Decreased diabetes risk over 9 year after 18-month oral L-arginine treatment in middle-aged subjects with impaired glucose tolerance and metabolic syndrome (extension evaluation of L-arginine study)

Abstract

Purpose: This study aimed to determine whether L-arginine supplementation lasting for 18 months maintained long-lasting effects on diabetes incidence, insulin secretion and sensitivity, oxidative stress, and endothelial function during 108 months among subjects at high risk of developing type 2 diabetes.

Methods: One hundred and forty-four middle-aged subjects with impaired glucose tolerance and metabolic syndrome were randomized in 2006 to an L-arginine supplementation (6.4 g orally/day) or placebo therapy lasting 18 months. This period was followed by a 90-month follow-up. The primary outcome was a diagnosis of diabetes during the 108 month study period. Secondary outcomes included changes in insulin secretion (proinsulin/c-peptide ratio), insulin sensitivity (IGI/HOMA-IR), oxidative stress (AOPPs), and vascular function. After the 18 month participation, subjects that were still free of diabetes and willing to continue their participation (104 subjects) were further followed until diabetes diagnosis, with a time span of about 9 years from baseline.

Results: Although results derived from the 18 month of the intervention study demonstrated no differences in the probability of becoming diabetics, at the end of the study, the cumulative incidence of diabetes was of 40.6% in the L-arginine group and of 57.4% in the placebo group. The adjusted HR for diabetes (L-arginine vs. placebo) was 0.66; 95% CI 0.48, 0.91; p < 0.02). Proinsulin/c-peptide ratio (p < 0.001), IGI/HOMA-IR (p < 0.01), and AOPP (p < 0.05) levels were ameliorated in L-arginine compared to placebo.

Conclusions: These results may suggest that the administration of L-arginine could delay the development of T2DM for a long period. This effect could be mediated, in some extent, by L-arginine-induced reduction in oxidative stress.

Trial registration: ClinicalTrials.gov NCT00917449.

Keywords: Endothelial function; Insulin secretion; L-Arginine; Oxidative stress; Prevention of type 2 diabetes.

Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Grants

Funding Italian Ministry of Health, Finalizzata no. 88, 2004.

Figures

Fig. 1

Trial profile. One hundred and forty-four subjects were randomized to the active arm (72 patients) or to the placebo arm (72 subjects). One hundred and thirty-four subjects (66 in l-arginine group and 68 in the placebo group) completed the treatment period (104 confirmed without diabetes, 30 cases diagnosed for diabetes, and 10 withdrawn). The 104 subjects confirmed without diabetes entered the 90-month postintervention follow-up. Of those, 92 subjects (47 and 45 subjects, respectively) completed the follow-up period with 12 subjects being withdrawn

Fig. 2

Kaplan–Meier estimates cumulative probability of remaining free of diabetes and of becoming/remaining NGT. The 2-h postload plasma glucose levels were measured at baseline and every 6 months. The outcomes were evaluated at the end of the study. a Total follow-up of cumulative probability of remaining free of diabetes in l-arginine (black boxes) and placebo groups (white boxes). As compared to placebo group, the HR was 0.66 (95% CI 0.48, 0.91; p < 0.05) in the l-arginine group. b Total follow-up of cumulative probability of becoming/remaining NGT in l-arginine (black boxes) and placebo groups (white boxes). As compared to placebo group, the HR was 1.38 (95% CI 0.99, 1.93; p = 0.33) in l-arginine group

Fig. 3

Mean glucose (a, c, e) and insulin (b, d, f) levels at baseline, at the end of the intervention study and at the end of the postintervention follow-up in l-arginine (black boxes) and in placebo (white boxes) groups during OGTT. *p < 0.05 vs. placebo

Fig. 4

a Mean fasting proinsulin, proinsulin/c-peptide ratio, IGI, HOMA-IR, and IGI/HOMA-IR ratio in 35 and in 22 persons in the l-arginine (black boxes) and placebo (white boxes) groups, respectively, that remained free of diabetes at the end of the postintervention follow-up during the total period of study (intervention study and postintervention follow-up period). *p < 0.05 vs. placebo; #p < 0.01 vs. placebo. b Change difference during the postintervention period compared to results of each variable obtained at the end of the intervention study for fasting proinsulin, proinsulin/c-peptide ratio, and IGI HOMA-IR and IGI/HOMA-IR ratio in 35 and in 22 subjects in the l-arginine (black boxes) and placebo (white boxes) groups, respectively, that remained free of diabetes at the end of the postintervention follow-up period. *p < 0.05 vs. placebo; **p < 0.01 vs. placebo. HOMA-IR homeostasis model assessment-insulin resistance, IGI insulinogenic index

Fig. 5

a Mean ADMA, AOPP, and EPCs levels in 35 and in 22 subjects in the l-arginine (black boxes) and placebo (white boxes) groups, respectively, that remained free of diabetes at the end of the postintervention follow-up during the total period of study (intervention study and postintervention follow-up period). *p < 0.05 vs. placebo; #p < 0.01 vs. placebo. b Change difference during the post intervention period compared to results of each variable obtained at the end of the intervention study for ADMA, AOPP, and EPCs in 35 and in 22 subjects in the l-arginine (black boxes) and placebo (white boxes) groups, respectively, that remained free of diabetes at the end of the postintervention follow-up period. *p < 0.05 vs. placebo; **p < 0.01 vs. placebo. ADMA asymmetric dimethylarginine, AOPP advanced oxidation protein products, EPCs endothelial progenitor cells