Dissociation between the insulin-sensitizing effect of rosiglitazone and its effect on hepatic and intestinal lipoprotein production.

Context: Despite its potent, well-documented insulin-sensitizing effects, rosiglitazone (RSG) does not effectively ameliorate the hypertriglyceridemia of insulin-resistant or diabetic individuals and has even been shown to slightly but significantly increase triglyceride-rich lipoproteins (TRL) in some studies. The mechanism of this effect is currently not known.

Objective: We investigated the effect of RSG treatment on TRL metabolism.

Enhancement of muscle glucose uptake by the vasopeptidase inhibitor, omapatrilat, is independent of insulin signaling and the AMP kinase pathway.

Omapatrilat (OMA), a vasopeptidase inhibitor (VPI), presently being tested in clinical trials for its antihypertensive properties, inhibits both angiotensin-converting enzyme and neutral endopeptidase, and raises tissue bradykinin levels. Recent studies from our laboratory and those of others have demonstrated that VPIs enhance muscle glucose uptake in animal models, and this effect is mediated by the bradykinin-nitric oxide pathway. The mechanism of the effect of OMA on muscle glucose uptake, however, is presently unknown.

Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans.

Objective: Whereas postprandial hyperlipidemia is a well-described feature of insulin-resistant states and type 2 diabetes, no previous studies have examined intestinal lipoprotein production rates (PRs) in relation to hyperinsulinemia or insulin resistance in humans.

Methods And Results: Apolipoprotein B-48 (apoB-48)-containing lipoprotein metabolism was examined in the steady-state fed condition with a 15-hour primed constant infusion of [D3]-l-leucine in 14 nondiabetic men with a broad range of body mass index (BMI) and insulin sensitivity. To examine the relationship between indices of insulin resistance and intestinal lipoprotein PR data were analyzed in 2 ways: by correlation and by comparing apoB-48 PRs in those whose fasting plasma insulin concentrations were above or below the median for the 14 subjects studied (60 pmol/L).

Atorvastatin induces insulin sensitization in Zucker lean and fatty rats.

Background: The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') have been implicated in preventing new onset type 2 diabetes, whereas the mechanism of this effect is not known. We investigated the effects of an HMG-CoA reductase inhibitor, atorvastatin, on insulin sensitization in Zucker lean and fatty rats.

Methods And Results: In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg/kg/day (ATORVA_50) and results were compared to Zucker lean and fatty rats treated with drug vehicle only (CONT).

Mechanism of highly active anti-retroviral therapy-induced hyperlipidemia in HIV-infected individuals.

The use of highly active anti-retroviral therapy (HAART) is associated with long-term adverse metabolic events including lipodystrophy, dyslipidemia, and insulin resistance. The purpose of the present study was to prospectively examine the mechanism of HAART-induced hyperlipidemia in HIV-seropositive, HAART-naive men prior to the development of frank lipodystrophy. Patient's (n = 13) weight, BMI, lean mass, and percent fat mass, waist circumference did not change after 8 weeks of treatment with HAART.

Hepatic lipase mRNA, protein, and plasma enzyme activity is increased in the insulin-resistant, fructose-fed Syrian golden hamster and is partially normalized by the insulin sensitizer rosiglitazone.

Postheparin plasma hepatic lipase (HL) activity has been shown to correlate with features of the metabolic syndrome and type 2 diabetes in humans. We examined HL postheparin plasma enzyme activity, hepatocyte mRNA, and protein mass in the insulin-resistant, fructose-fed Syrian golden hamster, and the response of the insulin-sensitizing peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Male Syrian golden hamsters were treated for 5 weeks with 1) normal diet (DIET group), 2) 60% fructose diet (FRUC group), or 3) 60% fructose and rosiglitazone (20 mmol .

Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer rosiglitazone: studies in the fructose-fed Syrian golden hamster.

We investigated whether intestinal lipoprotein overproduction in a fructose-fed, insulin-resistant hamster model is prevented with insulin sensitization. Syrian Golden hamsters were fed either chow, 60% fructose for 5 wk, chow for 5 wk with the insulin sensitizer rosiglitazone added for the last 3 wk, or 60% fructose plus rosiglitazone. In vivo Triton studies showed a 2- to 3-fold increase in the large (Svedberg unit > 400) and smaller (Sf 100-400) triglyceride-rich lipoprotein particle apolipoprotein B48 (apoB48) but not triglyceride secretion with fructose feeding in the fasted state (P < 0.

Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity.

Overweight individuals with reduced insulin sensitivity often have mild to moderate hypertriglyceridemia. To investigate the role of apolipoprotein (apo)C-III metabolism in the etiology of hypertriglyceridemia in these individuals, we investigated 10 male subjects with different body weights (body mass index, 24-34 kg/m(2)) and insulin sensitivity (homeostasis model assessment, 4.7-35.

Intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids in the fasting state: studies in insulin-resistant and insulin-sensitized Syrian golden hamsters.

It is not known whether intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids (FFA). We examined the effect of an intralipid and heparin infusion on the intestinal lipoprotein production rate (PR) in insulin-sensitive [chow-fed (CHOW)], insulin-resistant [60% fructose (FRUC) or 60% fat-fed (FAT)], and insulin-sensitized [FRUC or FAT plus rosiglitazone (RSG)-treated] Syrian Golden hamsters. After 5 wk of treatment, overnight-fasted hamsters underwent in vivo Triton WR-1339 studies for measurement of apolipoprotein B48 (apoB48) PR in large (Svedberg unit, >400) and small (Svedberg unit, 100-400) lipoprotein fractions, with an antecedent 90-min infusion of 20% intralipid and heparin (IH) to raise plasma FFA levels approximately 5- to 8-fold vs.

Rosiglitazone improves intestinal lipoprotein overproduction in the fat-fed Syrian Golden hamster, an animal model of nutritionally-induced insulin resistance.

We have recently shown that the fructose-fed Syrian Golden hamster, a non-diabetic animal model of nutritionally-induced insulin resistance and hyperlipidemia, is characterized by intestinal lipoprotein overproduction. In order to determine whether intestinal lipoprotein overproduction is specific to fructose feeding or applies generally to other models of insulin resistance, we studied intestinal lipoprotein production and the response to insulin sensitization in the high fat-fed Syrian Golden hamster. Syrian Golden Hamsters were fed either (1).

Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men.

Aims/hypothesis: A prolonged increase of plasma NEFA impairs acute glucose-stimulated insulin secretion (GSIS) in vitro and in vivo. Our study therefore examined the combined effect of increased plasma NEFA and glucose on GSIS in humans.

Methods: We examined GSIS on four occasions in eight obese men during a 10 mmol/l hyperglycaemic clamp and after a 24-h infusion of (i) normal saline, (ii) intralipid and heparin to raise plasma NEFA about two-fold above basal, (iii) 20% dextrose to raise plasma glucose to about 7.

Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I.

Background: We have shown previously that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, contributes to HDL lowering in humans by enhancing the clearance of HDL apolipoprotein (apo) A-I from the circulation. In the New Zealand White rabbit, an animal naturally deficient in hepatic lipase (HL), we demonstrated that TG enrichment of HDL per se is not sufficient to enhance HDL clearance in the absence of ex vivo lipolysis by HL. Here, we examined in the rabbit the interaction between in vivo HL lipolytic action and HDL TG enrichment on the subsequent metabolic clearance of HDL apoA-I.

Vasopeptidase inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats: Studies comparing a vasopeptidase inhibitor, angiotensin-converting enzyme inhibitor, and angiotensin II type I receptor blocker.

Background: ACE inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The vasopeptidase inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated.

Methods And Results: We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group).

Effect of atorvastatin on high-density lipoprotein apolipoprotein A-I production and clearance in the New Zealand white rabbit.

Background: HMG-CoA reductase inhibitors reduce the incidence of cardiovascular disease predominantly by their LDL-lowering effect. Recently, there has been great interest in the pleiotropic effects of statins, which appear to differ among the various agents in this class. Unlike other statins, atorvastatin exhibits a decline in its HDL-raising effect at higher doses in humans.

Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction.

Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction.

Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster.

To determine whether reduction of insulin resistance could ameliorate fructose-induced very low density lipoprotein (VLDL) oversecretion and to explore the mechanism of this effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted insulin-mediated suppression of the glucose production rate and to a approximately 2-fold increase in whole body insulin-mediated glucose disappearance rate (p < 0.001).

Lipolytically modified triglyceride-enriched HDLs are rapidly cleared from the circulation.

The precise biochemical mechanisms underlying the reduction of HDL levels in hypertriglyceridemic states are currently not known. In humans, we showed that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, enhances the clearance of HDL-associated apolipoprotein A-I (apoA-I) from the circulation. In the New Zealand White rabbit (an animal model naturally deficient in hepatic lipase [HL]), however, TG enrichment of HDL is not sufficient to alter the clearance of either the protein or lipid moieties of HDL.

The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states.

Hypertriglyceridemia and reduced plasma levels of high-density lipoprotein cholesterol (HDL-c) are the most frequent forms of dyslipidemia observed in insulin-resistant states, such as obesity, impaired fasting glucose, and Type 2 diabetes, and are highly atherogenic in these settings. The hypertriglyceridemia of insulin resistance is primarily due to an overproduction of very low-density lipoproteins (VLDL), and in some instances, is also due to reduced VLDL clearance and postprandial accumulation of VLDL, chylomicrons, and their remnants [i.e.

Postprandial remnant-like lipoproteins in hypertriglyceridemia.

It has been proposed that remnants of chylomicrons and very-low-density lipoproteins (VLDL) are atherogenic. We have used an immunochemical method to isolate remnant-like particles (RLP) and measured them in terms of their cholesterol and triglycerides (TG). RLP consist of apoB-48-containing triglyceride-rich lipoproteins and remnant-like VLDL containing apoB-100.

The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism.

Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n = 9) had an approximate twofold elevation of fasting and intravenous glucose-stimulated plasma insulin levels compared with both KPT-P (n = 7) and healthy control subjects (n = 15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects.

Triglyceride enrichment of HDL does not alter HDL-selective cholesteryl ester clearance in rabbits.

Triglyceride (TG) enrichment of high density lipoprotein (HDL), which occurs in hypertriglyceridemic states, significantly enhances the rate at which HDL apolipoprotein (apo)A-I is cleared from the circulation of healthy humans. In the New Zealand White (NZW) rabbit, a species naturally deficient in hepatic lipase (HL), TG enrichment of HDL requires prior lipolytic modification to enhance apoA-I clearance. However, the effect of TG enrichment of HDL on the subsequent clearance of HDL cholesteryl ester (CE) has not previously been examined in vivo.

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I).

Background: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available.

Objective: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV).

Design: Randomized, open-label, multi-center.

Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men.

Triglyceride (TG) enrichment of HDL resulting from cholesteryl ester transfer protein-mediated exchange with TG-rich lipoproteins may enhance the lipolytic transformation and subsequent metabolic clearance of HDL particles in hypertriglyceridemic states. The present study investigates the effect of TG enrichment of HDL on the clearance of HDL-associated apo A-I in humans. HDL was isolated from plasma of six normolipidemic men (mean age: 29.

Apolipoprotein B-48 and retinyl palmitate are not equivalent markers of postprandial intestinal lipoproteins.

This study compared retinyl palmitate and apolipoprotein (apo) B-48 as markers of postprandial triglyceride-rich lipoproteins. Nine non-diabetic men received an oral vitamin A-containing fat load. We measured retinyl palmitate, apoB-48, apoB-100, and triglyceride levels in Sf > 400, Sf 60-400 and Sf 20-60 lipoproteins.