| 1. |
- Broadaway, K Alaine, et al.
(författare)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 2. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 3. |
- Haljas, Kadri, et al.
(författare)
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Melatonin receptor 1B gene rs10830963 polymorphism, depressive symptoms and glycaemic traits
- 2018
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 50:8, s. 704-712
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between depression and type 2 diabetes is bidirectional. Underlying biological determinants remain elusive. We examined whether a common melatonin receptor 1B gene diabetes risk variant rs10830963 influenced the associations between depressive symptoms and glycaemic traits. Materials: The Prevalence, Prediction and Prevention of Diabetes-Botnia Study participants (n = 4,455) with no diabetes who underwent an oral glucose tolerance test were genotyped for rs10830963 and completed the Mental Health Inventory on depressive symptoms. Results: The rs10830963 did not influence significantly the associations between depressive symptoms and glycaemic traits. Yet, the addition of each copy of the minor G allele of the rs1080963 and higher depressive symptoms were both, independent of each other, associated significantly with higher glucose response (glucose area under the curve), higher insulin resistance (Insulin Sensitivity Index) and lower insulin secretion (Disposition Index). Depressive symptoms, but not rs1080963, were also significantly associated with higher fasting insulin, insulin area under the curve and insulin resistance (Homeostasis Model Assessment, Homeostasis Model Assessment-2); rs1080963, but not depressive symptoms, was significantly associated with higher fasting glucose and lower Corrected Insulin Response. Conclusions: Our study shows that the diabetes risk variant rs10830963 does not contribute to the known comorbidity between depression and type 2 diabetes.Key messages The association between depression and type 2 diabetes is bidirectional. We tested whether a common variant rs10830963 in the gene encoding Melatonin Receptor 1B influences the known association between depressive symptoms and glycaemic traits in a population-based sample from Western Finland. The MTNR1B genetic diabetes risk variant rs10830963 does not contribute to the known comorbidity between depression and type 2 diabetes. Depressive symptoms and rs10830963 are associated with a worse glycaemic profile independently of each other.
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| 4. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 5. |
- Lyssenko, Valeriya, et al.
(författare)
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Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 82-88
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
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| 6. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 7. |
- Prokopenko, Inga, et al.
(författare)
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A Central Role for GRB10 in Regulation of Islet Function in Man.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
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| 8. |
- Pyykkonen, Antti-Jussi, et al.
(författare)
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Association between depressive symptoms and metabolic syndrome is not explained by antidepressant medication: Results from the PPP-Botnia Study
- 2012
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 44:3, s. 279-288
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. To study whether the frequently reported association between depressive symptoms and the metabolic syndrome (MetS) and its individual components are secondary to the use of antidepressant medication and to established diabetes or cardiovascular diseases (CVD). Patients and methods. A population-based, random sample of 4,967 women and men aged 18-75 years. MetS was defined according to the new, harmonized criteria. Glucose tolerance was assessed by oral glucose tolerance test (OGTT). CVD, depressive symptoms, and use of antidepressant medication were self-reported. Results. The odds for having the MetS increased over 10% for each standard deviation increase in depressive symptoms. Users of antidepressant medication had more than 50% increased odds for having the MetS. Depressive symptoms were also associated with higher glucose response during the OGTT, higher serum triglyceride and lower HDL-cholesterol concentrations, and higher waist circumference, while use of antidepressant medication was associated with higher triglycerides, waist circumference, and systolic blood pressure. The associations of depressive symptoms were not secondary to use of antidepressant medication and were not explained by established diabetes or CVD. Discussion. Depressive symptoms, the MetS, and the individual components of MetS are related. These associations are not driven by use of antidepressant medication, established diabetes, or CVD.
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| 9. |
- Pyykkonen, Antti-Jussi, et al.
(författare)
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Depressive Symptoms, Antidepressant Medication Use, and Insulin Resistance The PPP-Botnia Study
- 2011
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 34:12, s. 2545-2547
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Although insulin resistance (IR) may underlie associations between depressive symptoms and diabetes, previous findings have been contradictory. We examined whether depressive symptoms associate with IR and insulin secretion, and, additionally, whether antidepressant medication use may modulate such associations. RESEARCH DESIGN AND METHODS-A total of 4,419 individuals underwent an oral glucose tolerance test (OGTT). Participants with previously or newly diagnosed diabetes are excluded from this sample. The homeostasis model assessment of IR (HOMA-IR) and corrected insulin response (CIR) were calculated. Depressive symptoms and antidepressant medication use were self-reported. RESULTS-After controlling for confounding factors, depressive symptoms were associated with higher fasting and 30-mM insulin during the OGTT and higher HOMA-IR but not CIR. Antidepressant medication use failed to modify these associations. CONCLUSIONS-Depressive symptoms are associated with IR but not with changes in insulin response when corrected for IR in individuals without previously or newly diagnosed diabetes.
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| 10. |
- Pyykkonen, Antti-Jussi, et al.
(författare)
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Sleep duration and insulin resistance in individuals without type 2 diabetes: The PPP-Botnia Study
- 2014
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 46:5, s. 324-329
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Both short and long sleep duration may increase risk of type 2 diabetes (diabetes). We studied if short and long sleep durations were associated with insulin resistance (IR) and insulin secretion in individuals without diabetes, and if the associations remained after we excluded individuals who reported more frequent and severe complaints of sleep apnea and insomnia. Participants and methods. An oral glucose tolerance test (OGTT) was performed for 722 adults without diabetes. Indices of IR and insulin secretion were calculated. Sleep duration and complaints of sleep apnea and insomnia were self-reported. Results. In comparison to average sleepers (6 - 9 h/night), short sleepers (< 6 h/night) had higher 120-min insulin and AUC glucose, and long sleepers (>= 9 h/night) had higher fasting and 120-min insulin, 120-min glucose, and HOMA(IR) and lower Insulin Sensitivity Index. After adjusting for confounders and after excluding individuals who reported more frequent and severe complaints of sleep apnea and insomnia, long sleep duration remained significantly associated with IR and insulin secretion. Discussion. Long but not short sleep duration is associated with IR and insulin secretion in individuals without diabetes whether or not accompanied by sleep complaints. Long sleepers may benefit from targeted preventions and interventions that aim at reducing risk of future diabetes.
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