The growth hormone (GH) response to GH-releasing hormone (GHRH) in patients with non-insulin-dependent diabetes mellitus (NIDDM) was found to be either decreased or normal. The recent introduction of a new and potent GH stimulus, GH-releasing peptide-6 (GHRP-6), allowed further investigation of the functional properties of somatotropes in a variety of metabolic diseases. The aim of the present study was to investigate the response of GH to GHRP-6, GHRH, and GHRP-6 + GHRH in NIDDM patients. Twenty-one patients with NIDDM were divided into two groups: group A, normal weight (body mass index [BMI], 23.31+/-0.62 kg/m2); and group B, overweight (BMI, 27.62+/-0.72 kg/m2). Eight normal-weight control subjects (group C) were studied. Each subject received GHRP-6 (90 microg intravenously [i.v.]), GHRH (100 microg i.v.), and GHRP-6 + GHRH on three separate occasions. There was no difference between the GH response after GHRP-6 in groups A, B, and C in terms of the GH peak (50.95+/-11.55, 51.96+/-7.71, and 70.07+/-15.59 mU/L, P>.05) and the area under the curve (AUC) for GH (2,340.06+/-617.36, 2,684.54+/-560.57, 3,462.78+/-1,223.53 mU/L/120 min, P>.05). A decreased GH response to GHRH was found in group B in comparison to group A (B v A: peak GH response, 8.25+/-1.90 v 22.19+/-8.81, P<.05; AUC GH, 479.62+/-84.0 v 1,443.21+/-743.76, P<.05). There was no difference in the GH response between group A and group C (peak GH response, 22.19+/-8.81 v 26.42+/-6.71, P>.05; AUC, 1,443.21+/-743.76 v 1,476.51+/-386.56, P>.05). There was a significant difference between the same parameters in group B versus group C (8.25+/-1.90 v 26.42+/-6.71, P<.05; AUC, 479.62+/-84.0 v 1,476.51+/-386.56, P<.05). The combined administration of GHRP-6 + GHRH elicited a synergistic GH response in NIDDM patients and controls. There was a significant difference between groups A and B for the GH peak (96.49+/-9.80 v 68.38+/-8.25, P<.05), whereas there was no difference for the AUC (5,111.13+/-703.77 v 3,425.95+/-459.67, P>.05). There was no difference in the peak GH after the combined test between group A and group C (96.49+/-9.80 v 139.82+/-24.16, P>.05), whereas the peak GH in the same test was significantly decreased in group B in comparison to group C (68.38+/-8.25 v 139.82+/-24.16, P<.05). The AUC for GH after combined GHRP-6 + GHRH in group A versus group C was not significantly different (5,111.13+/-703.77 v 9,274.71+/-1,541.46, P>.05), whereas there was a significant difference for the same test between group B and group C (3,425.95+/-459.67 v 9,274.71+/-1,541.46, P<.05). Our results demonstrate that normal-weight NIDDM patients have a preserved GH response to GHRP-6, GHRH, and GHRP-6 + GHRH, and overweight NIDDM patients have a blunted response to GHRH and GHRP-6 + GHRH. The preserved GH response to GHRP-6 in both diabetic groups suggests that the secretory potential of somatotropes is preserved in NIDDM patients. The impairment of the GH response to GHRH in overweight NIDDM patients could be a functional defect due to the obesity, since it could be overridden by administration of GHRP-6.