Elevated hepatocyte growth factor (HGF) levels and cardiovascular autonomic dysfunction are associated with a high mortality rate in patients with type 2 diabetes mellitus. We tested the hypothesis that elevated HGF is associated with insulin resistance and cardiovascular autonomic dysfunction in patients with type 2 diabetes mellitus not receiving insulin treatment. The study group consisted of 21 type 2 diabetes mellitus patients with high HGF levels (>0.26 ng/mL, 58 +/- 5 years old, high-HGF group). The control group consisted of 25 type 2 diabetes mellitus patients with normal HGF levels (<or=0.26 ng/mL, 58 +/- 9 years old, normal-HGF group). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. Early and delayed (123)I-MIBG myocardial uptake values were lower (P < .005 and P < .01, respectively) and the percentage of washout rate of (123)I-MIBG was higher (P < .001) in the high-HGF group than in the normal-HGF group. The fasting plasma insulin concentrations (P < .0001) and the homeostasis model assessment index values (P < .0001) were higher in the high-HGF group than in the normal-HGF group. Multiple regression analysis revealed that the level of HGF was independently predicted by the homeostasis model assessment index values and the myocardial uptake of (123)I-MIBG at the delayed phase. Our results demonstrate that high levels of HGF are associated with depressed cardiovascular autonomic function and insulin resistance in patients with type 2 diabetes mellitus.