The Differential Effects of Metformin on Markers of Endothelial Activation and Inflammation in Subjects with Impaired Glucose Tolerance: A Placebo-Controlled, Randomized Clinical Trial

Caballero, A. Enrique; Delgado, Adriano; Aguilar-Salinas, Carlos A.; Herrera, Alberto Naranjo; Castillo, José; Cabrera, Tatiana; Gómez-Pérez, Francisco J.; Rull, Juan

doi:10.1210/jc.2004-0019

Cited by 130 publications

(99 citation statements)

References 41 publications

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“…Metformin has been shown to improve an array of inflammatory events, including diabetes mellitus and postsurgical endotoxin-induced inflammation (38,39). Further, AICAR administration provides anti-inflammatory effects in vascular cells in vitro and in vivo (6,9,40).…”

Section: Discussionmentioning

confidence: 99%

AMPKα2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6

Gongol

Marin

Peng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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B-cell lymphoma-6 protein (Bcl-6) is a corepressor for inflammatory mediators such as vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and -3, which function to recruit monocytes to vascular endothelial cells upon inflammation. Poly [ADP ribose] polymerase 1 (PARP-1) is proinflammatory, in part through its binding at the Bcl-6 intron 1 to suppress Bcl-6 expression. We investigated the mechanisms by which PARP-1 dissociates from the Bcl-6 intron 1, ultimately leading to attenuation of endothelial inflammation. Analysis of the PARP-1 primary sequence suggested that phosphorylation of PARP-1 Serine 177 (Ser-177) by AMP-activated protein kinase (AMPK) is responsible for the induction of Bcl-6. Our results show that AMPK activation with treatment of 5-aminoimidazole-4-carboxamide ribonucleotide, metformin, or pulsatile shear stress induces PARP-1 dissociation from the Bcl-6 intron 1, increases Bcl-6 expression, and inhibits expression of inflammatory mediators. Conversely, AMPKα suppression or knockdown produces the opposite effects. The results demonstrate an anti-infamatory pathway linking AMPK, PARP-1, and Bcl-6 in endothelial cells.

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Section: Discussionmentioning

confidence: 99%

AMPKα2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6

Gongol

Marin

Peng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…[12][13][14] Metformin was also shown to improve endothelial dysfuntion. 15,16 Rosiglitazone therapy was shown to reduce serum C reactive protein levels in type 2 diabetic patients. 17 Furthermore, rosiglitazone therapy was shown to ameliorate endothelial dysfunction independent of glucose control.…”

Section: Introductionmentioning

confidence: 99%

Serum transforming growth factor-beta 1 levels in normoalbuminuric and normotensive patients with type 2 diabetes. Effect of metformin and rosiglitazone

Yener¹,

Çömlekçi²,

Akıncı³

et al. 2008

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OBJECTIVE: a)To determine serum Transforming Growth Factor-beta 1 (TGF-β1) levels in patients with type 2 diabetes who do not have diabetes related complications and in healthy controls, b) to evaluate the effects of metformin and rosiglitazone on TGF-β1 levels. DESIGN: In the washout period, 61 patients with Fasting Plasma Glucose levels (FPG) higher than 140 mg/dl, Postprandial Glucose (PPG) levels higher than 180 mg/dl and A1c levels exceeding 6.5% were treated with glimperide. After 4 weeks, 39 of these patients were randomised to receive either metformin or rosiglitazone for 12 weeks. Thirty healthy controls were also studied. RE-SULTS: There were no significant differences with regard to age, gender, body weight and BMI between patients and healthy controls. Type 2 diabetics had higher waist circumference, FPG, total cholesterol, LDL-cholesterol and triglyceride levels. Baseline TGF-β1 levels in diabetics were higher than in controls (29.84±7.04 ng/ml vs 11.37±4.06 ng/ml, p<0.001). Metformin or rosiglitazone did not significantly modify the TGF-β1 levels. In a multiple regression analysis FPG was the only variable that was significantly associated with plasma TGF-β1 levels. CON-CLUSION: The elevated levels of TGF-β1 in subjects with type 2 diabetes possibly indicate a tendency for renal and endothelial damage in such patients. The association of TGF-β1 with FPG possibly links poor diabetic control to vascular damage, leading to diabetic complications. Lack of changes in the levels of TGF-β1 after therapy may reflect inadequate therapy duration.

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“…In a large clinical trial with diabetic patients, pioglitazone reduced the composite of all-cause mortality, non-fatal myocardial infarction, and stroke (9). On the other hand, there is growing evidence that metformin improves insulin resistance, cardiovascular risk factors, and the development of diabetes mellitus (10,11). However, no studies have directly compared the effects of pioglitazone and metformin on IGT or early diabetic subjects.…”

Section: Introductionmentioning

confidence: 99%