Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex

Haider, Nida; Lebastchi, Jasmin; Jayavelu, Ashok Kumar; Batista, Thiago M.; Hui, Pei; Dreyfuss, Jonathan M.; Cárcamo-Orive, Iván; Knowles, Joshua W.; Mann, Matthias; Kahn, C. Ronald

doi:10.1172/jci151818

Cited by 33 publications

(32 citation statements)

References 61 publications

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“…The gene SOWAHB ( sosondowah ankyrin repeat domain family member B ) is part of the Ankyrin family, involved in membrane skeleton organisation, ionic transport, protein recognition as well as cell–cell adhesion regulation 54 . Moreover, SOWAHB is activated in response to insulin and possibly involved in insulin resistance 55 . Besides its effect on growth traits, significant nominal p -values were observed in the test of association with fatness traits at different ages (backfat thickness, cholesterol, Supplementary Table S6 ) suggesting a role in lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

SNP discovery and association study for growth, fatness and meat quality traits in Iberian crossbred pigs

Óvilo

Trakooljul

Núñez

et al. 2022

Sci Rep

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Iberian pigs and its crosses are produced to obtain high-quality meat products. The objective of this work was to evaluate a wide panel of DNA markers, selected by biological and functional criteria, for association with traits related to muscle growth, fatness, meat quality and metabolism. We used 18 crossbred Iberian pigs with divergent postnatal growth patterns for whole genome sequencing and SNP discovery, with over 13 million variants being detected. We selected 1023 missense SNPs located on annotated genes and showing different allele frequencies between pigs with makerdly different growth patterns. We complemented this panel with 192 candidate SNPs obtained from literature mining and from muscle RNAseq data. The selected markers were genotyped in 480 Iberian × Duroc pigs from a commercial population, in which phenotypes were obtained, and an association study was performed for the 1005 successfully genotyped SNPs showing segregation. The results confirmed the effects of several known SNPs in candidate genes (such as LEPR, ACACA, FTO, LIPE or SCD on fatness, growth and fatty acid composition) and also disclosed interesting effects of new SNPs in less known genes such as LRIG3, DENND1B, SOWAHB, EPHX1 or NFE2L2 affecting body weight, average daily gain and adiposity at different ages, or KRT10, NLE1, KCNH2 or AHNAK affecting fatness and FA composition. The results provide a valuable basis for future implementation of marker-assisted selection strategies in swine and contribute to a better understanding of the genetic architecture of relevant traits.

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Section: Discussionmentioning

confidence: 99%

SNP discovery and association study for growth, fatness and meat quality traits in Iberian crossbred pigs

Óvilo

Trakooljul

Núñez

et al. 2022

Sci Rep

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“…Furthermore, skeletal myoblasts generated from these iPSCs reflected the effect of inherent IR on insulin-stimulated biological pathways and signaling [12]. Also, a recent study generated iPSCs from IR individuals that were classified using the results for a steady state plasma glucose (SSPG)-derived from an insulin suppression test but with no fixed standard describing the family history of T2D in those subjects [18,19]. On the other hand, studying IR offspring of T2D parents, individuals at the highest genetic risk of developing T2D, may facilitate our understanding of the specific genetic contribution of IR in the development of T2D more robustly.…”

Section: Open Accessmentioning

confidence: 99%

iPSCs derived from insulin resistant offspring of type 2 diabetic patients show increased oxidative stress and lactate secretion

et al. 2022

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Background The genetic factors associated with insulin resistance (IR) are not well understood. Clinical studies on first-degree relatives of type 2 diabetic (T2D) patients, which have the highest genetic predisposition to T2D, have given insights into the role of IR in T2D pathogenesis. Induced pluripotent stem cells (iPSCs) are excellent tools for disease modeling as they can retain the genetic imprint of the disease. Therefore, in this study, we aimed to investigate the genetic perturbations associated with insulin resistance (IR) in the offspring of T2D parents using patient-specific iPSCs. Methods We generated iPSCs from IR individuals (IR-iPSCs) that were offspring of T2D parents as well as from insulin-sensitive (IS-iPSCs) individuals. We then performed transcriptomics to identify key dysregulated gene networks in the IR-iPSCs in comparison to IS-iPSCs and functionally validated them. Results Transcriptomics on IR-iPSCs revealed dysregulated gene networks and biological processes indicating that they carry the genetic defects associated with IR that may lead to T2D. The IR-iPSCs had increased lactate secretion and a higher phosphorylation of AKT upon stimulation with insulin. IR-iPSCs have increased cellular oxidative stress indicated by a high production of reactive oxygen species and higher susceptibility to H2O2 -induced apoptosis. Conclusions IR-iPSCs generated from offspring of diabetic patients confirm that oxidative stress and increased lactate secretion, associated with IR, are inherited in this population, and may place them at a high risk of T2D. Overall, our IR-iPSC model can be employed for T2D modeling and drug screening studies that target genetic perturbations associated with IR in individuals with a high risk for T2D.

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“…It can be adapted to 3D systems and generates contractile myofibers when combined with a biocompatible hydrgel for the generation of artificial human muscle [14]. Our system has been efficiently used with over 40 hPSC lines and is now used extensively in multiple laboratories for the modelling of muscular dystrophies or insulin resistance/type 2 diabetes [15][16][17][18]. However, the myotubes remain thin and contain few nuclei, suggesting that the last stage of the differentiation can be further improved.…”

Section: Introductionmentioning

confidence: 99%

Anabolic Factors and Myokines Improve Differentiation of Human Embryonic Stem Cell Derived Skeletal Muscle Cells

Ruan

Harney

Koay

et al. 2022

Cells

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Skeletal muscle weakness is linked to many adverse health outcomes. Current research to identify new drugs has often been inconclusive due to lack of adequate cellular models. We previously developed a scalable monolayer system to differentiate human embryonic stem cells (hESCs) into mature skeletal muscle cells (SkMCs) within 26 days without cell sorting or genetic manipulation. Here, building on our previous work, we show that differentiation and fusion of myotubes can be further enhanced using the anabolic factors testosterone (T) and follistatin (F) in combination with a cocktail of myokines (C). Importantly, combined TFC treatment significantly enhanced both the hESC-SkMC fusion index and the expression levels of various skeletal muscle markers, including the motor protein myosin heavy chain (MyHC). Transcriptomic and proteomic analysis revealed oxidative phosphorylation as the most up-regulated pathway, and a significantly higher level of ATP and increased mitochondrial mass were also observed in TFC-treated hESC-SkMCs, suggesting enhanced energy metabolism is coupled with improved muscle differentiation. This cellular model will be a powerful tool for studying in vitro myogenesis and for drug discovery pertaining to further enhancing muscle development or treating muscle diseases.

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Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex

Cited by 33 publications

References 61 publications

SNP discovery and association study for growth, fatness and meat quality traits in Iberian crossbred pigs

SNP discovery and association study for growth, fatness and meat quality traits in Iberian crossbred pigs

iPSCs derived from insulin resistant offspring of type 2 diabetic patients show increased oxidative stress and lactate secretion

Anabolic Factors and Myokines Improve Differentiation of Human Embryonic Stem Cell Derived Skeletal Muscle Cells

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