Hepatocyte growth factor as a potential index of complication in diabetes mellitus

Objective Diabetes mellitus (DM), characterized by the premature development of microvascular and macrovascular disease, shows a loss of vasodilatory properties of resistance vessels. However, the mechanisms of endothelial dysfunction in diabetes have not yet been clarified. Hepatocyte growth factor (HGF) in vascular cells was down-regulated by high glucose levels, potentially accelerating the endothelial dysfunction in DM. In this study, the serum HGF level was measured to investigate further the role of HGF in DM. Methods Tissue and circulating HGF levels were measured in the KKA(y) mouse, a rodent model of noninsulin-dependent diabetes mellitus (NIDDM), and lean C57 BL control mice. Then, serum HGF concentrations were measured in NIDDM patients without liver, kidney or lung damage. For the study of serum HGF concentration, 30 normotensive and age-matched 58 DM patients were studied. The 58 DM patients were divided into 26 patients without hypertension and 32 patients with hypertension [22 patients without hypertensive complications (WHO I) and 10 patients with hypertensive complications (WHO II + III)]. Results The serum HGF concentration in KKA(y) mice was significantly lower than that in control mice (P< 0.01), at 14 weeks of age when they exhibit features of diabetes. Similarly, tissue HGF concentrations in the heart and kidney were decreased significantly in KKA(y) mice compared with control C57 BL mice (P< 0.05). The serum HGF concentration showed a significant negative correlation with hemoglobin (Hb) A,, concentration (P< 0.01, r = -0.41). Since the serum HGF concentration is a potential index of the severity of hypertension, the serum levels of HGF in DM patients without and with hypertension were examined. The serum HGF concentration in DM patients without hypertension was significantly lower than that in normal subjects (P < 0.05), whereas that in DM patients with hypertension was significantly higher than that in normal subjects (P< 0.01). Moreover, the serum HGF concentration in DM patients with hypertensive complications was further higher than that in others (P< 0.01). Conclusion The present data showed that serum, cardiac and renal HGF concentrations in KKA(y) mice were significantly decreased compared with control mice. Therefore, a decrease in local HGF may be a trigger of endothelial dysfunction in DM. Clinical data also demonstrated a significant negative correlation between serum HGF and HbA(lc) concentrations in diabetic patients without complications. In contrast, the serum concentration of HGF was significantly elevated depending on the severity of hypertension. These results suggest that HGF may be a new index of complications such as hypertension in DM. J Hypertens 1998, 16:2019-2026 (C) 1998 Lippincott Williams & Wilkins.