| 1. |
- Garcia-Calzon, Sonia, et al.
(author)
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Epigenetic markers associated with metformin response and intolerance in drug-naive patients with type 2 diabetes
- 2020
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 12:561
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Journal article (peer-reviewed)abstract
- Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naive patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naive patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.
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| 2. |
- García-Calzón, Sonia, et al.
(author)
-
Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes
- 2020
-
In: Science Translational Medicine. - 1946-6234. ; 12:561
-
Journal article (peer-reviewed)abstract
- Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin- related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/ intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.
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| 3. |
- Miskelly, Michael G., et al.
(author)
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RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine
- 2024
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In: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 67:2, s. 356-370
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Roux-en-Y gastric bypass surgery (RYGB) frequently results in remission of type 2 diabetes as well as exaggerated secretion of glucagon-like peptide-1 (GLP-1). Here, we assessed RYGB-induced transcriptomic alterations in the small intestine and investigated how they were related to the regulation of GLP-1 production and secretion in vitro and in vivo.Methods: Human jejunal samples taken perisurgically and 1 year post RYGB (n=13) were analysed by RNA-seq. Guided by bioinformatics analysis we targeted four genes involved in cholesterol biosynthesis, which we confirmed to be expressed in human L cells, for potential involvement in GLP-1 regulation using siRNAs in GLUTag and STC-1 cells. Gene expression analyses, GLP-1 secretion measurements, intracellular calcium imaging and RNA-seq were performed in vitro. OGTTs were performed in C57BL/6j and iScd1-/- mice and immunohistochemistry and gene expression analyses were performed ex vivo.Results: Gene Ontology (GO) analysis identified cholesterol biosynthesis as being most affected by RYGB. Silencing or chemical inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme in the synthesis of monounsaturated fatty acids, was found to reduce Gcg expression and secretion of GLP-1 by GLUTag and STC-1 cells. Scd1 knockdown also reduced intracellular Ca2+ signalling and membrane depolarisation. Furthermore, Scd1 mRNA expression was found to be regulated by NEFAs but not glucose. RNA-seq of SCD1 inhibitor-treated GLUTag cells identified altered expression of genes implicated in ATP generation and glycolysis. Finally, gene expression and immunohistochemical analysis of the jejunum of the intestine-specific Scd1 knockout mouse model, iScd1-/-, revealed a twofold higher L cell density and a twofold increase in Gcg mRNA expression.Conclusions/interpretation: RYGB caused robust alterations in the jejunal transcriptome, with genes involved in cholesterol biosynthesis being most affected. Our data highlight SCD as an RYGB-regulated L cell constituent that regulates the production and secretion of GLP-1.
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