Increased adiponectin receptor-1 expression in adipose tissue of impaired glucose-tolerant obese subjects during weight loss.

OBJECTIVE: To investigate the mRNA expression of adiponectin, AdipoR1 and AdipoR2, the two recently cloned adiponectin receptors and peroxisome proliferator activated receptor (PPAR)gamma2 in adipose tissue of obese individuals before and during a very low calorie diet (VLCD) inducing weight loss. METHODS: Twenty-three non-diabetic obese subjects with normal (NGT, n = 11) or impaired glucose tolerance (IGT, n = 12) (age, 47 +/- 3 years; body mass index, 39.3 +/- 1.3 kg/m2) were studied before and after a 3-week 3.9 MJ diet daily without exercise. mRNA levels of nine IGT and six NGT subjects were measured by real-time PCR in s.c. abdominal adipose tissue. RESULTS: Metabolic parameters and insulin sensitivity were improved by VLCD in the IGT group, but minimally affected in the NGT group. VLCD increased expression of AdipoR1 in the IGT (P = 0.02), but not in the NGT group. Adiponectin, AdipoR2 and PPARgamma2 mRNA levels did not change during VLCD in any group. In the IGT, but not in the NGT group, AdipoR1 and AdipoR2 expressions were positively related to that of PPARgamma2 and, after VLCD, AdipoR1 and AdipoR2 expressions were positively related to each other and to that of adiponectin. CONCLUSION: In the NGT group, the 3-week VLCD inducing weight loss did not modify metabolic parameters, insulin sensitivity and the expression of the adiponectin system in adipose tissue. By contrast, in the IGT group, AdipoR1 expression increased and we found a coordinate regulation of the expression of adiponectin and its receptors. These modifications could participate, through adiponectin action on adipocytes, to the improved metabolic parameters observed in IGT subjects.

What kind of simple fasting index should be used to estimate insulin sensitivity in humans?

The hyperinsulinemic euglycemic glucose clamp method is the gold standard for measuring insulin resistance. However it is complex, and simple indexes have been developed. Some of them are based on formulae that calculate the product or the addition of fasting plasma insulin and glucose values whereas others are based on their ratios. We calculated several simple indexes of insulin resistance and compared them to hyperinsulinemic euglycemic clamp data in 111 subjects with a wide range of insulin resistance. We showed that indexes using insulin and glucose ratios in their formulae are poorly correlated with clamp measurements and give false evaluations, particularly in glucose-intolerant and type 2 diabetic subjects. Thus, whatever the glucose profile of study subjects, we suggest the use of a simple index based on the product or the addition of fasting plasma insulin and glucose values instead of their ratios to obtain insulin resistance evaluations close to the hyperinsulinemic euglycemic clamp technique.

[Lipoprotein (a), a cardiovascular risk factor: importance of its determination in current clinical practice]. / La lipoprotéine (a), un facteur de risque cardio-vasculaire: intérêt de sa détermination en pratique courante.

Lipoprotein (a) [Lp(a)] is a LDL-like particle linked to an apo-lipoprotein (a) which has high sequence homology with plasminogen that gives Lp(a) thrombogenic properties in addition to atherogenic capacity. Many epidemiological studies have shown that a high plasma level of Lp(a) is a risk factor for coronary, cerebral and peripheral atherosclerosis. Out of thirteen prospective studies, ten have confirmed this result. The negative results from the three remaining studies were probably due to either inadequate storage of the samples or preventive drug treatment given to the patients during the studies. This review of the literature clearly demonstrates the relationship between Lp(a) and atherosclerosis and the need to measure Lp(a) in order to better evaluate the risk of atherosclerotic vascular disease especially in patients with a hyper LDLemia, an early cardio- or cerebrovascular disease or a family history of atherosclerosis.

[Lipoprotein(a): risk factor for atherosclerotic vascular disease important to take into account in practice]. / La lipoprotéine(a), intérêt de son dosage pour évaluer le risque cardiovasculaire.

Coronary artery disease is a leading cause of death in France. Some of its risk factors are well identified such as age, smoking, high blood pressure and dyslipidemia, but some others such as lipoprotein (a) (Lp(a)) are still under investigation. Lp(a) is an LDL-like particle to which is linked an apolipoprotein (a). The latter shows a high sequence homology with plasminogen that gives Lp(a) thrombogenic properties in addition to its atherogenic capacity. Many epidemiological studies have shown that a high plasma level of Lp(a) is a risk factor for coronary, cerebral and peripheral atherosclerosis. Out of thirteen prospective studies, ten have confirmed this result. The negative results from the three remaining studies were probably due to either the inadequate storage of the samples or the preventive drug treatment given to the patients during the studies and to the lack of standardization of Lp(a) assays. More over it has been shown that beside high plasma Lp(a) level, the presence of a low molecular weight Apo(a) isoform is also related to a higher incidence of coronary artery disease. This review of the literature clearly demonstrates the relationship between Lp(a) and atherosclerosis, and the need to measure Lp(a) in order to better evaluate the risk of atherosclerotic vascular disease especially in patients with a hyper LDLemia an early cardio- or cerebrovascular disease or a family history of atherosclerosis. Management of patients with high Lp(a) concentrations should be directed at minimizing all other risk factors for atherosclerotic disease.

Adiponectin and leptin in Afro-Caribbean men and women with HIV infection: association with insulin resistance and type 2 diabetes.

AIM: Insulin resistance and type 2 diabetes (T2D) are commonly seen in human immunodeficiency virus (HIV) infection and are related to antiretroviral therapy. Adiponectin and leptin secreted by adipocytes are both linked to body-fat distribution and insulin sensitivity. The present study aimed to assess the prevalence of insulin resistance and T2D, and their association with adiponectin and leptin, in Afro-Caribbean men and women with HIV infection. METHODS: This cross-sectional study was conducted in an unselected sample of 237 HIV-1-infected patients. Clinical and metabolic parameters were measured, including fasting and postload plasma insulin, and circulating adiponectin and leptin levels. Insulin resistance was estimated by homoeostasis model assessment (HOMA-IR). Adjusted multiple logistic regressions were used to estimate the association of insulin resistance with adipokine levels and patients' characteristics. RESULTS: A total of 132 men (mean age: 49 years) and 105 women (mean age: 48 years) were included in the study. Prevalences of T2D and insulin resistance were higher in women than in men [16.2% vs 8.3% (P = 0.06) and 24% vs 9.9% (P < 10⁻³), respectively]. Abdominal obesity was found in 47% of women and in 7% of men (P < 10⁻4). Insulin resistance was independently associated with adiponectin in women and with leptin in men. CONCLUSION: Insulin resistance is frequent in Afro-Caribbean women with HIV infection. Overweight and obesity are major risk factors in such a population. Systematic screening for insulin resistance should be carried out in this population, which has a high prevalence of T2D.

Long-term treatment with interleukin-1beta induces insulin resistance in murine and human adipocytes.

AIMS/HYPOTHESIS: Adipose tissue inflammation has recently been implicated in the pathogenesis of insulin resistance and is probably linked to high local levels of cytokines. IL1B, a proinflammatory cytokine, may participate in this alteration. MATERIALS AND METHODS: We evaluated the chronic effect (1-10 days) of IL1B (0.1-20 ng/ml) on insulin signalling in differentiating 3T3-F442A and differentiated 3T3-L1 murine adipocytes and in human adipocytes. We also assessed expression of the gene encoding IL1B in adipose tissue of wild-type and insulin-resistant mice (diet-induced and genetically obese ob/ob mice). RESULTS: IL1B inhibited insulin-induced phosphorylation of the insulin receptor beta subunit, insulin receptor substrate 1, Akt/protein kinase B and extracellular regulated kinase 1/2 in murine and human adipocytes. Accordingly, IL1B suppressed insulin-induced glucose transport and lipogenesis. Long-term treatment of adipose cells with IL1B decreased cellular lipid content. This could result from enhanced lipolysis and/or decreased expression of genes involved in lipid metabolism (acetyl-CoA carboxylase, fatty acid synthase). Down-regulation of peroxisome proliferating-activated receptor gamma and CCAAT/enhancer-binding protein alpha in response to IL1B may have contributed to the altered phenotype of IL1B-treated adipocytes. Moreover, IL1B altered adipocyte differentiation status in long-term cultures. IL1B also decreased the production of adiponectin, an adipocyte-specific protein that plays a positive role in insulin sensitivity. Expression of the gene encoding IL1B was increased in epididymal adipose tissue of obese insulin-resistant mice. CONCLUSIONS/INTERPRETATION: IL1B is upregulated in adipose tissue of obese and insulin-resistant mouse models and may play an important role in the development of insulin resistance in murine and human adipose cells.

Systemic low-grade inflammation is related to both circulating and adipose tissue TNFalpha, leptin and IL-6 levels in obese women.

OBJECTIVE: We assessed the relationships between four circulating acute phase proteins and the circulating and adipose tissue levels of three adipocytokines. SUBJECTS: In all, 15 nondiabetic obese women with a body mass index (BMI) above 32 kg/m(2) were investigated. METHOD: Circulating concentrations of C-reactive protein (CRP), alpha 1 acid glycoprotein (AAG), fibrinogen, alpha 1 antitrypsin and both circulating and adipose tissue levels of interleukin (IL)-6, tumor necrosis factor (TNF)alpha and leptin were measured by either nephelometry or enzyme-linked immunosorbent assay. RESULTS: We found a strong positive correlation between both circulating and adipose tissue levels of IL-6, TNFalpha and leptin and serum CRP levels. All these adipose tissue adipocytokines were also positively correlated with serum AAG levels. These correlations disappeared when adjusted for fat mass, suggesting that the relationship observed was dependent on fat amount. CONCLUSION: Our results indicate a strong relationship between adipocytokines and inflammatory markers, and suggest that cytokines secreted by adipose tissue in obese subjects could play a role in increased inflammatory proteins secretion by the liver.

Effect of slow-release theophylline on nasal antigen challenge in subjects with allergic rhinitis.

It has been recognized recently that theophylline possesses anti-inflammatory effects that could be of clinical interest in patients with airway inflammatory diseases such as asthma and allergic rhinitis (AR). The aim of the present study was to explore the effect of theophylline on the nasal eosinophilic inflammatory response following allergen challenge in patients with AR. Fourteen subjects suffering from seasonal rhinitis with an early reaction after nasal allergen provocation were challenged outside the pollen season after pretreatment for 3 weeks with placebo or slow-release theophylline (Euphylong in a randomized double-blind, cross-over study. Nasal blocking index (NBI), nasal airway resistance and symptoms were recorded before, and 1 and 5 h after challenge; additionally, nasal lavage fluid was collected before, as well as 1 and 5 h after challenge. Eosinophil cationic protein (ECP) was measured in the lavage as well as the number of eosinophils before, and 1 h and 5 h after allergen challenge. After 3 weeks of treatment, baseline concentrations of ECP in nasal lavage amounted to 826+/-329 ng x L(-1) (placebo) and 936+/-351 ng x L(-1) (theophylline). The ECP levels did not increase during the early phase response. Five hours after challenge, ECP in the placebo group increased markedly (p<0.01), whereas no significant increase was observed during theophylline treatment. In parallel, the number of eosinophils in the nasal lavage fluid was lower during theophylline treatment. Additionally, theophylline therapy also significantly reduced the nasal symptoms and had some protective effect against nasal obstruction following allergen challenge. These results confirm the anti-inflammatory effects of theophylline and suggest that these effects may be of clinical benefit in patients with allergic rhinitis.