scholarly journals A Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia

2019 ◽  
Vol 12 (3) ◽  
pp. 195-201 ◽  
Author(s):  
Pitchai Balakumar ◽  
Nanjaian Mahadevan ◽  
Ramanathan Sambathkumar
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Therapeutic Option ◽  
Hdl Cholesterol ◽  
High Plasma ◽  
Cholesterol Concentration ◽  
Current Status ◽  
Peroxisome Proliferator ◽  
Diabetic Dyslipidemia ◽  
Low Hdl

Background: Diabetes mellitus and concomitant dyslipidemia, being referred to as ‘diabetic dyslipidemia’, are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated. Conclusion: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

scholarly journals Prevalence of obesity, hypertension and metabolic abnormalities in patients receiving long term cART: a case control study from South India

2017 ◽  
Vol 6 (7) ◽  
pp. 1620
Author(s):  
Vasudeva Acharya ◽  
Govind Gangadharan
Keyword(s):  
Diabetes Mellitus ◽  
Abdominal Obesity ◽  
Hdl Cholesterol ◽  
Cardiovascular Morbidity ◽  
Metabolic Abnormalities ◽  
Significant Difference ◽  
Low Hdl ◽  
Prevalence Of Obesity ◽  
Obesity Hypertension

Background: Combination antiretroviral therapy (cART) has improved the quality of life and survival of HIV-infected individuals. However, the long term intake of these drugs is associated with multiple metabolic abnormalities eventually leading to increased risk for cardiovascular morbidity and mortality.Methods: Forty five HIV-infected individuals who are on cART having CD4+ cell count of >200 cells/mm3 for at least 2 years were recruited as cases. Age and gender matched, otherwise healthy individuals were taken as controls. Both cases and controls were compared for the prevalence of obesity, abdominal obesity, hypertension, diabetes mellitus and lipid abnormalities.Results: We found higher prevalence of obesity (33.3% vs 26.7%), abdominal obesity (33.3% vs 17.8%), hypertension (33.3% vs 20%), impaired fasting glucose (IFG) (37.7% vs 8.9%), diabetes mellitus (26.7% vs 24.4%), high total cholesterol (33.3% vs 22.2%) and low HDL cholesterol (60% vs 46.7%) among cases compared to controls. The statistically significant difference was noted only for IFG (cases = 17, 37.7%, controls = 4, 8.9%, p value = 0.002). Low HDL cholesterol was the most common metabolic abnormality found in 27 (60%) cases and 21 (46.7%) controls.Conclusions: HIV-infected individuals receiving long term cART have higher prevalence of obesity, hypertension and dysregulations in glucose and lipid metabolism compared to general population and hence, the diagnosis and management of these abnormalities is very important to prevent cardiovascular morbidity and mortality.

Biallelic CAV1 null variants induce Congenital Generalized Lipodystrophy with achalasia

2021 ◽  
Author(s):  
Asuman Nur Karhan ◽  
Jamila Zammouri ◽  
Martine Auclair ◽  
Emilie Capel ◽  
Feramuz Demir Apaydın ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hdl Cholesterol ◽  
Membrane Microdomains ◽  
Phenotypic Traits ◽  
Major Protein ◽  
Genetic Transmission ◽  
Caveolin 1 ◽  
Congenital Generalized Lipodystrophy ◽  
Pathogenic Variants ◽  
Low Hdl

Objective : CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signalling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic and cellular characteristics of CGL3. Design/Methods: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n=9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress and premature senescence. Conclusions: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.

scholarly journals Development of a Genetic Score to Predict an Increase in HDL Cholesterol Concentration After a Dietary Intervention in Adults with Metabolic Syndrome

2019 ◽  
Vol 149 (7) ◽  
pp. 1116-1121 ◽  
Author(s):  
Martha Guevara-Cruz ◽  
Isabel Medina-Vera ◽  
Adriana Flores-López ◽  
Miriam Aguilar-López ◽  
Caren E Smith ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Dietary Intervention ◽  
Saturated Fat ◽  
Hdl Cholesterol ◽  
Cholesterol Concentration ◽  
Genetic Score ◽  
Before And After ◽  
Low Hdl ◽  
Genetic Predisposition Score ◽  
Mexican Adults

ABSTRACT Background Dietary intervention (DI) is a primary strategy to attenuate some of the metabolic abnormalities associated with metabolic syndrome (MetS), including low HDL cholesterol. There is no biomarker that can identify individuals who respond to DI by increasing HDL cholesterol. Objective The aim of this study was to assess the predictive power of a genetic predisposition score (GPS) in Mexican adults with MetS to identify HDL cholesterol responders to DI. Methods This study followed a prospective cohort design. Sixty-seven Mexican adults aged 20–60 y (21% men) with BMI ≥25 and ≤39.9 kg/m², who had at least 3 of 5 positive criteria for MetS, were included. Participants consumed a low saturated fat diet for 2.5 mo (<7% energy as saturated fat, <200 mg of cholesterol/d) and reduced their usual diet by ∼440 kcal/d, a reduction in total energy intake of about 25%. Anthropometry and serum biochemical markers, including HDL cholesterol, were measured before and after DI. A multilocus GPS was constructed using previously reported genetic variants associated with response to diet in subjects with MetS. GPS values, designed to predict the response of HDL cholesterol to the DI, were computed for each individual as the sum of the number of effect alleles across 14 SNPs. Results Individuals were dichotomized as high and low GPS according to median GPS (−2.12) and we observed a difference in HDL cholesterol changes on DI of +3 mg/dL (6.3%) in subjects with low GPS, whereas those with high GPS had HDL cholesterol decreases of −3 mg/dL (−7.9%) (P = 0.04). Conclusions Individuals with low GPS showed greater increases in their HDL cholesterol than those with high GPS. Therefore, the GPS can be useful for predicting the HDL cholesterol response to diet.

scholarly journals Diabeteses dyslipidaemia és atherosclerosis

2016 ◽  
Vol 157 (19) ◽  
pp. 746-752 ◽  
Author(s):  
László Márk ◽  
Győző Dani
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
High Risk ◽  
Statin Therapy ◽  
Ldl Cholesterol ◽  
Hdl Cholesterol ◽  
Small Dense Ldl ◽  
Target Values ◽  
Postprandial Triglyceride ◽  
Low Hdl

The incidence and the public health importance of diabetes mellitus are growing continuously. Despite the improvement observed in the latest years, the leading cause of morbidity and mortality of diabetics are cardiovascular diseases. The diagnosis of diabetes mellitus constitutes such a high risk as the known presence of vascular disease. Diabetic dyslipidaemia is characterised by high fasting and postprandial triglyceride levels, low HDL level, and slightly elevated LDL-cholesterol with domination of atherogenic small dense LDL. These are not independent components of the atherogenic dyslipidaemia, but are closely linked to each other. Beside the known harmful effects of low HDL and small dense LDL, recent findings confirmed the atherogenicity of the triglyceride-rich lipoproteins and their remnants. It has been shown that the key of this process is the overproduction and delayed clearance of triglyceride-rich lipoproteins in the liver. In this metabolism the lipoprotein lipase has a determining role; its function is accelerated by ApoA5 and attenuated by ApoC3. The null mutations of the ApoC3 results in a reduced risk of myocardial infarction, the loss-of-function mutation of ApoA5 was associated with a 60% elevation of triglyceride level and 2.2-times increased risk of myocardial infarction. In case of diabetes mellitus, insulin resistance, obesity, metabolic syndrome and chronic kidney disease the non-HDL-cholesterol is a better marker of the risk than the LDL-cholesterol. Its value can be calculated by subtraction of HDL-cholesterol from total cholesterol. Target values of non-HDL-cholesterol can be obtained by adding 0.8 mmol/L to the LDL-cholesterol targets (this means 3.3 mmol/L in high, and 2.6 mmol/L in very high risk patients). The drugs of first choice in the treatment of diabetic dyslipidaemia are statins. Nevertheless, it is known that even if statin therapy is optimal (treated to target), a considerable residual (lipid) risk remains. For its reduction treatment of low HDL-cholesterol and high triglyceride levels is obvious by the administration of fibrates. In addition to statin therapy, fenofibrate can be recommended. Orv. Hetil., 2016, 157(19), 746–752.

scholarly journals Increase in Pulse Pressure Relates to Diabetes Mellitus and Low HDL Cholesterol, but Not to Hyperlipidemia in Hypertensive Patients Aged 50 Years or Older.

2002 ◽  
Vol 25 (3) ◽  
pp. 335-341 ◽  
Author(s):  
Takako MIYAGI ◽  
Hiromi MURATANI ◽  
Yorio KIMURA ◽  
Koshiro FUKIYAMA ◽  
Yuhei KAWANO ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pulse Pressure ◽  
Hdl Cholesterol ◽  
Hypertensive Patients ◽  
Low Hdl

scholarly journals Agent-Based Modeling Predicts HDL-independent Pathway of Removal of Excess Surface Lipids from Very Low Density Lipoprotein

2018 ◽  
Author(s):  
Yared Paalvast ◽  
Jan Albert Kuivenhoven ◽  
Barbara M. Bakker ◽  
Albert .K. Groen
Keyword(s):  
Lipoprotein Metabolism ◽  
Hdl Cholesterol ◽  
High Plasma ◽  
Surface Lipid ◽  
Agent Based ◽  
Plasma Triglycerides ◽  
Excess Surface ◽  
Surface Lipids ◽  
Low Hdl ◽  
Experimental Findings

AbstractA hallmark of the metabolic syndrome is low HDL-cholesterol coupled with high plasma triglycerides (TG), but it is unclear what drives this close association. Plasma triglycerides and HDL cholesterol are thought to communicate through two distinct mechanisms. Firstly, excess surface lipids from VLDL released during lipolysis are transferred to HDL, thereby contributing to HDL directly but also indirectly through providing substrate for LCAT. Secondly, high plasma TG increases clearance of HDL through core-lipid exchange between VLDL and HDL via CETP and subsequent hydrolysis of the TG in HDL, resulting in smaller HDL and thus increased clearance rates.To test our understanding of how high plasma TG induces low HDL-cholesterol, making use of established knowledge, we developed a comprehensive agent-based model of lipoprotein metabolism which was validated using monogenic disorders of lipoprotein metabolism.By perturbing plasma TG in the model, we tested whether the current theoretical framework reproduces experimental findings. Interestingly, while increasing plasma TG through simulating decreased lipolysis of VLDL resulted in the expected decrease in HDL cholesterol, perturbing plasma TG through simulating increased VLDL production rates did not result in the expected HDL-TG relation at physiological lipid fluxes. However, model perturbations and experimental findings can be reconciled if we assume a pathway removing excess surface-lipid from VLDL that does not contribute to HDL cholesterol ester production through LCAT. In conclusion, our model simulations suggest that excess surface lipid from VLDL is cleared in part independently from HDL.Author summaryWhile it has long been known that high plasma triglycerides are associated with low HDL cholesterol, the reason for this association has remained unclear. One of the proposed mechanisms is that during catabolism of VLDL, lipoproteins rich in triglyceride, the excess surface of these particles become a source for the production of HDL cholesterol, and that therefore decreased catabolism of VLDL will lead to both higher plasma triglyceride and low HDL cholesterol. Another proposed mechanism is that during increased production of VLDL, there will be increased exchange of core lipids between VLDL and HDL, with subsequent hydrolysis of the triglyceride in HDL, leading to smaller HDL that is cleared more rapidly. To investigate these mechanisms further we developed a computational model based on established knowledge concerning lipoprotein metabolism and validated the model with known findings in monogenetic disorders. Upon perturbing the plasma triglycerides within the model by increasing the VLDL production rate, we unexpectedly found an increase in both triglyceride and HDL cholesterol. However, upon assuming that less excess surface lipid is available to HDL, HDL decreases in response to increased VLDL production. We therefore propose that there must be a pathway removing excess surface lipids that is independent from HDL.AbbreviationsPR(production rate)FCR(fractional catabolic rate)ppd(pool per day)SRB1(scavenger receptor B1)EL(endothelial lipase)HL(hepatic lipase)PLTP(phospholipid transfer protein)CETP(cholesteryl ester transfer protein)FC(free cholesterol)CE(cholesterol ester)PL(phospholipid)LpX(lipoprotein X).

scholarly journals Correlation of Uric Acid Levels and Parameters of Metabolic Syndrome

2017 ◽  
pp. 481-487 ◽  
Author(s):  
L. CIBIČKOVÁ ◽  
K. LANGOVÁ ◽  
H. VAVERKOVÁ ◽  
V. KUBÍČKOVÁ ◽  
D. KARÁSEK
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Uric Acid ◽  
Hdl Cholesterol ◽  
Cross Sectional Study ◽  
Anthropometric Parameters ◽  
Cross Sectional ◽  
Hypertriglyceridemic Waist ◽  
Low Hdl ◽  
Hypertriglyceridemic Waist Phenotype

Hyperuricemia has been described as associated with the risk of development metabolic syndrome; however the relationship between the uric acid level and particular parameters of metabolic syndrome remained unclear. We performed a cross-sectional study on a cohort of 833 dyslipidemic patients and correlated their levels of uric acid with parameters of insulin resistance, lipid metabolism, C-reactive protein, anthropometric parameters. We also defined patients with hypertriglyceridemic waist phenotype and compered their uric acid levels with those without this phenotype. We found that levels of uric acid are associated with parameters of metabolic syndrome. Specifically, dyslipidemia characteristic for metabolic syndrome (low HDL cholesterol and high triglycerides) correlates better with uric acid levels than parameters of insulin resistance. Also waist circumference correlates better with uric acid levels than body mass index. Patients with hypertriglyceridemic waist phenotype had higher levels of uric acid when compared with patients without this phenotype. Serum uric acid levels are even in low levels linearly correlated with parameters of metabolic syndrome (better with typical lipid characteristics than with parameters of insulin resistance) and could be associated with higher cardiovascular risk.

scholarly journals Re-highlighting the action of PPARγ in treating metabolic diseases

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1127 ◽  
Author(s):  
Sung Hee Choi ◽  
Sung Soo Chung ◽  
Kyong Soo Park
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adverse Effects ◽  
Metabolic Diseases ◽  
Experimental Studies ◽  
Peroxisome Proliferator ◽  
Post Translational Modification ◽  
Atherosclerotic Vascular Disease

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family and plays an important role in adipocyte differentiation, glucose homeostasis, and insulin sensitivity. Thiazolidinediones (TZDs), synthetic ligands of PPARγ, have been used for the treatment of diabetes mellitus for two decades. TZDs were expected to be amazing drugs not only for type 2 diabetes but also for metabolic syndrome and atherosclerotic vascular disease because they can reduce both insulin resistance and inflammation in experimental studies. However, serious unwanted effects pushed TZDs back to an optional second-tier drug for type 2 diabetes. Nevertheless, PPARγ is still one of the most important targets for the treatment of insulin resistance and diabetes mellitus, and novel strategies to modulate PPARγ activity to enhance its beneficial effects and reduce unwanted adverse effects are anticipated. Recent studies showed that post-translational modification (PTM) of PPARγ regulates PPARγ activity or stability and may be a novel way to optimize PPARγ activity with reduced adverse effects. In this review, we will focus on recent advances in PTM of PPARγ and the mechanisms regulating PPARγ function as well as in the development of PPARγ modulators or agonists.

scholarly journals Acute myocardial infarction in a 17-year-old Bangladeshi boy-possibility of existence of a Bangladeshi paradox

2016 ◽  
Vol 3 (3) ◽  
pp. 62
Author(s):  
Prabir Kumar Das ◽  
F. Hossain ◽  
M.R. Karim
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Hdl Cholesterol ◽  
Anterior Wall ◽  
Emerging Risk ◽  
Low Hdl ◽  
Artery Disease ◽  
Conventional Risk Factors

Coronary artery disease (CAD) and acute myocardial infarction (AMI) are  diseases of older age. AMI is uncommon in young age  and rare in adolescence. A seventeen years old Bangladeshi boy developing acute anterior wall MI is described here. Risk factor analysis for CAD revealed absence of most of the conventional risk factors, like  smoking, diabetes mellitus, hypertension. An  elevated lipoprotein(a) and a low HDL cholesterol  was detected in  blood  which are emerging risk factors  of  CAD  in young Bangladeshis.

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