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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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Przybycień P, Gąsior-Perczak D, Placha W. Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility. Cells 2022; 11:cells11162569. [PMID: 36010645 PMCID: PMC9406585 DOI: 10.3390/cells11162569] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 11/21/2022] Open
Abstract
Cannabinoids (CBs) are used to treat chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity. Recently, the medicinal use of CBs has attracted increasing interest as a new therapeutic in many diseases. Data indicate a correlation between CBs and PPARs via diverse mechanisms. Both the endocannabinoid system (ECS) and peroxisome proliferator-activated receptors (PPARs) may play a significant role in PCOS and PCOS related disorders, especially in disturbances of glucose-lipid metabolism as well as in obesity and fertility. Taking into consideration the ubiquity of PCOS in the human population, it seems indispensable to search for new potential therapeutic targets for this condition. The aim of this review is to examine the relationship between metabolic disturbances and obesity in PCOS pathology. We discuss current and future therapeutic interventions for PCOS and related disorders, with emphasis on the metabolic pathways related to PCOS pathophysiology. The link between the ECS and PPARs is a promising new target for PCOS, and we examine this relationship in depth.
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Affiliation(s)
- Piotr Przybycień
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Krakow, Poland
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
| | - Danuta Gąsior-Perczak
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
- Collegium Medicum, Jan Kochanowski University, 25-317 Kielce, Poland
| | - Wojciech Placha
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Krakow, Poland
- Correspondence: ; Tel.: +48-12-422-74-00
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Wu K, Li X, Xu Y, Zhang X, Guan Z, Zhang S, Li Y. SLC22A1 rs622342 Polymorphism Predicts Insulin Resistance Improvement in Patients with Type 2 Diabetes Mellitus Treated with Metformin: A Cross-Sectional Study. Int J Endocrinol 2020; 2020:2975898. [PMID: 32454819 PMCID: PMC7231067 DOI: 10.1155/2020/2975898] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/16/2020] [Accepted: 03/31/2020] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Metformin is the most widely used oral antidiabetic agent and can reduce insulin resistance (IR) effectively. Organic cation transporter 1 (encoded by SLC22A1) is responsible for the transport of metformin, and ataxia-telangiectasia-mutated (ATM) is a gene relating to the DNA repair and cell cycle control. The aim of this study was to evaluate if the genetic variants in SLC22A1 rs622342 and ATM rs11212617 could be effective predictors of islet function improvement in patients with type 2 diabetes mellitus (T2DM) on metformin treatment. METHODS This cross-sectional study included 111 patients with T2DM treated with metformin. Genotyping was performed by the dideoxy chain-termination method. The homeostatic indexes of IR (HOMA-IR) and beta-cell function (HOMA-BCF) were determined according to the homeostasis model assessment. RESULTS Fasting plasma glucose (FPG) levels, HbA1c levels, and HOMA-IR were significantly higher in patients with the rs622342 AA genotype than in those with C allele (P < 0.05). However, these significant differences were not observed between rs11212617 genotype groups. Further data analysis revealed that the association between the rs622342 polymorphism and HOMA-IR was gender related, and so was rs11212617 polymorphism and HOMA-BCF. HOMA-IR was significantly higher in males with rs622342 AA genotype than in those with C allele (P=0.021), and HOMA-BCF value was significantly higher in females carrying rs11212617 CC genotype than in those with A allele (P=0.038). The common logarithm (Lg10) of HOMA-BCF was positively correlated with the reciprocal of HbA1c (r = 0.629, P < 0.001) and negatively associated with Lg10 FPG (r = -0.708, P < 0.001). CONCLUSIONS The variant of rs622342 could be a predictor of insulin sensitivity in patients with T2DM treated with metformin. The association between the rs622342 polymorphism and HOMA-IR and the association between the rs11212617 polymorphism and HOMA-BCF were both gender related.
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Affiliation(s)
- Kunrong Wu
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Ji'nan 250014, China
| | - Xiaoli Li
- School of Pharmaceutical Sciences, Shandong First Medical University, Tai'an 271000, China
| | - Yuedong Xu
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan 250014, China
| | - Xiaoqian Zhang
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan 250014, China
| | - Ziwan Guan
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Ji'nan 250014, China
| | - Shufang Zhang
- School of Pharmaceutical Sciences, Shandong First Medical University, Tai'an 271000, China
| | - Yan Li
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Ji'nan 250014, China
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Hypertriglyceridemia is associated with impaired fasting glucose in normal-weight children. Pediatr Res 2018; 84:352-355. [PMID: 29970905 DOI: 10.1038/s41390-018-0027-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/13/2018] [Accepted: 04/08/2018] [Indexed: 11/08/2022]
Abstract
BACKGROUND Previous studies have suggested that elevated triglyceride levels may precede the appearance of glucose metabolic disturbances in adults; nonetheless, this hypothesis has not been tested in children. Hence, we evaluated whether hypertriglyceridemia is associated with impaired fasting glucose (IFG) in normal-weight children. METHODS Normal-weight healthy children aged 7-15 years were enrolled in a population-based cross-sectional population study and allocated into groups with and without hypertriglyceridemia. Hypertriglyceridemia was defined by serum triglyceride levels ≥100 and ≥130 mg/dL for children aged 7-9 and 10-15 years, respectively, and IFG by fasting plasma glucose levels ≥100 and <126 mg/dL. RESULTS A total of 1453 children with average age of 11.3 ± 2.4 years were enrolled in the study and allocated into the groups with (n = 172) and without (n = 1281) hypertriglyceridemia. In the overall population, the prevalence of hypertriglyceridemia and IFG was 11.8% and 11.2%, respectively. The logistic regression analysis adjusted by age, gender, BMI, waist circumference, and insulin levels showed that hypertriglyceridemia is associated with IFG in children aged 10-15 years (odds ratio (OR) = 1.67; 95% confidence interval (CI): 1.02-2.77, p = 0.04) but not in those aged 7-9 years (OR = 1.48; 95% CI: 0.39-5.58, p = 0.55). CONCLUSION Hypertriglyceridemia is associated with IFG in normal-weight children aged 10-15 years, but not in those aged 7-9 years.
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Abstract
This review is motivated by the need to question dogma that has not yielded significant improvements in outcomes of Type 2 Diabetes treatment: that insulin resistance is the driver of ß-Cell failure and resulting hyperglycemia. We highlight the fact that hyperlipidemia, insulin resistance, and hyperinsulinemia all precede overt diabetes diagnosis and can each induce the other when tested experimentally. New research highlights the importance of high levels of circulating insulin as both a driver of weight gain and insulin resistance. Data from our lab and others document that several nutrients and environmental toxins can stimulate insulin secretion at non-stimulatory glucose in the absence of insulin resistance. This occurs either by direct action on the ß-Cell or by shifting its sensitivity to known secretagogues. We raise the next logical question of whether ß-Cell dysfunction in Type 2 Diabetes is due to impaired function, defined as failure, or if chronic overstimulation of the ß-Cell that exceeds its capacity to synthesize and secrete insulin, defined as abuse, is the main abnormality in Type 2 Diabetes. These questions are important as they have direct implications for how to best prevent and treat Type 2 Diabetes.
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Affiliation(s)
- Karel Erion
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Barbara E Corkey
- Evans Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, MA, United States
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Ye DW, Rong XL, Xu AM, Guo J. Liver-adipose tissue crosstalk: A key player in the pathogenesis of glucolipid metabolic disease. Chin J Integr Med 2017; 23:410-414. [PMID: 28795382 DOI: 10.1007/s11655-017-2810-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Indexed: 02/06/2023]
Abstract
Glucolipid metabolic disease (GLMD), a complex of interrelated disorders in glucose and lipid metabolism, has become one of the leading chronic diseases causing public and clinical problem worldwide. As the metabolism of lipid and glucose is a highly coordinated process under both physiological and diseased conditions, the impairment in the signals corresponding to the metabolism of either lipid or glucose represents the common mechanism underlying the pathogenesis of GLMD. The liver and adipose tissue are the major metabolic organs responsible for energy utilization and storage, respectively. This review article aims to summarize the current advances in the investigation of the functional roles and the underling mechanisms of the interplay between the liver and adipose tissue in the modulation of GLMD development. Fibroblast growth factor 21 (FGF21) and adiponectin represent the two major hormones secreted from the liver and adipose tissues, respectively. FGF21 exerts pleiotropic effects on regulating glucose and lipid homeostasis majorly through inducing the expression and secretion of adiponectin. Therefore, FGF21-adiponectin axis functions as the key mediator for the crosstalk between the liver and adipose tissue to exert the beneficial effects on the maintenance of the homeostasis of energy consumption. The liver- and adipose tissue-derived factors with pleiotropic effects on regulating of lipid and glucose metabolism function as the key mediator for the crosstalk between these two highly active metabolic organs, thereby coordinating the initiation and development of GLMD.
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Affiliation(s)
- De-Wei Ye
- Guangdong Research Center of Metabolic Diseases of Integrated Western and Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.,Joint Laboratory between Guangdong and Hong Kong on Metabolic Disease, Guangdong Pharmaceutical University, Guangzhou, 510006, China.,State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China
| | - Xiang-Lu Rong
- Guangdong Research Center of Metabolic Diseases of Integrated Western and Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.,Joint Laboratory between Guangdong and Hong Kong on Metabolic Disease, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Ai-Min Xu
- Joint Laboratory between Guangdong and Hong Kong on Metabolic Disease, Guangdong Pharmaceutical University, Guangzhou, 510006, China. .,State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.
| | - Jiao Guo
- Guangdong Research Center of Metabolic Diseases of Integrated Western and Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.,Joint Laboratory between Guangdong and Hong Kong on Metabolic Disease, Guangdong Pharmaceutical University, Guangzhou, 510006, China
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Seghieri M, Tricò D, Natali A. The impact of triglycerides on glucose tolerance: Lipotoxicity revisited. DIABETES & METABOLISM 2017; 43:314-322. [PMID: 28693962 DOI: 10.1016/j.diabet.2017.04.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/19/2017] [Accepted: 04/27/2017] [Indexed: 12/22/2022]
Abstract
Elevated plasma triglycerides (TGs) are early key features of conditions associated with a dysregulation in glucose metabolism and may predict the development of type 2 diabetes (T2D) over time. Although the acute ingestion of lipid, either mixed with or shortly before the meal, is neutral or slightly beneficial on glucose tolerance, a short-term increase in plasma TGs induced by either an i.v. lipid infusion or a high-fat diet produces a deterioration of glucose control. Accordingly, chronic lowering of plasma TGs by fibrates improves glucose homeostasis and may also prevent T2D. The chronic effects of the elevation of dietary lipid intake are less clear, particularly in humans, being the quality of fat probably more important than total fat intake. Although on the bases of the available experimental and clinical evidence it cannot be easily disentangled, with respect to elevated non-esterified fatty acids (NEFA) the relative contribution of elevated TGs to glucose homeostasis disregulation seems to be greater and also more plausible. In conclusion, although the association between elevated plasma TGs and impaired glucose tolerance is commonly considered not causative or merely a consequence of NEFA-mediated lipotoxicity, the available data suggest that TGs per se may directly contribute to disorders of glucose metabolism.
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Affiliation(s)
- M Seghieri
- Department of clinical and experimental medicine, laboratory of metabolism, nutrition and atherosclerosis, university of Pisa, Pisa, Italy
| | - D Tricò
- Department of clinical and experimental medicine, laboratory of metabolism, nutrition and atherosclerosis, university of Pisa, Pisa, Italy
| | - A Natali
- Department of clinical and experimental medicine, laboratory of metabolism, nutrition and atherosclerosis, university of Pisa, Pisa, Italy.
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Natali A, Baldi S, Bonnet F, Petrie J, Trifirò S, Tricò D, Mari A. Plasma HDL-cholesterol and triglycerides, but not LDL-cholesterol, are associated with insulin secretion in non-diabetic subjects. Metabolism 2017; 69:33-42. [PMID: 28285650 DOI: 10.1016/j.metabol.2017.01.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 12/15/2016] [Accepted: 01/03/2017] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Experimental data support the notion that lipoproteins might directly affect beta cell function, however clinical data are sparse and inconsistent. We aimed at verifying whether, independently of major confounders, serum lipids are associated with alterations in insulin secretion or clearance non-diabetic subjects. METHODS Cross sectional and observational prospective (3.5yrs), multicentre study in which 1016 non-diabetic volunteers aged 30-60yrs. and with a wide range of BMI (20.0-39.9kg/m2) were recruited in a setting of University hospital ambulatory care (RISC study). MAIN OUTCOME MEASURES baseline fasting lipids, fasting and OGTT-induced insulin secretion and clearance (measured by glucose and C-peptide modeling), peripheral insulin sensitivity (by the euglycemic clamp). Lipids and OGTT were repeated in 980 subjects after 3.5years. RESULTS LDL-cholesterol did not show independent associations with fasting or stimulated insulin secretion or clearance. After accounting for potential confounders, HDL-cholesterol displayed negative and triglycerides positive independent associations with fasting and OGTT insulin secretion; neither with insulin clearance. Low HDL-cholesterol and high triglycerides were associated with an increase in glucose-dependent and a decrease in non-glucose-dependent insulin secretion. Over 3.5years both an HDL-cholesterol decline and a triglycerides rise were associated with an increase in fasting insulin secretion independent of changes in body weight or plasma glucose. CONCLUSIONS LDL-cholesterol does not seem to influence any major determinant of insulin bioavailability while low HDL-cholesterol and high triglycerides might contribute to sustain the abnormalities in insulin secretion that characterize the pre-diabetic state.
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Affiliation(s)
- Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Italy.
| | - Simona Baldi
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Fabrice Bonnet
- Service Endocrinologie-Diabétologie, Centre Hospitalo-Universitaire (CHU), University Rennes 1, Rennes, France
| | - John Petrie
- Institute of Cardiovascular and Medical Sciences BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Silvia Trifirò
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Andrea Mari
- CNR Institute of Neuroscience, Padova, Italy
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Han T, Cheng Y, Tian S, Wang L, Liang X, Duan W, Na L, Sun C. Changes in triglycerides and high-density lipoprotein cholesterol may precede peripheral insulin resistance, with 2-h insulin partially mediating this unidirectional relationship: a prospective cohort study. Cardiovasc Diabetol 2016; 15:154. [PMID: 27814764 PMCID: PMC5095985 DOI: 10.1186/s12933-016-0469-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 10/26/2016] [Indexed: 12/31/2022] Open
Abstract
Background Results of longitudinal researches regarding the temporal relationship between dyslipidemia and insulin resistance (IR) are inconsistent. This study assessed temporal relationships of blood lipids with IR and determined whether there are any mediating effects existed in these temporal relationships. Methods This study examined a longitudinal cohort of 3325 subjects aged 20–74 years from China with an average of 4.2 years follow-up. Measurements of fasting blood lipids, as well as fasting and 2-h serum glucose and insulin, were obtained at two time points. The Gutt index and HOMA-IR were calculated as indicators of peripheral IR and hepatic IR. A cross-lagged path analysis was performed to examine the temporal relationships between blood lipids and IR. A mediation analysis was used to examine mediating effect. Results After adjusting for covariates, the cross-lagged path coefficients from baseline TG and HDL-C to follow-up Gutt index were significantly greater than those from baseline Gutt index to follow-up TG and HDL-C (β1 = −0.131 vs β2 = −0.047, P < 0.001 for TG; β1 = 0.134 vs β2 = 0.023, P < 0.001 for HDL-C). The path coefficients from baseline TG and HDL-C to follow-up 2-h insulin were significantly greater than those from baseline 2-h insulin to follow-up TG and HDL-C (β1 = 0.125 vs β2 = 0.040, P < 0.001 for TG; β1 = −0.112 vs β2 = −0.026, P < 0.001 for HDL-C). 2-h insulin partially mediated the effect of TG/HDL-C on Gutt index with a 59.3% mediating effect for TG and 61.0% for HDL-C. Conclusions These findings provide strong evidence that dyslipidemia probably precede peripheral IR and that 2-h insulin partially mediates this unidirectional temporal relationship. Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0469-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tianshu Han
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China
| | - Yu Cheng
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China
| | - Shuang Tian
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China
| | - Li Wang
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China
| | - Xi Liang
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China
| | - Wei Duan
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China
| | - Lixin Na
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China.
| | - Changhao Sun
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, People's Republic of China.
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Kashi Z, Masoumi P, Mahrooz A, Hashemi-Soteh MB, Bahar A, Alizadeh A. The variant organic cation transporter 2 (OCT2)-T201M contribute to changes in insulin resistance in patients with type 2 diabetes treated with metformin. Diabetes Res Clin Pract 2015; 108:78-83. [PMID: 25662675 DOI: 10.1016/j.diabres.2015.01.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 11/30/2014] [Accepted: 01/13/2015] [Indexed: 12/26/2022]
Abstract
AIMS Insulin resistance is characterized by impaired biological response of peripheral tissues to the metabolic effects of insulin. Organic cation transporter 2 (OCT2) is responsible for 80% metformin clearance. Limited information is available on the potential relationship between genetic variants of OCT2 and insulin resistance. In this study, we examined the role of OCT2-T201M (602 C>T) variant in insulin resistance in patients with type 2 diabetes (T2D) who were treated with metformin. METHODS Serum concentrations of insulin and C-peptide were assessed using ELISA. Homeostasis model assessment for insulin resistance (HOMA-IR) and HOMA for beta cell function (HOMA-BCF) were determined. PCR-based restriction fragment length polymorphism was used to genotype the OCT2-T201M variant. RESULTS Patients with minor alleles had higher HbA1c concentrations (p=0.019), fasting glucose levels (p=0.023), HOMA-IR (p=0.03), and HOMA-BCF (p=0.26) than patients with common alleles. Multivariate analysis identified a significant association between the variables OCT2-T201M and gender, with HOMA-IR and HOMA-BCF (Wilks' λ=0.549, F=12.71, p<0.001 for OCT2-T201M and Wilks' λ=0.369, F=26.46, p<0.001 for gender. Changes in HOMA-BCF were inversely correlated with changes in fasting glucose levels (r=-0.412, p=0.008) and HbA1c (r=-0.257, p=0.114). CONCLUSIONS Our findings suggest that the loss-of-function variant OCT2-T201M (rs145450955) contribute to changes in insulin resistance and beta cell activity in patients with T2D treated with metformin. Moreover, gender as an independent variable has a significant relationship with HOMA-BCF.
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Affiliation(s)
- Zahra Kashi
- Diabetes Research Center, Imam Teaching Hospital, Mazandaran University of Medical Sciences, Sari, Iran
| | - Parisa Masoumi
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abdolkarim Mahrooz
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mohammad Bagher Hashemi-Soteh
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Adele Bahar
- Diabetes Research Center, Imam Teaching Hospital, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ahad Alizadeh
- Department of Epidemiology and Biostatistics, Faculty of Health, Tehran University of Medical Sciences, Tehran, Iran
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Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc Diabetol 2014; 13:159. [PMID: 25471221 PMCID: PMC4264548 DOI: 10.1186/s12933-014-0159-y] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 11/25/2014] [Indexed: 12/27/2022] Open
Abstract
The existence of an independent association between elevated triglyceride (TG) levels, cardiovascular (CV) risk and mortality has been largely controversial. The main difficulty in isolating the effect of hypertriglyceridemia on CV risk is the fact that elevated triglyceride levels are commonly associated with concomitant changes in high density lipoprotein (HDL), low density lipoprotein (LDL) and other lipoproteins. As a result of this problem and in disregard of the real biological role of TG, its significance as a plausible therapeutic target was unfoundedly underestimated for many years. However, taking epidemiological data together, both moderate and severe hypertriglyceridaemia are associated with a substantially increased long term total mortality and CV risk. Plasma TG levels partially reflect the concentration of the triglyceride-carrying lipoproteins (TRL): very low density lipoprotein (VLDL), chylomicrons and their remnants. Furthermore, hypertriglyceridemia commonly leads to reduction in HDL and increase in atherogenic small dense LDL levels. TG may also stimulate atherogenesis by mechanisms, such excessive free fatty acids (FFA) release, production of proinflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. Genetic studies strongly support hypertriglyceridemia and high concentrations of TRL as causal risk factors for CV disease. The most common forms of hypertriglyceridemia are related to overweight and sedentary life style, which in turn lead to insulin resistance, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Intensive lifestyle therapy is the main initial treatment of hypertriglyceridemia. Statins are a cornerstone of the modern lipids-modifying therapy. If the primary goal is to lower TG levels, fibrates (bezafibrate and fenofibrate for monotherapy, and in combination with statin; gemfibrozil only for monotherapy) could be the preferable drugs. Also ezetimibe has mild positive effects in lowering TG. Initial experience with en ezetimibe/fibrates combination seems promising. The recently released IMPROVE-IT Trial is the first to prove that adding a non-statin drug (ezetimibe) to a statin lowers the risk of future CV events. In conclusion, the classical clinical paradigm of lipids-modifying treatment should be changed and high TG should be recognized as an important target for therapy in their own right. Hypertriglyceridemia should be treated.
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Affiliation(s)
- Alexander Tenenbaum
- Cardiac Rehabilitation Institute, Sheba Medical Center, 52621, Tel-Hashomer, Israel. .,Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel-Aviv, Israel. .,Cardiovascular Diabetology Research Foundation, 58484, Holon, Israel.
| | - Robert Klempfner
- Cardiac Rehabilitation Institute, Sheba Medical Center, 52621, Tel-Hashomer, Israel. .,Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel-Aviv, Israel.
| | - Enrique Z Fisman
- Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel-Aviv, Israel. .,Cardiovascular Diabetology Research Foundation, 58484, Holon, Israel.
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Li N, van der Sijde MR, Bakker SJL, Dullaart RPF, van der Harst P, Gansevoort RT, Elbers CC, Wijmenga C, Snieder H, Hofker MH, Fu J. Pleiotropic effects of lipid genes on plasma glucose, HbA1c, and HOMA-IR levels. Diabetes 2014; 63:3149-58. [PMID: 24722249 DOI: 10.2337/db13-1800] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Dyslipidemia is strongly associated with raised plasma glucose levels and insulin resistance (IR), and genome-wide association studies have identified 95 loci that explain a substantial proportion of the variance in blood lipids. However, the loci's effects on glucose-related traits are largely unknown. We have studied these lipid loci and tested their association collectively and individually with fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and IR in two independent cohorts: 10,995 subjects from LifeLines Cohort Study and 2,438 subjects from Prevention of Renal and Vascular Endstage Disease (PREVEND) study. In contrast to the positive relationship between dyslipidemia and glucose traits, the genetic predisposition to dyslipidemia showed a pleiotropic lowering effect on glucose traits. Specifically, the genetic risk score related to higher triglyceride level was correlated with lower levels of FPG (P = 9.6 × 10(-10) and P = 0.03 in LifeLines and PREVEND, respectively), HbA1c (P = 4.2 × 10(-7) in LifeLines), and HOMA of estimated IR (P = 6.2 × 10(-4) in PREVEND), after adjusting for blood lipid levels. At the single nucleotide polymorphism level, 15 lipid loci showed a pleiotropic association with glucose traits (P < 0.01), of which eight (CETP, MLXIPL, PLTP, GCKR, APOB, APOE-C1-C2, CYP7A1, and TIMD4) had opposite allelic directions of effect on dyslipidemia and glucose levels. Our findings suggest a complex genetic regulation and metabolic interplay between lipids and glucose.
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Affiliation(s)
- Naishi Li
- Department of Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Marijke R van der Sijde
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | | | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Robin P F Dullaart
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Pim van der Harst
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ron T Gansevoort
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Clara C Elbers
- Department of Genetics, University of Pennsylvania, School of Medicine, Philadelphia, PA Department of Medical Genetics, Biomedical Genetics, University Medical Center, Utrecht, the Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Harold Snieder
- Department of Epidemiology, Genetic Epidemiology and Bioinformatics Unit, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marten H Hofker
- Department of Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jingyuan Fu
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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Adverse association between obesity and menopause in mice treated with bezafibrate, a pan peroxisome proliferator-activated receptor agonist. Menopause 2014; 20:1264-74. [PMID: 23632658 DOI: 10.1097/gme.0b013e31828f5e3c] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The goal of this study was to investigate the combined effects of ovariectomy (OVX) and high-fat diet (HF) on insulin sensitivity and pancreatic remodeling in C57BL/6 mice treated with bezafibrate. METHODS Female C57BL/6 mice were subjected to OVX or surgical procedure without removal of the ovary (SHAM). Animals received standard chow (SC; 10% lipids) or HF (60% lipids). After 13 weeks on the diets, the animals were subdivided into six groups based on diet, bezafibrate treatment, or both: SHAM-SC, SHAM-HF, SHAM-HFBz, OVX-SC, OVX-HF, and OVX-HFBz. After treatment for 5 weeks, the pancreas was removed and analyzed using morphometry, stereological tools, immunostaining, and multiplex assay kits. RESULTS SHAM-HF and OVX-HF mice showed increased fasting glucose levels, plasma insulin levels, homeostasis model of assessment for insulin resistance index, body mass, islet hypertrophy, β-cell mass, and insulin immunostaining, but decreased GLUT2 immunostaining. Bezafibrate treatment prevented islet hypertrophy and reduced body mass, plasma insulin levels, and homeostasis model of assessment for insulin resistance index. CONCLUSIONS OVX combined with HF accentuates the effects of menopause, leading to the development of insulin resistance. Bezafibrate treatment reduces body mass, plasma insulin levels, and pancreatic islet hypertrophy in mice fed HF.
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Fisman EZ, Tenenbaum A. Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol 2014; 13:103. [PMID: 24957699 PMCID: PMC4230016 DOI: 10.1186/1475-2840-13-103] [Citation(s) in RCA: 165] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 05/26/2014] [Indexed: 01/14/2023] Open
Abstract
Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.
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Affiliation(s)
- Enrique Z Fisman
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
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Lipid-lowering Therapies, Glucose Control and Incident Diabetes: Evidence, Mechanisms and Clinical Implications. Cardiovasc Drugs Ther 2014; 28:361-77. [DOI: 10.1007/s10557-014-6534-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Are hypertriglyceridemia and low HDL causal factors in the development of insulin resistance? Atherosclerosis 2014; 233:130-8. [DOI: 10.1016/j.atherosclerosis.2013.12.013] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 11/18/2013] [Accepted: 12/05/2013] [Indexed: 02/07/2023]
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Shiochi H, Ohkura T, Fujioka Y, Sumi K, Yamamoto N, Nakanishi R, Matsuzawa K, Izawa S, Ohkura H, Inoue K, Ueta E, Kato M, Taniguchi SI, Yamamoto K. Bezafibrate improves insulin resistance evaluated using the glucose clamp technique in patients with type 2 diabetes mellitus: a small-scale clinical study. Diabetol Metab Syndr 2014; 6:113. [PMID: 25360162 PMCID: PMC4213459 DOI: 10.1186/1758-5996-6-113] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 10/09/2014] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Bezafibrate is mainly used to treat hypertriglyceridemia. Studies have reported that bezafibrate also improves type 2 diabetes mellitus, but the mechanism has not been fully elucidated. We performed euglycemic hyperinsulinemic clamps (glucose clamp) and meal tolerance tests (MTT) to examine the effects of bezafibrate on insulin resistance in patients with type 2 diabetes mellitus. METHODS Twelve Japanese patients with type 2 diabetes mellitus and dyslipidemia (mean age: 59.5 years; fasting plasma glucose: 7.95 mmol/L; hemoglobin A1c [HbA1c]: 7.3%; body mass index: 26.5 kg/m(2)) underwent a glucose clamp and MTT before and after 12 weeks of treatment with 400 mg/day bezafibrate. The glucose infusion rate was measured during the glucose clamp. The patients took a test meal (460 kcal) in the MTT. Plasma glucose and immunoreactive insulin levels were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity, serum lipids, and liver function markers were also measured during the MTT. RESULTS Bezafibrate significantly increased the mean glucose infusion rate from 5.78 ± 1.94 to 6.78 ± 2.52 mg/kg/min (p < 0.05). HbA1c improved from 7.30 ± 0.55% to 7.02 ± 0.52% (p < 0.05). In the MTT, fasting plasma glucose decreased from 7.95 ± 1.15 to 6.98 ± 1.07 mmol/L (p < 0.05). The area under the plasma glucose curve from 0 to 180 min decreased significantly from 29.48 ± 5.07 to 27.12 ± 3.98 mmol/h/L (p < 0.05), whereas immunoreactive insulin was unchanged. Furthermore, bezafibrate also significantly improved serum lipids, with decreases in triglyceride levels from 1.84 ± 0.88 to 1.14 ± 0.41 mmol/L (p < 0.05), low-density lipoprotein cholesterol levels from 3.56 ± 0.83 to 2.92 ± 0.55 mmol/L (p < 0.05), and remnant-like particle cholesterol levels decreased from 0.25 ± 0.16 to 0.14 ± 0.06 mmol/L (p < 0.05), and increases in high-density lipoprotein cholesterol levels from 1.50 ± 0.24 to 1.66 ± 0.29 mmol/L (p < 0.05). CONCLUSIONS Bezafibrate improved glucose intolerance and peripheral insulin resistance in these Japanese patients with type 2 diabetes mellitus and dyslipidemia. Therefore, bezafibrate could be used to treat insulin resistance in patients with type 2 diabetes mellitus and dyslipidemia. TRIAL REGISTRATION University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000012462.
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Affiliation(s)
- Hideki Shiochi
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Tsuyoshi Ohkura
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Yohei Fujioka
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Keisuke Sumi
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Naoya Yamamoto
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Risa Nakanishi
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Kazuhiko Matsuzawa
- />Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, 683-8504 Japan
| | - Schoichiro Izawa
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Hiroko Ohkura
- />Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, 683-8504 Japan
| | - Kazuoki Inoue
- />Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, 683-8504 Japan
| | - Etsuko Ueta
- />School of Health Science, Tottori University Faculty of Medicine, Yonago, Tottori, 683-8504 Japan
| | - Masahiko Kato
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
| | - Shin-ichi Taniguchi
- />Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, 683-8504 Japan
| | - Kazuhiro Yamamoto
- />Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Nishi-chou 36-1, Yonago, Tottori, 683-8504 Japan
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Magliano DC, Bargut TCL, de Carvalho SN, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. Peroxisome proliferator-activated receptors-alpha and gamma are targets to treat offspring from maternal diet-induced obesity in mice. PLoS One 2013; 8:e64258. [PMID: 23700465 PMCID: PMC3658968 DOI: 10.1371/journal.pone.0064258] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 04/13/2013] [Indexed: 02/07/2023] Open
Abstract
AIM The aim of the present study was to evaluate whether activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma by Bezafibrate (BZ) could attenuate hepatic and white adipose tissue (WAT) abnormalities in male offspring from diet-induced obese dams. MATERIALS AND METHODS C57BL/6 female mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 49% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring received SC diet at weaning and were subdivided into four groups: SC, SC/BZ, HF and HF/BZ. Treatment with BZ (100 mg/Kg diet) started at 12 weeks of age and was maintained for three weeks. RESULTS The HF diet resulted in an overweight phenotype and an increase in oral glucose intolerance and fasting glucose of dams. The HF offspring showed increased body mass, higher levels of plasmatic and hepatic triglycerides, higher levels of pro-inflammatory and lower levels of anti-inflammatory adipokines, impairment of glucose metabolism, abnormal fat pad mass distribution, higher number of larger adipocytes, hepatic steatosis, higher expression of lipogenic proteins concomitant to decreased expression of PPARalpha and carnitine palmitoyltransferase I (CPT-1) in liver, and diminished expression of PPARgamma and adiponectin in WAT. Treatment with BZ ameliorated the hepatic and WAT abnormalities generated by diet-induced maternal obesity, with improvements observed in the structural, biochemical and molecular characteristics of the animals' livers and epididymal fat. CONCLUSION Diet-induced maternal obesity lead to alterations in metabolism, hepatic lipotoxicity and adverse liver and WAT remodeling in the offspring. Targeting PPAR with Bezafibrate has beneficial effects reducing the alterations, mainly through reduction of WAT inflammatory state through PPARgamma activation and enhanced hepatic beta-oxidation due to increased PPARalpha/PPARgamma ratio in liver.
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Affiliation(s)
- D'Angelo Carlo Magliano
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Thereza Cristina Lonzetti Bargut
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Simone Nunes de Carvalho
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcia Barbosa Aguila
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos Alberto Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
- * E-mail:
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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Tenenbaum A, Fisman EZ. Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention? Cardiovasc Diabetol 2012; 11:140. [PMID: 23150952 PMCID: PMC3502168 DOI: 10.1186/1475-2840-11-140] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2012] [Accepted: 10/31/2012] [Indexed: 01/11/2023] Open
Abstract
All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects. In clinical trials bezafibrate was highly effective for cardiovascular risk reduction in patients with metabolic syndrome and atherogenic dyslipidemia. The principal differences between bezafibrate and other fibrates are related to effects on glucose level and insulin resistance. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis. However, despite the increasing use of statins as monotherapy for low density lipoprotein- cholesterol (LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic dyslipidemia and insulin resistance, which is typical for T2DM and metabolic syndrome. Recently, concerns were raised regarding the development of diabetes in statin-treated patients. Combined bezafibrate/statin therapy is more effective in achieving a comprehensive lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of statins using the strategy of a combined statin/fibrate therapy.
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Affiliation(s)
- Alexander Tenenbaum
- Cardiac Rehabilitation Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
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Tenenbaum A, Fisman EZ. Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention? Cardiovasc Diabetol 2012. [PMID: 23150952 DOI: 10.1186/1475-2840-11-1401475-2840-11-140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects. In clinical trials bezafibrate was highly effective for cardiovascular risk reduction in patients with metabolic syndrome and atherogenic dyslipidemia. The principal differences between bezafibrate and other fibrates are related to effects on glucose level and insulin resistance. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis. However, despite the increasing use of statins as monotherapy for low density lipoprotein- cholesterol (LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic dyslipidemia and insulin resistance, which is typical for T2DM and metabolic syndrome. Recently, concerns were raised regarding the development of diabetes in statin-treated patients. Combined bezafibrate/statin therapy is more effective in achieving a comprehensive lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of statins using the strategy of a combined statin/fibrate therapy.
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Affiliation(s)
- Alexander Tenenbaum
- Cardiac Rehabilitation Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
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Tenenbaum A, Fisman EZ. Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction. Cardiovasc Diabetol 2012; 11:125. [PMID: 23057687 PMCID: PMC3489608 DOI: 10.1186/1475-2840-11-125] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 10/09/2012] [Indexed: 02/06/2023] Open
Abstract
Currently the world faces epidemic of several closely related conditions: obesity, metabolic syndrome and type 2 diabetes (T2DM). The lipid profile of these patients and those with metabolic syndrome is characterized by the concurrent presence of qualitative as well as quantitative lipoprotein abnormalities: low levels of HDL, increased triglycerides, and prevalence of LDL particles that are smaller and denser than normal. This lipid phenotype has been defined as atherogenic dyslipidemia. Overwhelming evidences demonstrate that all components of the atherogenic dyslipidemia are important risk-factors for cardiovascular diseases. Optimal reduction of cardiovascular risk through comprehensive management of atherogenic dyslipidemias basically depends of the presence of efficacious lipid-modulating agents (beyond statin-based reduction of LDL-C). The most important class of medications which can be effectively used nowadays to combat atherogenic dyslipidemias is the fibrates. From a clinical point of view, in all available 5 randomized control trials beneficial effects of major fibrates (gemfibrozil, fenofibrate, bezafibrate) were clearly demonstrated and were highly significant in patients with atherogenic dyslipidemia. In these circumstances, the main determinant of the overall results of the trial is mainly dependent of the number of the included appropriate patients with atherogenic dyslipidemia. In a meta-analysis of dyslipidemic subgroups totaling 4726 patients a significant 35% relative risk reduction in cardiovascular events was observed compared with a non significant 6% reduction in those without dyslipidemia. However, different fibrates may have a somewhat different spectrum of effects. Currently only fenofibrate was investigated and proved to be effective in reducing microvascular complications of diabetes. Bezafibrate reduced the severity of intermittent claudication. Cardinal differences between bezafibrate and other fibrates are related to the effects on glucose metabolism and insulin resistance. Bezafibrate is the only clinically available pan - (alpha, beta, gamma) PPAR balanced activator. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Among major fibrates, bezafibrate appears to have the strongest and fenofibrate the weakest effect on HDL-C. Current therapeutic use of statins as monotherapy is still leaving many patients with atherogenic dyslipidemia at high risk for coronary events because even intensive statin therapy does not eliminate the residual cardiovascular risk associated with low HDL and/or high triglycerides. As compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the association of a statin with a fibrate will also have a major impact on triglycerides, HDL and LDL particle size. Moreover, in the specific case of bezafibrate one could expect neutralizing of the adverse pro-diabetic effect of statins. Though muscle pain and myositis is an issue in statin/fibrate treatment, adverse interaction appears to occur to a significantly greater extent when gemfibrozil is administered. However, bezafibrate and fenofibrate seems to be safer and better tolerated. Combined fibrate/statin therapy is more effective in achieving a comprehensive lipid control and may lead to additional cardiovascular risk reduction, as could be suggested for fenofibrate following ACCORD Lipid study subgroup analysis and for bezafibrate on the basis of one small randomized study and multiple observational data. Therefore, in appropriate patients with atherogenic dyslipidemia fibrates- either as monotherapy or combined with statins - are consistently associated with reduced risk of cardiovascular events. Fibrates currently constitute an indispensable part of the modern anti-dyslipidemic arsenal for patients with atherogenic dyslipidemia.
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Affiliation(s)
- Alexander Tenenbaum
- Cardiac Rehabilitation Institute, Sheba Medical Center, Tel-Hashomer, 52621, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
- Cardiovascular Diabetology Research Foundation, Holon 58484, Israel
| | - Enrique Z Fisman
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
- Cardiovascular Diabetology Research Foundation, Holon 58484, Israel
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Abstract
A low plasma level of HDL cholesterol is an atherosclerotic risk factor; however, emerging evidence suggests that low HDL levels might also contribute to the pathophysiology of type 2 diabetes mellitus (T2DM) through direct effects on plasma glucose. In the past decade, animal and clinical studies have uncovered a previously undescribed spectrum of HDL actions, indicating that HDL may control glucose homeostasis through mechanisms including insulin secretion, direct glucose uptake by muscle via the AMP-activated protein kinase, and possibly enhanced insulin sensitivity. These effects are mediated by multiple cell types via mechanisms including preservation of cell function through cellular lipid removal and also via direct signaling events. We suggest a paradigm shift from HDL being a bystander to being an active player in diabetic pathophysiology, which raises the possibility that HDL elevation could be a novel therapeutic avenue for T2DM. The entry of HDL-raising agents of the cholesteryl ester transfer protein (CETP) inhibitor class into late-phase clinical trials creates potential for rapid clinical translation. This Review will discuss the emerging evidence for a role of HDL-mediated glucose regulation in the pathophysiology of T2DM, and will also outline the therapeutic potential for HDL elevation for the prevention and management of T2DM.
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Affiliation(s)
- Brian G Drew
- Metabolic and Vascular Physiology Laboratory, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, VIC 8008, Australia
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Mancini GBJ, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng D, Pope J. Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference. Can J Cardiol 2011; 27:635-62. [PMID: 21963058 DOI: 10.1016/j.cjca.2011.05.007] [Citation(s) in RCA: 132] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 05/19/2011] [Accepted: 05/19/2011] [Indexed: 12/24/2022] Open
Abstract
While the proportion of patients with significant statin-associated adverse effects or intolerance is very low, the increasing use and broadening indications have led to a significant absolute number of such patients commonly referred to tertiary care facilities and specialists. This report provides a comprehensive overview of the evidence pertaining to a broad variety of statin-associated adverse effects followed by a consensus approach for the prevention, assessment, diagnosis, and management. The overview is intended both to provide clarification of the untoward effects of statins and to impart confidence in managing the most common issues in a fashion that avoids excessive ancillary testing and/or subspecialty referral except when truly necessary. The ultimate goal is to ensure that patients who warrant cardiovascular risk reduction can be treated optimally, safely, and confidently with statin medications or alternatives when warranted.
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Affiliation(s)
- G B John Mancini
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Eslam M, Khattab MA, Harrison SA. Peroxisome proliferator-activated receptors and hepatitis C virus. Therap Adv Gastroenterol 2011; 4:419-31. [PMID: 22043232 PMCID: PMC3187680 DOI: 10.1177/1756283x11405251] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The prevalence of type 2 diabetes mellitus and insulin resistance are higher among people chronically infected with hepatitis C (CHC) when compared with the general population and people with other causes of chronic liver disease. Both insulin resistance and diabetes are associated with adverse outcomes across all stages of CHC, including the liver transplant population. CHC is also associated with the development of hepatic steatosis, a common histological feature present in approximately 55% (32-81%) of cases. There is a complex interrelationship between insulin resistance and hepatic steatosis and both are postulated to aggravate each other. The peroxisome proliferator-activated receptors (PPARs) are nuclear factors involved in the regulation of glucose, lipid homeostasis, inflammatory response, cell differentiation, and cell cycle. The relationship between hepatitis C virus replication and PPARs has been the focus of recent study. Given the availability of potent agonists, PPARs may represent a novel pharmacological target in the treatment of CHC.
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Affiliation(s)
- M. Eslam
- Department of Internal Medicine, Minia University, Minia, Egypt
| | - M. A. Khattab
- Department of Internal Medicine, Minia University, Minia, Egypt
| | - S. A. Harrison
- Division of Gastroenterology and Hepatology, Department of Medicine, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, TX 78234, USA
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25
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Noguchi T, Kobayashi J, Yagi K, Nohara A, Yamaaki N, Sugihara M, Ito N, Oka R, Kawashiri MA, Tada H, Takata M, Inazu A, Yamagishi M, Mabuchi H. Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: results from a crossover study. Atherosclerosis 2011; 217:165-170. [PMID: 21411093 DOI: 10.1016/j.atherosclerosis.2011.02.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 01/17/2011] [Accepted: 02/07/2011] [Indexed: 11/25/2022]
Abstract
BACKGROUND Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers. METHODS An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m², total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks. RESULTS Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p<0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p<0.001 vs. -32.9%, p<0.01) and increases in HDL-C (+18.0%, p<0.001 vs. +11.7%, p<0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p<0.01; non-HDL-C, -17.3%, p<0.01; apolipoprotein B, -15.1%, p<0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p<0.05) and metabolic markers (γ-GTP, -38.9%, p<0.01; adiponectin, +15.4%, p<0.05; urine 8-OHdG/Cre, -9.5%, p<0.05). CONCLUSION Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates.
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Affiliation(s)
- Tohru Noguchi
- Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
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26
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High Doses of Rosuvastatin are Superior to Low Doses of Rosuvastatin Plus Fenofibrate or n-3 Fatty Acids in Mixed Dyslipidemia. Lipids 2011; 46:521-8. [DOI: 10.1007/s11745-011-3538-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 12/07/2010] [Indexed: 01/29/2023]
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Tenenbaum A, Fisman EZ. "The metabolic syndrome... is dead": these reports are an exaggeration. Cardiovasc Diabetol 2011; 10:11. [PMID: 21269524 PMCID: PMC3036609 DOI: 10.1186/1475-2840-10-11] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 01/27/2011] [Indexed: 02/06/2023] Open
Abstract
The debates continue over the validity of the metabolic syndrome concept. The continuous increment of the obesity pandemic is almost worldwide paralleled by rising rates of metabolic syndrome prevalence. Then, it seems obvious that these debates drove the need for further investigations as well as a deeper cooperation between relevant national and international organizations regarding the issue. Instead, part of the scientific community elected to totally "dismiss" the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality rates. One of the ways to hit the metabolic syndrome is an utterly simplistic view on this concept as a predictive tool only. Of course, the presence of the metabolic syndrome possesses a definite predictive value, but first of all it is a widely accepted concept regarding a biological condition based on the complex and interrelated pathophysiological mechanisms starting from excess central adiposity and insulin resistance. Therefore, it is completely unfair to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to each other from the biological point of view. For example, in the criteria for metabolic syndrome (in contrast to Framingham score) age and cholesterol--presumably low density lipoprotein-cholesterol (LDL-C)--levels are not included, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. However, the metabolic syndrome identifies additional important residual vascular risk mainly associated with insulin resistance and atherogenic dyslipidemia (low high density lipoprotein-cholesterol (HDL-C), high triglycerides, small, dense LDL-C). Therefore, the metabolic syndrome could be a useful additional contributor in estimation of global cardiovascular risk beyond age, high LDL-C or other standard risk factors. The components of the metabolic syndrome have partially overlapping mechanisms of pathogenic actions mediated through common metabolic pathways. Therefore their total combined effect could be less than the summed of the individual effects. The concept that the metabolic syndrome is a consequence of obesity and insulin resistance, provides a useful "life-style changes" approach for prevention and treatment: caloric restriction, weight-loss and increased physical activity. The next step could theoretically be pharmacological interventions such as metformin, acarbose, fibrates, weight-loss drugs (currently only orlistat is practically available) and perhaps glucagon-like peptide-1 agonists. A third step should probably be kept for bariatric surgery.
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28
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Tremblay-Mercier J, Tessier D, Plourde M, Fortier M, Lorrain D, Cunnane SC. Bezafibrate mildly stimulates ketogenesis and fatty acid metabolism in hypertriglyceridemic subjects. J Pharmacol Exp Ther 2010; 334:341-6. [PMID: 20404010 DOI: 10.1124/jpet.110.166504] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Our objective was to determine whether bezafibrate, a hypotriglyceridemic drug and peroxisome proliferator-activated receptor (PPAR)-alpha agonist, is ketogenic and increases fatty acid oxidation in humans. We measured fatty acid metabolism and ketone levels in 13 mildly hypertriglycemic adults (67 +/- 11 years old) during 2 metabolic study days lasting 6 h, 1 day before and 1 day after bezafibrate (400 mg of bezafibrate per day for 12 weeks). beta-Hydroxybutyrate, triglycerides, free fatty acids, fatty acid profiles, insulin, and glucose were measured in plasma, and fatty acid beta-oxidation was measured in breath after an oral 50-mg dose of the fatty acid tracer [U-(13)C]linoleic acid. As expected, 12 weeks on bezafibrate decreased plasma triglycerides by 35%. Bezafibrate tended to raise postprandial beta-hydroxybutyrate, an effect that was significant after normalization to the fasting baseline values (p = 0.03). beta-Oxidation of [U-(13)C]linoleic acid increased by 30% (p = 0.03) after treatment. On the metabolic study day after bezafibrate treatment, postprandial insulin decreased by 26% (p = 0.01), and glucose concentrations were lower 2 to 5 h postprandially. Thus, in hypertriglyceridemic individuals, bezafibrate is mildly ketogenic and significantly changes fatty acid metabolism, effects that may be linked to PPARalpha stimulation and to moderately improved glucose metabolism.
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Affiliation(s)
- Jennifer Tremblay-Mercier
- Research Center on Aging, University Institute of Geriatrics of Sherbrooke, Sherbrooke, Quebec, Canada.
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29
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Tenenbaum A, Fisman EZ. "If it ain't broke, don't fix it": a commentary on the positive-negative results of the ACCORD Lipid study. Cardiovasc Diabetol 2010; 9:24. [PMID: 20550659 PMCID: PMC2893121 DOI: 10.1186/1475-2840-9-24] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Accepted: 06/15/2010] [Indexed: 12/11/2022] Open
Abstract
Even using intensive statin monotherapy, many patients fail to achieve all the desired lipid goals and remain at high residual risk of cardiovascular events. In view of the still unproven decisively intensive "statin as monotherapy" strategy and "residual risk" concept, it is logical to ask whether other strategies, particularly fibrate/statin combination therapy, could be more beneficial and safer. A clear benefit of fibrate monotherapy did emerge previously among patients with atherogenic dyslipidemia (particularly high triglycerides and low high density lipoprotein cholesterol [HDL-C]) typically present in the metabolic syndrome and type 2 diabetes. In contrast, in patients without atherogenic dyslipidemia this favorable effect was not demonstrated. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus. However, relevant patients with atherogenic dyslipidemia represented less than 17 percent of the ACCORD Lipid population (941 out of 5518 patients). In this prespecified subgroup, the patients benefited from fenofibrate therapy in addition to simvastatin similar to the previous "fibrate's as monotherapy" trials: the primary outcome rate was 12.4% in the fenofibrate group, versus 17.3% in the placebo group (28% crude HR reduction, CI less than 1, e.g. statistically significant findings). Among all other 4548 patients without atherogenic dyslipidemia such rates were 10.1% in both fenofibrate and placebo study groups. Authors concluded that in the overall cohort of patients the combination of fenofibrate and simvastatin did not reduce the rate of the cardiovascular events as compared with simvastatin alone. Thus, their results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the general patients with type 2 diabetes. A recent large meta-analysis regarding effects of fibrates on cardiovascular outcomes noted greater effect sizes in trials that recorded a higher mean baseline triglyceride concentration (p = 0.030). As expected, in a so called "general population", reflecting a blend of effects in patients with and without atherogenic dyslipidemia, a mean "diluted" effect of fibrate therapy was reduced, but still producing a significant 10% relative risk (RR) decrease in major cardiovascular events (p = 0.048) and a 13% RR reduction for coronary events (p < 0.0001). It should be pinpointed that the epidemiological characteristics of the ACCORD Lipid study depart from those seen in real clinical practice: among people with type 2 diabetes, there is a high prevalence of atherogenic dyslipidemia and metabolic syndrome. For example, an analysis of NHANES III data in adults aged >or=50 years showed that approximately 86% of patients with type 2 diabetes also had the metabolic syndrome. Therefore, an important finding of ACCORD Lipid study was the observation that fibrates may lead to cardiovascular risk reduction in patients with atherogenic dyslipidemia not only as monotherapy but in combination with statins as well. In conclusion, in patients with atherogenic dyslipidemia (high triglycerides and low HDL-C, fibrates -- either as monotherapy or combined with statins - were associated with reduced risk of cardiovascular events. In patients without dyslipidemia this favorable effect - as expected - was absent.
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Affiliation(s)
- Alexander Tenenbaum
- Cardiac Rehabilitation Institute, Sheba Medical Center, Tel-Hashomer, Israel.
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Hellemans KH, Hannaert JC, Denys B, Steffensen KR, Raemdonck C, Martens GA, Van Veldhoven PP, Gustafsson JA, Pipeleers D. Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase. PLoS One 2009; 4:e7266. [PMID: 19787047 PMCID: PMC2746288 DOI: 10.1371/journal.pone.0007266] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2009] [Accepted: 09/02/2009] [Indexed: 01/22/2023] Open
Abstract
Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/-) and LXRalphabeta(-/-)), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids.
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Affiliation(s)
- Karine H Hellemans
- Diabetes Research Center, Brussels Free University-VUB, and JDRF Center for Beta Cell Therapy in Diabetes, Brussels, Belgium.
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31
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Fisman EZ, Tenenbaum A. A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. Cardiovasc Diabetol 2009; 8:38. [PMID: 19619327 PMCID: PMC2723076 DOI: 10.1186/1475-2840-8-38] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Accepted: 07/20/2009] [Indexed: 02/07/2023] Open
Abstract
Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
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Affiliation(s)
- Enrique Z Fisman
- Sackler Faculty of Medicine, Tel-Aviv University, 69978 Ramat-Aviv, Tel-Aviv, Israel.
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