Ragaglitazar Improves Glycemic Control and Lipid Profile in Type 2 Diabetic Subjects

Saad, Mohammed F.; Greco, Susan; Osei, Kwame; Lewin, Andrew; Edwards, Christopher; Núñez, Miguel; Reinhardt, Rickey R.

doi:10.2337/diacare.27.6.1324

Cited by 92 publications

(41 citation statements)

References 23 publications

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“…In searching for a molecular link for the hematological system involvement, we note that the expression of PPAR ␥ in hematopoietic cells and its colocalization with the hematopoietic transcription factor PU.1 suggest a role in hematopoiesis ( 17,18 ). Interestingly, thiazolidinediones, which are artifi cial PPAR ␥ ligands, can cause nondilutional anemia ( 19 ) ( 20 ),cytopenias, and pancytopenia (21)(22)(23)(24). Although our study was not designed to study molecular or cellular mechanisms of the hematological abnormalities, we hypothesize that the multiple cytopenias might be caused either by abnormal bone marrow adipocytes, which are critical to support hematopoiesis ( 25,26 ), or an intrinsic hematopoietic defect causing a decreased survival or ineffi cient production.…”

Section: Assessment Of Dominant-negative Activity Of Mutant Ppargmentioning

confidence: 99%

Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency

Campeau

Astapova

Martins

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words peroxisome proliferator-activated receptor gamma • anemia • cytopenia Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant condition caused by PPARG mutations. Starting in adolescence, there is variable loss of adipose tissue in the face, gluteal area, and distal limbs with increased truncal adiposity and hepatic steatosis. A metabolic syndrome occurs with diabetes, hypertension, hypertriglyceridemia, and related complications ( 1 ). More than 15 FPLD3 families have been identifi ed, and in contrast to FPLD2, which is caused by LMNA mutations, no FPLD3 subject has yet been reported to have any muscular , neurological, or cardiac involvement. PPARG encodes a nuclear receptor involved in adipocyte differentiation, whereas LMNA encodes lamin A/C, an essential component of the nuclear envelope. We identifi ed a large family with a dominantly transmitted severe lipodystrophy. We identifi ed the causative mutation, characterized its effect on PPARG, and studied the phenotype to uncover never-before-reported features. MATERIALS AND METHODS Clinical studyThis clinical study was approved by the Laval University Hospital Center Institutional Review Board (Comité d'Éthique du Centre Hospitalier de l'Université Laval). Potential subjects were informed of our study by a letter distributed by affected family members Abstract Familial partial lipodystrophy (FPLD) is characterized by abnormal fat distribution and a metabolic syndrome with hypertriglyceridemia. We identifi ed a family with a severe form of FPLD3 with never-reported clinical features and a novel mutation affecting the DNA binding domain of PPAR ␥ (E157D). Apart from the lipodystrophy and severe metabolic syndrome, individuals presented musculoskeletal and hematological issues. E157D heterozygotes had a muscular habitus yet displayed muscle weakness and myopathy. Also, E157D heterozygotes presented multiple cytopenias and a susceptibility to autoimmune disease. In vitro studies showed that the E157D mutation does not decrease the receptor's affi nity to classical PPAR response elements or its responsiveness to a PPAR ␥ agonist, yet it severely reduces its target gene transcription. Microarray experiments demonstrated a decreased activation of a wide array of genes, including genes involved in the PPAR response, the immune response, hematopoiesis, and metabolism in muscle. In addition, a subset of genes with cryptic PPAR response elements was activated. In summary, we describe a large family with a novel PPAR ␥ mutation, which extends the clinical phenotype of FPLD3 to include muscular, immune, and hematological features. Together, our results support the role of PPAR ␥ in controlling homeostasis of multiple systems beyond lipid metabolism. -Campeau, P. M., O. Astapova, R. Martins, J. Bergeron, P. Couture, R. A. Hegele, T. Leff, and C. Gagné. Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPAR ␥ defi ciency.

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Section: Assessment Of Dominant-negative Activity Of Mutant Ppargmentioning

confidence: 99%

Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency

Campeau

Astapova

Martins

et al. 2012

Journal of Lipid Research

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“…All cases of systemic oedema (pretibial or facial) reported in a trial of troglitazone therapy occurred at about 2 months [23]. Patients withdrew early from a 12-week TZD study due to oedema, and effects on both white blood cell count and haemoglobin levels have been reported to occur with 4 weeks of treatment [24]. These investigators found that many of the actions of pioglitazone occur early and are maintained.…”

Section: Introductionmentioning

confidence: 97%

The insulin sensitiser pioglitazone does not influence skin microcirculatory function in patients with type 2 diabetes treated with insulin

et al. 2006

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Aims/hypothesis: Insulin resistance is associated with abnormal microvascular function. Treatment with insulin sensitisers may provoke oedema, suggesting microvascular effects. The mechanisms underlying the peripheral oedema observed during glucose-lowering treatment with thiazolidinediones are unclear. Therefore we examined the effect of pioglitazone on microvascular variables involved in oedema formation. Methods:: Subjects (40-80 years) with type 2 diabetes and on insulin were randomised to 9 weeks of pioglitazone therapy (30 mg/day; n=14) or placebo (n=15). The following assessments were performed at baseline and 9 weeks: microvascular filtration capacity; isovolumetric venous pressure; capillary pressure; capillary recruitment following venous or arterial occlusion; postural vasoconstriction; and maximum blood flow. A number of haematological variables were also measured including vascular endothelium growth factor (VEGF), IL-6 and C-reactive protein (CRP). Results: Pioglitazone did not significantly influence any microcirculatory variable as compared with placebo (analysis of covariance [ANCOVA] for microvascular filtration capacity for the two groups, p=0.26). Mean VEGF increased with pioglitazone (61.1 pg/ml), but not significantly more than placebo (9.76 pg/ml, p=0.94).HbA 1c levels and the inflammatory markers IL-6 and CRP decreased with pioglitazone compared with placebo (ANCOVA: p=0.009, p=0.001 and p=0.004, respectively). Conclusions/interpretation: Pioglitazone improved glycaemic control and inflammatory markers over 9 weeks but had no effect on microcirculatory variables associated with oedema or insulin resistance in type 2 diabetic patients treated with insulin.

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“…For example, both glycemic efficacy and edema formation are dose-dependent features of TZD therapy (10). Furthermore, peroxisome proliferator-activated receptor (PPAR)␥ agonists with more potent glucose-lowering effects seem to be associated with a higher incidence of edema formation (12). Besides a metabolic effect, insulin also has important vascular properties at several sites of the vascular tree.…”

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confidence: 99%

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

et al. 2006

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OBJECTIVE -The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention.RESEARCH DESIGN AND METHODS -In a randomized, double-blind, placebocontrolled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N-monomethyl-L-arginine-acetate (L-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemiceuglycemic clamp (120 min, 120 mU/m 2 per min).RESULTS -As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or L-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35-6.87, P ϭ 0.0005) and increased plasma volume by 255 ml/1.73 m 2 (80 -430, P ϭ 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R 2 ϭ 0.53, P ϭ 0.001).CONCLUSIONS -Rosiglitazone improved insulin sensitivity but had no effect on NOdependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation. Diabetes Care 29:581-587, 2006T hiazolidinedione (TZD) derivatives improve insulin sensitivity and hence are valuable in the treatment of type 2 diabetes (1). Important adverse effects are fluid retention and peripheral edema formation. The precise mechanism(s) of these adverse effects are unclear and probably are multifactorial (2).Although multiple factors are involved, the existence of an initial trigger or main mechanism could be of clinical importance. In theory, the initial trigger of fluid retention may originate either from kidney, heart, or peripheral circulation. As TZD treatment is associated with a reduction in blood pressure (3-6), a primary renal mechanism seems unlikely. A primary cardiac origin also seems improbable, because long-term studies with rosiglitazone have not revealed any negative effect on myocardial structure or function (7).The combination of blood pressure reduction, fluid retention, and edema formation is compatible with changes in the peripheral circulation resulting in capillary leakage. This may be induced by certain actions of TZDs, such as improved insulin-mediated vasodilatation, direct vasoa...

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Ragaglitazar Improves Glycemic Control and Lipid Profile in Type 2 Diabetic Subjects

Cited by 92 publications

References 23 publications

Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency

Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency

The insulin sensitiser pioglitazone does not influence skin microcirculatory function in patients with type 2 diabetes treated with insulin

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

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