These data suggest that hyperprolactinaemia is associated with insulin resistance related to increased BMI and low-grade inflammation independently of BMI. Short-term cabergoline therapy can reduce the inflammatory markers.

Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal-regulated kinase (ERK)1/2, and nuclear factor-B (NF-B) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-B. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKCdependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-B pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes. Diabetes

We examined the effects of dietary n-3 polyunsaturated and saturated fatty acids on the development of the atherogenic process in mice and on the macrophage ability to secrete several effector molecules that may be involved in the atherogenic process. The secretion of inflammatory proteins such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) and the production of lipoprotein lipase (LPL), nitrogen oxide (NO2), and prostaglandin E2 (PGE2) were evaluated in peritoneal macrophages isolated from atherosclerosis-susceptible C57BL/6J mice. The mice were assigned at random to three experimental groups: the first group was fed a semi-defined control diet (control diet); the second group was maintained on the control diet supplemented with 10% menhaden oil (menhaden diet); and the third group received the control diet supplemented with 10% palm oil plus 2% cholesterol (saturated fat diet). Macrophages derived from mice fed the menhaden diet showed a suppression of their basal TNF-alpha mRNA expression and production. They also presented a dramatically decreased ability to express TNF-alpha and IL-1 beta mRNAs in response to exposure to lipopolysaccharide (LPS) compared with the macrophages from the control group. LPL mRNA and protein expression were downregulated after 6 and 15 weeks of menhaden-diet feeding. Significantly higher NO2 production in response to interferon gamma was found, both after 6 and 15 weeks of diet feeding, in the menhaden group compared with the control group. In addition, prostaglandin production and macrophage tumoricidal activity in response to LPS were decreased in this group compared with the control group. Macrophages derived from the saturated fat group did not show any significant alterations in TNF-alpha, LPL, NO2, or PGE2 secretion compared with controls. Interestingly, we observed a progressive increase of the LPS-induced IL-1 beta gene expression and secretion among macrophages harvested from mice receiving the dietary supplement of saturated fatty acids. At 6 and 15 weeks histologic examination of the atherosclerotic lesions did not reveal any important lesions in the control and menhaden groups, whereas a gradual development of fatty streaks was observed in the menhaden experimental diets for 10 additional weeks resulted in a major development of lesions in the control group, whereas only slight lesions were observed in the menhaden group.(ABSTRACT TRUNCATED AT 400 WORDS)

Gliclazide administration to NIDDM patients inhibits the increased adhesiveness of diabetic monocytes to endothelial cells and reduces the production of TNF-alpha by these cells. These results suggest that treatment of NIDDM subjects with gliclazide may be beneficial in the prevention of atherosclerosis associated with NIDDM.

Recent data suggest that plasma leptin may represent a cardiovascular risk factor in diabetic patients. To gain further insight into the role of leptin in atherogenesis associated with diabetes, we investigated in the present study the role of this hormone in the regulation of macrophage lipoprotein lipase (LPL), a proatherogenic cytokine overexpressed in patients with type 2 diabetes. Treatment of human macrophages with leptin (1-10 nmol/l) increased LPL expression, at both the mRNA and protein levels. Pretreatment of these cells with anti-leptin receptor (Ob-R) antibody, protein kinase C (PKC) inhibitors, calphostin C, and GF109203X, or the antioxidant N-acetylcysteine (NAC) blocked the effects of leptin. Similar results were observed in leptintreated J774 macrophages. In these cells, leptin increased the membrane expression of conventional PKC isoforms and downregulation of endogenous PKC expression abolished the effects of leptin on macrophage LPL expression. In leptin-treated J774 cells, enhanced LPL synthetic rate and increased binding of nuclear proteins to the activated protein-1 (AP-1) consensus sequence of the LPL gene promoter were also observed. This latter effect was abrogated by GF109203X. Overall, these data demonstrate that binding of leptin at the macrophage cell surface increases, through oxidative stress-and PKC-dependent pathways, LPL expression. This effect appears to be exerted at the transcriptional level and to involve AP-1 activation.

Abstract-Lectin-like oxidized LDL receptor-1 (LOX-1) is a newly identified receptor for oxidized LDL that is expressed by vascular cells. LOX-1 is upregulated in aortas of diabetic rats and thus may contribute to the pathogenesis of human diabetic atherosclerosis. In this study, we examined the regulation of human monocyte-derived macrophage (MDM) LOX-1 expression by high glucose and the role of LOX-1 in glucose-induced foam cell formation. Incubation of human MDMs with glucose (5.6 to 30 mmol/L) enhanced, in a dose-and time-dependent manner, LOX-1 gene and protein expression. Induction of LOX-1 gene expression by high glucose was abolished by antioxidants, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear factor-B (NF-B), and activated protein-1 (AP-1) inhibitors. In human MDMs cultured with high glucose, increased expression of PKC␤ 2 and enhanced phosphorylation of extracellular signal-regulated protein kinase 1/2 was observed. Activation of these kinases was inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the PKC␤ inhibitor LY379196. High glucose also enhanced the binding of nuclear proteins extracted from human MDMs to the NF-B and AP-1 regulatory elements of the LOX-1 gene promoter. This effect was abrogated by NAC and PKC/MAPK inhibitors. Finally, high glucose induced human macrophage-derived foam cell formation through a LOX-1-dependent pathway. Overall, these results demonstrate that high glucose concentrations enhance LOX-1 expression in human MDMs and that this effect is associated with foam cell formation. Pilot data showing that MDMs of patients with type 2 diabetes overexpress LOX-1 support the relevance of this work to human diabetic atherosclerosis. Key Words: macrophages Ⅲ lectin-like oxidized low-density lipoprotein receptor-1 Ⅲ glucose Ⅲ diabetes Ⅲ foam cell formation T he prevalence, incidence, and mortality from all forms of cardiovascular diseases are increased in patients with diabetes. 1 Among the cardiovascular risk factors documented in diabetes, hyperglycemia appears as an independent risk factor for diabetic macrovascular complications. 2 Mechanisms through which hyperglycemia may promote the development of diabetic cardiovascular disease include glycoxidation and lipoxidation, increased oxidative stress, and protein kinase C (PKC) activation. [3][4][5][6][7][8] One of the earliest events in atherogenesis is the accumulation of oxidized LDL (oxLDL) in the intima and the subsequent uptake of this modified lipoprotein by macrophages, leading to foam cell formation. 9 One limiting factor for oxLDL uptake by endothelial cells is lectin-like oxLDL receptor-1 (LOX-1), a newly identified vascular receptor for oxLDL. 10 -12 Accumulating evidence indicates a key role for LOX-1 in atherogenesis. First, uptake of oxLDL by endothelial cells through LOX-1 induces endothelial dysfunction. Second, the two main LOX-1 ligands, oxLDL and advanced glycation end products (AGE), are implicated in the pathogenesis of atherosclerosis. 5,9 Third, expression of LOX-1 b...

Objective: To document the double burden of malnutrition and cardiometabolic risk factors (CMRF) in adults and its occurrence according to different sociodemographic parameters. Design: Population-based cross-sectional observational study. We first randomly selected 330 households stratified by tertile of the income levels proxy as low, middle and high income. Setting: Northern district of Ouagadougou, the capital city of Burkina Faso. Subjects: In each income stratum, 110 individuals aged 25-60 years and who had lived permanently in Ouagadougou for at least 6 months were randomly selected, followed with collection of anthropometric, socio-economic and clinical data, and blood samples. Results: The overall obesity/overweight prevalence was 24?2 % and it was twice as high in women as in men (34?1 % v. 15?5 %, P , 0?001). Hypertension, hyperglycaemia and low HDL cholesterol prevalence was 21?9 %, 22?3 % and 30?0 %, respectively, without gender difference. The prevalence of the metabolic syndrome was 10?3 %. Iron depletion and vitamin A deficiency affected 15?7 % and 25?7 % of participants, respectively, with higher rates in women. Coexistence of at least one nutritional deficiency and one CMRF was observed in 23?5 % of participants, and this 'double burden' was significantly higher in women than in men (30?4 % v. 16?1 %, P 5 0?008) and in the low income group. Conclusions: CMRF are becoming a leading nutritional problem in adults of Ouagadougou, while nutritional deficiencies persist. The double nutritional burden exacerbates health inequities and calls for action addressing both malnutrition and nutrition-related chronic diseases.

A population-based cross-sectional study was carried out in the northern neighbourhoods of Ouagadougou (Burkina Faso), to examine the relationship of nutritional deficiencies and cardiometabolic risk factors (CMRF) with lifestyle in adults. We randomly selected 330 households stratified by income tertile. In each income stratum, 110 individuals aged 25–60 years and having lived in Ouagadougou for at least 6 months were randomly selected. We performed anthropometric, dietary intake and physical activity measurements, and blood sample collection. Cluster analysis of dietary intake identified two dietary patterns: ‘urban’ (29 % of subjects) and ‘traditional’ (71 %). The ‘urban’ cluster exhibited a higher intake of fat and sugar, whereas a higher intake of plant protein, complex carbohydrate and fibre was observed in the ‘traditional’ pattern. Female sex, low income and lack of education were associated with the ‘traditional’ cluster, as well as Fe and vitamin A deficiency. CMRF prevalence (abdominal obesity, hypertension, hyperglycaemia, dyslipidaemia) was similar in both clusters. Subjects in the ‘traditional’ cluster spent more time in physical activity and had less sedentary time than those in the ‘urban’ cluster. ‘Traditional’ dietary pattern, low income, female sex and sedentary time were significant contributing factors to the double burden of malnutrition. The rapid nutrition transition is reflected in this co-occurrence of CMRF and nutritional deficiencies. This stresses the need for prevention strategies addressing both ends of the nutrition spectrum.