| 81. |
- Raverdy, Violeta, et al.
(författare)
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Data-driven subgroups of type 2 diabetes, metabolic response, and renal risk profile after bariatric surgery : a retrospective cohort study
- 2022
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Ingår i: The Lancet Diabetes and Endocrinology. - 2213-8587. ; 10:3, s. 167-176
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Tidskriftsartikel (refereegranskat)abstract
- Background: A novel data-driven classification of type 2 diabetes has been proposed to personalise anti-diabetic treatment according to phenotype. One subgroup, severe insulin-resistant diabetes (SIRD), is characterised by mild hyperglycaemia but marked hyperinsulinaemia, and presents an increased risk of diabetic nephropathy. We hypothesised that patients with SIRD could particularly benefit from metabolic surgery. Methods: We retrospectively related the newly defined clusters with the response to metabolic surgery in participants with type 2 diabetes from independent cohorts in France (the Atlas Biologique de l'Obésite Sévère [ABOS] cohort, n=368; participants underwent Roux-en-Y gastric bypass or sleeve gastrectomy between Jan 1, 2006, and Dec 12, 2017) and Brazil (the metabolic surgery cohort of the German Hospital of San Paulo, n=121; participants underwent Roux-en-Y gastric bypass between April 1, 2008, and March 20, 2016). The study outcomes were type 2 diabetes remission and improvement of estimated glomerular filtration rate (eGFR). Findings: At baseline, 34 (9%) of 368 patients, 314 (85%) of 368 patients, and 17 (5%) of 368 patients were classified as having SIRD, mild obesity-related diabetes (MOD), and severe insulin deficient diabetes (SIDD) in the ABOS cohort, respectively, and in the São Paulo cohort, ten (8%) of 121 patients, 83 (69%) of 121 patients, and 25 (21%) of 121 patients were classified as having SIRD, MOD, and SIDD, respectively. At 1 year, type 2 diabetes remission was reported in 26 (81%) of 32 and nine (90%) of ten patients with SIRD, 167 (55%) of 306 and 42 (51%) of 83 patients with MOD, and two (13%) of 16 and nine (36%) of 25 patients with SIDD, in the ABOS and São Paulo cohorts, respectively. The mean eGFR was lower in patients with SIRD at baseline and increased postoperatively in these patients in both cohorts. In multivariable analysis, SIRD was associated with more frequent type 2 diabetes remission (odds ratio 4·3, 95% CI 1·8–11·2; p=0·0015), and an increase in eGFR (mean effect size 13·1 ml/min per 1·73 m2, 95% CI 3·6–22·7; p=0·0070). Interpretation: Patients in the SIRD subgroup had better outcomes after metabolic surgery, both in terms of type 2 diabetes remission and renal function, with no additional surgical risk. Data-driven classification might help to refine the indications for metabolic surgery.
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| 82. |
- Reinbothe, Thomas, et al.
(författare)
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The human L-type calcium channel Ca(v)1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes.
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 56:2, s. 340-349
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Voltage-gated calcium channels of the L-type have been shown to be essential for rodent pancreatic beta cell function, but data about their presence and regulation in humans are incomplete. We therefore sought to elucidate which L-type channel isoform is functionally important and its association with inherited diabetes-related phenotypes. METHODS: Beta cells of human islets from cadaver donors were enriched using FACS to study the expression of the genes encoding voltage-gated calcium channel (Ca(v))1.2 and Ca(v)1.3 by absolute quantitative PCR in whole human and rat islets, as well as in clonal cells. Single-cell exocytosis was monitored as increases in cell capacitance after treatment with small interfering (si)RNA against CACNA1D (which encodes Ca(v)1.3). Three single nucleotide polymorphisms (SNPs) were genotyped in 8,987 non-diabetic and 2,830 type 2 diabetic individuals from Finland and Sweden and analysed for associations with type 2 diabetes and insulin phenotypes. RESULTS: In FACS-enriched human beta cells, CACNA1D mRNA expression exceeded that of CACNA1C (which encodes Ca(v)1.2) by approximately 60-fold and was decreased in islets from type 2 diabetes patients. The latter coincided with diminished secretion of insulin in vitro. CACNA1D siRNA reduced glucose-stimulated insulin release in INS-1 832/13 cells and exocytosis in human beta cells. Phenotype/genotype associations of three SNPs in the CACNA1D gene revealed an association between the C allele of the SNP rs312480 and reduced mRNA expression, as well as decreased insulin secretion in vivo, whereas both rs312486/G and rs9841978/G were associated with type 2 diabetes. CONCLUSION/INTERPRETATION: We conclude that the L-type calcium channel Ca(v)1.3 is important in human glucose-induced insulin secretion, and common variants in CACNA1D might contribute to type 2 diabetes.
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| 83. |
- Rogers, Miranda, et al.
(författare)
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Genetically proxied impaired GIPR signaling and risk of 6 cancers
- 2023
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Ingår i: iScience. - 2589-0042. ; 26:6
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.
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| 84. |
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| 85. |
- Salunkhe, Vishal A., et al.
(författare)
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Digital lifestyle treatment improves long-term metabolic control in type 2 diabetes with different effects in pathophysiological and genetic subgroups
- 2023
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Ingår i: Npj Digital Medicine. - 2398-6352. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- To address the unmet need for scalable solutions for lifestyle treatment, we developed a new digital method to promote behavioral change. Here we report that patients with type-2 diabetes in Sweden (n = 331) exposed to the intervention have significantly improved HbA1c during a median follow-up of 1038 days (4 mmol/mol compared with matched controls; P = 0.009). This is paralleled by reduced body weight, ameliorated insulin secretion, increased physical activity, and cognitive eating restraints. Participants with high BMI and insulin resistance have an even larger response, as have non-risk allele carriers for the FTO gene. The findings open a new avenue for scalable lifestyle management with sustained efficacy and highlight a previously unrecognized opportunity for digital precision treatment based on genetics and individual pathophysiology. ClinicalTrials.gov NCT04624321.
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| 86. |
- Sandholm, Niina, et al.
(författare)
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Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes
- 2014
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Ingår i: Diabetologia. - Berlin Heidelberg : Springer-Verlag. - 0012-186X .- 1432-0428. ; 57:6, s. 1143-1153
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients withtype 1 diabetes from seven studies.RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic associationobserved at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.
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| 87. |
- Schrader, Silja, et al.
(författare)
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Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns That Associate With Future Diabetic Complications
- 2022
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 45:7, s. 1621-1630
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Type 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications. RESEARCH DESIGN AND METHODS Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications. RESULTS We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue. CONCLUSIONS We identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.
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| 88. |
- Schrader, Silja, et al.
(författare)
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Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns, Which Associate With Future Diabetic Complications
- 2022
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 45:7, s. 1621-1630
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Type 2 diabetes (T2D) was recently reclassified into severe insulin deficient diabetes (SIDD), severe insulin resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications.RESEARCH DESIGN AND METHODS: Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications.RESULTS: We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue.CONCLUSIONS: We identified differential epigenetic patterns between T2D subgroups, which associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.
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| 89. |
- Simonsen, Johan R, et al.
(författare)
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Genetic factors affect the susceptibility to bacterial infections in diabetes
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes increases the risk of bacterial infections. We investigated whether common genetic variants associate with infection susceptibility in Finnish diabetic individuals. We performed genome-wide association studies and pathway analysis for bacterial infection frequency in Finnish adult diabetic individuals (FinnDiane Study; N = 5092, Diabetes Registry Vaasa; N = 4247) using national register data on antibiotic prescription purchases. Replication analyses were performed in a Swedish diabetic population (ANDIS; N = 9602) and in a Finnish non-diabetic population (FinnGen; N = 159,166). Genome-wide data indicated moderate but significant narrow-sense heritability for infection susceptibility (h2 = 16%, P = 0.02). Variants on chromosome 2 were associated with reduced infection susceptibility (rs62192851, P = 2.23 × 10-7). Homozygotic carriers of the rs62192851 effect allele (N = 44) had a 37% lower median annual antibiotic purchase rate, compared to homozygotic carriers of the reference allele (N = 4231): 0.38 [IQR 0.22-0.90] and 0.60 [0.30-1.20] respectively, P = 0.01). Variants rs6727834 and rs10188087, in linkage disequilibrium with rs62192851, replicated in the FinnGen-cohort (P < 0.05), but no variants replicated in the ANDIS-cohort. Pathway analysis suggested the IRAK1 mediated NF-κB activation through IKK complex recruitment-pathway to be a mediator of the phenotype. Common genetic variants on chromosome 2 may associate with reduced risk of bacterial infections in Finnish individuals with diabetes.
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| 90. |
- Slieker, Roderick C, et al.
(författare)
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Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes : an IMIRHAPSODY Study
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:11, s. 2683-2693
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
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