| 1. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 2. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 3. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 4. |
- Surendran, Praveen, et al.
(författare)
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Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
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| 5. |
- Tuomi, Maria, et al.
(författare)
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Stomping in silence : Conceptualizing trampling effects on soils in polar tundra
- 2021
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Ingår i: Functional Ecology. - : Wiley. - 0269-8463 .- 1365-2435. ; 35:2, s. 306-317
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Forskningsöversikt (refereegranskat)abstract
- Ungulate trampling modifies soils and interlinked ecosystem functions across biomes. Until today, most research has focused on temperate ecosystems and mineral soils while trampling effects on cold and organic matter-rich tundra soils remain largely unknown. We aimed to develop a general model of trampling effects on soil structure, biota, microclimate and biogeochemical processes, with a particular focus on polar tundra soils. To reach this goal, we reviewed literature about the effects of trampling and physical disturbances on soils across biomes and used this to discuss the knowns and unknowns of trampling effects on tundra soils. We identified the following four pathways through which trampling affects soils: (a) soil compaction; (b) reductions in soil fauna and fungi; (c) rapid losses in vegetation biomass and cover; and (d) longer term shifts in vegetation community composition. We found that, in polar tundra, soil responses to trampling pathways 1 and 3 could be characterized by nonlinear dynamics and tundra-specific context dependencies that we formulated into testable hypotheses. In conclusion, trampling may affect tundra soil significantly but many direct, interacting and cascading responses remain unknown. We call for research to advance the understanding of trampling effects on soils to support informed efforts to manage and predict the functioning of tundra systems under global changes. A free Plain Language Summary can be found within the Supporting Information of this article.
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| 6. |
- van Zuydam, NR, et al.
(författare)
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A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 67:7, s. 1414-1427
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Tidskriftsartikel (refereegranskat)abstract
- Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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| 7. |
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| 8. |
- Ahlqvist, Emma, et al.
(författare)
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A link between GIP and osteopontin in adipose tissue and insulin resistance.
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:6, s. 2088-2094
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Tidskriftsartikel (refereegranskat)abstract
- Low grade inflammation in obesity is associated with accumulation of the macrophagederived cytokine osteopontin in adipose tissue and induction of local as well as systemic insulin resistance. Since GIP (glucose-dependent insulinotropic polypeptide) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate osteopontin (OPN) expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13±}0.04 vs 0.04±}0.01, P<0.05) and correlated inversely with measures of insulin sensitivity (r=-0.24, P=0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with lower amount of the exon 9 containing isoform required for transmembrane activity. Carriers of the A-allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone, but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of GIPR rs10423928 A-allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.
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| 9. |
- Albrechtsen, A., et al.
(författare)
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Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 56:2, s. 298-310
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Tidskriftsartikel (refereegranskat)abstract
- Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
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| 10. |
- Andersen, Mette, et al.
(författare)
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Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes
- 2014
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 57:9, s. 1859-1868
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA). Methods We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n=911) or type 1 diabetes (n=406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n=4,002). Results Variants in the ZMIZ1 (rs12571751, p=4.1 x 10(-5)) and TCF7L2 (rs7903146, p=5.8 x 10(-4)) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p=0.0012), HHEX (rs1111875, p=0.0024 in Finns) and MTNR1B (rs10830963, p=0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p=9.5 x 10(-4) in Finns), TP53INP1 (rs896854, p=0.005), CDKAL1 (rs7756992, p=7.0 x 10(-4); rs7754840, p=8.8 x 10(-4)) and PROX1 (rs340874, p=0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p=3.2 x 10(-6)) and HNF1A (rs2650000, p=0.0012). Conclusions/interpretation LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.
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| 11. |
- Bergman, Michael, et al.
(författare)
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International Diabetes Federation Position Statement on the 1-hour post-load plasma glucose for the diagnosis of intermediate hyperglycaemia and type 2 diabetes
- 2024
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Ingår i: Diabetes Research and Clinical Practice. - 0168-8227. ; 209
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Tidskriftsartikel (refereegranskat)abstract
- Many individuals with intermediate hyperglycaemia (IH), including impaired fasting glycaemia (IFG) and impaired glucose tolerance (IGT), as presently defined, will progress to type 2 diabetes (T2D). There is confirmatory evidence that T2D can be prevented by lifestyle modification and/or medications, in people with IGT diagnosed by 2-h plasma glucose (PG) during a 75-gram oral glucose tolerance test (OGTT). Over the last 40 years, a wealth of epidemiological data has confirmed the superior value of 1-h plasma glucose (PG) over fasting PG (FPG), glycated haemoglobin (HbA1c) and 2-h PG in populations of different ethnicity, sex and age in predicting diabetes and associated complications including death. Given the relentlessly rising prevalence of diabetes, a more sensitive, practical method is needed to detect people with IH and T2D for early prevention or treatment in the often lengthy trajectory to T2D and its complications. The International Diabetes Federation (IDF) Position Statement reviews findings that the 1-h post-load PG ≥ 155 mg/dL (8.6 mmol/L) in people with normal glucose tolerance (NGT) during an OGTT is highly predictive for detecting progression to T2D, micro- and macrovascular complications, obstructive sleep apnoea, cystic fibrosis-related diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and mortality in individuals with risk factors. The 1-h PG of 209 mg/dL (11.6 mmol/L) is also diagnostic of T2D. Importantly, the 1-h PG cut points for diagnosing IH and T2D can be detected earlier than the recommended 2-h PG thresholds. Taken together, the 1-h PG provides an opportunity to avoid misclassification of glycaemic status if FPG or HbA1c alone are used. The 1-h PG also allows early detection of high-risk people for intervention to prevent progression to T2D which will benefit the sizeable and growing population of individuals at increased risk of T2D. Using a 1-h OGTT, subsequent to screening with a non-laboratory diabetes risk tool, and intervening early will favourably impact the global diabetes epidemic. Health services should consider developing a policy for screening for IH based on local human and technical resources. People with a 1-h PG ≥ 155 mg/dL (8.6 mmol/L) are considered to have IH and should be prescribed lifestyle intervention and referred to a diabetes prevention program. People with a 1-h PG ≥ 209 mg/dL (11.6 mmol/L) are considered to have T2D and should have a repeat test to confirm the diagnosis of T2D and then referred for further evaluation and treatment. The substantive data presented in the Position Statement provides strong evidence for redefining current diagnostic criteria for IH and T2D by adding the 1-h PG.
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| 12. |
- Dwivedi, Om Prakash, et al.
(författare)
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Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease
- 2023
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Ingår i: iScience. - 2589-0042. ; 26:5
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Tidskriftsartikel (refereegranskat)abstract
- Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12 and CRYAB) to construct a transcriptional “stress score” that reflected long-term decline of kidney function and could even identify normoalbuminuric individuals showing early decline. We thus provide workflow and web-resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.
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| 13. |
- Hermann, Florian M., et al.
(författare)
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An insulin hypersecretion phenotype precedes pancreatic beta cell failure in MODY3 patient-specific cells
- 2023
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Ingår i: Cell Stem Cell. - : Elsevier. - 1934-5909 .- 1875-9777. ; 30:1, s. 38-51
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Tidskriftsartikel (refereegranskat)abstract
- MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient -specific HNF1A+/R272C R cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 0 cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 0 cells. Our findings identify a pathogenic mechanism leading to 0 cell failure in MODY3.
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| 14. |
- Hermann, Florian M., et al.
(författare)
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An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells
- 2023
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 30:1, s. 8-51
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Tidskriftsartikel (refereegranskat)abstract
- MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C β cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 β cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 β cells. Our findings identify a pathogenic mechanism leading to β cell failure in MODY3.
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| 15. |
- Jujić, Amra, et al.
(författare)
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Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality : a prospective study
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:5, s. 1043-1054
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.Methods: GIP concentrations were successfully measured during OGTTs in two independent populations (Malmo Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.Results: In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 x 10(-5)) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD.Conclusions/interpretation: In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.
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| 16. |
- Jujić, Amra, et al.
(författare)
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Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 44:1, s. 224-230
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE While existing evidence supports beneficial cardiovascular effects of glucagon-like peptide 1 (GLP-1), emerging studies suggest that glucose-dependent insulinotropic peptide (GIP) and/or signaling via the GIP receptor may have untoward cardiovascular effects. Indeed, recent studies show that fasting physiological GIP levels are associated with total mortality and cardiovascular mortality, and it was suggested that GIP plays a role in pathogenesis of coronary artery disease. We investigated the associations between fasting and postchallenge GIP and GLP-1 concentrations and subclinical atherosclerosis as measured by mean intima-media thickness in the common carotid artery (IMTmeanCCA) and maximal intima-media thickness in the carotid bifurcation (IMTmaxBulb).RESEARCH DESIGN AND METHODS Participants at reexamination within the Malmö Diet and Cancer–Cardiovascular Cohort study (n = 3,734, mean age 72.5 years, 59.3% women, 10.8% subjects with diabetes, fasting GIP available for 3,342 subjects, fasting GLP-1 available for 3,299 subjects) underwent oral glucose tolerance testing and carotid ultrasound.RESULTS In linear regression analyses, each 1-SD increment of fasting GIP was associated with increased (per mm) IMTmeanCCA (β = 0.010, P = 0.010) and IMTmaxBulb (β = 0.014; P = 0.040) in models adjusted for known risk factors and glucose metabolism. In contrast, each 1-SD increment of fasting GLP-1 was associated with decreased IMTmaxBulb (per mm, β = −0.016, P = 0.014). These associations remained significant when subjects with diabetes were excluded from analyses.CONCLUSIONS In a Swedish elderly population, physiologically elevated levels of fasting GIP are associated with increased IMTmeanCCA, while GLP-1 is associated with decreased IMTmaxBulb, further emphasizing diverging cardiovascular effects of these two incretin hormones.
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| 17. |
- Lampinen, Jussi, et al.
(författare)
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Acceptance of near-natural greenspace management relates to ecological and socio-cultural assigned values among European urbanites
- 2021
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Ingår i: Basic and Applied Ecology. - : Elsevier BV. - 1439-1791 .- 1618-0089. ; 50, s. 119-131
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Tidskriftsartikel (refereegranskat)abstract
- Grasslands are widespread elements of urban greenspace providing recreational, psychological and aesthetic benefits to city residents. Two urban grassland types of contrasting management dominate urban greenspaces: frequently mown, species-poor short-cut lawns and less intensively managed, near-natural tall-grass meadows. The higher conservation value of tall-grass meadows makes management interventions such as converting short-cut lawns into tall-grass meadows a promising tool for urban biodiversity conservation. The societal success of such interventions, however, depends on identifying the values urban residents assign to different types of urban grasslands, and how these values translate to attitudes towards greenspace management. Using 2027 questionnaires across 19 European cities, we identify the assigned values that correlate with people's personal greenspace use and their preferences for different types of urban grasslands to determine how these values relate to the agreement with a scenario of converting 50% of their cities' short-cut lawns into tall-grass meadows. We found that most people assigned nature-related values, such as wildness, to tall-grass meadows and utility-related values, such as recreation, to short-cut lawns. Positive value associations of wildness and species richness with tall-grass meadows, and social and nature related greenspace activities, positively correlated with agreeing to convert short-cut lawns into tall-grass meadows. Conversely, disapproval of lawn conversion correlated with positive value associations of cleanliness and recreation potential with short-cut lawns. Here, people using greenspaces for nature-related activities were outstandingly positive about lawn conversion. The results show that the plurality of values assigned to different types of urban grasslands should be considered in urban greenspace planning. For example, tall-grass meadows could be managed to also accommodate the values associated with short-cut lawns, such as tidiness and recreation potential, to support their societal acceptance.
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| 18. |
- Lampousi, Anna Maria, et al.
(författare)
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Antioxidant Nutrients and Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes : A Swedish Case-Control Study and Mendelian Randomization Analysis
- 2023
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Ingår i: Nutrients. - 2072-6643. ; 15:11
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Tidskriftsartikel (refereegranskat)abstract
- Antioxidant vitamins C and E are inversely associated with type 1 diabetes (T1D). We investigated if antioxidants are also associated with latent autoimmune diabetes in adults (LADA), with low (LADAlow) and high (LADAhigh) autoantibody levels, type 2 diabetes (T2D), and estimates of beta cell function (HOMA-B) and insulin resistance (HOMA-IR). We used Swedish case-control data with incident cases of LADA (n = 584) and T2D (n = 1989) and matched population-based controls (n = 2276). Odds ratios (OR) and 95% confidence intervals (CI) were calculated per one standard deviation higher beta-carotene, vitamin C, vitamin E, selenium, and zinc intakes. Two-sample Mendelian randomization (MR) analyses assessed causality between genetically predicted circulating antioxidants and LADA, T1D, and T2D, using summary statistics from genome-wide association studies. Among the antioxidants, vitamins C and E were inversely associated with LADAhigh (OR 0.84, CI 0.73, 0.98 and OR 0.80, CI 0.69, 0.94 respectively), but not with LADAlow or T2D. Vitamin E was also associated with higher HOMA-B and lower HOMA-IR. MR analyses estimated an OR of 0.50 (CI 0.20, 1.25) for the effect of vitamin E on T1D, but did not support causal relationships between antioxidants and either LADA or T2D. In conclusion, vitamin E may have a protective effect on autoimmune diabetes, possibly through preserved beta cell function and less insulin resistance.
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| 19. |
- Lyssenko, Valeriya, et al.
(författare)
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Pleiotropic Effects of GIP on Islet Function Involve Osteopontin
- 2011
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 60:9, s. 2424-2433
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of beta-cell viability and proliferation. RESULTS-The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS-These findings support beta-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional beta-cell mass in humans. Diabetes 60:2424-2433, 2011
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| 20. |
- Mikryukov, Vladimir, et al.
(författare)
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Connecting the multiple dimensions of global soil fungal diversity
- 2023
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Ingår i: Science advances. - 2375-2548. ; 9:48
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Tidskriftsartikel (refereegranskat)abstract
- How the multiple facets of soil fungal diversity vary worldwide remains virtually unknown, hindering the management of this essential species-rich group. By sequencing high-resolution DNA markers in over 4000 topsoil samples from natural and human-altered ecosystems across all continents, we illustrate the distributions and drivers of different levels of taxonomic and phylogenetic diversity of fungi and their ecological groups. We show the impact of precipitation and temperature interactions on local fungal species richness (alpha diversity) across different climates. Our findings reveal how temperature drives fungal compositional turnover (beta diversity) and phylogenetic diversity, linking them with regional species richness (gamma diversity). We integrate fungi into the principles of global biodiversity distribution and present detailed maps for biodiversity conservation and modeling of global ecological processes.
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| 21. |
- Nethander, Maria, 1980, et al.
(författare)
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An atlas of genetic determinants of forearm fracture.
- 2023
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Ingår i: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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| 22. |
- Olofsson, Johan, et al.
(författare)
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Long-Term Experiments Reveal Strong Interactions Between Lemmings and Plants in the Fennoscandian Highland Tundra
- 2014
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Ingår i: Ecosystems (New York. Print). - : Springer Science and Business Media LLC. - 1432-9840 .- 1435-0629. ; 17:4, s. 606-615
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Tidskriftsartikel (refereegranskat)abstract
- Both the theory and the observations suggest that, there are strong links between herbivores and plants in terrestrial ecosystems; although, the effect of herbivores on plant community biomass is often attributed to variations in plant palatability. The existence of a strong link is commonly tested by constructing exclosures that exclude herbivores during a period of time. We here present data from two long-term (9 and 20 years, respectively) herbivore exclosure studies in lemming habitats on arctic tundra in northernmost Norway. The exclusion of all mammalian herbivores triggered strong increases in community level plant biomass and substantial changes in plant community composition. Palatable plants like graminoids and large bryophytes, as well as unpalatable plants like evergreen ericoids, deciduous shrubs, and lichens were all favored by excluding lemmings. These results reveal that a substantial increase in community biomass which occurs only when plant species capable of accumulating biomass are present, and palatability is a poor predictor of long-term responses of plants to excluding herbivores.
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| 23. |
- Pervjakova, Natalia, et al.
(författare)
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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:19, s. 3377-3391
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Tidskriftsartikel (refereegranskat)abstract
- Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (p < 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
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| 24. |
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| 25. |
- Prokopenko, Inga, et al.
(författare)
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Variants in MTNR1B influence fasting glucose levels
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81
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Tidskriftsartikel (refereegranskat)abstract
- To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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