New Drugs for the Treatment of Diabetes Mellitus

McGuire, Darren K.; Inzucchi, Silvio E.

doi:10.1161/circulationaha.107.704080

Cited by 108 publications

(66 citation statements)

References 91 publications

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“…However, full PPAR␥ agonists also stimulate adipocyte differentiation in vitro and induce weight gain in vivo, motivating a search for selective modulators that activate a subset of PPAR␥-regulated genes with reduced side effects (7,35). Here, we reveal that electrophilic NO 2 -FA derivatives, products of the oxidizing and nitrating conditions promoted by inflammation, bind to and react avidly with the redox-sensitive LBD Cys-285 of PPAR␥ (Fig.…”

Section: Discussionmentioning

confidence: 82%

“…This receptor is expressed primarily in adipose tissue, muscle, and macrophages, where it regulates glucose uptake, lipid metabolism/ storage, and cell proliferation/differentiation (3)(4)(5). Thus, PPAR␥ ligands and allied downstream signaling events play a pivotal role in both the development and treatment of DM (6,7). This is underscored by the observation that mutations in the C-terminal helix 12 of the ligand-binding domain (LBD) of PPAR␥ (e.g.…”

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confidence: 99%

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Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Schöpfer

Cole

Groeger

et al. 2010

Journal of Biological Chemistry

155

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The peroxisome proliferator-activated receptor-␥ (PPAR␥) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPAR␥ include lipids and antihyperglycemic drugs such as thiazolidinediones (TZDsThe rapidly expanding global burden of type II diabetes mellitus (DM) 3 and the concomitant increased risk for cardiovascular disease (1, 2) have motivated better understanding of relevant cell signaling pathways and potential therapeutic strategies. One major characteristic of metabolic syndrome and DM is insulin resistance, leading to hyperglycemia and dyslipidemia. Following initial clinical use of TZDs as anti-hyperglycemic agents to treat DM in the late 1990s, the nuclear receptor PPAR␥ was discovered as their molecular target. This receptor is expressed primarily in adipose tissue, muscle, and macrophages, where it regulates glucose uptake, lipid metabolism/ storage, and cell proliferation/differentiation (3-5). Thus, PPAR␥ ligands and allied downstream signaling events play a pivotal role in both the development and treatment of DM (6, 7). This is underscored by the observation that mutations in the C-terminal helix 12 of the ligand-binding domain (LBD) of PPAR␥ (e.g. P467L or V290M) are linked with severe insulin resistance and the onset of juvenile DM (8).The oxidizing inflammatory milieu contributing to the pathogenesis of obesity, diabetes, and cardiovascular disease also promotes diverse biomolecule oxidation, nitrosation, and nitration reactions by O 2 and ⅐ NO-derived species. Although oxidized fatty acids typically propagate proinflammatory conditions, the recently detected class of NO 2 -FA act as anti-inflammatory mediators. Nitroalkene derivatives of oleic acid (OA-NO 2 ) and linoleic acid (LNO 2 ) have been detected in healthy human blood and murine cardiac tissue. The levels of free/unesterified OA-NO 2 are ϳ1-3 nM in human plasma (9, 10), with OA-NO 2 produced at increased rates and present at higher concentrations during inflammatory and metabolic stress (11-13). The signaling actions of NO 2 -FA are primarily ascribed to the electrophilic olefinic carbon situated ␤ to the electron-withdrawing NO 2 substituent, facilitating kinetically rapid and reversible Michael addition with nucleophilic amino acids (i.e. Cys and His) (14). NO 2 -FA adduction of proteins and GSH occurs in model systems and clinically, with this reaction

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Schöpfer

Cole

Groeger

et al. 2010

Journal of Biological Chemistry

155

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“…4,5 In animal models of obesity and T2D, thiazolidinedione (TZD) therapy attenuates myocardial triglyceride (mTG) deposition and normalises left ventricular (LV) systolic dysfunction. [6][7][8] As substantial controversy exists surrounding the cardiac effects of these commonly used glucose-lowering medications, 9,10 we conducted a nested imaging sub-study within a 6-month, randomised controlled clinical trial of rosiglitazone on cardiovascular performance. The sub-study assessed the effects of rosiglitazone on mTG content and its association with measures of cardiac structure and function in patients with T2D and increased CVD risk.…”

Section: Introductionmentioning

confidence: 99%

The effects of rosiglitazone on myocardial triglyceride content in patients with type 2 diabetes: A randomised, placebo-controlled trial

McGavock

Szczepaniak

Ayers

et al. 2011

Diabetes and Vascular Disease Research

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IntroductionThe excessive cardiovascular disease (CVD) burden associated with type 2 diabetes mellitus (T2D) is conventionally attributed to a clustering of traditional risk factors including hyperglycaemia, hypertension, dyslipidaemia and obesity. More recently, studies by our group and others have demonstrated that individuals with impaired glucose tolerance and T2D have increased triglyceride content within the myocardium. [1][2][3] This ectopic lipid deposition is purported to contribute to changes in cardiac structure and function frequently seen in individuals with glucose intolerance, referred to as 'diabetic cardiomyopathy'. 4,5 In animal models of obesity and T2D, thiazolidinedione (TZD) therapy attenuates myocardial triglyceride (mTG) deposition and normalises left ventricular (LV) systolic dysfunction. [6][7][8] As substantial controversy exists surrounding the cardiac effects of these commonly used glucose-lowering medications, 9,10 we conducted a nested imaging sub-study within a 6-month, randomised controlled clinical trial of rosiglitazone on cardiovascular performance. The sub-study assessed the effects of rosiglitazone on mTG content and its association with measures of cardiac structure and function in patients with T2D and increased CVD risk. Our a-priori hypothesis was that 6 months of rosiglitazone therapy would significantly reduce mTG content in patients with T2D, which would be associated with improved LV performance. AbstractThis was a nested sub-study of a randomised placebo-controlled trial of the effect of 6 months of treatment with rosiglitazone added to existing therapy on myocardial triglyceride (mTG) content in patients with type 2 diabetes (T2D) and prevalent cardiovascular disease (CVD) or at least one additional risk factor. The primary endpoint, mTG content, was measured with cardiac 1 H-magnetic resonance spectroscopy. Of the 99 randomised participants selected for the imaging sub-study, 49 (48%) had complete and interpretable spectroscopy data (age = 58 years, duration of T2D = 9.5 years; 57% women and 69% non-white). There was no significant change in mTG in either group (−0.1 ± 0.6% and −0.05 ± 0.8% respectively) and the changes in mTG were not associated with changes in left ventricular structure or function. Compared with placebo, treatment with rosiglitazone for 6 months had no discernible effect on mTG or left ventricular function in this population with long-standing diabetes and CVD. Keywords Research design and methodsThis was a sub-study nested within a single-centre, prospective, randomised, double-blind, placebo-controlled, parallel-group trial evaluating the cardiovascular effects of rosiglitazone in patients with T2D and elevated CVD risk, with the study design and primary study results previously published (NCT00424762). 11,12 In the present sub-study, we assessed the effects of rosiglitazone on 1 H-magnetic resonance spectroscopy (MRS)-derived mTG content and MRI-derived measures of LV structure and function. The study protocol was approved by the UT Southw...

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“…1 As the clinical use of TZDs has increased, a number of signals have emerged regarding increased risk for peripheral oedema, and more ominously, increased risk for the development of new or worsening heart failure (HF). These observations have spawned a cascade of commentaries and meta-analyses in the peer-reviewed literature, [2][3][4][5] position statements from professional organisations, 6 and product labelling language, initially moderately cautionary and more recently amplified under guidance of the Food and Drugs Administration (FDA) with regard to the HF risk associated with this class of medications. 7,8 While the cautionary advice has been fairly rigorous, the mechanistic and clinical understanding of the observed peripheral oedema and worsening HF symptoms remains rudimentary.…”

Section: Introductionmentioning

confidence: 99%

The effect of rosiglitazone on integrated cardiovascular performance, cardiac structure, function and myocardial triglyceride: trial design and rationale

McGuire¹,

See

Abdullah³

et al. 2009

Diabetes and Vascular Disease Research

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T he thiazolidinedione (TZD) class of medications has been associated with increased risk for peripheral oedema, as well as incident and worsening heart failure (HF). The mechanism of these observed effects remains unclear. Here we present the rationale and study design for a randomised clinical trial designed to evaluate the cardiac effects of rosiglitazone on integrated cardiovascular performance, cardiac structure and function.The study is a randomised, single-centre, doubleblind, placebo-controlled, parallel-group clinical trial to evaluate the effect of rosiglitazone on integrated cardiovascular performance in a cohort of patients with type 2 diabetes mellitus (T2DM) at increased risk for developing heart failure (HF). Participants will be randomised to receive rosiglitazone or matching placebo for six months. All subjects will undergo maximal treadmill cardiopulmonary exercise testing at baseline and after six months on study drug, with the primary trial end point of peak oxygen uptake indexed to fat-free mass (VO 2peak -FFM). Approximately two-thirds of the study cohort will undergo cardiac magnetic resonance imaging (MRI) and spectroscopy (MRS) at baseline and after six months of study therapy to assess cardiac structure, function and myocardial triglyceride content.While concerns for peripheral oedema and HF continue to confound clinical use of TZD medications, the direct cardiac effects of these drugs remain poorly understood and the clinical relevance of these clinical observations remains unclear. The present study will combine a series of state-of-the-art assessments to evaluate the cardiac effects of rosiglitazone treatment. (ClinicalTrials.gov NCT00424762).

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New Drugs for the Treatment of Diabetes Mellitus

Cited by 108 publications

References 91 publications

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

The effects of rosiglitazone on myocardial triglyceride content in patients with type 2 diabetes: A randomised, placebo-controlled trial

The effect of rosiglitazone on integrated cardiovascular performance, cardiac structure, function and myocardial triglyceride: trial design and rationale

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