Plasma Nitrate Levels Are Related to Metabolic Syndrome and Are Not Altered by Treatment with DPP-4 Inhibitor Linagliptin: A Randomised, Placebo-Controlled Trial in Patients with Early Type 2 Diabetes Mellitus.

Melanie Reijrink,Harry Van Goor,Bernadette O Fernandez,Douwe J Mulder,Jan-Luuk Hillebrands,Martin Feelisch,Riemer H J A Slart,Anniek M Van Roon,Hiddo J L Heerspink,Stefanie A De Boer

doi:10.3390/antiox10101548

Abstract

The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tissue dysfunction and insulin resistance (IR). Dipeptidyl peptidase-4 (DPP-4) inhibitors have the potentially beneficial side effect of increasing NO availability. In this study, nitrate and nitrite levels and the effects of DPP-4 inhibitor linagliptin were investigated in relation to metabolic syndrome (MetS) markers. Treatment-naive patients with early type 2 diabetes mellitus (T2DM) (n = 40, median age 63 IQR (55–67) years, 63% male, mean HbA1c 45 ± 4.4 mmol/mol) were randomized (1:1) to linagliptin (5 mg/day) or placebo. MetS-related markers (body mass index (BMI), triglycerides, HOMA-IR, gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and adiponectin), plasma levels of nitrate, nitrite, total free thiols (TFT) and vegetable intake were estimated at baseline and after 4 and 26 weeks of treatment. Plasma nitrate, but not nitrite, correlated positively with vegetable intake (r = 0.38, p = 0.018) and was inversely associated with HOMA-IR (r = −0.44, p = 0.006), BMI (r = −0.35, p = 0.028), GGT (r = −0.37, p = 0.019) and CRP (r = −0.34, p = 0.034). The relationship between nitrate and HOMA-IR remained significant after adjusting for BMI, CRP, vegetable intake and GGT. With stable vegetable intake, nitrate and nitrite, TFT, adipokines and CRP did not change after 26 weeks of linagliptin treatment. While plasma nitrate is inversely associated with MetS, linagliptin treatment does not significantly influence nitrate and nitrite concentrations, oxidative stress, adipose tissue function and systemic inflammation.

Highlights

Type 2 diabetes mellitus (T2DM) is a worldwide health problem and it is often associated with metabolic syndrome (MetS) [1,2]
The major finding of our study is the inverse relationship between plasma nitrate levels and HOMA-insulin resistance (IR), BMI, GGT and systemic inflammation and its association with vegetable intake
These data show that circulating nitrate levels, but not nitrite, are closely related to MetS and that linagliptin treatment does not significantly affect the concentration of nitric oxide (NO) metabolites, oxidative stress, adipose tissue function and systemic inflammation in patients with early type 2 diabetes mellitus (T2DM)

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a worldwide health problem and it is often associated with metabolic syndrome (MetS) [1,2]. According to the World Health Organisation, Antioxidants 2021, 10, 1548. Obesity and IR have been shown to produce a state of oxidative stress and low-grade inflammation [4,5], leading to adipose and vascular tissue dysfunction, resulting in cardiovascular complications [5]. Interventions aiming at reducing cardiovascular risk by decreasing oxidative stress and inflammation should preferably start in patients with incipient T2DM. Systemic oxidative stress is strongly associated with increased cardiovascular risk in patients with T2DM [6,7,8], specific underlying mechanisms remain unclear and require further study

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