As highlighted by the International Diabetes Federation, abdominal obesity is a significant underlying cause of the cluster of cardiovascular and metabolic risk factors that comprise the metabolic syndrome. This association is largely due to an increase in intra-abdominal adipose tissue. Intra-abdominal adipose tissue is linked to several cardiometabolic risk factors via multiple pathways. Increased lipolysis raises systemic free fatty acid levels and through a link to the liver via the portal vein, intra-abdominal adipose tissue does the same. This results in hepatic insulin resistance, increased small, dense LDL particles, and reduced HDL cholesterol.
Oral cannabinoid therapy reduces progression of atherosclerosis Apr 7, 2005 Michael O'Riordan Geneva, Switzerland - Treatment with low-dose -9-tetrahydrocannabinol (THC) significantly reduced atherosclerotic disease progression in mice, exerting its influence through a pleiotropic effect on immune function, according to the results of a recent study. Researchers suggest that THC and other cannabinoids, which are active at CB2, the cannabinoid receptor expressed on immune cells, may be valuable in treating atherosclerosis. &quot;We have shown that relatively low doses of THC initiated after manifestation of clinically detectable artery lesions significantly inhibit atherosclerosis progression in mice,&quot; write Dr Sabine Steffens (University Hospital, Geneva, Switzerland) and colleagues in the April 6, 2005 issue of Nature . &quot;This antiatherosclerotic effect is probably mediated by the CB2 receptor, as it is strongly expressed by macrophages and T lymphocytes within atherosclerotic lesions. Furthermore, the inhibitory effects of THC on atherosclerosis progression are abolished in the presence of a CB2-receptor antagonist.&quot; Previous studies have highlighted various immunosuppressive and anti-inflammatory effects of THC, the major active component of marijuana. In support of the immunomodulatory role of cannabinoids, the CB2 receptor has been identified on several types of immune cells, including -cells, T-cells, and monocytes. The researchers hypothesized that THC could alter inflammatory processes crucial in atherosclerosis, thus limiting disease progression. In this study, Steffens and colleagues fed apolipoprotein-E-knockout mice a high-cholesterol diet for five weeks. After five weeks, half of the mice were treated with 1 mg/kg THC for six weeks and the other half served as controls. After 11 weeks on the high-cholesterol diet, there was a marked progression of atherosclerotic lesions in the aortic roots of the control mice, but disease progression was significantly slowed in the THC-treated mice. To confirm that the antiatherosclerotic effect was mediated through the CB2 receptor, experiments were performed with THC in the presence of a CB2 antagonist. They found that the inhibitory effect of THC on atherosclerotic lesion progression was completely abolished in the presence of the antagonist. To unravel the possible mechanism of action, an analysis of the lesions in the THC-treated mice revealed these mice had fewer plaque-infiltrating macrophages than the control mice. Vascular microscopy also revealed significantly reduced leukocyte adhesion in the mice treated with THC, suggesting an effect on immune function, write the authors. These immunosuppressive properties of THC were confirmed in vitro, with spleen cells extracted from the mice showing limited proliferation and impaired production of interferon- , a cytokine involved in atherosclerosis, and reduced leukocyte migration. The results, conclude Steffens et al, suggest that cannabinoid therapy that specifically targets the CB2 receptor may represent a potential target for treating atherosclerosis. Smoking marijuana still bad for you! Dr Michael Roth (David Geffen School of Medicine, Los Angeles, CA), the author of an accompanying News and Views with the published paper, said it is important not to misinterpret the data. &quot;The findings by Steffens et al are striking, but they should not be taken to mean that smoking marijuana is beneficial for the heart,&quot; he cautioned. &quot;The dose-response curve to THC in this study was very narrow and U-shaped, with higher and lower concentrations failing to produce protective effects. It would be difficult to achieve such specific concentrations in the blood by smoking marijuana.&quot; Roth notes that THC binds to and activates the CB1 and CB2 receptors with similar affinity. Smoking marijuana exerts its psychotropic influence mainly by binding to CB1 receptors in the brain, resulting in an increase in blood pressure and pulse rate. &quot;These effects lower the exercise threshold for angina and are an independent risk factor for heart attack and stroke,&quot; he writes. Moreover, smoking marijuana also increases the concentration of carboxyhemoglobin in the blood, impairing oxygen delivery. He agreed with the researchers, writing that the advantage of these positive effects will mean developing drugs that target the CB2 receptor alone. Sources Steffens S, Veillard NR, Arnaud C, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005; 434; 782-786. Roth MD. Marijuana and your heart. Nature 2005; 434:708-709.
RIO-Diabetes: Rimonabant effective in patients with type 2 diabetes Jun 13, 2005 Michael O'Riordan San Diego, CA - Another piece of the rimonabant puzzle fell into place this past weekend, with researchers providing data on the use of the selective CB1 endocannabinoid blocker in patients with type 2 diabetes. This most recent study, presented at the American Diabetes Association annual meeting in San Diego, CA, showed that the drug improves glycemic control and reduces body weight, waist size, and other lipid parameters in a group of overweight type 2 diabetic patients. &quot;I think we have a new approach with rimonabant that targets multiple cardiovascular risk factors in these high-risk type 2 diabetic subjects,&quot; said lead investigator Dr André Scheen (University of Liège, Belgium). &quot;The drug was able to achieve better glycemic control and, in contrast to other drugs, was able to obtain better weight and waist reduction, which is very important in these patients.&quot; First study of rimonabant in diabetic patients Dr André Scheen The RIO-Diabetes trial, as the study is known, is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial comparing 5 mg and 20 mg of rimonabant with placebo in type 2 diabetic subjects for a period of one year. In total, 1045 individuals were included in the study, which was conducted in 150 centers in 11 countries. The primary end point of the trial was change in body weight and waist circumference; secondary end points included changes in HbA1c levels and other risk factors such as dyslipidemia, blood pressure, and metabolic syndrome. All patients included in the study were on background antidiabetic therapy metformin or one of several sulfonylurea drugs for at least six months before study entry and a hypocaloric diet of approximately 600 kcal per day. During the late-breaking clinical trials session, data were presented only on the 20-mg dose, as the effects observed with the 5-dose were deemed &quot;modest,&quot; said Scheen. After one year, significant reductions in weight and waist circumference were observed, with rimonabant reducing body weight by more than 5 kg. Approximately half of the patients treated with the drug lost at least 5% of their baseline body weight. Similar reductions were also observed in the other rimonabant nondiabetic studies, but these newest results show the agent is capable of tackling weight in a group of patients typically resistant to weight-loss efforts, Scheen said. Patients treated with rimonabant 20 mg also achieved a significant reduction in HbA1c levels compared with placebo. From an average baseline value of 7.3%, which Scheen called &quot;good control of blood glucose levels in this patient population,&quot; HbA1c levels were further reduced 0.7%, a significant reduction (p<0.001). Scheen noted that 43% reduced HbA1c to less than 6.5%, despite already being treated with other antidiabetic agents. Changes in weight and waist size in the rimonabant- and placebo-treated groups End point Rimonabant 20 mg (n=339) Placebo (n=348) p Weight (kg) -5.3 -1.4 <0.001 Waist circumference (cm) -5.2 -1.9 <0.001 HDL cholesterol and triglyceride parameters in the rimonabant- and placebo-treated groups End point Rimonabant 20 mg (n=339) Placebo (n=348) Percent difference (compared with placebo) p Change in HDL cholesterol (mg/dL) 6.6 2.7 8.4 <0.001 Change in triglycerides (mg/dL) -31.2 3.6 16.4 <0.001 To download tables as slides, click on slide logo below Investigators report that the reduction in HbA1c levels could not be explained away by reductions in body weight. Statistical analyses showed that the effect of the reduction was independent of weight loss, with approximately 0.4% of the reduction attributed to an independent effect associated with the use of rimonabant. In addition to improvements in HDL cholesterol and triglyceride levels, the researchers also found reductions in systolic blood pressure and in the number of patients with the metabolic syndrome. Scheen pointed out that safety and tolerability data in RIO-Diabetes are similar to data presented in the RIO-Europe , RIO-North America , and RIO-Lipids studies, all part of Sanofi-Aventis's phase 3 program for the drug. The most common side effect in this most recent study was nausea and vomiting, which led to discontinuation in 1.5% of patients in the rimonabant 20-mg group. Drug action beneficial for diabetic patients During a morning press conference discussing the results, Scheen explained that rimonabant exerts its beneficial effects in diabetic patients in the brain but also in adipose tissue, the gastrointestinal tract, liver, and muscle. All these targets may help to reduce diabetic dyslipidemia, insulin resistance, and intra-abdominal fat. Scheen stressed that mechanisms are still being studied. Regarding treatment, he added the data are limited but currently point to using rimonabant in combination with metformin or sulfonylurea. He added that as type 2 diabetes is a chronic disease, rimonabant would likely be prescribed long term, much like a statin in the treatment of hypercholesterolemia.
Women @ Heart - The Link Between Visceral Fat and Athersicerosis
Women @ Heart The link between visceral fat and Athersclerosis By Ashraf Reda MD Prof and Head of Cardiology Dep Menofia university
<ul><li>Describe the pathophysiology of intra-abdominal adiposity. </li></ul><ul><li>Define the role of intra-abdominal adiposity as a major cause of cardiometabolic disease. </li></ul><ul><li>Discuss current research related to CB1 blockade as a novel approach to cardiometabolic disease management. </li></ul>
Effect of plasma FFA FFA TG Adipose tissue FFA HL HL HDL3 HDL2 LDL LDL VLDL Liver TG CE CETP TG CE CETP
Dyslipidemia not hyperlipidemia <ul><li>We have to think both quantitavely and qualitatively </li></ul><ul><li>Looking at total cholesterol or LDL level is not enough </li></ul>
Lipid profile among patients with ACS in cardiology dep. Menofia university TC < 200mg/dl 25/40 62.5 160.3 No % Mean (mg/dl) Mean BNP 943.2 (N: up to 350) TC > 200mg/dl 15/40 37.5 238.9 Mean BNP 1376 Data from file: Reda et al 2003 TGs < 200 32/40 80 137.2 Mean BNP 988 TGs > 200 8/40 20 254 Mean BNP 1599.7
Abdominal obesity and not BMI Body fat distribution not body weight
--- --- Adiponectin TNF-a Muscle Adipose tissue ---- ---- FA oxidation FFA clearance Glucose uptake Insulin sensetivity + + CB1 Lipoprotein lipase activity Fat accumulation in adipose T Adeponectin
Activation of CB2 receptor may stop atherosclerosis progression eg: TetraHydroCannabinol (THC) by stimulating CB2 in mice Smoking marijuana still bad for you! <ul><li>Oral cannabinoid therapy reduces progression of atherosclerosis </li></ul>but <ul><li>Blocking CB1 receptors can decrease intraabdominal obesity </li></ul>
Blocking the over-activated endocannbinoid system CB1 blockade Central CB1 Blockade Perepheral CB1 blockade (Adipose tissue) Eess abdominal fat Adeponectin Insulin Resistence Alter the atherogenic lipid profile CRP Food intake
Changes in weight and waist size in the rimonabant- and placebo-treated groups Scheen A. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA. <0.001 -1.9 -5.2 Waist circumference (cm) <0.001 -1.4 -5.3 Weight (kg) p Placebo (n=348) Rimonabant 20 mg (n=339) End point
HDL cholesterol and triglyceride parameters in the rimonabant- and placebo-treated groups Scheen A. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA. <0.001 16.4 3.6 -31.2 Change in triglycerides (mg/dL) <0.001 8.4 2.7 6.6 Change in HDL cholesterol (mg/dL) p Percent difference (compared with placebo) Placebo (n=348) Rimonabant 20 mg (n=339) End point
<ul><li>Higher subcutaneous adipose tissue as well as higher intermuscular adipose tissue was significantly associated with metabolic syndrome in normal-weight and overweight, but not in obese, men, and not in women. </li></ul>Visceral, subcutaneous fat linked to metabolic syndrome, even in normal-weight individuals Apr 11, 2005 Shelley Wood <ul><li>The association between higher visceral fat and metabolic syndrome was particularly noticeable in normal-weight and overweight men and women, but less so in the obese. </li></ul>
<ul><li>Describe the pathophysiology of intra-abdominal adiposity. </li></ul><ul><li>Define the role of intra-abdominal adiposity as a major cause of cardiometabolic disease. </li></ul><ul><li>Discuss current research related to CB1 blockade as a novel approach to cardiometabolic disease management. </li></ul>CONCLUSIONS