Key questions resulting from the JUPITER trial assessing cardiovascular disease intervention with rosuvastatin

This paper presents an analysis of the recently published Justification for the Use of statins in Prevention (JUPITER: an intervention trial evaluating rosuvastatin) trial, which tested the statin rosuvastatin in apparently healthy individuals with no prior cardiovascular (CVD) disease and with normal plasma low density lipoprotein (LDL) cholesterol concentrations but with raised plasma high sensitivity C-reactive protein (hsCRP) levels. The rate of the combined primary CVD endpoint was significantly reduced in the treatment arm after a median of under 2 years. The JUPITER trial is distinct from previous studies examining statin use in primary prevention groups because the target group for drug therapy was apparently healthy men and women at low or intermediate risk for developing CVD. On the basis of JUPITER’s findings, there are key questions that should be assessed on the therapeutic intervention of CVD regarding: the primary prevention groups that should be targeted for statin therapy, the utility of targets in addition to plasma LDL cholesterol levels, and the need to consider the metabolic state of individuals targeted for therapy (including the presence of obesity and inflammation). The conclusion from the current analysis is that the JUPITER results warrant further LDL cholesterol lowering than is currently targeted in primary prevention groups that have a pre-existing condition or lifestyle that elevates CVD risk but still do not have a high global CVD risk (as assessed with current algorithms). This group is not captured in current widely used CVD risk calculations, however, with the identification of useful biomarkers, such as hsCRP, this group can be better identified and targeted for intervention

The impairment of glucoregulatory responses to stress in diabetes

grantor: University of TorontoIn diabetic dogs, during centrally-induced stress, glycemic control deteriorates substantially because the metabolic clearance rate of glucose (MCR) does not increase to match the rise in glucose production, as it does in normal dogs. This thesis examined whether defective MCR responses in diabetes during stress can be ameliorated by: (1) acute correction of hyperglycemia with basal insulin; (2) beta-adrenergic blockade; and (3) normoglycemic hyperinsulinemic clamps. With correction of hyperglycemia with basal insulin, glycemic control deteriorated because MCR did not rise during stress. Beta-blockade, with basal insulin infusion, prevented deteriorating glycemia, since MCR responses were nearly normalized and the increment in glucose production was suppressed. Normoglycemic hyperinsulinemic clamps prevented deteriorating glycemia by suppressing the glucose production rise, but MCR responses were not improved. Thus, beta-blockade, but not the acute correction of hyperglycemia with basal insulin, nor normoglycemic hyperinsulinemic clamps, prevented deteriorating glycemia during stress in diabetes by near-normalization of MCR responses.M.Sc

PCSK9 and resistin at the crossroads of the atherogenic dyslipidemia

The atherogenic dyslipidemia is a pathophysiological lipid triad, composed of high triglycerides and low-density lipoprotein and low high-density lipoprotein. The dyslipidemia is highly prevalent in individuals who are obese, insulin resistant and those with Type 2 diabetes and is the major contributing factor to the high atherosclerotic cardiovascular disease risk in these subjects. The primary initiating event in atherogenic dyslipidemia development is the hepatic overproduction of very-low-density lipoprotein (VLDL). The intracellular and extracellular protein triggers of hepatic VLDL production were not known until the recent identification of the causal roles of PCSK9 and resistin. Both PCSK9 and resistin act in large part by targeting and reducing the hepatic degradation of VLDL apoB through distinctly different mechanisms. In the current review, we discuss both the individual roles and the interaction of these proteins in driving atherogenic dyslipidemia, and thus, atherosclerotic cardiovascular disease progression in humans. We further explore the important therapeutic implications of these finding

Effect of JTT-501 on net hepatic glucose balance and peripheral glucose uptake in alloxan-induced diabetic dogs

JTT-501, a new insulin sensitizer, improves peripheral glucose uptake in insulin-resistant animals such as KK-Ay mice and Zucker fatty rats. However, the effect of JTT-501 on hepatic glucose metabolism has not been addressed. To investigate this effect, experiments were performed on 6 alloxan-diabetic dogs. Three experiments were conducted for each dog: the treatment experiment, which followed a 10-day oral treatment with JTT-501 30 mg · kg- 1 · d-1, and 2 control experiments 2 weeks before and 2 weeks after the treatment experiment. A hyperinsulinemic-hyperglycemic clamp was performed with the tracer dilution method (intraportal insulin infusion rate, 18 pmol · kg-1 · min-1). Arterial hyperglycemia (~10 mmol/L) was maintained by adjusting the peripheral glucose infusion rate. After a 45-minute basal period (period I), portal glucose infusion (22.2 μmol · kg-1 min-1) was administered for 120 minutes (period II). This was followed by a 90-minutes recovery period (period III). JTT-501 increased insulin-stimulated glucose utilization (P < .05) and enhanced insulin-mediated suppression of glucose production (P < .05) in periods I and III. Net hepatic glucose balance (NHGB) determined by the arterial-venous (A-V) difference method was increased by JTT-501 in period II (P < .01). We conclude that JTT-501 enhances both hepatic and peripheral insulin sensitivity and therefore may have important therapeutic effects in type 2 diabetes. Copyright (C) 2000 by W.B. Saunders Company.Link_to_subscribed_fulltex

Adipocyte hypertrophy, fatty liver and metabolic risk factors in South Asians: the Molecular Study of Health and Risk in Ethnic Groups (mol-SHARE).

OBJECTIVE: We sought to determine if differences in the distribution and characteristics of adipose tissue between South Asians and white Caucasians account for differences in risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: We recruited 108 healthy South Asians (36.8 years) and white Caucasians (34.2 years) within three BMI strata. Body composition, adipocyte size, abdominal fat area, and hepatic adiposity were assessed and related to fasting glucose, insulin, lipids and adiponectin. RESULTS: After adjustment for age, sex, and BMI, South Asians compared to white Caucasians had higher ln fasting insulin (mean difference (MD): 0.44; 95% CI: 0.20-0.69), lower HDL cholesterol (md: -0.13; 95% CI:-0.26 to -0.01), and lower adiponectin (md: -2.38; 95% CI: -3.59 to -1.17). South Asians also had more body fat (md: 2.69; 95% CI: 0.70 to 4.69), lower lean muscle mass (md: -3.25; 95%CI: -5.35 to -1.14), increased waist to hip ratio (md: 0.03; 95% CI: 0.01-0.05), less superficial subcutaneous abdominal adipose tissue (md: -2.94; 95% CI: -5.56 to-0.32), more deep/visceral to superficial adipose tissue ratio (md 0.34; 95% CI: 0.02 to 0.65), and more liver fat (md: 7.43%; 95% CI: 2.30 to 12.55%). Adipocyte area was increased in South Asians compared to white Caucasians (md: 64.26; 95% CI: 24.3 to 104.1) units(2). Adjustment for adipocyte area attenuated the ethnic differences in insulin (md: 0.22; 95% CI: -0.07 to 0.51), HDL (md: -0.01; 95% CI: -0.16 to 0.13) and adiponectin (md: -1.11; 95% CI: -2.61 to 0.39). Adjustment for differences in adipocyte area and fat distribution attenuated the ethnic difference in liver fat (md: 5.19; 95% CI: 0.31 to 10.06). CONCLUSION: South Asians have an increased adipocyte area compared to white Caucasians. This difference accounts for the ethnic differences in insulin, HDL cholesterol, adiponectin, and ectopic fat deposition in the liver