndrome. Irrespective of the type of diabetes mellitus, whether it is auto- immune Type 1 diabetes, secondary to insulin resistance in Type 2 diabetes or rarer forms, the common underlying features are a relative lack of insulin secretion by the pancreatic β cells resulting in progressive hyperglycemia and the consequent tissue complications (FIGURE 1). Before the advent of insulin therapy in the 1920s, patients with Type 1 diabetes rapidly died from the severe catabolic effects of abso- lute insulin deficiency and diabetic ketoacido- sis. After the discovery and use of insulin, it became clear that despite insulin treatment, tis- sue damage continued to occur in people with diabetes. In the current absence of a cure for diabetes, much effort is focused on the preven- tion of diabetic complications. Only by under- standing how these complications arise can rational molecular interventions be developed. Importance of blood glucose control Key clinical studies have shown that increasing chronic hyperglycemia in both Type 1 and 2 diabetes leads to a remarkably similar increased risk of diabetic end-organ complications. The pivotal intervention studies, termed the Diabetes Control and Complications Trial (DCCT) [1] and UK Prospective Diabetes Study (UKPDS) [2], in Type 1 and 2 diabetes, respectively, have demonstrated that chronic hyperglycemia leads to microvascular complica- tions and that tighter blood glucose control over time helps to prevent the onset and develop- ment of these complications. The gold standard test of glycemic control is the HbA1c measure- ment, and for each 1% increase in HbA1c above normal, there is a 37% increased risk in the microvascular complications of diabetic kid- ney disease (nephropathy), diabetic eye disease (retinopathy) and diabetic neuropathy. Hemo- dynamic factors such as hypertension as well as the metabolic changes of dyslipidemia, both of which are commonly linked to insulin resist- ance, impact in a major way, particularly on macrovascular disease in diabetes. The 10–18-year epidemiological extensions of the DCCT and UKPDS clinical trials have more recently indicated in abstract form that chronic hyperglycemia also contributes to adverse macrovascular outcomes, including cardio- and cerebrovascular disease. Thus, the degree of hyperglycemia is a major factor causing diabetes CONTENTS Diabetes & the common pathway to complications Importance of blood glucose control The many faces of diabetes Growth factor excess & deficiency: contrasting paradigms of growth factors in diabetes complications Growth factors & renal hyperfiltration Glomerulosclerosis & growth factors Growth factor action in wound healing Impaired wound healing Growth factor regulation & therapy in diabetic wounds Conclusion Expert commentary & five-year view Key issues References For reprint orders, please contact reprints@future-drugs.com