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Zhao Y, Yue R. White adipose tissue in type 2 diabetes and the effect of antidiabetic drugs. Diabetol Metab Syndr 2025; 17:116. [PMID: 40186308 PMCID: PMC11969724 DOI: 10.1186/s13098-025-01678-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 03/19/2025] [Indexed: 04/07/2025] Open
Abstract
White adipose tissue (WAT) is highly flexible and was previously considered a passive location for energy storage. Its endocrine function has been established for several years, earning it the title of an "endocrine organ" due to its ability to secrete many adipokines that regulate metabolism. WAT is one of the core tissues that influence insulin sensitivity. Its dysfunction enhances insulin resistance and type 2 diabetes (T2D) progression. However, T2D may cause WAT dysfunction, including changes in distribution, metabolism, adipocyte hypertrophy, inflammation, aging, and adipokines and free fatty acid levels, which may exacerbate insulin resistance. This review used PubMed to search WAT dysfunction in T2D and the effects of these changes on insulin resistance. Additionally, we described and discussed the effects of antidiabetic drugs, including insulin therapy, sulfonylureas, metformin, glucose-like peptide-1 receptor agonists, thiazolidinediones, and sodium-dependent glucose transporters-2 inhibitors, on WAT parameters under T2D conditions.
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Affiliation(s)
- Yixuan Zhao
- Chengdu University of Traditional Chinese Medicine, Hospital of Chengdu, University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan Province, 610072, P. R. China
| | - Rensong Yue
- Chengdu University of Traditional Chinese Medicine, Hospital of Chengdu, University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan Province, 610072, P. R. China.
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2
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Zaki HA, Iftikhar H, Shallik NA, Shaban E, Al-Marri NDR, Bashir I, Elhadad A, Zoghlami F, Abdalrubb A. A Systematic Review and Meta-Analysis of Randomized Controlled Trials Comparing the Effects of Biguanides (Metformin) and Thiazolidinediones on Glucose Tolerance and Insulin Sensitivity in Patients With Type II Diabetes Mellitus. Cureus 2023; 15:e39445. [PMID: 37362539 PMCID: PMC10289479 DOI: 10.7759/cureus.39445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2023] [Indexed: 06/28/2023] Open
Abstract
Type II diabetes mellitus (T2DM) is a global epidemic affecting people of all ages in developed and developing countries. The disease is usually characterized by insulin resistance and glucose intolerance; therefore, oral antidiabetic drugs such as thiazolidinediones (TZDs) and biguanide metformin are used to counter these defects. Due to the varied action mechanisms of TZDs and Metformin, their effects on insulin sensitivity and glucose tolerance may differ. Therefore, the current study was carried out to compare the effects of Metformin and TZDs on insulin sensitivity and glucose tolerance among patients with T2DM. Two methods, including using a well-outlined search strategy in 5 electronic databases including ScienceDirect, Google Scholar, PubMed, Scopus, and Embase, and a manual search which involved going through the reference lists of studies from the electronic databases were used to retrieve studies published between 2000 and 2022. Additionally, data analysis of outcomes retrieved from the studies eligible for inclusion and the methodological quality was carried out using the Review Manager software (RevMan 5.4.1) and STATA. The meta-analysis has shown that TZDs have a significantly better overall effect on fasting plasma glucose (FPG) (SMD:0.61; 95% CI:0.06, 1.16: p = 0.03) and insulin sensitivity than Metformin (Mean QUICKI: 0.306 ± 0.019 vs. 0.316 ± 0.019, respectively; p=0.0003). However, the TZDs and Metformin offer the same effect on glycemic control as assessed using HBA1c levels (MD: 0.10; 95% CI: -0.20, 0.40; p = 0.52). TZDs offer better insulin sensitivity and glucose tolerance improvements compared to Metformin. This evidence contradicts the current guidelines by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE), which recommend the use of Metformin as the first-line drug monotherapy for patients with T2DM.
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Affiliation(s)
- Hany A Zaki
- Emergency Medicine, Hamad Medical Corporation, Doha, QAT
| | - Haris Iftikhar
- Emergency Medicine, Hamad Medical Corporation, Doha, QAT
| | - Nabil A Shallik
- Anaesthesiology, Weill Cornell Medical College in Qatar, Doha, QAT
- Anaesthesiology, Hamad Medical Corporation, Doha, QAT
| | - Eman Shaban
- Cardiology, Al Jufairi Diagnosis And Treatment, Doha, QAT
| | | | - Israr Bashir
- Emergency Medicine, Hamad Medical Corporation, Doha, QAT
| | - Awny Elhadad
- Emergency Department, United Lincolnshire Hospitals, Lincoln, GBR
| | - Fatma Zoghlami
- Emergency Department, Hamad General Hospital, Qatar, QAT
| | - Abeer Abdalrubb
- Endocrinology and Diabetes, Hamad Medical Corporation, Doha, QAT
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Abdalla MMI. Salivary resistin level and its association with insulin resistance in obese individuals. World J Diabetes 2021; 12:1507-1517. [PMID: 34630903 PMCID: PMC8472494 DOI: 10.4239/wjd.v12.i9.1507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/11/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
The escalating global burden of type 2 diabetes mellitus necessitates the implementation of strategies that are both more reliable and faster in order to improve the early identification of insulin resistance (IR) in high-risk groups, including overweight and obese individuals. The use of salivary biomarkers offers a promising alternative to serum collection because it is safer, more comfortable, and less painful to obtain saliva samples. As obesity is the foremost contributory factor in IR development, the adipocytokines such as leptin, adiponectin, resistin, and visfatin secreted from the adipose tissue have been studied as potential reliable biomarkers for IR. Measurement of salivary adipokines as predictors for IR has attracted widespread attention because of the strong correlation between their blood and salivary concentrations. One of the adipokines that is closely related to IR is resistin. However, there are conflicting findings on resistin's potential role as an etiological link between obesity and IR and the reliability of measuring salivary resistin as a biomarker for IR. Hence this study reviewed the available evidence on the potential use of salivary resistin as a biomarker for IR in order to attempt to gain a better understanding of the role of resistin in the development of IR in obese individuals.
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Giandalia A, Alibrandi A, Giorgianni L, Lo Piano F, Consolo F, Longo Elia G, Asztalos B, Cucinotta D, Squadrito G, Russo GT. Resistin levels and inflammatory and endothelial dysfunction markers in obese postmenopausal women with type 2 diabetes mellitus. Diabetol Metab Syndr 2021; 13:98. [PMID: 34496965 PMCID: PMC8427860 DOI: 10.1186/s13098-021-00715-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/29/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Obesity-associated coronary heart disease (CHD) risk is higher in women than in men with type 2 diabetes (T2DM). Resistin, an adipokine secreted by adispose tissue, may contribute to this higher risk. AIMS To explore the relationships among resistin levels and common inflammatory and endothelial dysfunction markers and CHD risk in obese post-menopausal T2DM women. METHODS Serum levels of resistin, hsCRP, IL-6, Soluble vascular cell adhesion molecule (sVCAM), homocysteine (tHcy), HOMA-IR and metabolic parameters were determined in a group of 132 T2DM women with and without documented CHD and in 55 non-diabetic women. RESULTS Resistin, sVCAM, IL-6 and tHcy levels were comparable in T2DM and controls. CHD women showed higher resistin, sVCAM and tHcy levels than those without CHD, and for resistin this difference remained significant after age-adjustment (P = 0.013); conversely hsCRP were ~ 2X higher in T2DM women than in controls (P = 0.0132) without any difference according to CHD history. At univariate analysis resistin levels were significantly associated with age, waist circumference, hypertension, tHcy, hsPCR, sVCAM, IL-6, HDL-cholesterol, triglycerides and creatinine levels, but only creatinine, triglycerides, hsCRP, IL-6 and sVCAM were independently associated to resistin levels at stepwise regression analysis. Resistin levels were independently associated to CHD, increasing the risk by 1.15 times (0.986-1.344 95% CI), together with age, tHcy, LDL-C and hypertension. CONCLUSIONS Circulating resistin levels were comparable in obese/overweight T2DM and control women. In T2DM women, resistin levels correlated with markers of renal function, systemic inflammation and endothelial dysfunction and were independently associated with a higher CHD risk.
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Affiliation(s)
- A Giandalia
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
| | - A Alibrandi
- Unit of Statistical and Mathematical Sciences, Department of Economics, University of Messina, Messina, Italy
| | - L Giorgianni
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - F Lo Piano
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - F Consolo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - G Longo Elia
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - B Asztalos
- Lipid Metabolism Laboratory, JM-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - D Cucinotta
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - G Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - G T Russo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
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DİK B, COŞKUN D, BAHÇİVAN E, ÜNEY K. Potential antidiabetic activity of benzimidazole derivative albendazole and lansoprazole drugs in different doses in experimental type 2 diabetic rats. Turk J Med Sci 2021; 51:1579-1586. [PMID: 33641315 PMCID: PMC8283501 DOI: 10.3906/sag-2004-38] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 02/27/2021] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND/AIM The aim of this study is to determine the effects of different concentrations of albendazole and lansoprazole, which were benzimidazole derivatives, on endocrinologic and biochemical parameters in experimental type 2 diabetic (T2D) rats. MATERIALS AND METHODS In this study, 46 male Wistar Albino rats were used. Animals were divided as healthy control (0.1 mL/rat/day saline, s.c, n = 6), diabetes control (0.1 mL/rat/day saline, s.c, n = 8), diabetes+low-dose albendazole (5 mg/kg, oral, n = 8), diabetes+high- dose albendazole (10 mg/kg, oral n = 8), diabetes+low-dose lansoprazole (15 mg/kg, subcutaneous, n = 8), and diabetes+high-dose lansoprazole (30 mg/kg, subcutaneous, n = 8). All groups were treated for 8 weeks. The blood samples were analyzed by autoanalyzer and ELISA kits for biochemical and endocrinological parameters, respectively. RESULTS Glucose, HbA1c, triglyceride, low density cholesterol (LDL), leptin, and Homeostatic Model Assessment for insulin resistance (HOMA-IR) levels increased and insulin and HOMA-β levels decreased in the diabetic rats compared to the healthy control group. The glucose, HbA1c, and triglyceride levels were partially decreased; however, insulin and HOMA-β levels were increased by low-dose albendazole therapy. The high dose of lansoprazole treatment increased insulin level. CONCLUSION The lansoprazole and albendazole treatments can be a potential drug or combined with antidiabetic drugs in T2D treatment by Adenosine 5′-monophosphate activated protein kinase (AMPK), peroxisome proliferator-activated receptor (PPAR), incretin-like effect and other antidiabetic mechanisms. It may be beneficial to create an effective treatment strategy by developing more specific substances with benzimidazole scaffold.
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Affiliation(s)
- Burak DİK
- Department of Pharmacology and Toxicology, Veterinary Faculty, SelÇuk University, KonyaTurkey
| | - Devran COŞKUN
- Department of Pharmacology and Toxicology, Veterinary Faculty, Siirt University, SiirtTurkey
| | - Emre BAHÇİVAN
- Department of Pharmacology and Toxicology, Veterinary Faculty, Kafkas University, KarsTurkey
| | - Kamil ÜNEY
- Department of Pharmacology and Toxicology, Veterinary Faculty, SelÇuk University, KonyaTurkey
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Su KZ, Li YR, Zhang D, Yuan JH, Zhang CS, Liu Y, Song LM, Lin Q, Li MW, Dong J. Relation of Circulating Resistin to Insulin Resistance in Type 2 Diabetes and Obesity: A Systematic Review and Meta-Analysis. Front Physiol 2019; 10:1399. [PMID: 31803062 PMCID: PMC6877503 DOI: 10.3389/fphys.2019.01399] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/30/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Resistin, a cysteine-rich polypeptide encoded by the RETN gene, which plays an important role in many mechanisms in rodent studies, including lipid metabolism, inflammation and insulin resistance. Nevertheless, the relationship between resistin and insulin resistance in humans is under debate. The present study was designed to clarify the correlation between resistin and insulin resistance. Methods: A systematic literature search was performed using PubMed, Embase and Cochrane Library until March 3, 2019 with the keywords "resistin" and "insulin resistance." Funnel plots and Egger's test were used to detect publication bias. A random-effects model was used to calculate the pooled effect size. Subgroup analysis and meta regression was performed to identify the sources of heterogeneity. Results: Fifteen studies were included in our systematic review. Among them, 10 studies with Pearson coefficients were used for meta-analysis. We found resistin levels were weakly correlated with insulin resistance in those with T2DM and obesity (r = 0.21, 95% CI: 0.06-0.35, I 2 = 59.7%, P = 0.003). Nevertheless, subgroup analysis suggested that circulating resistin levels were significantly positively correlated with insulin resistance in individuals with hyperresistinemia (≥14.8 ng/ml) (r = 0.52, 95% CI: 0.35-0.68, I 2 = 0.0%, P = 0.513). And there was no relationship between circulating resistin and insulin resistance in those with normal circulating resistin levels (<14.8 ng/ml) (r = 0.08, 95% CI: -0.01-0.18, I 2 = 0.0%, P = 0.455). Publication bias was insignificant (Egger's test P = 0.592). Conclusion: In T2DM and obese individuals, resistin levels were positively correlated with insulin resistance in those with hyperresistinemia, but not in those with normal circulating resistin levels.
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Affiliation(s)
- Kai-zhen Su
- Clinical Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Yan-run Li
- Clinical Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Di Zhang
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Jun-hua Yuan
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Cai-shun Zhang
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Yuan Liu
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Li-min Song
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Qian Lin
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Man-wen Li
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
| | - Jing Dong
- Special Medicine Department, Medical College, Qingdao University, Qingdao, China
- Physiology Department, Medical College, Qingdao University, Qingdao, China
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Zhang Y, Li Y, Yu L, Zhou L. Association between serum resistin concentration and hypertension: A systematic review and meta-analysis. Oncotarget 2017; 8:41529-41537. [PMID: 28525369 PMCID: PMC5522312 DOI: 10.18632/oncotarget.17561] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 04/19/2017] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Recent studies have suggested the involvement of adipokines in the pathogenesis of cardiovascular diseases, including hypertension. In this study, we evaluated the significance of serum resistin levels in hypertensive patients using a meta-analysis approach. MATERIALS AND METHODS Relevant articles were retrieved by searching the following databases: PubMed, Embase, Ovid Medline, ISI Web of Knowledge. The retrieved studies were subjected to a thorough screening procedure to identify case-control studies that contained the required data. Data were extracted from each study and analyzed by Stata software and Review Manager software. In total, 14 case-control studies, containing 718 hypertensive patients and 645 normotensive controls, were included in this study. The major result of the meta-analysis revealed a statistically significant association between serum resistin concentration and hypertension (SMD = 0.85, 95% CI: [0.15, 1.54]), and the association was more obvious in Asian and Hispanic populations, diabetic population and studies with larger size cohorts. Publication bias was a low probability event for overall comparisons. CONCLUSIONS Based on our results, we conclude that serum resistin level in hypertensive patients is higher than normotensive controls, indicating resistin might be a risk factor for hypertension.
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Affiliation(s)
- Yuxiang Zhang
- The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Pharmacology Graduate Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Public Health Certificate Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yixing Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning, 530004, P.R. China
| | - Lin Yu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning, 530004, P.R. China
| | - Lei Zhou
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning, 530004, P.R. China
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Shang N, Xu H, Rindflesch TC, Cohen T. Identifying plausible adverse drug reactions using knowledge extracted from the literature. J Biomed Inform 2014; 52:293-310. [PMID: 25046831 DOI: 10.1016/j.jbi.2014.07.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 06/06/2014] [Accepted: 07/10/2014] [Indexed: 01/08/2023]
Abstract
Pharmacovigilance involves continually monitoring drug safety after drugs are put to market. To aid this process; algorithms for the identification of strongly correlated drug/adverse drug reaction (ADR) pairs from data sources such as adverse event reporting systems or Electronic Health Records have been developed. These methods are generally statistical in nature, and do not draw upon the large volumes of knowledge embedded in the biomedical literature. In this paper, we investigate the ability of scalable Literature Based Discovery (LBD) methods to identify side effects of pharmaceutical agents. The advantage of LBD methods is that they can provide evidence from the literature to support the plausibility of a drug/ADR association, thereby assisting human review to validate the signal, which is an essential component of pharmacovigilance. To do so, we draw upon vast repositories of knowledge that has been extracted from the biomedical literature by two Natural Language Processing tools, MetaMap and SemRep. We evaluate two LBD methods that scale comfortably to the volume of knowledge available in these repositories. Specifically, we evaluate Reflective Random Indexing (RRI), a model based on concept-level co-occurrence, and Predication-based Semantic Indexing (PSI), a model that encodes the nature of the relationship between concepts to support reasoning analogically about drug-effect relationships. An evaluation set was constructed from the Side Effect Resource 2 (SIDER2), which contains known drug/ADR relations, and models were evaluated for their ability to "rediscover" these relations. In this paper, we demonstrate that both RRI and PSI can recover known drug-adverse event associations. However, PSI performed better overall, and has the additional advantage of being able to recover the literature underlying the reasoning pathways it used to make its predictions.
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Affiliation(s)
- Ning Shang
- School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, United States.
| | - Hua Xu
- School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, United States
| | | | - Trevor Cohen
- School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, United States
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Sakaue S, Kamigaki M, Yoshimura H, Nishimura M. Effects of replacing metformin with pioglitazone on glycemic control in japanese patients with poorly controlled type 2 diabetes mellitus: A 12-week, open-label, prospective study. Curr Ther Res Clin Exp 2014; 69:364-77. [PMID: 24692813 DOI: 10.1016/j.curtheres.2008.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2008] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance. OBJECTIVES The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change. METHODS This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration >7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase). RESULTS Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m(2)) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P < 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P < 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal. CONCLUSIONS Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline.
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Affiliation(s)
- Shinji Sakaue
- First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan
| | - Mitsunori Kamigaki
- First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan
| | - Haruhiko Yoshimura
- Department of Internal Medicine, Iwamizawa Municipal General Hospital, Iwamizawa, Japan
| | - Masaharu Nishimura
- First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan
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10
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Lexis CP, van der Horst IC, Lipsic E. Effects of metformin on insulin resistance in heart failure. Which came first: the chicken or the egg? Eur J Heart Fail 2014; 14:1197-8. [DOI: 10.1093/eurjhf/hfs155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Chris P.H. Lexis
- Department of Cardiology; University of Groningen, University Medical Center Groningen; Groningen The Netherlands
| | - Iwan C.C. van der Horst
- Department of Cardiology; University of Groningen, University Medical Center Groningen; Groningen The Netherlands
- Department of Critical Care; University of Groningen, University Medical Center Groningen; Groningen The Netherlands
| | - Erik Lipsic
- Department of Cardiology; University of Groningen, University Medical Center Groningen; Groningen The Netherlands
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Bays H, Blonde L, Rosenson R. Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients? Expert Rev Cardiovasc Ther 2014; 4:871-95. [PMID: 17173503 DOI: 10.1586/14779072.4.6.871] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
An increase in bodyweight is generally associated with an increased risk of excessive fat-related metabolic diseases (EFRMD), including Type 2 diabetes mellitus, hypertension and dyslipidemia. However, not all patients who are overweight have EFRMD, and not all patients with EFRMD are significantly overweight. The adipocentric paradigm provides the basis for a unifying, pathophysiological process whereby fat gain in susceptible patients leads to fat dysfunction ('sick fat'), and wherein pathological abnormalities in fat function (adiposopathy) are more directly related to the onset of EFRMD than increases in fat mass (adiposity) alone. But just as worsening fat function worsens EFRMD, improved fat function improves EFRMD. Peroxisome proliferator-activated receptor-gamma agonists increase the recruitment, proliferation and differentiation of preadipocytes ('healthy fat') and cause apoptosis of hypertrophic and dysfunctional (including visceral) adipocytes resulting in improved fat function and improved metabolic parameters associated with EFRMD. Weight loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favorable effects upon fat storage (lipogenesis and fat distribution), nutrient metabolism (such as free fatty acids), favorable effects upon adipose tissue factors involved in metabolic processes and inflammation, and enhanced 'cross-talk' with other major organ systems. In some cases, weight loss therapeutic agents may even affect metabolic parameters and adipocyte function independently of weight loss alone, suggesting that the benefit of these agents in improving EFRMD may go beyond their efficacy in weight reduction. This review describes how adiposopathy interventions may affect fat function, and thus improve EFRMD.
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Affiliation(s)
- Harold Bays
- L-MARC Research Center, Medical Director/President, 3288 Illinois Avenue, Louisville, KY 40213, USA.
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Yuan H, Weng C, Yang Y, Huang L, Xing X. Resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin. Med Hypotheses 2013; 81:969-71. [DOI: 10.1016/j.mehy.2013.08.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 03/15/2013] [Accepted: 08/11/2013] [Indexed: 01/07/2023]
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Cyclolepis genistoides D. Don (palo azul) promotes differentiation of adipocytes and regulates adipokine expression. Nutr Res 2013; 33:922-31. [DOI: 10.1016/j.nutres.2013.07.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2013] [Revised: 07/12/2013] [Accepted: 07/15/2013] [Indexed: 02/05/2023]
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Hutchins AM, Brown BD, Cunnane SC, Domitrovich SG, Adams ER, Bobowiec CE. Daily flaxseed consumption improves glycemic control in obese men and women with pre-diabetes: a randomized study. Nutr Res 2013; 33:367-75. [PMID: 23684438 DOI: 10.1016/j.nutres.2013.02.012] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 02/26/2013] [Accepted: 02/28/2013] [Indexed: 12/30/2022]
Abstract
The study hypothesis was that fasting glucose, insulin, fructosamine, C-reactive protein, and interleukin-6 decrease and adiponectin increases with daily flaxseed consumption in overweight or obese individuals with pre-diabetes. In this randomized, cross-over study overweight or obese men and postmenopausal women (n = 25) with pre-diabetes consumed 0, 13, or 26 g ground flaxseed for 12 weeks. Glucose, insulin, homeostatic model assessment (HOMA-IR), and normalized percent of α-linolenic fatty acid (ALA) were significantly different by treatment (multiple analysis of variance, P = .036, P = .013, P = .008, P = .024 respectively). Paired t tests showed glucose decreased on the 13 g intervention compared to the 0 g period [13 g = -2.10 ± 1.66 mg/L (mean ± SEM), 0 g = 9.22 ± 4.44 mg/L, P = .036]. Insulin decreased on the 13 g intervention but not the 26 g (P = .021) and 0 g (P = .013) periods (13 g = -2.12 ± 1.00 mU/L, 26 g = 0.67 ± 0.84 mU/L, 0 g = 1.20 ± 1.16 mU/L). HOMA-IR decreased on the 13 g period but not on the 26 g (P = .012) and 0 g (P = .008) periods (13 g = -0.71 ± 0.31, 26 g = 0.27 ± 0.24, 0 g = 0.51 ± 0.35). The α-linolenic fatty acid decrease for the 0 g period was different than the 13 g (P = .024) and 26 g (P = .000) periods (13 g = 0.20 ± 0.04, 26 g = 0.35 ± 0.07, 0 g = -0.01 ± 0.07). Fructosamine, high sensitivity C-reactive protein, adiponectin, and high-sensitivity interleukin-6 had no significant differences. Flaxseed intake decreased glucose and insulin and improved insulin sensitivity as part of a habitual diet in overweight or obese individuals with pre-diabetes.
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Affiliation(s)
- Andrea M Hutchins
- Department of Health Sciences, University of Colorado Colorado Springs, Colorado Springs, CO 80918, USA.
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Gómez-Díaz RA, Talavera JO, Pool EC, Ortiz-Navarrete FV, Solórzano-Santos F, Mondragón-González R, Valladares-Salgado A, Cruz M, Aguilar-Salinas CA, Wacher NH. Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. Metabolism 2012; 61:1247-55. [PMID: 22424822 DOI: 10.1016/j.metabol.2012.02.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Revised: 02/06/2012] [Accepted: 02/06/2012] [Indexed: 01/15/2023]
Abstract
The objective was to determine the effect of metformin on the concentrations of resistin and other markers of insulin resistance or inflammation (C-reactive protein, cytokines, body weight, HbA1c, among others) in minors with glucose intolerance. Patients aged 4 to 17 years with glucose intolerance were studied. They were randomized to receive 850 mg of either metformin or placebo twice daily for 12 weeks, during which all followed an iso-caloric diet and an exercise program. High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin, adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases were measured at the beginning and at the end of the period. Fifty-two patients were included, 11.9±2.6 years old; 28 (12 males/16 females) received metformin and 24 placebo (11 males/13 females). Baseline characteristics were similar between groups (except for body mass index, which in the metformin group was slightly higher). Percentage weight loss was greater in the metformin group (-5.86% vs 2.75%, P<.05). At study end, there were statistically significant differences in resistin concentrations, even after adjusting for confounding variables (F=7.714; P<.006). Also, metformin was associated with a significant decrease in HOMA-IR index (P=.032) and HbA1c levels (P=.001), but no change was observed in the concentration of other markers of inflammation. Metformin resulted in significant reductions of plasma resistin levels in minors with glucose intolerance. This change is independent of its effects on body weight. In contrast, metformin did not alter the concentration of inflammatory markers.
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Affiliation(s)
- Rita A Gómez-Díaz
- Unidad de Investigación Médica en Epidemiología Clínica, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico Ciy, Mexico
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Zheng JQ, Wang K, Pei D, Chen YL, Chang YL, Hsu CH, Huang TM, Lin MY, Lin PY, Lin JD. Improvement of abnormal liver enzymes after rosiglitazone treatment in Chinese type 2 diabetes. Indian J Pharmacol 2012; 44:372-6. [PMID: 22701249 PMCID: PMC3371462 DOI: 10.4103/0253-7613.96340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 02/20/2012] [Accepted: 02/28/2012] [Indexed: 01/22/2023] Open
Abstract
Objectives: Insulin resistance is one of the important underlying abnormalities of type 2 diabetes. The effect of thiazolidinedione on liver functions has been controversial in different studies. In this study, we evaluated the effect of rosiglitazone on liver enzymes in subjects with type 2 diabetes with and without abnormal liver function. Materials and Methods: Seventy-three patients with type 2 diabetes taking rosiglitazone 4 mg daily were enrolled in this 3-month study. Forty-two of them had normal liver function (NLF), and 31 had abnormal liver function (ABLF). Blood biochemistries were collected monthly during the treatment period. Results: At baseline, other than age and liver enzymes, there were no differences in body mass index, fasting plasma glucose, hemoglobin A1c (HbA1c), and lipid profiles between the NLF and ABLF groups. At the end of the treatment, HbA1c was lowered in both groups, but only significantly in the ABLF group (P = 0.027). More importantly, serum concentrations of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the ABLF group decreased significantly (AST: 57.8 ± 26.5 to 47.5 ± 20.2 U/L, P = 0.006; ALT 66.6 ± 35.0 to 51.9 ± 23.5 UL, P = 0.004), while in the NLF group, a similar change was not found. Conclusion: After 3-month rosiglitazone treatment in subjects with type 2 diabetes with mildly elevated liver enzymes, significant improvement in AST and ALT were observed. Our study provides some hints that rosiglitazone might not be contraindicated in subjects with diabetes with abnormal liver function as previously thought, but further well-designed studies are necessary to clarify this issue.
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Affiliation(s)
- Jing-Quan Zheng
- Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Catholic Fu-Jen University, Taipei, Taiwan, ROC
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Regulation of LYRM1 gene expression by free fatty acids, adipokines, and rosiglitazone in 3T3-L1 adipocytes. EXPERIMENTAL DIABETES RESEARCH 2011; 2012:820989. [PMID: 22110480 PMCID: PMC3205718 DOI: 10.1155/2012/820989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 08/13/2011] [Accepted: 08/18/2011] [Indexed: 11/24/2022]
Abstract
LYR motif containing 1 (LYRM1) is a novel gene that is abundantly expressed in the adipose tissue of obese subjects and is involved in insulin resistance. In this study, free fatty acids (FFAs) and tumor necrosis factor-α (TNF-α) are shown to upregulate LYRM1 mRNA expression in 3T3-L1 adipocytes. Conversely, resistin and rosiglitazone exert an inhibitory effect on LYRM1 mRNA expression. These results suggest that the expression of LYRM1 mRNA is affected by a variety of factors that are related to insulin sensitivity. LYRM1 may be an important mediator in the development of obesity-related insulin resistance.
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Lau CH, Muniandy S. Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study. Cardiovasc Diabetol 2011; 10:8. [PMID: 21251282 PMCID: PMC3036610 DOI: 10.1186/1475-2840-10-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2010] [Accepted: 01/21/2011] [Indexed: 12/12/2022] Open
Abstract
Background Adiponectin and resistin are adipokines which modulate insulin action, energy, glucose and lipid homeostasis. Meta-analyses showed that hypoadiponectinemia and hyperresistinemia are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS) and cardiovascular disease. The aim of this study was to propose a novel adiponectin-resistin (AR) index by taking into account both adiponectin and resistin levels to povide a better indicator of the metabolic homeostasis and metabolic disorders. In addition, a novel insulin resistance (IRAR) index was proposed by integration of the AR index into an existing insulin resistance index to provide an improved diagnostic biomarker of insulin sensitivity. Methods In this case control study, anthropometric clinical and metabolic parameters including fasting serum total adiponectin and resistin levels were determined in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40-70 years old. Significant differences in continuous variables among subject groups were confirmed by ANCOVA or MANCOVA test using 1,000 stratified bootstrap samples with bias corrected and accelerated (BCa) 95% CI. Spearman's rho rank correlation test was used to test the correlation between two variables. Results The AR index was formulated as 1+log10(R0)-log10(A0). The AR index was more strongly associated with increased risk of T2DM and MS than hypoadiponectinemia and hyperresistinemia alone. The AR index was more strongly correlated with the insulin resistance indexes and key metabolic endpoints of T2DM and MS than adiponectin and resistin levels alone. The AR index was also correlated with a higher number of MS components than adiponectin and resistin levels alone. The IRAR index was formulated as log10(I0G0)+log10(I0G0)log10(R0/A0). The normal reference range of the IRAR index for insulin sensitive individuals was between 3.265 and 3.538. The minimum cut-off values of the IRAR index for insulin resistance assessment were between 3.538 and 3.955. Conclusions The novel AR and IRAR indexes are cost-effective, precise, reproducible and reliable integrated diagnostic biomarkers of insulin sensitivity for screening subjects with increased risk of future development of T2DM and MS.
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Affiliation(s)
- Cia-Hin Lau
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
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Salpeter SR, Greyber E, Pasternak GA, Salpeter EE, Cochrane Metabolic and Endocrine Disorders Group. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010; 2010:CD002967. [PMID: 20393934 PMCID: PMC7138050 DOI: 10.1002/14651858.cd002967.pub4] [Citation(s) in RCA: 172] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. SELECTION CRITERIA Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. DATA COLLECTION AND ANALYSIS The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. MAIN RESULTS Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. AUTHORS' CONCLUSIONS There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.
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Affiliation(s)
- Shelley R Salpeter
- Stanford University, and Santa Clara Valley Medical CenterMedicine2400 Moorpark Ave, Suite 118San JoseCAUSA95128
| | - Elizabeth Greyber
- Santa Clara Valley Medical CenterMedicine2400 Moorpark Ave, Suite 118San JoseCAUSA95128
| | - Gary A Pasternak
- Santa Clara Valley Medical CenterMedicine2400 Moorpark Ave, Suite 118San JoseCAUSA95128
| | - Edwin E Salpeter
- Cornell UniversityCenter for Radiophysics and Space Research612 Space Sciences BuildingIthacaNYUSA14853
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Salpeter SR, Greyber E, Pasternak GA, Salpeter Posthumous EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010:CD002967. [PMID: 20091535 DOI: 10.1002/14651858.cd002967.pub3] [Citation(s) in RCA: 171] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. SELECTION CRITERIA Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. DATA COLLECTION AND ANALYSIS The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. MAIN RESULTS Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. AUTHORS' CONCLUSIONS There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.
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Affiliation(s)
- Shelley R Salpeter
- Medicine, Stanford University, and Santa Clara Valley Medical Center, 2400 Moorpark Ave, Suite 118, San Jose, CA, USA, 95128
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Osawa H, Tabara Y, Kawamoto R, Ohashi J, Ochi M, Onuma H, Nishida W, Yamada K, Nakura J, Miki T, Makino H, Kohara K. PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes are synergistically associated with plasma resistin in the Japanese general population. Clin Endocrinol (Oxf) 2009; 71:341-5. [PMID: 19178525 DOI: 10.1111/j.1365-2265.2008.03465.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor gamma (PPARgamma) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARgamma ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at -420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARgamma Pro12Ala polymorphism, resistin SNP-420, and plasma resistin. DESIGN, PATIENTS AND MEASUREMENTS We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA. RESULTS Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARgamma than those with Pro/Ala and Ala/Ala genotypes (mean +/- SE, 11.6 +/- 0.2 vs. 10.4 +/- 0.5 microg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARgamma , Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (beta) = 1.03, P = 0.0384). The effects of the Pro/Pro genotype of PPARgamma (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (beta = 4.76, P = 0.011). CONCLUSIONS The PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population.
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Affiliation(s)
- Haruhiko Osawa
- Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
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Schernthaner G. Pleiotropic effects of thiazolidinediones on traditional and non-traditional atherosclerotic risk factors. Int J Clin Pract 2009; 63:912-29. [PMID: 19490202 DOI: 10.1111/j.1742-1241.2009.02025.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The thiazolidinediones pioglitazone and rosiglitazone have established efficacy in improving insulin sensitivity, glycaemic control, dyslipidaemia, hypertension and microalbuminuria in patients with type 2 diabetes. As specific agonists of peroxisome proliferator-activated receptor-gamma, thiazolidinediones have also demonstrated protective effects on a variety of atherosclerosis biomarkers and surrogate measures of cardiovascular disease. AIM This paper reviews the evidence for pleiotropic effects on a variety of non-traditional atherosclerotic risk factors. DISCUSSION Thiazolidinediones attenuate circulating levels of pro-inflammatory mediators in patients with type 2 diabetes, including C-reactive protein, interleukin-6, CD40L, monocyte chemoattractant protein-1 and metalloproteinase-9. These agents also increase levels of the vascular protective adipokine, adiponectin. The clinical significance of these findings is supported by evidence of improved endothelial dysfunction, reduced carotid intima media thickness and improvements in stenosis following coronary artery stent implantation in patients treated with thiazolidinediones. Limited data suggest that thiazolidinediones might also improve the circulating levels and functional activity of angiogenic endothelial progenitor cells, which independently predict the incidence of cardiovascular events and death. It should be noted that the US Food and Drug Administration and the European Medicines Agency have requested changes to the prescribing information for rosiglitazone to highlight the possibility of an increased risk with this agent in patients with ischaemic heart disease; on review, no such amendment was required for the pioglitazone prescribing information. Both agencies continue to suggest that the benefits of both thiazolidinediones outweight any possible detrimental effects. Further research remains to be conducted to elucidate the potentially differential vascular protective effects of thiazolidinediones. In the US, there are black box heart failure warnings for both agents. CONCLUSION In light of the established importance of reducing cardiovascular risk in patients with type 2 diabetes, current evidence continues to support the use of pioglitazone within multifactorial risk management strategies.
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Affiliation(s)
- G Schernthaner
- Department of Medicine, Rudolfstiftung Hospital, Vienna, Austria.
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Tomaru T, Steger DJ, Lefterova MI, Schupp M, Lazar MA. Adipocyte-specific expression of murine resistin is mediated by synergism between peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding proteins. J Biol Chem 2009; 284:6116-25. [PMID: 19126543 DOI: 10.1074/jbc.m808407200] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Resistin antagonizes insulin action in mouse, making it a potential therapeutic target for treating metabolic diseases such as diabetes. To better understand how mouse resistin gene (Retn) expression is restricted to fat tissue, we identified an adipocyte-specific enhancer located approximately 8.8-kb upstream of the transcription start site. This region contains a binding site for the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARgamma), and binds endogenous PPARgamma together with its partner retinoid-X receptor alpha (RXRalpha). It also contains three binding sites for CCAAT/enhancer-binding protein (C/EBP), and is bound by endogenous C/EBPalpha and C/EBPbeta in adipocytes. Exogenous expression of PPARgamma/RXRalpha and C/EBPalpha in non-adipocyte cells synergistically drives robust expression from the enhancer. Although PPARgamma ligands repress Retn transcription in adipocytes, rosiglitazone paradoxically stimulates the enhancer activity, suggesting that the enhancer is not directly involved in negative regulation. Unlike expression of Retn in mouse, human resistin (RETN) is expressed primarily in macrophages. Interestingly, the region homologous to the mouse Retn enhancer in the human gene contains all three C/EBP elements, but is not conserved for the sequence bound by PPARgamma. Furthermore, it displays little or no binding by PPARgamma in vitro. Taken together, the data suggest that a composite enhancer binding both PPARgamma and C/EBP factors confers adipocyte-specific expression to Retn in mouse, and its absence from the human gene may explain the lack of adipocyte expression in humans.
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Affiliation(s)
- Takuya Tomaru
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149, USA
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Lv Q, Wang Y, Wang W, Wang L, Zhou X. Effect of pioglitazone on visfatin expression in 3T3-L1 adipocytes and SD rats. Endocr Res 2009; 34:130-41. [PMID: 19878073 DOI: 10.3109/07435800903287061] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE To investigate the effect of pioglitazone on visfatin expression. METHODS We studied the effect of pioglitazone on visfatin expression in 3T3-L1 adipocytes and serum concentrations and tissue expression of visfatin in normal Sprague-Dawley rats and rats with insulin resistance induced by high-fat diet (HF). Metabolic and anatomical parameters of the rats were also performed. RESULTS In 3T3-L1 adipocytes, visfatin expression increased during the differentiation and it was not regulated by pioglitazone. In the rats, 12 weeks of HF feeding induced obesity and increased fast blood glucose (FBG), serum insulin and circulating visfatin. Pioglitazone treatment ameliorated insulin resistance with concomitant reduction in serum visfatin, free fatty acid, and triglyceride (TG) of the rats fed HF. Compared with subcutaneous adipose tissue and muscle, visfatin protein expression was much higher in visceral adipose tissue on both diets (p < 0.05 for all). Visfatin expression decreased in visceral adipose tissue but not subcutaneous adipose tissue or muscle after pioglitazone treatment in HF-fed rats. Visfatin expression in the rats fed chow diet was not affected by pioglitazone. Additionally, we demonstrated that serum visfatin was positively correlated with visceral adipose tissue weight, visfatin in visceral adipose tissue, TG and FBG (p < 0.05 for all). CONCLUSION Visfatin is preferentially produced by visceral fat and peroxisome proliferator-activated receptor-gamma agonist ameliorates the development of insulin resistance in HF-fed rats with a major decrease in visfatin expression, the effect of pioglitazone on visfatin in HF-fed rats is dependent on glucose and lipid metabolism in the animals.
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Affiliation(s)
- Qihuan Lv
- Department of Endocrinology, Institute of Endocrinology & Metabolism, Anhui Medical University, Anhui, China
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Tanabe J, Tamasawa N, Yamashita M, Matsuki K, Murakami H, Matsui J, Sugimoto K, Yasujima M, Suda T. Effects of combined PPARgamma and PPARalpha agonist therapy on reverse cholesterol transport in the Zucker diabetic fatty rat. Diabetes Obes Metab 2008; 10:772-9. [PMID: 17970759 DOI: 10.1111/j.1463-1326.2007.00810.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIM We investigated the effects of the combined therapy of PPARgamma and PPARalpha agonists on HDL metabolism, especially concerning reverse cholesterol transport (RCT), using Zucker diabetic fatty rats (ZDF/Crl-Lepr fa rats) that are the rodent model for type 2 diabetes with obesity, hyperlipidaemia and insulin resistance. METHODS The ZDF rats were divided into four medicated groups as follows: pioglitazone as a PPARgamma agonist (5 mg/kg/day; P group, n = 6), fenofibrate as a PPARalpha agonist (30 mg/kg/day; F group, n = 6), both these medications (P + F group, n = 6) and no treatment (UNT group, n = 6). Non-diabetic rats (ZDF/GmiCrl-lean, CON group, n = 6) served as controls. We evaluated HDL particle size and messenger RNA (mRNA) levels of the following factors: liver X receptor alpha (L x R alpha), ATP-binding cassette A1 (ABCA1) and ABCG1 which are regulated by PPARs and are related to early stage RCT. RESULTS The significant increase in HDL particle size was demonstrated in rats of the F and P + F groups, although changes in plasma HDL-cholesterol levels were not significant. In accordance with this finding, mRNA levels of ABCG1 in the liver increased significantly. CONCLUSIONS These findings suggest the efficacy of combined therapy with PPARgamma and PPARalpha in improving lipid metabolism, partly through the enhanced RCT, and insulin resistance in type 2 diabetes mellitus.
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Affiliation(s)
- J Tanabe
- Third Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan
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Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 2008; 60:311-57. [PMID: 18922966 DOI: 10.1124/pr.108.00001] [Citation(s) in RCA: 296] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
Steatosis of the liver may arise from a variety of conditions, but the molecular basis for lipid droplet formation is poorly understood. Although a certain amount of lipid storage may even be hepatoprotective, prolonged lipid storage can result in an activation of inflammatory reactions and loss of metabolic competency. Apart from drug-induced steatosis, certain metabolic disorders associated with obesity, insulin resistance, and hyperlipidemia give also rise to nonalcoholic fatty liver diseases (NAFLD). It is noteworthy that advanced stages of nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis. In this regard, the lipid droplets (LDs) have been discovered to be metabolically highly active structures that play major roles in lipid transport, sorting, and signaling cascades. In particular, LDs maintain a dynamic communication with the endoplasmic reticulum (ER) and the plasma membrane via sphingolipid-enriched domains of the plasma membrane-the lipid rafts. These microdomains frequently harbor receptor tyrosine kinases and other signaling molecules and connect extracellular events with intracellular signaling cascades. Here, we review recent knowledge on the molecular mechanisms of drug and metabolically induced hepatic steatosis and its progression to steatohepatitis (NASH). The contribution of cytokines and other signaling molecules, as well as activity of nuclear receptors, lipids, transcription factors, and endocrine mediators toward cellular dysfunction and progression of steatotic liver disease to NASH is specifically addressed, as is the cross-talk of different cell types in the pathogenesis of NAFLD. Furthermore, we provide an overview of recent therapeutic approaches in NASH therapy and discuss new as well as putative targets for pharmacological interventions.
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Affiliation(s)
- Nora Anderson
- Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany
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Osawa H, Ochi M, Tabara Y, Kato K, Yamauchi J, Takata Y, Nishida W, Onuma H, Shimizu I, Fujii Y, Miki T, Ohashi J, Makino H. Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes. Clin Endocrinol (Oxf) 2008; 69:74-80. [PMID: 18081734 DOI: 10.1111/j.1365-2265.2007.03154.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes (T2DM) susceptibility by enhancing promoter activity. We also showed that serum resistin was positively correlated with G at SNP-420, the duration of T2DM, and HbA1c in T2DM. The aim of this study was to determine the relation between serum resistin and factors related to the metabolic syndrome (MetS) in T2DM. DESIGN, PATIENTS AND MEASUREMENTS We analysed 238 Japanese T2DM subjects (124 males and 114 females, age 60.2 +/- 11.3 years, body mass index (BMI) 24.1 +/- 3.9) whose overnight fasting sera were available. Serum resistin was measured using ELISA. RESULTS Serum resistin was higher in subjects with either obesity (P = 0.041), low HDL (P = 0.004), high triglycerides (TG) (P = 0.019), hypertension (HT) (P = 0.001) or atherosclerosis (P = 0.012). Simple regression analysis revealed that serum resistin was correlated with lower HDL, TG and high-sensitivity C-reactive protein (hsCRP). Multiple regression analysis (or logistic regression analysis for HT), adjusted for age, gender, BMI and the duration of T2DM, revealed that serum resistin was correlated with lower HDL (P = 0.008), TG (P = 0.041), HT (P = 0.031) and hsCRP (P = 0.004). Serum resistin was positively correlated with the number of MetS factors, independent of age, gender and the duration of T2DM (P < 0.001). Adjustment by either thiazolidinedione (TZD) treatment or hsCRP had no effects on these findings. CONCLUSIONS Serum resistin was positively correlated with the accumulation of MetS factors in T2DM.
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Affiliation(s)
- Haruhiko Osawa
- Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime Prefectural Hospital, Ehime, Japan.
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Abstract
BACKGROUND AND AIMS Adiponectin is a hormone mainly produced by white adipose tissue. Decreased levels of adiponectin are linked with visceral obesity, insulin resistance states, and cardiovascular diseases. Recently, several studies have pointed out an increase in adiponectin serum levels in subjects undergoing treatment with thiazolidinediones (TZD). The aim of this study is to systematically review the current state of evidence of the effect of TZD on adiponectin serum level with special attention to avoid publication bias. MATERIALS AND METHODS An extensive literature search was performed. Meta Analysis Version 2.0 computer program was used to calculate statistical differences in means and 95% confidence interval (CI). Publication bias was assessed using different statistical approaches. RESULTS In the meta-analysis including 19 studies the overall standardized mean difference was 0.94 (95% CI, 0.81-1.06) which means that subjects treated with TZDs on average had means of adiponectin concentration that were about 1 standard deviation higher than the comparison groups even after controlling for possible biases. CONCLUSIONS The results obtained agree with a moderate increase of serum adiponectin. The results clearly reveal an increase of endogenous serum adiponectin levels by intake of TZDs and may point to a potential new option to manage obesity-related diseases.
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Affiliation(s)
- N Riera-Guardia
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
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Derosa G, Salvadeo SA, D'Angelo A, Fogari E, Ragonesi PD, Ciccarelli L, Piccinni MN, Ferrari I, Gravina A, Maffioli P, Cicero AF. Rosiglitazone Therapy Improves Insulin Resistance Parameters in Overweight and Obese Diabetic Patients Intolerant To Metformin. Arch Med Res 2008; 39:412-9. [DOI: 10.1016/j.arcmed.2007.12.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2007] [Accepted: 12/18/2007] [Indexed: 10/22/2022]
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Kadoglou NPE, Iliadis F, Angelopoulou N, Perrea D, Liapis CD, Alevizos M. Beneficial effects of rosiglitazone on novel cardiovascular risk factors in patients with Type 2 diabetes mellitus. Diabet Med 2008; 25:333-40. [PMID: 18307460 DOI: 10.1111/j.1464-5491.2007.02375.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Impaired exercise capacity, adiponectin, MMPs and TIMPs have all been implicated in the development of cardiovascular disease. The aim of our study was to determine the effects of rosiglitazone on these factors in diabetic patients. METHODS Seventy individuals with Type 2 diabetes were assigned randomly to either a rosiglitazone group (8 mg/day, RG) or a control group (CG) for 6 months. All participants took gliclazide 160 mg plus metformin 1700 mg in stable dose. None of the individuals had diabetic complications or had previously participated in an exercise programme. Anthropometric parameters, VO2 peak, oxygen pulse, glycaemic indices, lipid profile, adiponectin, insulin resistance, blood pressure and serum MMP-9, TIMP-1, TIMP-2 levels were assessed at baseline and at the end of the study. After Bonferroni adjustment, a P-value < 0.017 was assumed to be statistically significant. RESULTS Rosiglitazone treatment significantly increased VO2 peak (P < 0.0001), the duration of the exercise test (P < 0.0001), oxygen pulse (P = 0.010) and TIMP-2 levels (P = 0.008) in comparison with CG. Insulin resistance, hyperglycaemia, diastolic blood pressure and MMP-9 levels were also reduced (P < 0.017). Fat mass, lipid profile, TIMP-1 levels and MMP9 : TIMP-1 ratio were unaltered after rosiglitazone treatment. There were no significant changes in these parameters in control subjects. In univariate analysis, the rosiglitazone-induced increment of VO2 peak was associated with alterations in plasma adiponectin (r = 0.691), HOMA-IR (r = -0.782) and HbA(1c) (r = -0.676) (P < 0.017). These relationships retained significance after multiple regression analysis (P = 0.005). CONCLUSIONS Rosiglitazone treatment increases cardiorespiratory fitness and modulates favourably serum adiponectin, MMP-9 and TIMP-2 levels. Whether these effects produce cardiovascular benefits in the long term requires further investigation.
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Affiliation(s)
- N P E Kadoglou
- 1st Propedeutic Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece.
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31
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Yi L, He J, Liang Y, Yuan D, Gao H, Zhou H. Simultaneously quantitative measurement of comprehensive profiles of esterified and non-esterified fatty acid in plasma of type 2 diabetic patients. Chem Phys Lipids 2007; 150:204-16. [PMID: 17880934 DOI: 10.1016/j.chemphyslip.2007.08.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2006] [Revised: 07/20/2007] [Accepted: 08/14/2007] [Indexed: 11/28/2022]
Abstract
Fatty acids, having intimate relationship with type 2 diabetes mellitus (DM2), are not only the main energy source as nutrients, but also signaling molecules in insulin secretion. In this work, we developed a two-step rapid method to comprehensive profiling of esterified fatty acid (EFA) and non-esterified fatty acid (NEFA) using KOH-CH3OH to methylate EFA followed by H2SO4-CH3OH to methylate NEFA. Its applications to fatty acids profiling of type 2 diabetic patients and health controls were also presented. The t-test results informed that 16 NEFAs and 7 EFAs had distinct differences between type 2 diabetes and health controls. Furthermore, quantitative alterations of fatty acids in plasma of type 2 diabetic patients treated with rosiglitazone were obtained by this method. Our research results indicated that the dynamic changes of NEFAs are various. Some decreased linearly, such as C18:0, C18:3n-6 and C22:6, and some changed nonlinearly, such as C18:3n-3 and C22:4. All results informed that fatty acid profiles could provide comprehensive and accurate information for not only discrimination between DM2 patients and health controls, but also evaluation alterations of fatty acids during therapeutic process.
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Affiliation(s)
- Lunzhao Yi
- Research Center of Modernization of Chinese Medicines, Central South University, Changsha 410083, PR China
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Tarquini R, Lazzeri C, Laffi G, Gensini GF. Adiponectin and the cardiovascular system: from risk to disease. Intern Emerg Med 2007; 2:165-76. [PMID: 17909707 DOI: 10.1007/s11739-007-0027-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2006] [Accepted: 10/27/2006] [Indexed: 01/16/2023]
Abstract
Adiponectin is known to play a role in fatty acid and glucose metabolism through a change in insulin sensitivity and activation of fuel oxidation by AMP-activated protein kinase. Adiponectin can be considered an important factor able to modulate the adipovascular axis which, through genomic and environmental influences, affects the cardiovascular risk milieu, from the pre-metabolic syndrome-- through the metabolic syndrome--to the overt atherosclerotic process and its clinical manifestations. Hypoadiponectinaemia can be viewed as an early sign of a complex cardiovascular risk factor predisposing to the atherosclerosis process as well as a contributing factor accelerating the progress of the atherosclerotic plaque. In addition, adiponectin per se holds a protective role thanks to its anti-inflammatory and antiatherogenic properties. The early identification of patients "at cardiovascular risk" means in the current practice to search for indexes of metabolic derangements and pro-inflammatory status (adiponectin) from adolescence and childhood.
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Affiliation(s)
- R Tarquini
- Internal Medicine Department, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy.
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33
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Kadoglou NPE, Iliadis F, Liapis CD, Perrea D, Angelopoulou N, Alevizos M. Beneficial effects of combined treatment with rosiglitazone and exercise on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 2007; 30:2242-4. [PMID: 17586747 DOI: 10.2337/dc07-0341] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Nikolaos P E Kadoglou
- 1st Propedeutic Department Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece.
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Kelly AS, Bank AJ. The cardiovascular effects of the thiazolidinediones: a review of the clinical data. J Diabetes Complications 2007; 21:326-34. [PMID: 17825758 DOI: 10.1016/j.jdiacomp.2006.03.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2006] [Revised: 03/23/2006] [Accepted: 03/28/2006] [Indexed: 11/28/2022]
Abstract
Beyond glycemic control, the thiazolidinediones (TZDs) provide numerous cardiovascular benefits. Clinical data support a role for the TZDs in lowering blood pressure, correcting dyslipidemia, improving vascular structure and function, decreasing inflammation, improving the adipokine profile, reducing systemic oxidative stress, and possibly in stabilizing coronary plaques that may be prone to rupture. Data from the first outcomes trial assessing a TZD in reducing cardiovascular morbidity and mortality have recently been reported. Results were promising, but not conclusive. Therefore, other large studies currently underway should provide greater insight into the role of the TZDs in modifying cardiovascular risk in patients with type 2 diabetes. Reported side effects of the TZDs include fluid retention, worsening of heart failure, and weight gain. Recent research is beginning to clarify the mechanisms associated with these potential side effects and may result in the expanded use of this drug class in patients with heart failure. Because of the unique mechanism of action of this drug class that addresses a fundamental pathophysiolgical phenomenon in type 2 diabetes, namely, improving insulin resistance, and the growing body of evidence supporting cardiovascular benefits, strong consideration should be given to utilizing the TZDs early in the clinical course of diabetes.
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Affiliation(s)
- Aaron S Kelly
- Laboratory of Preventive Vascular Medicine, Department of Research, St Paul Heart Clinic, St Paul, MN 55102, USA.
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Hsieh CH, He CT, Lee CH, Wu LY, Hung YJ. Both slow-release and regular-form metformin improve glycemic control without altering plasma visfatin level in patients with type 2 diabetes mellitus. Metabolism 2007; 56:1087-92. [PMID: 17618954 DOI: 10.1016/j.metabol.2007.03.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2006] [Accepted: 03/20/2007] [Indexed: 11/27/2022]
Abstract
Both slow-release (SR) and regular-release (RR) metformin were effective in the treatment of type 2 diabetes mellitus. We compare the efficacy, safety, and effects on serum adipocytokines and inflammatory markers of both regimens in patients with type 2 diabetes mellitus. A prospective, randomized, double-blind study enrolled 55 patients with type 2 diabetes mellitus, which were randomly assigned to receive either metformin SR or RR (at a maximal dosage of 2000 mg/d for 12 weeks). Glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, adipocytokines, C-reactive protein, and insulin resistance and pancreatic beta-cell function were measured before and after treatment. Significant decreases (P<.001) in mean HbA1c and fasting plasma glucose levels were observed in each group. However, the mean changes in HbA1c from baseline to end point in the 2 groups were not significantly different. Changes in metabolic parameters were similar except that a decreased total cholesterol level was observed in the metformin RR group. Neither regimen treatment had any influence on insulin resistance, but metformin RR improved beta-cell function. Neither regimen had an effect on serum adipocytokines or inflammatory markers. Once-daily metformin SR was as safe and effective as metformin RR in type 2 diabetic patients. Neither dosage form affected serum adipocytokines and inflammatory markers.
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Affiliation(s)
- Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, ROC
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Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Rosiglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007; 2007:CD006063. [PMID: 17636824 PMCID: PMC7389529 DOI: 10.1002/14651858.cd006063.pub2] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Diabetes has long been recognised as a strong, independent risk factor for cardiovascular disease, a problem which accounts for approximately 70% of all mortality in people with diabetes. Prospective studies show that compared to their non-diabetic counterparts, the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four. The two biggest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control. Theoretical benefits of the peroxisome proliferator activated receptor gamma (PPAR-gamma) activator rosiglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus. OBJECTIVES To assess the effects of rosiglitazone in the treatment of type 2 diabetes. SEARCH STRATEGY Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. SELECTION CRITERIA Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial quality and extracted data. Pooling of studies by means of fixed-effects meta-analysis could be performed for adverse events only. MAIN RESULTS Eighteen trials which randomised 3888 people to rosiglitazone treatment were identified. Longest duration of therapy was four years with a median of 26 weeks. Published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised (OR 2.27, 95% confidence interval (CI) 1.83 to 2.81). The single large RCT (ADOPT - A Diabetes Outcomes Progression Trial) indicated increased cardiovascular risk. New data on raised fracture rates in women reveal extensive action of rosiglitazone in various body tissues. AUTHORS' CONCLUSIONS New studies should focus on patient-oriented outcomes to clarify the benefit-risk ratio of rosiglitazone therapy. Safety data and adverse events of all investigations (published and unpublished) should be made available to the public.
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Affiliation(s)
- B Richter
- Universitaetsklinikum Duesseldorf, Heinrich-Heine University, Department of General Practice, Moorenstr. 5, Duesseldorf, Germany, 40225.
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Hamilton G, Proitsi P, Jehu L, Morgan A, Williams J, O'Donovan MC, Owen MJ, Powell JF, Lovestone S. Candidate gene association study of insulin signaling genes and Alzheimer's disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci. Am J Med Genet B Neuropsychiatr Genet 2007; 144B:508-16. [PMID: 17440948 DOI: 10.1002/ajmg.b.30503] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Epidemiological evidence supports the existence of a possible link between type II diabetes mellitus (T2DM) and late-onset Alzheimer's disease (LOAD). Polymorphisms from candidate genes for T2DM were genotyped in a two-stage approach to identify novel risk factors for LOAD. One hundred fifty-two polymorphisms were initially genotyped in a case:control cohort: nine SNPs showed individual association with disease status under at least one genetic model, while an additional two SNPs showed a haplotype association. In a replication study, we confirmed significant association of SNPs within three genes--PPARgamma, SOS2, and PCK1--with Alzheimer's disease. In particular, our data suggest that the effect of variants within these genes might be influenced by gender.
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Affiliation(s)
- Gillian Hamilton
- MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, Kings College London, Denmark Hill, London, UK.
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Abstract
Weight gain and obesity are major risk factors for conditions and diseases ranging from insulin resistance and type 2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease. A chronic, subacute state of inflammation often accompanies the accumulation of excess lipid in adipose tissue and liver (hepatic steatosis), evidenced by changes in both inflammatory cells and biochemical markers of inflammation. These changes can be seen in the involved tissues and systemically, in terms of elevated circulating levels of inflammatory markers. The link between obesity and inflammation has therefore raised the important question of whether obesity-induced inflammation plays a pathogenic role in the development and progression of these disorders. We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus.
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Kim HJ, Kang ES, Kim DJ, Kim SH, Ahn CW, Cha BS, Nam M, Chung CH, Lee KW, Nam CM, Lee HC. Effects of rosiglitazone and metformin on inflammatory markers and adipokines: decrease in interleukin-18 is an independent factor for the improvement of homeostasis model assessment-beta in type 2 diabetes mellitus. Clin Endocrinol (Oxf) 2007; 66:282-9. [PMID: 17224000 DOI: 10.1111/j.1365-2265.2006.02723.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE We examined the individual pharmacological effects of the addition of rosiglitazone and metformin to glimepiride on inflammatory markers and adipokines in patients with type 2 diabetes mellitus. We analysed the relationships between these variables, the measurements of insulin sensitivity and beta-cell function in patients treated with rosiglitazone plus glimepiride. DESIGN AND PATIENTS One hundred twenty (120) patients with type 2 diabetes mellitus were randomized and treated with glimepiride plus rosiglitazone or glimepiride plus metformin for 12 weeks. The plasma concentrations of the inflammatory markers and adipokines were measured at baseline and after 12 weeks. MEASUREMENTS Markers of insulin sensitivity and beta-cell function were determined by the quantitative insulin sensitivity check index (QUICKI) and the homeostasis model assessment of beta-cell function (HOMA-beta), respectively. Plasma concentrations of adiponectin were measured by radioimmunoassay. Plasma concentrations of resistin, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-18 (IL-18) were measured using ELISA. RESULTS Improvements in fasting insulin level, QUICKI and HOMA-beta were noted in the rosiglitazone-treated group. Only the QUICKI value improved in the metformin-treated group. Adiponectin concentrations significantly increased in the rosiglitazone-treated group after 12 weeks. Significant decreases in resistin, C-reactive protein, TNF-alpha, IL-6 and IL-18 were seen in the rosiglitazone-treated patients but not in the metformin-treated patients. The independent risk factor for the HOMA-beta change according to stepwise multivariate regression analysis was a change in IL-18. CONCLUSIONS Rosiglitazone, but not metformin, improved the plasma concentrations of inflammatory markers and adipokines in patients with type 2 diabetes mellitus. A decrease in IL-18 is an independent factor for the improvement of HOMA-beta in type 2 diabetes mellitus.
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Affiliation(s)
- Hyeong Jin Kim
- Division of Endocrinology, Department of Internal Medicine, Kwandong University College of Medicine, Myongji Hospital, Koyang, Korea
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Ajjan RA, Grant PJ. Cardiovascular disease prevention in patients with type 2 diabetes: The role of oral anti-diabetic agents. Diab Vasc Dis Res 2006; 3:147-58. [PMID: 17160909 DOI: 10.3132/dvdr.2006.023] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Multiple risk factor intervention is essential in order to prevent cardiovascular (CV) disease in patients with diabetes. Therefore, to reduce atherothrombotic events, an ideal oral anti-diabetic agent should be able to modulate most, and preferably all, cardiovascular risk factors associated with diabetes. Of the currently available agents, the insulin sensitisers (metformin, thiazolidinediones) seem to have most promise in cardiovascular protection. Metformin has a positive effect on several CV risk factors; outcome studies have shown that this agent reduces cardiac events in overweight subjects with diabetes. In a similar manner, thiazolidinediones (rosiglitazone, pioglitazone) have a wide spectrum of activity, favourably modulating most risk factors, with evidence to suggest a reduction in CV events with this class of drugs. Agents in the sulphonylurea group have beneficial, though inconsistent, effects on some risk factors but outcome studies have failed to show a cardioprotective role for these agents. New classes of drugs to manage type 2 diabetes are currently at various stages of development and their role in prevention of cardiovascular disease awaits evaluation. At present, first-line management of insulin-resistant type 2 diabetes should utilise metformin, with the addition of thiazolidinediones and sulphonylureas to achieve optimal glycaemic control.
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Affiliation(s)
- Ramzi A Ajjan
- Acadamic Unit of Molecular Vascular Medicine, Leeds Institute of Genetics Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, UK
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Yi LZ, He J, Liang YZ, Yuan DL, Chau FT. Plasma fatty acid metabolic profiling and biomarkers of type 2 diabetes mellitus based on GC/MS and PLS-LDA. FEBS Lett 2006; 580:6837-45. [PMID: 17141227 DOI: 10.1016/j.febslet.2006.11.043] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Accepted: 11/16/2006] [Indexed: 01/06/2023]
Abstract
Metabolic profiling has increasingly been used as a probe in disease diagnosis and pharmacological analysis. Herein, plasma fatty acid metabolic profiling including non-esterified fatty acid (NEFA) and esterified fatty acid (EFA) was investigated using gas chromatography/mass spectrometry (GC/MS) followed by multivariate statistical analysis. Partial least squares-linear discrimination analysis (PLS-LDA) model was established and validated to pattern discrimination between type 2 diabetic mellitus (DM-2) patients and health controls, and to extract novel biomarker information. Furthermore, the PLS-LDA model visually represented the alterations of NEFA metabolic profiles of diabetic patients with abdominal obesity in the treated process with rosiglitazone. The GC/MS-PLS-LDA analysis allowed comprehensive detection of plasma fatty acid, enabling fatty acid metabolic characterization of DM-2 patients, which included biomarkers different from health controls and dynamic change of NEFA profiles of patients after treated with medicine. This method might be a complement or an alternative to pathogenesis and pharmacodynamics research.
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Affiliation(s)
- Lun-Zhao Yi
- Research Center of Modernization of Chinese Medicines, Central South University, Changsha 410083, PR China
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Efstathiou SP, Tsiakou AG, Tsioulos DI, Panagiotou TN, Pefanis AV, Achimastos AD, Mountokalakis TD. Prognostic significance of plasma resistin levels in patients with atherothrombotic ischemic stroke. Clin Chim Acta 2006; 378:78-85. [PMID: 17173885 DOI: 10.1016/j.cca.2006.10.023] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2006] [Revised: 10/28/2006] [Accepted: 10/28/2006] [Indexed: 02/06/2023]
Abstract
BACKGROUND Resistin (RSN) is an adipocytokine involved in insulin resistance, obesity and atherosclerosis. This study aimed to investigate the association between plasma RSN and outcome after ischemic stroke. METHODS RSN measured within 24 h after the event was related to functional outcome and 5-year survival in 211 subjects with first-ever atherothrombotic ischemic stroke. Prognosis was assessed by the Kaplan Meier and the Cox techniques. RESULTS The probabilities of death were 80.4%, 46.2% and 15.7% (p<0.001) for patients stratified according to tertiles of RSN (>30 ng/mL, 20-30 ng/mL and<20 ng/mL, respectively). The proportion of dependency (modified Rankin Scale score>or=3) was greater in 5-year survivors with RSN in the upper tertile (6/11 [54.5%]) compared to the middle (20/56 [35.7%]) and the lowest tertile (8/43 [18.6%]; p<0.01). C-reactive protein levels (hazard ratio [HR] 3.96 [95% CI 2.06, 8.91]; p<0.001), coronary heart disease (2.69 [1.62, 6.23]; p<0.001), RSN levels (2.12 [1.31, 5.08] p<0.001), National Institute of Health Stroke Scale score (2.02 [1.23, 4.49]; p<0.01) and age (1.84 [1.19, 3.93]; p<0.01) were independent predictors of death. CONCLUSIONS High plasma RSN appears to be associated with increased risk of 5-year mortality or disability after atherothrombotic ischemic stroke, independently of other adverse predictors.
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Affiliation(s)
- Stamatis P Efstathiou
- Center for the Prevention of Cardiovascular Disease, Hygeias Melathron, Third University Department of Medicine, Medical School, Sotiria Hospital, Athens, Greece.
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Chung SS, Choi HH, Cho YM, Lee HK, Park KS. Sp1 mediates repression of the resistin gene by PPARγ agonists in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2006; 348:253-8. [PMID: 16876120 DOI: 10.1016/j.bbrc.2006.07.048] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2006] [Accepted: 07/12/2006] [Indexed: 11/20/2022]
Abstract
Resistin is an adipokine related to obesity and insulin resistance. Expression of the resistin gene is repressed by the treatment of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, thiazolidinediones (TZDs). In this study, we investigated the mechanism by which TZDs inhibit the resistin gene expression. Resistin gene expression was decreased by TZD in fully differentiated 3T3-L1 adipocytes, which was abolished after treatment of cycloheximide (a protein synthesis inhibitor). TZD could not repress the expression of the resistin gene in the presence of mithramycin A (an Sp1 binding inhibitor). Sp1 binding site of the resistin promoter (-122/-114bp) was necessary for the repression. Further investigation of the effect of TZDs on the modification of Sp1 showed that the level of O-glycosylation of Sp1 was decreased in this process. These results suggest that PPARgamma activation represses the expression of the resistin gene by modulating Sp1 activity.
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Affiliation(s)
- S S Chung
- Genome Research Center for Diabetes and Endocrine Disease, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
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Perseghin G, Burska A, Lattuada G, Alberti G, Costantino F, Ragogna F, Oggionni S, Scollo A, Terruzzi I, Luzi L. Increased serum resistin in elite endurance athletes with high insulin sensitivity. Diabetologia 2006; 49:1893-900. [PMID: 16685503 DOI: 10.1007/s00125-006-0267-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2006] [Accepted: 03/12/2006] [Indexed: 11/25/2022]
Abstract
AIMS/HYPOTHESIS Resistin is an adipokine associated with obesity and type 2 diabetes in animal models, but in humans its role remains uncertain. This study was undertaken to test whether serum resistin is related to insulin resistance and markers of low-grade inflammation in elite athletes taken as a model of extreme insulin sensitivity. SUBJECTS MATERIALS AND METHODS: In 23 elite athletes (sprinters, middle-distance and marathon runners) and in 72 sedentary men including lean and obese individuals with NGT, and obese individuals with IGT or new-onset type 2 diabetes, we assessed insulin sensitivity using a whole-body insulin-sensitivity index (WBISI) derived from a 3-h OGTT; energy homeostasis was also assessed by means of indirect calorimetry, along with circulating adipokines and low-grade pro-inflammatory cyto-chemokines. RESULTS Professional athletes had increased WBISIs (p<0.001) and lipid oxidation (p<0.03); they also showed higher serum resistin concentrations (p<0.001), although the pro-inflammatory chemokines were not increased in comparison with the other study groups. Resistin was independently associated only with fasting plasma NEFA. Increased resistin was detected in the middle-distance and marathon runners, but not in the sprinters when compared with the lean, young, sedentary individuals. CONCLUSIONS/INTERPRETATION Serum resistin concentration is increased in elite athletes, providing evidence against the notion that resistin levels reflect insulin resistance in humans, as seen in animal studies. Increased resistin was observed in aerobic-endurance, but not sustained-power athletes and this feature appeared to be independently associated with parameters of fatty acid metabolism.
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Affiliation(s)
- G Perseghin
- Internal Medicine, Section of Nutrition/Metabolism and Unit of Clinical Spectroscopy, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy.
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Avramoglu RK, Basciano H, Adeli K. Lipid and lipoprotein dysregulation in insulin resistant states. Clin Chim Acta 2006; 368:1-19. [PMID: 16480697 DOI: 10.1016/j.cca.2005.12.026] [Citation(s) in RCA: 193] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2005] [Revised: 12/15/2005] [Accepted: 12/20/2005] [Indexed: 12/30/2022]
Abstract
Insulin resistant states are commonly associated with an atherogenic dyslipidemia that contributes to significantly higher risk of atherosclerosis and cardiovascular disease. Indeed, disorders of carbohydrate and lipid metabolism co-exist in the majority of subjects with the "metabolic syndrome" and form the basis for the definition and diagnosis of this complex syndrome. The most fundamental defect in these patients is resistance to cellular actions of insulin, particularly resistance to insulin-stimulated glucose uptake. Insulin insensitivity appears to cause hyperinsulinemia, enhanced hepatic gluconeogenesis and glucose output, reduced suppression of lipolysis in adipose tissue leading to a high free fatty acid flux, and increased hepatic very low density lipoprotein (VLDL) secretion causing hypertriglyceridemia and reduced plasma levels of high density lipoprotein (HDL) cholesterol. Although the link between insulin resistance and dysregulation of lipoprotein metabolism is well established, a significant gap of knowledge exists regarding the underlying cellular and molecular mechanisms. Emerging evidence suggests that insulin resistance and its associated metabolic dyslipidemia result from perturbations in key molecules of the insulin signaling pathway, including overexpression of key phosphatases, downregulation and/or activation of key protein kinase cascades, leading to a state of mixed hepatic insulin resistance and sensitivity. These signaling changes in turn cause an increased expression of sterol regulatory element binding protein (SREBP) 1c, induction of de novo lipogensis and higher activity of microsomal triglyceride transfer protein (MTP), which together with high exogenous free fatty acid (FFA) flux collectively stimulate the hepatic production of apolipoprotein B (apoB)-containing VLDL particles. VLDL overproduction underlies the high triglyceride/low HDL-cholesterol lipid profile commonly observed in insulin resistant subjects.
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Affiliation(s)
- Rita Kohen Avramoglu
- Clinical Biochemistry Division, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8
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Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2006:CD002967. [PMID: 16437448 DOI: 10.1002/14651858.cd002967.pub2] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Metformin is an oral anti-hyperglycemic agent used in the treatment of type 2 diabetes mellitus. The results of the UK Prospective Diabetes Study indicate that metformin treatment is associated with a reduction in total mortality compared to other anti-hyperglycemic treatments. Metformin, however, is thought to increase the risk of lactic acidosis, and is considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES To assess the incidence of fatal and nonfatal lactic acidosis with metformin use compared to placebo and other glucose-lowering treatments in patients with type 2 diabetes mellitus. A secondary objective was to evaluate the blood lactate levels for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY A search was performed of The Cochrane Library (up to 8/2005), MEDLINE (up to 8/2005), EMBASE (up to 11/2000), OLD MEDLINE, and REACTIONS (up to 8/2005), in order to identify all studies of metformin treatment from 1966 to August 2005. The Cumulated Index Medicus was used to search relevant articles from 1959 to 1965. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Date of latest search: August 2005. SELECTION CRITERIA Prospective trials in patients with type 2 diabetes that lasted longer than one month were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Observational cohort studies of metformin treatment lasting greater than one month were also included. DATA COLLECTION AND ANALYSIS Two reviewers independently selected trials to be included, assessed study quality and extracted data. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for placebo or other treatments. The upper limit for the true incidence of cases in the metformin and non-metformin groups were calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed effect model for continuous data. MAIN RESULTS Pooled data from 206 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 47,846 patient-years of metformin use or in 38,221 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals the upper limit for the true incidence of metformin-associated lactic acidosis was 6.3 cases per 100,000 patient-years, and the upper limit for the true incidence of lactic acidosis in the non-metformin group was 7.8 cases per 100,000 patient-years. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to placebo or other non-biguanide therapies. The mean lactate levels were slightly lower for metformin treatment compared to phenformin (WMD -0.75 mmol/L, 95% CI -0.86 to -0.15). AUTHORS' CONCLUSIONS There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments if prescribed under the study conditions.
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Samaha FF, Szapary PO, Iqbal N, Williams MM, Bloedon LT, Kochar A, Wolfe ML, Rader DJ. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol 2005; 26:624-30. [PMID: 16357312 DOI: 10.1161/01.atv.0000200136.56716.30] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND PPAR-gamma agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-gamma agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-gamma agonists have not been fully tested in nondiabetic patients with metabolic syndrome. METHODS AND RESULTS We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P=0.89), and an increase in total cholesterol (+8% versus -1%; P=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P<0.001), and lowered resistin (-6% versus +4%; P=0.009), C-reactive protein (-32% versus +36%, P=0.002), interleukin (IL)-6 (-22% versus +4%, P<0.001), and soluble tumor-necrosis factor-alpha receptor-2 (-5% versus +7%, P<0.001). CONCLUSIONS These findings suggest that rosiglitazone, presumably through its PPAR-gamma agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.
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Affiliation(s)
- Frederick F Samaha
- Cardiovascular Division, Department of Medicine, Cardiovascular Institute, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
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Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin--the classical, resistin--the controversical, adiponectin--the promising, and more to come. Best Pract Res Clin Endocrinol Metab 2005; 19:525-46. [PMID: 16311215 DOI: 10.1016/j.beem.2005.07.008] [Citation(s) in RCA: 308] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they are increasingly shown to affect several aspects in the pathogenesis of obesity-related diseases. The cloning of the ob gene is consistent with this concept and suggests that body fat content in adult rodents is regulated by a negative feedback loop centred in the hypothalamus. In recent years, a number of additional signalling molecules secreted by adipose tissue have been discovered, commonly referred to as 'adipocytokines'. Among these, adiponectin is perhaps the most interesting and promising compound for the clinician since it has profound protective actions in the pathogenesis of diabetes and cardiovascular disease. Adiponectin is low in obese subjects and, in particular, insulin-resistant patients. In contrast, resistin seems to be of greater relevance in relation to the immune stress response than in the regulation of glucose homeostasis. However, inflammatory processes have recently been connected with the development of atherosclerosis. Finally, little is known regarding the clinical relevance of visfatin. Recent research has revealed many functions of adipocytokines extending far beyond metabolism, such as immunity, cancer and bone formation. This report aims to review some of the recent topics of adipocytokine research that may be of particular importance.
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Affiliation(s)
- Antje Koerner
- University Hospital for Children and Adolescents, University of Leipzig, Oststrasse 21-25, Germany.
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Reynaert H, Geerts A, Henrion J. Review article: the treatment of non-alcoholic steatohepatitis with thiazolidinediones. Aliment Pharmacol Ther 2005; 22:897-905. [PMID: 16268963 DOI: 10.1111/j.1365-2036.2005.02682.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
It is generally accepted that non-alcoholic fatty liver disease will be the most frequent liver disease in the near future and that the management of patients with non-alcoholic fatty liver disease will be a challenge for hepatologists in the next decades. Non-alcoholic fatty liver disease is considered the hepatic manifestation of the metabolic syndrome, in which insulin resistance plays a crucial role. Although steatosis will often not progress to severe liver disease, in some patients, it results in cirrhosis and even hepatocellular carcinoma. Therefore, it is important to identify those patients at risk for developing fibrosis. Age, diabetes, obesity and hypertriglyceridaemia are independent risk factors for fibrosis in patients with elevated serum alanine aminotransferase levels and steatosis on ultrasound. The presence of multiple metabolic disorders increases the risk. Apart from diet, exercise and correction of underlying metabolic abnormalities, no specific treatment is available at the moment. Theoretically, thiazolidinediones are an attractive way to treat non-alcoholic fatty liver disease, because they improve insulin resistance. Some preliminary studies with thiazolidinediones were encouraging, as steatosis, inflammation and fibrosis improved in a substantial number of patients. Although no serious side effects occurred in the pilot studies, we should look vigilantly for hepatotoxicity, as the first generation thiazolidinediones proved to be toxic for the liver.
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Affiliation(s)
- H Reynaert
- Department of Gastroenterology-Hepatology, University Hospital AZ-VUB, Brussels, Belgium.
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Szapary PO, Bloedon LT, Samaha FF, Duffy D, Wolfe ML, Soffer D, Reilly MP, Chittams J, Rader DJ. Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome. Arterioscler Thromb Vasc Biol 2005; 26:182-8. [PMID: 16284192 DOI: 10.1161/01.atv.0000195790.24531.4f] [Citation(s) in RCA: 115] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic patients with metabolic syndrome (MetSyn). METHODS AND RESULTS Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.001). Changes in HDL-C were correlated to changes in adiponectin (r=0.34; P=0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% (P<0.001). PIO reduced median C-reactive protein levels by 31% (P<0.001) and mean resistin levels by 10% (P=0.02) while increasing mean serum levels of adiponectin by 111% (P<0.001) compared with placebo. PIO did not affect weight and modestly decreased insulin resistance. CONCLUSIONS In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.
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Affiliation(s)
- Philippe O Szapary
- Division of General Internal Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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