Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk

917-100 8-Epi-Prostaglandin F2α(8-Isoprostane), a Novel Marker of Lipid Peroxidation, is Elevated and Inversely Correlated to Serum Antioxidant Vitamins in Smokers

Oxidative modification of lipoproteins is thought to be an essential event in atherosclerosis. Current methods of quantifying lipid peroxidation in vivo are technically difficult and/or nonspecific. A simple, clinically reliable test is needed to assess an individual's degree of lipid peroxidation which could be a powerful predictor of cardiovascular disease risk. 8-lsoprostane is a chemically stable prostanoid resulting from free radical catalyzed peroxidation of arachidonic acid. This molecule is produced by oxidation of low density lipoprotein and is present in both plasma and urine. To evaluate this novel marker of in vivo lipid peroxidation, we compared 24 hour urinary levels of 8-isoprostane in healthy smokers (n=15) and nonsmokers (n=9) with a competitive enzyme immunoassay. Serum was also obtained for analysis of lipid and antioxidant vitamin levels. Smokers were found to have higher levels of urinary 8-isoprostane than nonsmokers and these levels were inversely correlated with serum beta carotene (P=0.04, r=-0.44) and vitamin C (P=0.01, r=-0.52). No significant differences were detected in lipid profiles between smokers and nonsmokers.8-lsoprostaneMean ± SEMP-ValueNonsmokers1.55±0.22P=0.002Smokers2.77±0.21Values=μg/24 hoursConclusionUrinary 8-isoprostane is elevated in smokers and may provide a sensitive, specific and noninvasive method for assessment of in vivo lipid peroxidation. Further studies are indicated to determine whether elevated 8-isoprostane identifies individuals at risk for developing atherosclerosis

Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management

Background: Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. Methods: Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). Findings: IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. Interpretation: Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. Funding: Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments. © 2022Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes

BACKGROUND: Obesity and type 2 diabetes (T2DM) are associated with increased circulating free fatty acids and triacylglycerols. However, very little is known about specific molecular lipid species associated with these diseases. In order to gain further insight into this, we performed plasma lipidomic analysis in a rodent model of obesity and insulin resistance as well as in lean, obese and obese individuals with T2DM. METHODOLOGY/PRINCIPAL FINDINGS: Lipidomic analysis using liquid chromatography coupled to mass spectrometry revealed marked changes in the plasma of 12 week high fat fed mice. Although a number of triacylglycerol and diacylglycerol species were elevated along with of a number of sphingolipids, a particularly interesting finding was the high fat diet (HFD)-induced reduction in lysophosphatidylcholine (LPC) levels. As liver, skeletal muscle and adipose tissue play an important role in metabolism, we next determined whether the HFD altered LPCs in these tissues. In contrast to our findings in plasma, only very modest changes in tissue LPCs were noted. To determine when the change in plasma LPCs occurred in response to the HFD, mice were studied after 1, 3 and 6 weeks of HFD. The HFD caused rapid alterations in plasma LPCs with most changes occurring within the first week. Consistent with our rodent model, data from our small human cohort showed a reduction in a number of LPC species in obese and obese individuals with T2DM. Interestingly, no differences were found between the obese otherwise healthy individuals and the obese T2DM patients. CONCLUSION: Irrespective of species, our lipidomic profiling revealed a generalized decrease in circulating LPC species in states of obesity. Moreover, our data indicate that diet and adiposity, rather than insulin resistance or diabetes per se, play an important role in altering the plasma LPC profile

Actos Now for the prevention of diabetes (ACT NOW) study

Abstract Background Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial. Methods/Design 602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated. Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance. Conclusion ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM. Trial Registration clinical trials.gov identifier: NCT0022096

Elevated Non-Esterified Fatty Acid Concentrations during Bovine Oocyte Maturation Compromise Early Embryo Physiology

Elevated concentrations of serum non-esterified fatty acids (NEFA), associated with maternal disorders such as obesity and type II diabetes, alter the ovarian follicular micro-environment and have been associated with subfertility arising from reduced oocyte developmental competence. We have asked whether elevated NEFA concentrations during oocyte maturation affect the development and physiology of zygotes formed from such oocytes, using the cow as a model. The zygotes were grown to blastocysts, which were evaluated for their quality in terms of cell number, apoptosis, expression of key genes, amino acid turnover and oxidative metabolism. Oocyte maturation under elevated NEFA concentrations resulted in blastocysts with significantly lower cell number, increased apoptotic cell ratio and altered mRNA abundance of DNMT3A, IGF2R and SLC2A1. In addition, the blastocysts displayed reduced oxygen, pyruvate and glucose consumption, up-regulated lactate consumption and higher amino acid metabolism. These data indicate that exposure of maturing oocytes to elevated NEFA concentrations has a negative impact on fertility not only through a reduction in oocyte developmental capacity but through compromised early embryo quality, viability and metabolism

Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans

The authors describe a new approach to studying cellular lipid profiles and propose a compensatory mechanism that may help maintain the normal membrane function of adipocytes in the context of obesity