Jean Michel Petit

Adiponectin Is an Important Determinant of ApoA-I Catabolism

Objective—Plasma concentration of adiponectin is positively correlated with high-density lipoprotein (HDL) cholesterol level. However, the role of adiponectin on HDL metabolism remains unknown. This prompted us to perform an in vivo kinetic study of apoA-I, the main apolipoprotein of HDL, using stable isotopes, in 22 subjects with a wide range of plasma adiponectin, including 11 patients with metabolic syndrome (8 with type 2 diabetes, 3 without type 2 diabetes) and 11 normal individuals. Methods and Results—In the 22 studied subjects, plasma adiponectin levels ranged from 2.57 to 14.44 &mgr;g/mL and apoA-I fractional catabolic rate (FCR) values ranged from 0.142 to 0.340 day−1. A strong negative correlation was found between adiponectin and apoA-I FCR (r=−0.66, P<0.001) in the whole studied population and, to a similar extent, in patients with metabolic syndrome (r=−0.73, P=0.010) and normal subjects (r=−0.68, P=0.020), separately. In multivariable analysis, apoA-I FCR was associated negatively with adiponectin (P=0.005) and positively with HDL triglycerides/cholesterol ratio (P=0.006), but not with age, sex, body mass index (BMI), waist circumference, plasma triglycerides, HDL cholesterol, fasting glycemia, and QUICKI. Both adiponectin and HDL triglycerides/cholesterol ratio explained 62% of the variance of apoA-I FCR and adiponectin on its own explained 43%. Conclusions—Our kinetic study shows a strong negative correlation between adiponectin and apoA-I FCR, which can explain the positive link between HDL cholesterol and adiponectin. This association is independent of obesity, insulin resistance, and the content of triglycerides within HDL particles. These data suggest that adiponectin may have a direct role on HDL catabolism.

Association between Insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy

Summary: Insulin resistance (IR) in the context of highly active antiretroviral therapy (HAART) is becoming more common in HIV‐infected patients. Patients with chronic hepatitis C virus (HCV) infection have an increased risk of IR and type 2 diabetes mellitus. A cross‐sectional study was performed to investigate whether chronic HCV infection constitutes a risk factor for IR in HIV‐HCV‐coinfected patients undergoing HAART. Inclusion criteria were positive HCV viremia and a sustained increase of alanine aminotransferase of at least twice the normal value. A total of 29 HIV‐HCV patients, 76 HIV patients, and 121 HCV controls were tested for IR and body mass index (BMI). IR was measured using the homeostasis model assessment. In HIV‐HCV and HIV patients, fat redistribution and lipid profile were assessed. There was no significant difference in age, CD4 cell count, HIV viral load, or duration of HAART between the HIV‐HCV and HIV groups. HIV‐HCV patients and HCV controls had a significant increase in IR when compared with HIV patients (0.25 ± 0.28 and 0.21 ± 0.34 versus 0.04 ± 0.37; p = .01 and p = .003, respectively). Lipoatrophy was observed more frequently in HIV‐HCV patients in comparison with HIV patients (41% versus 14%; p = .003). In HIV‐HCV patients, total cholesterol and triglyceride levels were significantly lower than in HIV patients. In multivariate analysis, IR, BMI, triglyceride levels, and peripheral fat wasting were the independent variables associated with HCV infection. Our findings suggest that chronic HCV infection is a significant factor associated with the development of metabolic abnormalities and with modifications in body composition in HIV patients receiving antiretroviral treatment.

Visceral fat area as a new independent predictive factor of survival in patients with metastatic renal cell carcinoma treated with antiangiogenic agents.

Purpose. A better identification of patients who are more likely to benefit from vascular endothelial growth factor-targeted therapy is warranted in metastatic renal cell carcinoma (mRCC). As adipose tissue releases angiogenic factors, we determined whether parameters such as visceral fat area (VFA) were associated with outcome in these patients. Experimental Design. In 113 patients with mRCC who received antiangiogenic agents (bevacizumab, sunitinib, or sorafenib) (n = 64) or cytokines (n = 49) as first-line treatment, we used computed tomography to measure VFA and subcutaneous fat area (SFA). We evaluated associations linking body mass index (BMI), SFA, and VFA to time to progression (TTP) and overall survival (OS). Results. High SFA and VFA values were significantly associated with shorter TTP and OS. By multivariate analysis, high VFA was independently associated with shorter TTP and OS. These results were internally validated using bootstrap analysis. By contrast, VFA was not associated with survival in the cytokine group. In the whole population, interaction between VFA and treatment group was significant for TTP and OS, thereby confirming the results. Conclusion. Our study provides the first evidence that high VFA could be a predictive biomarker from shorter survival in patients given first-line antiangiogenic agents for mRCC.

Macrovascular Disease Is Associated With Increased Plasma Apolipoprotein A-IV Levels in NIDDM

Apolipoprotein A-IV (apoA-IV) might play an important role in lipoprotein metabolism, including modulation of triglyceride-rich lipoprotein catabolism, reverse cholesterol transport and cholesteryl ester transfer protein (CETP) activity. Increased apoA-IV levels have been reported in plasma from NIDDM patients. The aim of the present study was to look for a possible association between plasma apoA-FV level and prevalence of macrovascular disease in NIDDM. One hundred and thirty-six NIDDM patients were studied (71 men, 65 women). Macrovascular disease was assessed in each patient by a standardized questionnaire, physical examination, resting electrocardiogram (ECG), and laboratory evaluation (ankle/arm blood pressure ratio, continuous wave Doppler velocimetry). Moreover, patients without any history of coronary heart disease and showing a normal resting ECG underwent a bicycle exercise test or a dipyridamole thallium scintigraphy to detect possible silent myocardial ischemia. Among the 136 NIDDM patients, 56 had macrovascular disease. ApoA-IV levels were significantly higher in NIDDM patients with macrovascular disease than in NIDDM patients without macrovascular disease (20.9 ± 8.6 vs. 13.3 ± 5.3 mg/dl; P < 0.001). The influence of different factors, such as age, BMI, cigarette smoking, hypertension, total cholesterol, triglycerides, HDL cholesterol, apoA-IV level, apoA-IV phenotype, fasting glycemia, fasting C-peptide, and microalbuminuria, on the prevalence of macrovascular disease was analyzed using a logistic regression model. In the univariate analysis, apoA-IV level (P < 0.00001), age (P = 0.0087), hypertension (P = 0.012), microalbuminuria (P = 0.018), triglycerides (P = 0.02), and fasting C-peptide (P = 0.03) were positively associated with macrovascular disease. In the multivariate analysis, macrovascular disease was positively associated only with apoA-IV (P < 0.0001) and age (P = 0.003) and negatively associated with HDL cholesterol (P = 0.013). These results indicate that increased plasma apoA-IV level is associated with an increased prevalence of macrovascular disease in NIDDM. Moreover, apoA-IV, in NIDDM patients, appears to be a better marker for macrovascular disease than triglycerides.

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 (&bgr;=0.273, P<0.0001), apolipoprotein (apo) B (&bgr;=0.258, P<0.0001), and liver fat (&bgr;=0.191, P=0.002) and negatively with high-density lipoprotein cholesterol (&bgr;=−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. Conclusion—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.

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.

HCV and Diabetes Mellitus: Influence of Nosocomial Transmission With the Use of a Finger Stick Device

HCV and Diabetes Mellitus: Influence of Nosocomial Transmission With the Use of a Finger Stick Device

Specific phenotype associated with diabetes mellitus secondary to chronic hepatitis C infection

Aim  A link between chronic hepatitis C virus (HCV) infection, Type 2 diabetes mellitus and insulin resistance has been suggested by several studies. However, HCV infection appears to be associated with insulin resistance but not with the metabolic syndrome. The aim of this study was to determine whether chronic HCV infection had an impact on the clinical characteristics of Type 2 diabetes.

3q27.3 microdeletional syndrome: a recognisable clinical entity associating dysmorphic features, marfanoid habitus, intellectual disability and psychosis with mood disorder

Background Since the advent of array-CGH, numerous new microdeletional syndromes have been delineated while others remain to be described. Although 3q29 subtelomeric deletion is a well-described syndrome, there is no report on 3q interstitial deletions. Methods We report for the first time seven patients with interstitial deletions at the 3q27.3q28 locus gathered through the Decipher database, and suggest this locus as a new microdeletional syndrome. Results The patients shared a recognisable facial dysmorphism and marfanoid habitus, associated with psychosis and mild to severe intellectual disability (ID). Most of the patients had no delay in gross psychomotor acquisition, but had severe impaired communicative and adaptive skills. Two small regions of overlap were defined. The first one, located on the 3q27.3 locus and common to all patients, was associated with psychotic troubles and mood disorders as well as recognisable facial dysmorphism. This region comprised several candidate genes including SST, considered a candidate for the neuropsychiatric findings because of its implication in interneuronal migration and differentiation processes. A familial case with a smaller deletion allowed us to define a second region of overlap at the 3q27.3q28 locus for marfanoid habitus and severe ID. Indeed, the common morphological findings in the first four patients included skeletal features from the marfanoid spectrum: scoliosis (4/4), long and thin habitus with leanness (average Body Mass Index of 15 (18.5<N<25)) (4/4), arachnodactyly (3/4) and pectus excavatum (2/4)). This phenotype could be explained by the deletion of the AHSG gene, which encodes a secreted protein implicated in bone maturation and the TGFb signalling pathway. Conclusions We report on a new microdeletional syndrome that associates with a recognisable facial dysmorphism and marfanoid habitus including scoliosis, neuropsychiatric disorders of the psychotic spectrum and moderate to severe ID.

Uptake in the pancreatic uncinate process on the : How to distinguish physiological from pathological uptake?111: How to distinguish physiological from pathological uptake?in-octreotide scintigraphy: How to distinguish physiological from pathological uptake?

Background The aim of this study was to assess the relevance of physiological 111In-octreotide uptake in the head of pancreas and to establish its imaging features in comparison with pathological uptake in patients with neuroendocrine tumors (NET). Patients and methods We retrospectively reviewed all patients that underwent 111In-octreotide single-photon emission tomography (SPECT) scintigraphy in our institution. Only patients with an isolated uptake in the head of the pancreas were included. 111In-octreotidescintigraphy consisted in planar whole-body and abdominal SPECT/computed tomography (CT) images acquired at 6 and 30 h’ postinjection. Different imaging features of the pancreatic focalized uptake were assessed: its precise location on the pancreas head, shape, intensity [visually and quantitatively by calculating the pancreatic to hepatic uptake ratio (L/H ratio)] and intensity changes. Results Thirteen patients out of 230 were included. Among them, a pancreatic NET was confirmed in five patients. On 111In-octreotide SPECT/CT, two of these had uptake located in the uncinate process, and three had uptake focused in the right lateral borders or in the whole head. SPECT images demonstrated high uptake (L/H ratio >2) in four patients out of five. In the eight remaining patients, pancreatic NET was ruled out. For all of these physiological cases, SPECT/CT acquisitions revealed that the uptake was both located in the uncinate process and with an L/H ratio below 2. Conclusion The simple criteria of localization and uptake quantification can help to discriminate between a possible physiological uptake in the uncinate process of the pancreatic head and a pathological uptake induced by a NET.