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| 2. |
- Ahlqvist, Emma, et al.
(författare)
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Novel subgroups of adult-onset diabetes and their association with outcomes : a data-driven cluster analysis of six variables
- 2018
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Ingår i: The Lancet Diabetes and Endocrinology. - 2213-8587 .- 2213-8595. ; 6:5, s. 361-369
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDiabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.MethodsWe did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.FindingsWe identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.InterpretationWe stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.
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| 3. |
- Ahlqvist, Emma, et al.
(författare)
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Subtypes of type 2 diabetes determined from clinical parameters
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:10, s. 2086-2093
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Forskningsöversikt (refereegranskat)abstract
- Type 2 diabetes (T2D) is defined by a single metabolite, glucose, but is increasingly recognized as a highly heterogeneous disease, including individuals with varying clinical characteristics, disease progression, drug response, and risk of complications. Identification of subtypes with differing risk profiles and disease etiologies at diagnosis could open up avenues for personalized medicine and allow clinical resources to be focused to the patients who would be most likely to develop diabetic complications, thereby both im-proving patient health and reducing costs for the health sector. More homogeneous populations also offer increased power in experimental, genetic, and clinical studies. Clinical parameters are easily available and reflect relevant disease pathways, including the effects of both genetic and environmental exposures. We used six clinical parameters (GAD autoantibodies, age at diabetes onset, HbA1c, BMI, and measures of insulin resistance and insulin secretion) to cluster adult-onset diabetes patients into five subtypes. These sub-types have been robustly reproduced in several populations and associated with different risks of complications, comor-bidities, genetics, and response to treatment. Importantly, the group with severe insulin-deficient diabetes (SIDD) had increased risk of retinopathy and neuropathy, whereas the severe insulin-resistant diabetes (SIRD) group had the highest risk for diabetic kidney disease (DKD) and fatty liver, empha-sizing the importance of insulin resistance for DKD and hepatosteatosis in T2D. In conclusion, we believe that sub-classification using these highly relevant parameters could provide a framework for personalized medicine in diabetes.
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| 4. |
- Ahlqvist, Emma, et al.
(författare)
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Towards improved precision and a new classification of diabetes mellitus
- 2022
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Ingår i: Journal of Endocrinology. - 1479-6805. ; 252:3, s. 59-70
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Forskningsöversikt (refereegranskat)abstract
- Type 2 diabetes (T2D) is one of the fastest increasing diseases worldwide. Although it is defined by a single metabolite, glucose, it is increasingly recognized as a highly heterogeneous disease with varying clinical manifestations. Identification of different subtypes at an early stage of disease when complications might still be prevented could hopefully allow for more personalized medicine. An important step towards precision medicine would be to target the right resources to the right patients, thereby improving patient health and reducing health costs for the society. More well-defined disease populations also offer increased power in experimental, genetic and clinical studies. In a recent study, we used six clinical variables (GAD autoantibodies, age at onset of diabetes, HbA1c, BMI, and simple measures of insulin resistance and insulin secretion (so called HOMA estimates) to cluster adult-onset diabetes patients into five subgroups. These subgroups have been robustly reproduced in several populations worldwide and are associated with different risks of diabetic complications and responses to treatment. Importantly, the group with severe insulin-deficient diabetes (SIDD) had increased risk of retinopathy and neuropathy, whereas the severe insulin-resistant diabetes (SIRD) group has the highest risk for diabetic kidney disease (DKD) and fatty liver. This emphasizes the key role of insulin resistance in the pathogenesis of DKD and fatty liver in T2D. In conclusion, this novel sub-classification, breaking down T2D in clinically meaningful subgroups, provides the prerequisite framework for expanded personalized medicine in diabetes beyond what is already available for monogenic and to some extent type 1 diabetes.
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- 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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| 6. |
- Dwivedi, Om Prakash, et al.
(författare)
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Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
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| 7. |
- 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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| 8. |
- Lessmark, Anna, et al.
(författare)
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Lipid-Associated Variants near ANGPTL3 and LPL Show Parent-of-Origin Specific Effects on Blood Lipid Levels and Obesity
- 2022
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 13:1, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Parent-of-origin effects (POE) and sex-specific parental effects have been reported for plasma lipid levels, and a strong relationship exists between dyslipidemia and obesity. We aim to explore whether genetic variants previously reported to have an association to lipid traits also show POE on blood lipid levels and obesity. Families from the Botnia cohort and the Hungarian Transdanubian Biobank (HTB) were genotyped for 12 SNPs, parental origin of alleles were inferred, and generalized estimating equations were modeled to assess parental-specific associations with lipid traits and obesity. POE were observed for the variants at the TMEM57, DOCK7/ANGPTL3, LPL, and APOA on lipid traits, the latter replicated in HTB. Sex-specific parental effects were also observed; variants at ANGPTL3/DOCK7 showed POE on lipid traits and obesity in daughters only, while those at LPL and TMEM57 showed POE on lipid traits in sons. Variants at LPL and DOCK7/ANGPTL3 showed POE on obesity-related traits in Botnia and HTB, and POE effects on obesity were seen to a higher degree in daughters. This highlights the need to include analysis of POEs in genetic studies of complex traits.
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| 9. |
- Mansour Aly, Dina, et al.
(författare)
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Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53, s. 1534-1542
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.
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| 10. |
- Ottosson-Laakso, Emilia, et al.
(författare)
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Glucose-induced Changes in Gene Expression in Human Pancreatic Islets - Causes or Consequences of Chronic Hyperglycemia
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:12, s. 3013-3028
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of gene expression in islets from type 2 diabetic patients might be causally involved in the development of hyperglycemia or it could develop as a consequence of hyperglycemia, i.e. glucotoxicity. To separate the genes potentially causally involved in pathogenesis from those likely to be secondary to the hyperglycemia we exposed islets from human donors to normal or high glucose concentrations for 24 hours and analyzed gene expression. We compared these findings with gene expression in islets from donors with normal glucose tolerance (NGT) and hyperglycemia (HG, including T2D). The genes whose expression changed in the same direction after short-term glucose exposure as in T2D were considered most likely to be a consequence of hyperglycemia. Genes whose expression changed in HG but not after short-term glucose exposure, in particular genes that also correlated with insulin secretion, were considered the strongest candidates for causal involvement in T2D. E.g. ERO1LB, DOCK10, IGSF11 and PRR14L were down-regulated in HG and correlated positively with insulin secretion suggesting a protective role while TMEM132C was up-regulated in HG and correlated negatively with insulin secretion suggesting a potential pathogenic role.This study provides a catalogue of gene expression changes in human pancreatic islets after exposure to glucose.
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