2018
DOI: 10.2337/db17-1539
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Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes

Abstract: In type 2 diabetes (T2D), hepatic insulin resistance is strongly associated with nonalcoholic fatty liver disease (NAFLD). In this study, we hypothesized that the DNA methylome of livers from patients with T2D compared with livers of individuals with normal plasma glucose levels can unveil some mechanism of hepatic insulin resistance that could link to NAFLD. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that hypomethylation at a CpG site in (encoding platelet-derive… Show more

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Cited by 70 publications
(61 citation statements)
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“…Insulin acts via the insulin receptor to increase glucose uptake in all metabolic tissues while suppressing gluconeogenesis and inducing lipogenesis in the liver (Saltiel and Kahn, 2001;Samuel and Shulman, 2016;Vecchio et al, 2018). PDGF-AA acts through PDGFR-α and/or PDGFR-β to suppress hepatocyte insulin sensitivity (Abderrahmani et al, 2018), while PDGF-BB decreases insulin sensitivity in both the liver and white adipose tissue (Raines et al, 2011;Onogi et al, 2017). SCF promotes Pgc1α transcription and mitochondrial biogenesis in brown fat (Huang et al, 2014).…”
Section: Epidermal Growth Factormentioning
confidence: 99%
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“…Insulin acts via the insulin receptor to increase glucose uptake in all metabolic tissues while suppressing gluconeogenesis and inducing lipogenesis in the liver (Saltiel and Kahn, 2001;Samuel and Shulman, 2016;Vecchio et al, 2018). PDGF-AA acts through PDGFR-α and/or PDGFR-β to suppress hepatocyte insulin sensitivity (Abderrahmani et al, 2018), while PDGF-BB decreases insulin sensitivity in both the liver and white adipose tissue (Raines et al, 2011;Onogi et al, 2017). SCF promotes Pgc1α transcription and mitochondrial biogenesis in brown fat (Huang et al, 2014).…”
Section: Epidermal Growth Factormentioning
confidence: 99%
“…Both PDGFA overexpression and hypomethylation at a CpG site in PDGFA are associated with an increased risk of developing insulin resistance, type 2 diabetes, and steatohepatitis. In obese patients, increased liver PDGF-AA levels are positively associated with insulin resistance (Abderrahmani et al, 2018). In humans, PDGF-BB levels in urine are significantly increased in type 2 diabetic patients as compared to healthy individuals (Bessa et al, 2012).…”
Section: Pdgf-a and Pdgf-bmentioning
confidence: 99%
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“…This state is associated with lipids accumulation not only in adipose tissue, but also in other tissues, such as skeletal muscle and the liver. Lipids storage in non-adipose tissue is thought to lead to several metabolic disturbances, including insulin resistance, type 2 diabetes (T2D) and cardiovascular disease [1][2][3][4]. Obesity has reached epidemic proportions worldwide, therefore insulin resistance and type 2 diabetes have become one of the most common chronic metabolic disorders.…”
Section: Introductionmentioning
confidence: 99%
“…Hepatic insulin resistance is mainly manifested by ineffective inhibition of the gluconeogenesis by insulin, which in consequence leads to an increase in blood glucose level. Excessive intrahepatic lipids accumulation is closely related to the occurrence of insulin resistance and non-alcoholic fatty liver disease (NAFLD) [1][2][3]. Most publications regarding hepatic insulin resistance and NAFLD in association with hepatic lipids, refer to triacylglycerols and cholesterol, which accumulate in the liver in the largest amount [5,6].…”
Section: Introductionmentioning
confidence: 99%