Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.

BACKGROUND We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P = 0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P = 0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels. JAMA. 2000;284:1263-1270

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The enhanced synthesis of fatty acids in the liver and adipose tissue in response to insulin is critically dependent on the transcription factor SREBP-1c (sterol-regulatory-element-binding protein 1c). Insulin increases the expression of the SREBP-1c gene in intact liver and in hepatocytes cultured in vitro. To learn the mechanism of this stimulation, we analysed the activation of the rat SREBP-1c promoter and its truncated or mutated congeners driving a luciferase reporter gene in transiently transfected rat hepatocytes. The rat SREBP-1c promoter contains binding sites for LXR (liver X receptor), Sp1, NF-Y (nuclear factor-Y) and SREBP itself. We have found that each of these sites is required for the full stimulatory response of the SREBP-1c promoter to insulin. Mutation of either the putative LXREs (LXR response elements) or the SRE (sterol response element) in the proximal SREBP-1c promoter reduced the stimulatory effect of insulin by about 50%. Insulin and the LXR agonist TO901317 increased the association of SREBP-1 with the SREBP-1c promoter. Ectopic expression of LXRalpha or SREBP-1c increased activity of the SREBP-1c promoter, and this effect is further enhanced by insulin. The Sp1 and NF-Y sites adjacent to the SRE are also required for full activation of the SREBP-1c promoter by insulin. We propose that the combined actions of the SRE, LXREs, Sp1 and NF-Y elements constitute an insulin-responsive cis-acting unit of the SREBP-1c gene in the liver.

Abstract-Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% (PϽ0.001). Cilostazol also increased plasma high density lipoprotein cholesterol (HDL-C) (10%) and apolipoprotein (apo) A1 (5.7%) significantly (PϽ0.001 and PϽ0.01, respectively). Both HDL 3 and HDL 2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL 2 . Individuals with baseline hypertriglyceridemia (Ͼ140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, PϽ0.002) increase in the apoA1 to apoB ratio. ilostazol is a vasodilator and platelet aggregation inhibitor that has been marketed since 1988 in Japan for treatment of ischemic symptoms of peripheral vascular disease. Cilostazol {6[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)-quinolinone} is a 2-oxoquinolone derivative (molecular weight, 369.47) that has a plasma half-life of 10.5Ϯ4.4 hours after oral administration (Figure 1). Cilostazol inhibits both primary and secondary platelet aggregation in response to ADP, collagen, epinephrine, and arachidonic acid.1,2 The antiplatelet and vasodilator properties of cilostazol have been attributed to its ability to elevate intracellular levels of cAMP.3 Cilostazol is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Japanese studies performed in diabetic patients have indicated that, in addition to its vasodilator and antiplatelet properties, cilostazol may also favorably modify plasma lipoproteins by increasing HDL cholesterol (HDL-C) and reducing triglycerides. 4 The purpose of the present study was to determine whether cilostazol favorably modifies plasma lipoproteins in a general population of patients with stable IC. Methods Patient PopulationThe study included subjects with documented chronic, stable, symptomatic IC secondary to peripheral arterial disease (PAD). PAD was defined as an ankle-brachial index (ABI) Յ0.90; termination of walking on a variable-load, constant-speed treadmill due to IC (Ͼ54 and Ͻ805 m); and a Doppler-measured drop of Ն10 mm Hg in blood pressure of 1 ankle after the treadmill test. For patients without a qualifying ABI, a 20 -mm Hg drop in postexe...

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity. Expression of the PDK genes is elevated in diabetes, leading to the decreased oxidation of pyruvate to acetyl-CoA. In these studies we have investigated the transcriptional regulation of the PDK4 gene by the estrogenrelated receptors (ERR␣ and ERR␥). The ERRs are orphan nuclear receptors whose physiological roles include the induction of fatty acid oxidation in heart and muscle. Previously, we found that the peroxisome proliferator-activated receptor ␥ coactivator (PGC-1␣) stimulates the expression of PDK4. Here we report that ERR␣ and ERR␥ stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1␣ to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERR␣ and ERR␥. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1␣. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1␣ from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression. The pyruvate dehydrogenase complex (PDC)3 catalyzes the irreversible oxidative decarboxylation of pyruvate to acetylCoA (1). Long term changes in PDC activity entail changes in PDC phosphorylation, whereas short term inhibition is mediated by the reaction products acetyl-CoA and NADH (1, 2). The pyruvate dehydrogenase kinases (PDK) decrease PDC activity via phosphorylation, whereas the pyruvate dehydrogenase phosphatases activate the PDC activity by dephosphorylation (3, 4). There are three serine phosphorylation sites on the ␣-subunit of pyruvate dehydrogenase (E1) that are targeted by PDKs, and phosphorylation of the ␣-subunit of the E1 element completely inhibits the activity of PDC (4). There is increased phosphorylation of PDC in the heart and skeletal muscle in starvation and diabetes, allowing pyruvate to be conserved while fatty acid oxidation is increased (5-7). In diabetes the decrease in PDC activity is due primarily to the increased PDK activity (5).Four PDK isoenzymes (PDK1, -2, -3, -4) have been identified and characterized in mammalian tissues (1). The expression patterns of the PDK isoforms are tissue-specific (8). The PDK2 and PDK4 isoforms are highly expressed in liver, heart, and skeletal muscle (9). PDK2 and PDK4 gene expression is elevated with diabetes and starvation, with PDK4 being the most highly regulated isoform (2, 4). Insulin administration and refeeding inhibit the induction of PDK4 gene expression in the skeletal muscles and heart of diabetic and fasted animals, respectively (7, 10). In Morris hepatoma cells, long chain fatty acids, glucocorticoids, and peroxisome...