Influence of glycemic control on gain in VO2 peak, in patients with type 2 diabetes enrolled in cardiac rehabilitation after an acute coronary syndrome. The prospective DARE study.

BACKGROUND: Gain in VO2 peak after cardiac rehabilitation (CR) following an acute coronary syndrome (ACS), is associated with reduced mortality and morbidity. We have previously shown in CR, that gain in VO2 peak is reduced in Type 2 diabetic patients and that response to CR is impaired by hyperglycemia. METHODS: We set up a prospective multicenter study (DARE) whose primary objective was to determine whether good glycemic control during CR may improve the gain in VO2 peak. Sixty four type 2 diabetic patients, referred to CR after a recent ACS, were randomized to insulin intensive therapy or a control group with continuation of the pre-CR antidiabetic treatment. The primary objective was to study the effect of glycemic control during CR on the improvement of peak VO2 by comparing first the 2 treatment groups (insulin intensive vs. control) and second, 2 pre-specified glycemic control groups according to the final fructosamine level (below and above the median). RESULTS: At the end of the CR program, the gain in VO2 peak and the final fructosamine level (assessing glycemic level during CR) were not different between the 2 treatment groups. However, patients who had final fructosamine level below the median value, assessing good glycemic control during CR, showed significantly higher gain in VO2 peak (3.5 ± 2.4 vs. 1.7 ± 2.4 ml/kg/min,p = 0.014) and ventilatory threshold (2.7 ± 2.5 vs. 1.2 ± 1.9 ml/kg/min,p = 0.04) and a higher proportion of good CR-responders (relative gain in VO2 peak ≥ 16 %): 66 % vs. 36 %, p = 0.011. In multivariate analysis, gain in VO2 peak was associated with final fructosamine level (p = 0.010) but not with age, gender, duration of diabetes, type of ACS, insulin treatment or basal fructosamine. CONCLUSIONS: The DARE study shows that, in type 2 diabetes, good glycemic control during CR is an independent factor associated with gain in VO2 peak. This emphasizes the need for good glycemic control in CR for type 2 diabetic patients. TRIAL REGISTRATION: Trial registered as NCT00354237 (19 July 2006).

Retinol-binding protein 4 is an independent factor associated with triglycerides and a determinant of very low-density lipoprotein-apolipoprotein B100 catabolism in type 2 diabetes mellitus.

OBJECTIVE: Retinol-binding protein 4 (rbp4) is an adipokine secreted by adipocytes and liver, whose levels are elevated in type 2 diabetes mellitus (T2DM). Plasma levels of rbp4 and triglycerides are strongly correlated in T2DM. However, we do not know whether this association is direct or indirect via liver fat content, and the link between rbp4 and triglyceride metabolism remains unknown. METHODS AND RESULTS: Liver fat measurement by proton spectroscopy was performed in 221 patients with T2DM, and an in vivo kinetic study with stable isotopes was carried out in 14 patients with T2DM. In multivariate analysis, triglycerides were associated positively with rbp4 (ß=0.273, P<0.0001), apolipoprotein (apo) B (ß=0.258, P<0.0001), and liver fat (ß=0.191, P=0.002) and negatively with high-density lipoprotein cholesterol (ß=-0.442, P<0.0001). rbp4 was correlated positively with apoB100 very-low-density lipoprotein (VLDL) pool (r=0.62, P=0.017) and negatively with VLDL-apoB100 total fractional catabolic rate (r=-0.66, P=0.001). In multivariate analysis, rbp4 (P=0.015), plasma triglycerides (P=0.024), and sex (P=0.026) were independently associated with VLDL-apoB100 total fractional catabolic rate. CONCLUSIONS: In T2DM, plasma rbp4 level is associated with plasma triglycerides, independently of liver fat content. There is a strong independent negative correlation between plasma rbp4 and VLDL-apoB100 total fractional catabolic rate. These data suggest that rbp4 may be involved in the pathophysiology of hypertriglyceridemia in T2DM by reducing VLDL catabolism.

Liver methylene fraction by dual- and triple-echo gradient-echo imaging at 3.0T: Correlation with proton MR spectroscopy and estimation of robustness after SPIO administration.

PURPOSE: To assess the systematic errors in liver methylene fraction (LMF) resulting from fat-fat interference effects with dual- and triple-echo gradient-recalled-echo Dual/Triple GRE) sequences and to test the robustness of these sequences after iron overloading. MATERIALS AND METHODS: Forty type-2 diabetic patients underwent LMF measurement by 3.0T ¹H magnetic resonance spectroscopy (corrected for T1 and T2 decays) as the reference standard and liver fat fraction (%Fat) measurement by four Dual/Triple GRE sequences with 20° and 60° flip angle (α), corrected for T1 recovery. The same four sequences were repeated in eight patients after ferumoxide injection. Corrections for systematic errors were determined from the linear regressions (spectroscopy LMF values over Dual/Triple GRE %Fat values). Robustness was tested using Wilcoxon's signed-rank test. RESULTS: Fat-fat interference effects produced a ∼10% relative systematic error and T2* decay produced a 1.9%-4.2% absolute systematic error in LMF. When comparing before and after ferumoxide, dual-echo imaging with α = 20° and α = 60°, even when corrected, showed absolute differences of 7.23% [2.81%-10.25%] (P = 0.0117) and 5.65% [1.89%-8.216.8%] (P = 0.0117), respectively; compared to only 1.17% [0.08%-2.83%] (P = 0.0251) and 1.15% [0.37%-2.73%] (P = 0.2626) with triple-echo imaging and α = 20° and α = 60°, respectively. CONCLUSION: Triple-echo imaging with α = 60° corrected for both T1 recovery and fat-fat interference effects is robust after superparamagnetic iron oxide (SPIO) administration and can reliably quantify LMF.

PNPLA3 polymorphism influences liver fibrosis in unselected patients with type 2 diabetes.

CONTEXT: Recently, it has been shown that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC) and liver fibrosis independent of visceral adiposity and insulin resistance. OBJECTIVE: In this study, we set out to determine whether the PNPLA3 rs738409 polymorphism was associated with liver fibrosis in unselected patients with type 2 diabetes. DESIGN, SETTING AND PARTICIPANTS: Two hundred and thirty-four patients with type 2 diabetes were included in this study. MAIN OUTCOME MEASURES: LFC was evaluated using (1) H-MR spectroscopy; fibrosis was measured using the non-invasive FibroTest(®). RESULTS: Advanced liver fibrosis (stage F2 or above) was observed in 10.2% of the patients while 149 (63.6%) patients had steatosis. The prevalence of steatosis and fibrosis was higher in minor G allele carriers than that in C allele homozygote carriers (70.3 vs 57.1%; P=0.04 and 14.7 vs 7.5%; P=0.07 respectively). In multivariate analysis, the predictive variables for advanced liver fibrosis were age (≥60) (P=0.005), sex (female) (P=0.004) and rs 738409 PNPLA3 polymorphism (P=0.01); body mass index (BMI) and LFC were not associated with liver fibrosis. CONCLUSIONS: This study confirms that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fibrosis was related to the rs738409 polymorphism independent of BMI or LFC.

Identification of an oral microbiota signature associated with an impaired orosensory perception of lipids in insulin-resistant patients.

AIMS: Type 2 diabetes leads to multiple sensory dysfunctions affecting notably the gustatory sensitivity. Although this sensory defect, by impacting food choices, might lead to unhealthy eating behavior, underlying mechanisms remains poorly studied. We have recently reported that the composition of microbiota in contact with circumvallate gustatory papillae might affect the orosensory perception of lipids in lean and normoglycemic obese subjects. This finding has prompted us to explore whether such a phenomenon also occurs in diabetic obese patients. METHODS: The composition of microbiota surrounding the circumvallate papillae was analyzed in combination with the linoleic acid perception thresholds in male insulin-resistant patients and weight-matched healthy controls. Two complementary comparisons were performed: (1) controls vs diabetic and (2) diabetic low-lipid tasters versus diabetic high-lipid tasters. RESULTS: Despite subtle modifications in the oral microbiota composition, comparison of orosensory lipid perception in controls and diabetic subjects did not lead to discriminating data due to the large inter-individual variability of linoleic acid perception thresholds. In contrast, specific bacterial signatures were found by comparing diabetic low- and high-lipid tasters leading to differential molecular pathways. Surprisingly, a lower fatty taste perception was mainly found in patients treated with metformin and/or statins, suggesting a possible side effect of these antidiabetic and/or hypolipidemic drugs on taste acuity. CONCLUSIONS: Collectively, these data show that the diabetic patients with defective fatty taste detection are characterized by a specific microbiota metabolism at the circumvallate papillae levels, this occurrence seeming amplified by drugs commonly used to counteract the damaging metabolic effects of T2D. Trial registration for original previous studies: ClinicalTrials.gov #NCT02028975.

Different criteria of cardiac resynchronization therapy and their prognostic value for worsening heart failure or major arrhythmic events in patients with idiopathic dilated cardiomyopathy.

There are still controversies about pertinent criteria for cardiac resynchronization therapy (CRT) and prophylactic indications for biventricular cardioverter-defibrillators, particularly in idiopathic dilated cardiomyopathy (IDC). This study compared several criteria for resynchronization therapy in IDC among those of several completed trials. In 201 patients with IDC, the relative risk for (1) death from heart failure (HF) or heart transplantation and (2) sudden death or sustained ventricular tachyarrhythmia were calculated separately according to the inclusion criteria of the Multisite Stimulation in Cardiomyopathy (MUSTIC), InSync, Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Pacing Therapies for Congestive Heart Failure (PATH-CHF), Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION), and CONTAK studies. The percentage of patients meeting the criteria ranged from 6% for those of MUSTIC to 23% for those of CONTAK. In a follow-up of 51 +/- 42 months, 28 patients died (15 from progressive HF, 13 from sudden death), 20 underwent heart transplantation, and 12 had sustained ventricular tachyarrhythmia. Relative risks of worsening HF ranged from 3.14 (95% confidence interval [CI] 1.41 to 6.99, p = 0.005) for the MIRACLE criteria to 4.63 (95% CI 1.76 to 12.2, p = 0.0019) for the MUSTIC criteria. Only the CONTAK criteria were significantly associated with a risk for major arrhythmic events (2.65, 95% CI 1.19 to 5.95, p = 0.018). Arrhythmic events constituted 16% of all cardiac events for the MUSTIC patients, 11% for InSync patients, 31% for PATH-CHF patients, 36% for MIRACLE patients, 38% for COMPANION patients, and 42% for CONTAK patients. In conclusion, in IDC, the less restrictive criteria for CRT were associated with the greatest risk for arrhythmic events. In contrast, patients with the MUSTIC criteria for CRT mainly had a risk for worsening HF and may not benefit from biventricular cardioverter-defibrillators.

ApoA-II HDL Catabolism and Its Relationships With the Kinetics of ApoA-I HDL and of VLDL1, in Abdominal Obesity.

We study the associations between apoA-II fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and apoA-I and show that, in abdominally obese individuals, apoA-II FCR is positively and independently associated with both apoA-I FCR and VLDL1-TG indirect FCR.

Liver fat content is negatively associated with atherosclerotic carotid plaque in type 2 diabetic patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is independently associated with atherosclerosis in nondiabetic individuals. In type 2 diabetic patients, the link between fatty liver and atherosclerosis is less clear. Here, we assessed whether liver fat content evaluated using (1)H-magnetic resonance spectroscopy ((1)H-MRS) was independently associated with prevalent carotid plaque as a marker of atherosclerosis in type 2 diabetic patients. METHODS: One hundred and forty-four prospectively enrolled patients with type 2 diabetes underwent liver fat content measurement using (1)H-MRS and carotid plaque assessment using ultrasound. Multiple logistic regressions were used to identify factors associated with carotid plaque. RESULTS: Mean ± SD liver fat content was 9.86±8.12%. Carotid plaque prevalence was 52.1% (75/144). Patients without plaque were younger (P=0.006) and had a smaller visceral fat area (P=0.015), lower reported prevalence of previous cardiovascular events or current statin therapy (P=0.002), and higher liver fat content than those with plaque (P=0.009). By multivariable logistic regression, increased liver fat content independently predicted the absence of carotid plaque [odds ratios (ORs), 0.94; 95% confidence intervals (CIs), 0.89-0.99; P=0.017]. CONCLUSIONS: Liver fat content measured by (1)H-MRS is higher in type 2 diabetic patients without carotid plaque compared to those with plaque. This study suggests that increased liver fat content could be associated with a relative protection against carotid atherosclerosis in patients with type 2 diabetes mellitus.

Obesity interferes with the orosensory detection of long-chain fatty acids in humans.

BACKGROUND: The association between the orosensory detection of lipids, preference for fatty foods, and body mass index (BMI; in kg/m(2)) is controversial in humans. OBJECTIVE: We explored the oral lipid-sensing system and the orosensory-induced autonomic reflex system in lean and obese subjects. DESIGN: Lean (BMI: 19 to <25; n = 30) and obese (BMI >30; n = 29) age-matched men were enrolled. Their oral threshold sensitivity to linoleic acid (LA) was determined by using a 3-alternative forced-choice ascending procedure, and their eating habits were established by the analysis of 4 consecutive 24-h food-consumption diaries. The effect of brief oral lipid stimulations on plasma triglyceride [(TG)pl] concentrations was analyzed in overnight-fasted lean and obese individuals subjected to a whole-mouth stimulation (sip-and-spit procedure) with a control or 1% LA emulsions for 5 min according to a within-subject randomized design. RESULTS: A large distribution of LA detection was shown in both groups. Mean detection thresholds were 0.053% (wt:wt) and 0.071% (wt:wt) in lean and obese subjects, respectively. No relation between the LA detection threshold and BMI was observed. The 5 subjects who detected only the higher concentration of LA (5% wt:wt) or were unable to distinguish properly between control and LA emulsions were obese. An analysis of dietary habits showed that these obese LA nontasters consumed more lipids and energy than did all other subjects. Brief whole-mouth stimulations (sip-and-spit procedure) with a control or 1% LA emulsion revealed an LA-mediated rise in (TG)pl concentrations in overnight-fasted, lean subjects. The origin of this change seemed to be hepatic. This (TG)pl upregulation was not shown in obese subjects, which suggested that obesity led to disturbances in the oral-brainstem-periphery loop. CONCLUSION: Altogether, these data strongly suggest that obesity may interfere with the orosensory system responsible for the detection of free long-chain fatty acids in humans. This trial was registered at clinicaltrials.gov as NCT02028975.

Interrelationships between the kinetics of VLDL subspecies and HDL catabolism in abdominal obesity: a multicenter tracer kinetic study.

CONTEXT: Low plasma high-density lipoprotein (HDL) cholesterol is a major abnormality in abdominal obesity. This relates due to accelerated HDL catabolism, but the underlying mechanism requires further elucidation. The relationships between HDL catabolism and other variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, liver fat, or visceral adiposity, remain to be investigated. OBJECTIVES: Our aim was to study the associations between HDL apolipoprotein (apo)-A-I fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and estimates of liver and visceral and sc fat. DESIGN: We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity. RESULTS: In a multivariate analysis, among the morphological and biological parameters that may predict apoA-I FCR, liver fat (ß = .400, P = .003), and VLDL1-apoB (ß = .307, P = .020) were independently associated with apoA-I FCR. In a multivariate analysis, among the kinetic parameters, VLDL1-triglycerides (TGs) indirect FCR (ß = -.357, P = .001), VLDL1-TG production rate (ß = 0.213, P = .048), and apoA-II FCR (ß = .667, P < .0001) were independently associated with apoA-I FCR. After adjustment for VLDL1-TG production rate, liver fat was no more correlated with apoA-I FCR. No association between apoA-I FCR and visceral fat was observed. CONCLUSIONS: We show that VLDL1 is an important independent determinant of apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and the production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by VLDL1-TG production. These data indicate that, in abdominal obesity, dysfunctional VLDL1 metabolism is an important modulator of HDL apoA-I catabolism.

Specifically PNPLA3-mediated accumulation of liver fat in obese patients with type 2 diabetes.

CONTEXT: Recently, it has been shown in the general population that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC), independently of visceral adiposity and insulin resistance. OBJECTIVE: In this study, we set out to determine whether LFC, evaluated using (1)H-MR spectroscopy, was associated with PNPLA3 rs738409 polymorphism in people with type 2 diabetes. We also evaluated the influence of this polymorphism on the relationship between LFC and either visceral adiposity or carotid intima media thickness (CIMT). DESIGN, SETTINGS, AND PARTICIPANTS: A total of 218 type 2 diabetic patients were included in this study. MAIN OUTCOME MEASURES: LFC, area of visceral fat, and CIMT were measured. RESULTS: A total of 139 (63.7%) patients had steatosis. The rs738409 minor G allele was associated with LFC. The number of patients with steatosis was significantly higher among minor G allele carriers in comparison to C allele homozygote carriers (70.3 vs. 57.2%; P=0.04) In the subgroup of C allele homozygote carriers, LFC correlated with body mass index (r=0.27; P=0.003) and visceral fat area (r=0.30; P=0.002), but not with CIMT. In the subgroup of minor G allele carriers, LFC correlated inversely with CIMT (r=-0.23; P=0.03), but not with body mass index or with visceral fat area. In multivariate logistic regression, the relationship between the highest quartile of CIMT and steatosis was different according to adiponutrin polymorphism. CONCLUSIONS: This study confirms that in people with type 2 diabetes, LFC is related to rs738409 polymorphism. The lack of a relationship with visceral obesity and the inverse correlation with CIMT suggest that fatty liver associated with the minor G allele of the PNPLA3 rs738409 polymorphism may not be linked to metabolic disorders.

Nonalcoholic fatty liver is not associated with carotid intima-media thickness in type 2 diabetic patients.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome, and type 2 diabetes. Several studies suggest that NAFLD is independently associated with an increased risk of cardiovascular disease in nondiabetic subjects. In type 2 diabetic subjects, the link between fatty liver and atherosclerosis is less clear. In this study, we set out to determine, whether fatty liver content, evaluated using 1H-magnetic resonance spectroscopy, a very precise imaging technique, was associated with atherosclerosis in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 101 patients with type 2 diabetes mellitus were included in this study. Liver fat (1H-magnetic resonance spectroscopy) and carotid intima media thickness (IMT) were measured. RESULTS: Sixty-one (60.3%) patients had steatosis (hepatic triglyceride content greater than 5.5%). Liver fat content was correlated with fasting serum triglycerides (r = 0.22; P = 0.02) and alanine aminotransferase (r = 0.42; P = 0.0001). Sixty-eight percent of subjects with severe steatosis (hepatic triglyceride content greater than 15%) had aspartate aminotransferase in the normal range. Age was strongly correlated with IMT (r = 0.37; P = 0.0002). Steatosis did not correlate with IMT (r = -0.03; P = 0.75). There was no significant difference between the two groups (with and without hepatic steatosis) for IMT values. CONCLUSIONS: this study suggests that in people with type 2 diabetes, fatty liver is not associated with cardiovascular disease. In a diabetic population, it seems that fatty liver is not a determinant factor associated with carotid IMT.