Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study

Tripathy, Devjit; Daniele, Giuseppe; Fiorentino, Teresa Vanessa; Perez-Cadena, Zandra; Chavez-Velasquez, Alberto; Kamath, Subhash; Fanti, Paolo; Jenkinson, Christopher P.; Andreozzi, Francesco; Federici, Massimo; Gastaldelli, Amalia; DeFronzo, Ralph A.; Folli, Franco

doi:10.1007/s00125-013-2976-z

Cited by 76 publications

(57 citation statements)

References 42 publications

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“…Therefore, sclerostin-mediated inhibition of Wnt signaling might directly cause adipogenesis and adipose tissue insulin resistance, which are present in T2DM and in prediabetes (38). Given that obesity is a major risk factor for developing T2DM, changes in components of the Wnt signaling pathway could conceivably contribute to the increased risk of diabetes development by affecting adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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OBJECTIVEA gene mutation of the Wnt/b-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/b-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and b-cell function. RESEARCH DESIGN AND METHODSWe performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTSSclerostin levels were higher in IGR compared with NGT (50.8 6 2.4 vs. 38.7 6 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = 20.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = 20.52 and r = 20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with b-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r 2 associated with HOMA-IR (r 2 change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r 2 change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONSSclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.

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Section: Discussionmentioning

confidence: 99%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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“…The TACE-TIMP3 dyad, as well as the ADAM17/ TACE metalloprotease, are anomalously regulated in humans with type 2 diabetes and obesity, which can, potentially, modulate the levels of bioactive fractalkine (45)(46)(47). Moreover, fractalkine is involved in the regulation of insulin secretion by pancreatic b-cells (48).…”

Section: Discussionmentioning

confidence: 99%

Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity

et al. 2014

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Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow–derived cells or only in bone marrow–derived cells. We show that a functional TLR4 in bone marrow–derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow–derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.

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“…Thiazolidinediones (TZDs), a class of anti-diabetic drugs that are potent activators of PPARγ, also modulate adipocyte development and function. The potent insulin-sensitizing activities of TZDs have been effective in diminishing the progression from impaired glucose tolerance to T2DM [29], [30]. However, undesirable side effects have led to recent decreases in the use of TZDs as therapeutics [31]–[33].…”

Section: Discussionmentioning

confidence: 99%

Artemisia scoparia Enhances Adipocyte Development and Endocrine Function In Vitro and Enhances Insulin Action In Vivo

et al. 2014

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BackgroundFailure of adipocytes to expand during periods of energy excess can result in undesirable metabolic consequences such as ectopic fat accumulation and insulin resistance. Blinded screening studies have indicated that Artemisia scoparia (SCO) extracts can enhance adipocyte differentiation and lipid accumulation in cultured adipocytes. The present study tested the hypothesis that SCO treatment modulates fat cell development and function in vitro and insulin sensitivity in adipose tissue in vivo.Methods In vitro experiments utilized a Gal4-PPARγ ligand binding domain (LBD) fusion protein-luciferase reporter assay to examine PPARγ activation. To investigate the ability of SCO to modulate adipogenesis and mature fat cell function in 3T3-L1 cells, neutral lipid accumulation, gene expression, and protein secretion were measured by Oil Red O staining, qRT-PCR, and immunoblotting, respectively. For the in vivo experiments, diet-induced obese (DIO) C57BL/6J mice were fed a high-fat diet (HFD) or HFD containing 1% w/w SCO for four weeks. Body weight and composition, food intake, and fasting glucose and insulin levels were measured. Phospho-activation and expression of insulin-sensitizing proteins in epididymal adipose tissue (eWAT) were measured by immunoblotting.ResultsEthanolic extracts of A. scoparia significantly activated the PPARγ LBD and enhanced lipid accumulation in differentiating 3T3-L1 cells. SCO increased the transcription of several PPARγ target genes in differentiating 3T3-L1 cells and rescued the negative effects of tumor necrosis factor α on production and secretion of adiponectin and monocyte chemoattractant protein-1 in fully differentiated fat cells. DIO mice treated with SCO had elevated adiponectin levels and increased phosphorylation of AMPKα in eWAT when compared to control mice. In SCO-treated mice, these changes were also associated with decreased fasting insulin and glucose levels.ConclusionSCO has metabolically beneficial effects on adipocytes in vitro and adipose tissue in vivo, highlighting its potential as a metabolically favorable botanical supplement.

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Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study

Abstract: This study was funded by TAKEDA.

Cited by 76 publications

References 42 publications

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity

Artemisia scoparia Enhances Adipocyte Development and Endocrine Function In Vitro and Enhances Insulin Action In Vivo

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