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.

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.

[18F]FDG Uptake in Adipose Tissue Is Not Related to Inflammation in Type 2 Diabetes Mellitus.

PURPOSE: 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake is a marker of metabolic activity and is therefore used to measure the inflammatory state of several tissues. This radionuclide marker is transported through the cell membrane via glucose transport proteins (GLUTs). The aim of this study is to investigate whether insulin resistance (IR) or inflammation plays a role in [18F]FDG uptake in adipose tissue (AT). PROCEDURES: This study consisted of an in vivo clinical part and an ex vivo mechanistic part. In the clinical part, [18F]FDG uptake in abdominal visceral AT (VAT) and subcutaneous AT (SAT) was determined using PET/CT imaging in 44 patients with early type 2 diabetes mellitus (T2DM) (age 63 [54-66] years, HbA1c [6.3 ± 0.4 %], HOMA-IR 5.1[3.1-8.5]). Plasma levels were measured with ELISA. In the mechanistic part, AT biopsies obtained from 8 patients were ex vivo incubated with [18F]FDG followed by autoradiography. Next, a qRT-PCR analysis was performed to determine GLUT and cytokine mRNA expression levels. Immunohistochemistry was performed to determine CD68+ macrophage infiltration and GLUT4 protein expression in AT. RESULTS: In vivo VAT [18F]FDG uptake in patients with T2DM was inversely correlated with HOMA-IR (r = - 0.32, p = 0.034), and positively related to adiponectin plasma levels (r = 0.43, p = 0.003). Ex vivo [18F]FDG uptake in VAT was not related to CD68+ macrophage infiltration, and IL-1ß and IL-6 mRNA expression levels. Ex vivo VAT [18F]FDG uptake was positively related to GLUT4 (r = 0.83, p = 0.042), inversely to GLUT3 (r = - 0.83, p = 0.042) and not related to GLUT1 mRNA expression levels. CONCLUSIONS: In vivo [18F]FDG uptake in VAT from patients with T2DM is positively correlated with adiponectin levels and inversely with IR. Ex vivo [18F]FDG uptake in AT is associated with GLUT4 expression but not with pro-inflammatory markers. The effect of IR should be taken into account when interpreting data of [18F]FDG uptake as a marker for AT inflammation.

Angiogenic T cells are decreased in people with type 2 diabetes mellitus and recruited by the dipeptidyl peptidase-4 inhibitor Linagliptin: A subanalysis from a randomized, placebo-controlled trial (RELEASE study).

Angiogenic T (Tang) cells are mediators of vascular repair, and are characterized by surface expression of CXCR4. This receptor for stromal cell-derived factor-1α (SDF-1α) is cleaved by dipeptidyl peptidase-4 (DPP-4). Tang cell levels were investigated in people with type 2 diabetes mellitus (T2DM) compared with matched healthy controls and after treatment with the DPP-4 inhibitor Linagliptin. People with T2DM were randomized to 5 mg/day Linagliptin (n = 20) or placebo (n = 21) for 26 weeks. Tang cell frequency was identified in peripheral blood mononuclear cells (CD3+ CD31+ CXCR4+ ) and levels of endothelial progenitor cells (EPCs) (CD34+ CD133+ KDR+ ) were also assessed in whole blood. Circulating Tang cell levels were significantly lower in people with T2DM compared with the healthy control group. SDF-1α levels increased significantly in Linagliptin-treated people with T2DM compared to placebo, and a trend was observed in change of Tang cell levels, while EPC count did not change. In conclusion, circulating Tang cell levels were considerably lower in people with T2DM, while a trend was observed in recruitment of Tang cells after 26 weeks of treatment with Linagliptin. These data suggest that DPP-4 inhibitors may potentially exert beneficial effects on bone marrow-driven vascular repair.

Visceral adipose tissue volume is associated with premature atherosclerosis in early type 2 diabetes mellitus independent of traditional risk factors.

BACKGROUND AND AIMS: Type 2 diabetes mellitus (T2DM) is commonly associated with abdominal obesity, predominantly with high visceral adipose tissue (VAT), and is accompanied by premature atherosclerosis. However, the association between VAT and subcutaneous adipose tissue (SAT) with premature atherosclerosis and (i.e. arterial) inflammation is not completely understood. To provide more insight into this association, we investigated the association between arterial 18F-fluordeoxyglucose (FDG) positron emission tomography (PET) uptake, as a measure of arterial inflammation, and metabolic syndrome (MetS) markers in early T2DM patients. METHODS: Forty-four patients with early T2DM, without glucose lowering medication, were studied (median age 63 [IQR 54-66] years, median BMI 30.4 [IQR 27.5-35.8]). Arterial inflammation was quantified using glucose corrected maximum standardized uptake value (SUVmax) FDG of the aorta, carotid, iliac, and femoral arteries, and corrected for background activity (blood pool) as target-to-background ratio (meanTBR). VAT and SAT volumes (cm3) were automatically segmented using computed tomography (CT) between levels L1-L5. Non-alcoholic fatty liver disease (NAFLD) was assessed by liver function test and CT. RESULTS: VAT volume, but not SAT volume, correlated with meanTBR (r = 0.325, p = 0.031). Linear regression models showed a significant association, even after sequential adjustment for potentially influencing MetS components. Interaction term VAT volume * sex and additional components including HbA1c, insulin resistance, NAFLD, adiponectin, leptin, and C- reactive protein (CRP) did not change the independent association between VAT volume and meanTBR. CONCLUSIONS: CT-assessed VAT volume is positively associated with FDG-PET assessed arterial inflammation, independently of factors thought to potentially mediate these effects. These findings suggest that VAT in contrast to SAT is linked to early atherosclerotic changes in T2DM patients.

Performance Evaluation of a Semi-automated Method for [18F]FDG Uptake in Abdominal Visceral Adipose Tissue.

PURPOSE: Severity of abdominal obesity and possibly levels of metabolic activity of abdominal visceral adipose tissue (VAT) are associated with an increased risk for cardiovascular disease (CVD). In this context, the purpose of the current study was to evaluate the reproducibility and repeatability of a semi-automated method for assessment of the metabolic activity of VAT using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/x-ray computed tomography (CT). PROCEDURES: Ten patients with lung cancer who underwent two baseline whole-body [18F]FDG PET/low-dose (LD) CT scans within 1 week were included. Abdominal VAT was automatically segmented using CT between levels L1-L5. The initial CT-based segmentation was further optimized using PET data with a standardized uptake value (SUV) threshold approach (range 1.0-2.5) and morphological erosion (range 0-5 pixels). The [18F]FDG uptake in SUV that was measured by the automated method was compared with manual analysis. The reproducibility and repeatability were quantified using intraclass correlation coefficients (ICCs). RESULTS: The metabolic assessment of VAT on [18F]FDG PET/LDCT scans expressed as SUVmean, using an automated method showed high inter and intra observer (all ICCs > 0.99) and overall repeatability (ICC = 0.98). The manual method showed reproducible inter observer (all ICCs > 0.92), but less intra observer (ICC = 0.57) and less overall repeatability (ICC = 0.78) compared with the automated method. CONCLUSIONS: Our proposed semi-automated method provided reproducible and repeatable quantitative analysis of [18F]FDG uptake in VAT. We expect this method to aid future research regarding the role of VAT in development of CVD.

Effect of linagliptin on pulse wave velocity in early type 2 diabetes: A randomized, double-blind, controlled 26-week trial (RELEASE).

AIMS: To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on aortic pulse wave velocity (PWV) as a surrogate marker of arterial stiffness and early atherosclerosis in people with early type 2 diabetes. METHODS: A total of 45 people with type 2 diabetes (median [interquartile range] age 63 [54-66] years, 61% men, mean ± standard deviation glycated haemoglobin [HbA1c] 6.3% ± 0.4% [45 ± 4.6 mmol/mol]), without cardiovascular disease and naïve to antidiabetic treatment, were randomized (1:1) to treatment with linagliptin 5 mg once daily or placebo for 26 weeks in a double-blind fashion. PWV was assessed at baseline, 4 and 26 weeks of treatment, and again at 30, 4 weeks after treatment. The primary endpoint was between-group difference in PWV (corrected for systolic blood pressure [SBP]) at week 26. Secondary endpoints included differences in central SBP and augmentation index (AIx). RESULTS: Compared with placebo, 26 weeks of linagliptin decreased PWV by an average of 0.91 m/s (95% confidence interval -1.76 to -0.06; P = .035). PWV returned to baseline after 4 weeks washout. Differences in central SBP and AIx were not different between linagliptin and placebo. Linagliptin decreased HbA1c (-0.4%; P < .001), fasting plasma glucose (-0.7 mmol/L; P = .002) and triglycerides (-0.49 mmol/L; P = .019) as compared with placebo. The changes in body weight, cholesterol and high-sensitivity C-reactive protein did not differ between groups. CONCLUSIONS: Linagliptin decreased aortic PWV in people with early-stage type 2 diabetes as compared with placebo after 26 weeks of treatment. These results suggest that linagliptin has a favourable effect on arterial stiffness.

Arterial Stiffness Is Positively Associated With 18F-fluorodeoxyglucose Positron Emission Tomography-Assessed Subclinical Vascular Inflammation in People With Early Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes is accompanied by premature atherosclerosis and arterial stiffness. The underlying association remains incompletely understood. The possible relationship between subclinical arterial inflammation assessed by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and arterial stiffness was investigated in patients with early type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 44), without cardiovascular disease and any type of antidiabetic medication, were studied (median age 63 years [interquartile range 54-66], men:women 27:17). Arterial inflammation was quantified as the FDG uptake maximal standardized uptake value (SUVmax). SUVmax was corrected for the prescan glucose level. A target-to-background ratio (TBR) was calculated by dividing the SUVmax of the arteries by the SUVmean of the caval veins (blood pool). TBRs were calculated for four individual segments (carotid arteries, ascending aorta and aortic arch, descending and abdominal aorta, and iliac and femoral arteries) and averaged for the total aortic tree (meanTBR). Arterial stiffness was assessed as central systolic blood pressure (cSBP), carotid-femoral pulse wave velocity (PWV), and augmentation index (AIx). RESULTS: The meanTBR was significantly associated with PWV (R = 0.47, P = 0.001) and cSBP (R = 0.45, P = 0.003) but not with AIx. TBR of each separate segment was also significantly associated with PWV and cSBP. In a multiple linear regression model including age, sex, BMI, hemoglobin A1c (HbA1c), hs-CRP, cholesterol, cSBP, and PWV, PWV was the strongest determinant of meanTBR. CONCLUSIONS: In patients with type 2 diabetes, FDG-PET/CT-imaged subclinical arterial inflammation is positively associated with determinants of arterial stiffness.