| 1. |
- Arora, Geeti P, et al.
(författare)
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Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 286:2, s. 192-206
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia.METHODS: 85 GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N=398, Finnish), STORK/STORK-G (N=780, Norwegian).RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations.CONCLUSIONS: GDM is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences. This article is protected by copyright. All rights reserved.
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| 2. |
- Ling, Charlotte, et al.
(författare)
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Impact of the peroxisome proliferator activated receptor-gamma coactivator-1 beta (PGC-1 beta) Ala203Pro polymorphism on in vivo metabolism, PGC-1 beta expression and fibre type composition in human skeletal muscle
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:8, s. 1615-1620
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Peroxisome proliferator activated receptor-gamma coactivator-lp (PGC-1 beta, also known as PPARGCIB) expression is reduced in skeletal muscle from patients with type 2 diabetes mellitus and in elderly subjects. Ala203Pro, a common variant in the PGC-1 beta gene is associated with obesity. The aim of this study was to investigate whether the PGC-1 beta Ala203Pro polymorphism influences the age-related decline in skeletal muscle PGC-1 beta expression, in vivo metabolism and markers for muscle fibre type composition. Materials and methods The PGC-1 beta Ala203Pro polymerphism was genotyped in 110 young (age 28.0 +/- 1.9 years) and 86 elderly (age 62.4 +/- 2.0 years) twins and related to muscle PGC-1 beta expression, in vivo metabolism and markers for fibre type composition. Results Insulin-stimulated non-oxidative glucose metabolism (NOGM; p=0.025) and glycolytic flux rate (GF; p=0.026) were reduced in young Ala/Ala carriers compared with carriers of a 203Pro allele. In addition, a regression analysis, correcting for covariates, showed that the PGC-1 beta 203Pro allele was positively related to insulin-stimulated NOGM and GF in the young twins. While muscle expression of PGC-1 beta was reduced in elderly compared with young carriers of the Ala/Ala genotype (p <= 0.001), there was no significant age-related decline in PGC-1 beta expression in carriers of the 203Pro allele (p >= 0.4). However, a regression analysis, correcting for covariates, showed that only age was significantly related to muscle PGC-1 beta expression. Finally, PGC-1 beta expression correlated positively with markers for oxidative fibres in human muscle. Conclusions/interpretation This study suggests that young carriers of a PGC-1 beta 203Pro allele have enhanced insulin-stimulated glucose metabolism and may be protected against an age-related decline in PGC-1 beta expression in muscle.
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| 3. |
- Ling, Charlotte, et al.
(författare)
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Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.
- 2004
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 114:10, s. 1518-1526
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Tidskriftsartikel (refereegranskat)abstract
- Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) and PGC-1ß genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1{alpha} gene. Insulin increased and aging reduced skeletal muscle PGC-1{alpha} and PGC-1ß mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1{alpha} Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1{alpha} in a complex fashion. Whereas expression of PGC-1{alpha} in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1ß expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1{alpha} and PGC-1ß expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1{alpha} and PGC-1ß on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
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| 4. |
- Nilsson, Emma A, et al.
(författare)
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Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:9, s. 2962-2976
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Tidskriftsartikel (refereegranskat)abstract
- Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
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| 5. |
- Nilsson, Emma A, et al.
(författare)
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Genetic and Nongenetic Regulation of CAPN10 mRNA Expression in Skeletal Muscle.
- 2005
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:10, s. 3015-3020
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Tidskriftsartikel (refereegranskat)abstract
- The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes–associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.
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| 6. |
- Rönn, Tina, et al.
(författare)
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Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle.
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 51:7, s. 1159-1168
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Reduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to contribute to insulin resistance and type 2 diabetes. Moreover, a set of genes influencing oxidative phosphorylation (OXPHOS) is downregulated in diabetic muscle. Here we studied whether genetic, epigenetic and non-genetic factors influence a component of the respiratory chain, COX7A1, previously shown to be downregulated in skeletal muscle from patients with type 2 diabetes. The specific aims were to: (1) evaluate the impact of genetic (single nucleotide polymorphisms [SNPs]), epigenetic (DNA methylation) and non-genetic (age) factors on the expression of COX7A1 in human skeletal muscle; and (2) investigate whether common variants in the COX7A1 gene are associated with increased risk of type 2 diabetes. METHODS: COX7A1 mRNA expression was analysed in muscle biopsies from young (n = 110) and elderly (n = 86) non-diabetic twins and related to measures of in vivo metabolism. Genetic variants (three SNPs) from the COX7A1 locus were genotyped in the twins and in two independent type 2 diabetes case-control cohorts (n = 1466 and 6380, respectively). DNA methylation of the COX7A1 promoter was analysed in a subset of twins (ten young, ten elderly) using bisulphite sequencing. RESULTS: While DNA methylation of the COX7A1 promoter was increased in muscle from elderly compared with young twins (19.9 +/- 8.3% vs 1.8 +/- 2.7%; p = 0.035), the opposite was found for COX7A1 mRNA expression (elderly 1.00 +/- 0.05 vs young 1.68 +/- 0.06; p = 0.0005). The heritability of COX7A1 expression was estimated to be 50% in young and 72% in elderly twins. One of the polymorphisms investigated, rs753420, influenced basal COX7A1 expression in muscle of young (p = 0.0001) but not of elderly twins. The transcript level of COX7A1 was associated with increased in vivo glucose uptake and [Formula: see text] (p = 0.009 and p = 0.001, respectively). We did not observe any genetic association between COX7A1 polymorphisms and type 2 diabetes after correcting for multiple testing. CONCLUSIONS/INTERPRETATION: Our results provide further evidence for age as a factor influencing DNA methylation and expression of OXPHOS genes, and thereby in vivo metabolism.
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| 7. |
- Ström, Kristoffer, et al.
(författare)
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N1-methylnicotinamide is a signalling molecule produced in skeletal muscle coordinating energy metabolism
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a major health problem, and although caloric restriction and exercise are successful strategies to lose adipose tissue in obese individuals, a simultaneous decrease in skeletal muscle mass, negatively effects metabolism and muscle function. To deeper understand molecular events occurring in muscle during weight-loss, we measured the expressional change in human skeletal muscle following a combination of severe caloric restriction and exercise over 4 days in 15 Swedish men. Key metabolic genes were regulated after the intervention, indicating a shift from carbohydrate to fat metabolism. Nicotinamide N-methyltransferase (NNMT) was the most consistently upregulated gene following the energy-deficit exercise. Circulating levels of N1-methylnicotinamide (MNA), the product of NNMT activity, were doubled after the intervention. The fasting-fed state was an important determinant of plasma MNA levels, peaking at ~18 h of fasting and being lowest ~3 h after a meal. In culture, MNA was secreted by isolated human myotubes and stimulated lipolysis directly, with no effect on glucagon or insulin secretion. We propose that MNA is a novel myokine that enhances the utilization of energy stores in response to low muscle energy availability. Future research should focus on applying MNA as a biomarker to identify individuals with metabolic disturbances at an early stage.
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