| 1. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 2. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 3. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 4. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 5. |
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| 6. |
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| 7. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 8. |
- Wessel, Jennifer, et al.
(författare)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Jain, Ruchi, et al.
(författare)
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Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes
- 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
- Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual beta-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.
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| 15. |
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| 18. |
- Ahrén, Bo, et al.
(författare)
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Changes in Prandial Glucagon Levels after 2-year Treatment with Vildagliptin or Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin Monotherapy.
- 2010
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 33:4, s. 730-732
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Tidskriftsartikel (refereegranskat)abstract
- Objective - To determine if the dipeptidyl peptidase 4 inhibitor vildagliptin more effectively than the sulfonylurea glimepiride inhibits glucagon levels during meal. Research design and methods - Glucagon responses to a standard meal were measured at baseline and study endpoint (mean 1.8 years) in a trial evaluating add-on therapy to metformin with vildagliptin 50 mg bid compared to glimepiride up to 6 mg qd in type 2 diabetes (baseline HbA1c 7.3+/-0.6%). Results - HbA(1c) and prandial glucose AUC(0-2h) were reduced similarly in both groups, while prandial insulin AUC(0-2h) increased to a greater extent by glimepiride. Prandial glucagon AUC(0-2h) (baseline 66.6+/-2.3 pmol.h/l) decreased by 3.4+/-1.6 pmol.h/l by vildagliptin group (n=137) and increased by 3.8+/-1.7 pmolh/l by glimepiride group (n=121). The between-group difference was 7.3+/-2.1 pmol.h/l (p<0.001). Conclusion - Vildagliptin therapy but not glimepiride improves post-prandial alpha-cell function, which persists for at least 2 years.
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| 19. |
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| 20. |
- Ferrannini, E, et al.
(författare)
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Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans
- 2022
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Ingår i: Frontiers in cardiovascular medicine. - : Frontiers Media SA. - 2297-055X. ; 8, s. 790289-
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Tidskriftsartikel (refereegranskat)abstract
- Proteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms.AimWe aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits.Materials and MethodsThe CAPIRE study (ClinicalTrials.gov Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45–75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD+) or completely clean arteries (CAD−) and either ≤ 1 risk factor (RF+) or ≥3 risk factors (RF−) (based on history, blood pressure, glycemia, lipids, and smoking).ResultsOf 544 individuals, 39% were atypical (93 CAD+/RF−; 120 CAD−/RF+) and 61% typical (102 CAD+/RF+; 229 CAD−/RF−). In the comparison with CAD+/RF− adjusted for sex and age, CAD−/RF+ was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUCROC's of 0.72–0.81 (overall p = 1.0e−38). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA1c, and smoking.ConclusionsIn a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA1c. These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets.
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| 21. |
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| 22. |
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| 23. |
- Ferrannini, E., et al.
(författare)
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Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man
- 2020
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495. ; 102
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Tidskriftsartikel (refereegranskat)abstract
- Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1 g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications. © 2019 Elsevier Inc.
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| 24. |
- Ferrannini, E., et al.
(författare)
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Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: the RISC Study
- 2011
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54:6, s. 1507-1516
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Tidskriftsartikel (refereegranskat)abstract
- The natural history and physiological determinants of glucose intolerance in subjects living in Europe have not been investigated. The aim of this study was to increase our understanding of this area. We analysed the data from a population-based cohort of 1,048 non-diabetic, normotensive men and women (aged 30-60 years) in whom insulin sensitivity was measured by the glucose clamp technique (M/I index; average glucose infusion rate/steady-state insulin concentration) and beta cell function was estimated by mathematical modelling of the oral glucose tolerance test at baseline and 3 years later. Seventy-seven per cent of the participants had normal glucose tolerance (NGT) and 5% were glucose intolerant both at baseline and follow up; glucose tolerance worsened in 13% (progressors) and improved in 6% (regressors). The metabolic phenotype of the latter three groups was similar (higher prevalence of familial diabetes, older age, higher waist-to-hip ratio, higher fasting and 2 h plasma glucose, higher fasting and 2 h plasma insulin, lower insulin sensitivity and reduced beta cell glucose sensitivity with increased absolute insulin secretion). Adjusting for these factors in a logistic model, progression was predicted by insulin resistance (bottom M/I quartile, OR 2.52 [95% CI 1.51-4.21]) and beta cell glucose insensitivity (bottom quartile, OR 2.39 [95% CI 1.6-3.93]) independently of waist-to-hip ratio (OR 1.44 [95% CI 1.13-1.84] for one SD). At follow up, insulin sensitivity and beta cell glucose sensitivity were unchanged in the stable NGT and stable non-NGT groups, worsened in progressors and improved in regressors. Glucose tolerance deteriorates over time in young, healthy Europids. Progressors, regressors and glucose-intolerant participants share a common baseline phenotype. Insulin sensitivity and beta cell glucose sensitivity predict and track changes in glucose tolerance independently of sex, age and obesity.
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| 25. |
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| 26. |
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| 27. |
- Matthews, D. R., et al.
(författare)
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Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study
- 2010
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 12:9, s. 780-789
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Tidskriftsartikel (refereegranskat)abstract
- Methods: A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. Results: In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c < 7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response (IR) was sustained for a mean (s.d.) of 309 (244) days with vildagliptin versus 270 (223) days for glimepiride (p < 0.001) (IR = nadir HbA1c where change from baseline >= 0.5% or HbA1c < 6.5% within the first six months of treatment. After IR was detected, sustained response = time between nadir and an increase of > 0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. Conclusions: Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.
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| 28. |
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| 29. |
- Scott, Robert A., et al.
(författare)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 30. |
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| 31. |
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| 32. |
- Antonelli, A, et al.
(författare)
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Autoimmunity to CD38 and GAD in Type I and Type II diabetes: CD38 and HLA genotypes and clinical phenotypes
- 2002
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 45:9, s. 1298-1306
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis. Autoantibodies against CD38 have been found in some patients with Type II (non-insulin-dependent) diabetes mellitus and have been shown to stimulate insulin secretion by cultured human islets. We tested whether this new form of autoimmunity, (i) overlaps with anti-GAD autoimmunity, (ii) identifies an insulin-deficient phenotype, (iii) is under the influence of genetic factors. Methods. We screened 496 adults by immuno-blot analysis in the Botnia Study (298 with Type II and 98 with Type I (insulin-dependent) diabetes mellitus, 100 non-diabetic control subjects). Results. CD38-autoantibodies were found in 8.4% of Type II diabetic patients (p<0.003 vs 0% of control subjects), particularly in anti-GAD positive (14% vs 6% of anti-GAD negative, p=0.0004). CD38ab were also found in 4% of Type I diabetic patients; in the whole study group, 59% of anti-CD38 positive had DQB1 *02 compared with 38% of anti-CD38 negative (p=0.04). On the OGTT, beta-cell function (as the ratio of insulin-to-glucose areas) was impaired (p=0.02) only in association with anti-GAD positivity (3.2 +/- 3.1 U/mol, mean +/- SD) but not in anti-CD38 positive patients (5.6 +/- 2.9) as compared with patients free of autoimmunity (4.5 +/- 4.6, p=NS). In 44 Type II diabetic patients (22 negative and 22 positive for anti-CD38), no mutations were detected in any of the 8 exons, 5' end of intron 1 or the 5' and 3' untranslated regions of the CD38 gene. The previously described missense mutation (Arg140Trp) in exon 3 was not found in this cohort. There was no association between the PvUII polymorphism and clinical phenotype. Conclusion. Anti-CD38 autoimmunity identifies a clinical phenotype similar to non-autoimmune Type II diabetes, with relative preserved beta-cell function and weak genetic influence.
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| 33. |
- Ferrannini, Ele, et al.
(författare)
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Early Metabolic Markers of the Development of Dysglycemia and Type 2 Diabetes and Their Physiological Significance
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:5, s. 1730-1737
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Tidskriftsartikel (refereegranskat)abstract
- Metabolomic screening of fasting plasma from nondiabetic subjects identified alpha-hydroxybutyrate (alpha-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. To test the predictivity of alpha-HB and L-GPC for incident dysglycemia, alpha-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively. In both cohorts, alpha-HB was a positive correlate and L-GPC a negative correlate of insulin sensitivity, with alpha-HB reciprocally related to indices of beta-cell function derived from the oral glucose tolerance test (OGTT). In follow-up, alpha-HB was a positive predictor (adjusted odds ratios 1.25 [95% CI 1.00-1.60] and 1.26 [1.07-1.48], respectively, for each standard deviation of predictor), and L-GPC was a negative predictor (0.64 [0.48-0.85] and 0.67 [0.54-0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting glucose. Corresponding areas under the receiver operating characteristic curve were 0.791 (RISC) and 0.783 (Botnia), similar in accuracy when substituting cc-JIB and L-GPC with 2-h OGTT glucose concentrations. When their activity was examined, alpha-JIB inhibited and L-GPC stimulated glucose-induced insulin release in INS-le cells. alpha-JIB and L-GPC are independent predictors of worsening glucose tolerance, physiologically consistent with a joint signature of IR and beta-cell dysfunction. Diabetes 62:1730-1737, 2013
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| 34. |
- Ferrannini, E., et al.
(författare)
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Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy
- 2009
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 11:2, s. 157-166
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Tidskriftsartikel (refereegranskat)abstract
- To examine the efficacy and safety of vildagliptin vs. glimepiride as add-on therapy to metformin in patients with type 2 diabetes mellitus in a 52-week interim analysis of a large, randomized, double-blind, multicentre study. The primary objective was to demonstrate non-inferiority of vildagliptin vs. glimepiride in glycosylated haemoglobin (HbA(1c)) reduction at week 52. Patients inadequately controlled on metformin monotherapy (HbA(1c) 6.5-8.5%) and receiving a stable dose of metformin (mean dose 1898 mg/day; mean duration of use 36 months) were randomized 1:1 to receive vildagliptin (50 mg twice daily, n = 1396) or glimepiride (titrated up to 6 mg/day; mean dose 4.5 mg/day, n = 1393). Non-inferiority of vildagliptin was demonstrated (97.5% confidence interval 0.02%, 0.16%) with a mean (SE) change from baseline HbA(1c) (7.3% in both groups) to week 52 endpoint of -0.44% (0.02%) with vildagliptin and -0.53% (0.02%) with glimepiride. Although a similar proportion of patients reached a target HbA(1c) level of < 7% with vildagliptin and glimepiride (54.1 and 55.5%, respectively), a greater proportion of patients reached this target without hypoglycaemia in the vildagliptin group (50.9 vs. 44.3%; p < 0.01). Fasting plasma glucose (FPG) reductions were comparable between groups (mean [SE] -1.01 [0.06] mmol/l and -1.14 [0.06] mmol/l respectively). Vildagliptin significantly reduced body weight relative to glimepiride (mean [SE] change from baseline -0.23 [0.11] kg; between-group difference -1.79 kg; p < 0.001) and resulted in a 10-fold lower incidence of hypoglycaemia than glimepiride (1.7 vs. 16.2% of patients presenting at least one hypoglycaemic event; 39 vs. 554 hypoglycaemic events, p < 0.01). No severe hypoglycaemia occurred with vildagliptin compared with 10 episodes with glimepiride (p < 0.01), and no patient in the vildagliptin group discontinued because of hypoglycaemia compared with 11 patients in the glimepiride group. The incidence of adverse events (AEs), serious AEs and adjudicated cardiovascular events was 74.5, 7.1 and 0.9%, respectively, in patients receiving vildagliptin, and 81.1, 9.5 and 1.6%, respectively, in patients receiving glimepiride. When metformin alone fails to maintain sufficient glycaemic control, the addition of vildagliptin provides comparable efficacy to that of glimepiride after 52 weeks and displays a favourable AE profile, with no weight gain and a significant reduction in hypoglycaemia compared with glimepiride.
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| 35. |
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| 36. |
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| 37. |
- Ingelsson, Erik, et al.
(författare)
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Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans
- 2010
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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 59:5, s. 1266-1275
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Konferensbidrag (refereegranskat)abstract
- OBJECTIVE-Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS-We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS-The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS-Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Diabetes 59:1266-1275, 2010
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| 38. |
- Ingelsson, Erik, et al.
(författare)
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Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:5, s. 1266-1275
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
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| 39. |
- Kozakova, M, et al.
(författare)
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Obesity and carotid artery remodeling.
- 2015
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Ingår i: Nutrition & diabetes. - : Springer Science and Business Media LLC. - 2044-4052. ; 5, s. 177-177
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Tidskriftsartikel (refereegranskat)abstract
- The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP).
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| 40. |
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| 41. |
- Lee, Sunjae, et al.
(författare)
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Integrated Network Analysis Reveals an Association between Plasma Mannose Levels and Insulin Resistance
- 2016
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 24:1, s. 172-184
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the biological processes that are altered in obese subjects, we generated cell-specific integrated networks (INs) by merging genome-scale metabolic, transcriptional regulatory and protein-protein interaction networks. We performed genome-wide transcriptomics analysis to determine the global gene expression changes in the liver and three adipose tissues from obese subjects undergoing bariatric surgery and integrated these data into the cell-specific INs. We found dysregulations in mannose metabolism in obese subjects and validated our predictions by detecting mannose levels in the plasma of the lean and obese subjects. We observed significant correlations between plasma mannose levels, BMI, and insulin resistance (IR). We also measured plasma mannose levels of the subjects in two additional different cohorts and observed that an increased plasma mannose level was associated with IR and insulin secretion. We finally identified mannose as one of the best plasma metabolites in explaining the variance in obesity-independent IR.
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| 42. |
- Mardinoglu, Adil, 1982, et al.
(författare)
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Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes
- 2018
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Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 27, s. 151-155
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Tidskriftsartikel (refereegranskat)abstract
- Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles.
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| 43. |
- Mardinoglu, Adil, 1982, et al.
(författare)
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Plasma Mannose Levels Are Associated with Incident Type 2 Diabetes and Cardiovascular Disease
- 2017
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 26:2, s. 281-283
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Plasma mannose levels are elevated in subjects with insulin resistance independently of obesity. Here, we found that elevated plasma mannose levels are strong markers of future risk of several chronic diseases including T2D, CVD, and albuminuria, and that it may contribute to their development rather than just being a novel biomarker.
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| 44. |
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| 45. |
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| 46. |
- Xie, Weijia, et al.
(författare)
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Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 62:6, s. 2141-2150
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Tidskriftsartikel (refereegranskat)abstract
- Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity–related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites—glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)—and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.
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