| 1. |
- 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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| 2. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 4. |
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| 5. |
- Al-Amily, Israa Mohammad, et al.
(författare)
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The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic -cell in rodent
- 2019
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Ingår i: Pflugers Archiv-European Journal of Physiology. - : Springer Science and Business Media LLC. - 0031-6768 .- 1432-2013. ; 471:4, s. 633-645
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Tidskriftsartikel (refereegranskat)abstract
- We have recently shown that the G protein-coupled receptor 142 (GPR142) is expressed in both rodent and human pancreatic -cells. Herein, we investigated the cellular distribution of GPR142 within islets and the effects of selective agonists of GPR142 on glucose-stimulated insulin secretion (GSIS) in the mouse islets and INS-1832/13 cells. Double-immunostaining revealed that GPR142 immunoreactivity in islets mainly occurs in insulin-positive cells. Potentiation of GSIS by GPR142 activation was accompanied by increased cAMP content in INS-1832/13 cells. PKA/Epac inhibition markedly suppressed the effect of GPR142 activation on insulin release. Gpr142 knockdown (Gpr142-KD) in islets was accompanied by elevated release of MCP-1, IFN, and TNF during culture period and abolished the modulatory effect of GPR142 activation on the GSIS. Gpr142-KD had no effect on Ffar1, Ffar2, or Ffar3 mRNA while reducing Gpr56 and increasing Tlr5 and Tlr7 mRNA expression. Gpr142-KD was associated with an increased expression of Chrebp, Txnip, RhoA, and mitochondrial Vdac1 concomitant with a reduced Pdx1, Pax6, and mitochondrial Vdac2 mRNA levels. Long-term exposure of INS-1832/13 cells to hyperglycemia reduced Gpr142 and Vdac2 while increased Chrebp, Txnip, and Vdac1 mRNA expression. GPR142 agonists or Bt(2)-cAMP counteracted this effect. Glucotoxicity-induced decrease of cell viability in Gpr142-KD INS-1 cells was not affected by GPR142-agonists while Bt(2)-cAMP prevented it. The results show the importance of Gpr142 in the maintenance of pancreatic -cell function in rodents and that GPR142 agonists potentiate GSIS by an action, which most likely is due to increased cellular generation of second messenger molecule cAMP.
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| 6. |
- Almqvist, Catarina, et al.
(författare)
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LifeGene - A large prospective population-based study of global relevance
- 2011
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Ingår i: European Journal of Epidemiology. - Stockholm : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 26:1, s. 67-77
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Tidskriftsartikel (refereegranskat)abstract
- Studying gene-environment interactions requires that the amount and quality of the lifestyle data is comparable to what is available for the corresponding genomic data. Sweden has several crucial prerequisites for comprehensive longitudinal biomedical research, such as the personal identity number, the universally available national health care system, continuously updated population and health registries and a scientifically motivated population. LifeGene builds on these strengths to bridge the gap between basic research and clinical applications with particular attention to populations, through a unique design in a research-friendly setting. LifeGene is designed both as a prospective cohort study and an infrastructure with repeated contacts of study participants approximately every 5 years. Index persons aged 18-45 years old will be recruited and invited to include their household members (partner and any children). A comprehensive questionnaire addressing cutting-edge research questions will be administered through the web with short follow-ups annually. Biosamples and physical measurements will also be collected at baseline, and re-administered every 5 years thereafter. Event-based sampling will be a key feature of LifeGene. The household-based design will give the opportunity to involve young couples prior to and during pregnancy, allowing for the first study of children born into cohort with complete pre-and perinatal data from both the mother and father. Questions and sampling schemes will be tailored to the participants' age and life events. The target of LifeGene is to enrol 500,000 Swedes and follow them longitudinally for at least 20 years.
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| 7. |
- Amisten, Stefan, et al.
(författare)
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Activation of imidazoline receptor I-2, and improved pancreatic beta-cell function in human islets
- 2018
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Ingår i: Journal of Diabetes and Its Complications. - : Elsevier BV. - 1056-8727. ; 32:9, s. 813-818
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The impact of BL11282, an imidazoline receptor (NISCH) agonist, on potentiation of glucose-stimulated insulin secretion (GSIS) from isolated human non-diabetic (ND) and type 2 diabetic (T2D) islets was investigated. Methods: Analysis of mRNA was performed by RNA-sequencing and qPCR Insulin and cAMP by RIA and EUSA respectively. Results: RNA-sequencing data revealed that NISCH is highly expressed in fat tissues, islets, liver and muscles, with eight detectable splice variants of transcripts in islets. NISCH had a positive correlation with GLP-1 (GLP1R) and GIP (GIPR) receptor transcripts. The expression of NISCH was confirmed by qPCR in human islets. NISCH and GLP1R were comparably higher expressed in mouse islets compared to human islets. GSIS was dose-dependently potentiated by BL11282 from incubated islets of ND and T2D human islet donors. The insulinotropic action of BL11282 was associated with increased cAMP. While the harmful effect of high glucose on reductive capacity of islet cells was enhanced by glibenclamide during long-term culture, it was counteracted by BL11282 or Bt2-cAMP. BL11282 also increased proliferation of INS-1 cells during long-time culture. Conclusion: Our data suggest that BL11282 potentiates GSIS by an action involving cAMP/PKA system and BL11282 could be an attractive insulinotropic and beta-cell protective agent. (C) 2018 Elsevier Inc. All rights reserved.
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| 8. |
- Andersen, Caroline, et al.
(författare)
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Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 56:2, s. 252-258
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Tidskriftsartikel (refereegranskat)abstract
- Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy. We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35-80 years) from Swedish cohorts from SkAyenne (n = 272) and Vasterbotten (n = 100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin-OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA(1c) a parts per thousand yen7.0% (a parts per thousand yen53 mmol/mol) at follow-up. The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m(2); p < 0.001) and follow-up (BMI 27.9 vs 30.2 kg/m(2); p < 0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p < 0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p < 0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR = 1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA(1c), BMI at diagnosis, follow-up time and duration of insulin treatment. Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy.
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| 9. |
- Arvidsson, Daniel, et al.
(författare)
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Vigorous Physical Activity may be Important for the Insulin Sensitivity in Immigrants From the Middle East and Native Swedes
- 2015
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Ingår i: Journal of Physical Activity & Health. - : Human Kinetics. - 1543-3080 .- 1543-5474. ; 12:2, s. 273-281
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare physical activity measures and their associations with insulin sensitivity, beta-cell function and body mass index (BMI) between Iraqi immigrants and native Swedes. Methods: A cross-sectional study of 493 Iraqis (58% men) and 469 Swedes (54% men) aged 30 to 75 years living in the city of Malmo, Sweden. Accelerometry was used for physical activity measures (sedentary time, breaks in sedentary time, moderate and vigorous physical activity, total counts). Insulin sensitivity index and oral disposal index were determined from an oral glucose tolerance test and BMI by body weight and height. Results: Iraqi men were less physically active than Swedish men, while the physical activity was more similar in the women. BMI was a strong predictor of insulin sensitivity and beta-cell function and frequently associated with the physical activity measures. BMI modified the associations of insulin sensitivity and beta-cell function with the physical activity measures to such extent that only VPA and total counts show direct associations with insulin sensitivity in addition to the indirect associations via BMI. Iraqi women demonstrated weaker associations compared with Swedish women. Conclusions: Physical activity and performed at vigorous intensity may be important mainly for the insulin sensitivity in Iraqi immigrants and native Swedes.
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| 10. |
- Asplund, Olof, et al.
(författare)
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Islet Gene View-a tool to facilitate islet research
- 2022
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Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%), and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2, impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.
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