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- Diamanti, Klev, 1987-, et al.
(författare)
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Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes, and normal tissues
- 2022
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Ingår i: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 3:10
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Tidskriftsartikel (refereegranskat)abstract
- Environmental and genetic factors cause defects in pancreatic islets driving type 2 diabetes (T2D) together with the progression of multi-tissue insulin resistance. Mass spectrometry proteomics on samples from five key metabolic tissues of a cross-sectional cohort of 43 multi-organ donors provides deep coverage of their proteomes. Enrichment analysis of Gene Ontology terms provides a tissue-specific map of altered biological processes across healthy, prediabetes (PD), and T2D subjects. We find widespread alterations in several relevant biological pathways, including increase in hemostasis in pancreatic islets of PD, increase in the complement cascade in liver and pancreatic islets of PD, and elevation in cholesterol biosynthesis in liver of T2D. Our findings point to inflammatory, immune, and vascular alterations in pancreatic islets in PD that are hypotheses to be tested for potential contributions to hormonal perturbations such as impaired insulin and increased glucagon production. This multi-tissue proteomic map suggests tissue-specific metabolic dysregulations in T2D. © 2022 The Author(s)
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- Kamble, Prasad G., et al.
(författare)
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Proof-of-concept for CRISPR/Cas9 gene editing in human preadipocytes : Deletion of FKBP5 and PPARG and effects on adipocyte differentiation and metabolism
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- CRISPR/Cas9 has revolutionized the genome-editing field. So far, successful application in human adipose tissue has not been convincingly shown. We present a method for gene knockout using electroporation in preadipocytes from human adipose tissue that achieved at least 90% efficiency without any need for selection of edited cells or clonal isolation. We knocked out the FKBP5 and PPARG genes in preadipocytes and studied the resulting phenotypes. PPARG knockout prevented differentiation into adipocytes. Conversely, deletion of FKBP51, the protein coded by the FKBP5 gene, did not affect adipogenesis. Instead, it markedly modulated glucocorticoid effects on adipocyte glucose metabolism and, furthermore, we show some evidence of altered transcriptional activity of glucocorticoid receptors. This has potential implications for the development of insulin resistance and type 2 diabetes. The reported method is simple, easy to adapt, and enables the use of human primary preadipocytes instead of animal adipose cell models to assess the role of key genes and their products in adipose tissue development, metabolism and pathobiology.
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- Kamble, Prasad G., et al.
(författare)
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Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue : assessment of adipogenesis and adipocyte glucose and lipid turnover.
- 2018
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Ingår i: Adipocyte. - : Informa UK Limited. - 2162-3945 .- 2162-397X. ; 7:4, s. 285-296
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Tidskriftsartikel (refereegranskat)abstract
- Protective mechanisms of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala polymorphism in type 2 diabetes (T2D) are unclear. We obtained adipose tissue (AT) before and 3 h after oral glucose (OGTT) in carriers and non-carriers of the Ala allele (12 Pro/Pro, 15 Pro/Ala, and 13 Ala/Ala). Adipogenesis, adipocyte glucose uptake and lipolysis as well as PPARγ target genes expression were investigated and compared between the genotype groups. On fasting and post-OGTT, neither basal nor insulin-stimulated adipocyte glucose uptake differed between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro (p<0.05) also accompanied with a higher antilipolytic effect of insulin post-OGTT (p<0.01). The adipocyte size was similar across groups. Preadipocyte differentiation rates between Pro/Pro and Ala/Ala were unchanged. In conclusion, no major differences in AT differentiation, glucose uptake, lipolysis or expression of PPARγ target genes were observed between different PPARγ Pro12Ala genotypes. Albeit small, our study may suggest that other pathways in AT or effects exerted in other tissues might contribute to the Pro12Ala-mediated protection against T2D.
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- Sidibeh, Cherno O, 1987-, et al.
(författare)
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FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes
- 2018
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Ingår i: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 62:1, s. 116-128
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Here, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1. Methods Human SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 nondiabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes. Results FKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake. Conclusions FKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.
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