| 1. |
- Ahlqvist, Emma, et al.
(author)
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A common variant upstream of the PAX6 gene influences islet function in man.
- 2012
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55, s. 94-104
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man. METHODS: A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets. RESULTS: rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro. CONCLUSIONS/INTERPRETATION: A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
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| 2. |
- Ahluwalia, Tarunveer S., et al.
(author)
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A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
- 2019
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 62:2, s. 292-305
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6). Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.
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| 3. |
- Almgren, Peter, et al.
(author)
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Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study.
- 2011
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54, s. 2811-2819
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: To study the heritability and familiality of type 2 diabetes and related quantitative traits in families from the Botnia Study in Finland. METHODS: Heritability estimates for type 2 diabetes adjusted for sex, age and BMI are provided for different age groups of type 2 diabetes and for 34 clinical and metabolic traits in 5,810 individuals from 942 families using a variance component model (SOLAR). In addition, family means of these traits and their distribution across families are calculated. RESULTS: The strongest heritability for type 2 diabetes was seen in patients with age at onset 35-60 years (h (2) = 0.69). However, including patients with onset up to 75 years dropped the h (2) estimates to 0.31. Among quantitative traits, the highest h (2) estimates in all individuals and in non-diabetic individuals were seen for lean body mass (h (2) = 0.53-0.65), HDL-cholesterol (0.52-0.61) and suppression of NEFA during OGTT (0.63-0.76) followed by measures of insulin secretion (insulinogenic index [IG(30)] = 0.41-0.50) and insulin action (insulin sensitivity index [ISI] = 0.37-0.40). In contrast, physical activity showed rather low heritability (0.16-0.18), whereas smoking showed strong heritability (0.57-0.59). Family means of these traits differed two- to fivefold between families belonging to the lowest and highest quartile of the trait (p < 0.00001). CONCLUSIONS/INTERPRETATION: To detect stronger genetic effects in type 2 diabetes, it seems reasonable to restrict inclusion of patients to those with age at onset 35-60 years. Sequencing of families with extreme quantitative traits could be an important next step in the dissection of the genetics of type 2 diabetes.
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| 4. |
- Alyass, Akram, et al.
(author)
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Modelling of OGTT curve identifies 1 h plasma glucose level as a strong predictor of incident type 2 diabetes: results from two prospective cohorts
- 2015
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:1, s. 87-97
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Journal article (peer-reviewed)abstract
- Aims/hypothesis The relevance of the OGTT in predicting type 2 diabetes is unclear. We assessed the performance of 14 OGTT glucose traits in type 2 diabetes prediction. Methods We studied 2,603 and 2,386 Europeans from the Botnia study and Malmo Prevention Project (MPP) cohorts with baseline OGTT data. Over a follow-up period of 4.94 years and 23.5 years, 155 (5.95%) and 467 (19.57%) participants, respectively, developed type 2 diabetes. The main outcome was incident type 2 diabetes. Results One-hour plasma glucose (1h-PG) was a fair/good predictor of incident type 2 diabetes in the Botnia study and MPP (AUC for receiver operating characteristic [AUC(ROC)] 0.80 [0.77, 0.84] and 0.70 [0.68, 0.73]). 1h-PG alone outperformed the prediction model of multiple clinical risk factors (age, sex, BMI, family history of type 2 diabetes) in the Botnia study and MPP (AUC(ROC) 0.75 [0.72, 0.79] and 0.67 [0.64, 0.70]). The same clinical risk factors added to 1h-PG modestly increased prediction for incident type 2 diabetes (Botnia, AUC(ROC) 0.83 [0.80, 0.86]; MPP, AUC(ROC) 0.74 [0.72, 0.77]). 1h-PG also outperformed HbA(1c) in predicting type 2 diabetes in the Botnia cohort. A 1h-PG value of 8.9 mmol/l and 8.4 mmol/l was the optimal cut-point for initial screening and selection of high-risk individuals in the Botnia study and MPP, respectively, and represented 30% and 37% of all participants in these cohorts. High-risk individuals had a substantially increased risk of incident type 2 diabetes (OR 8.0 [5.5, 11.6] and 3.8 [3.1, 4.7]) and captured 75% and 62% of all incident type 2 diabetes in the Botnia study and MPP. Conclusions/interpretation1h-PG is a valuable prediction tool for identifying adults at risk for future type 2 diabetes.
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| 5. |
- Dayeh, Tasnim, et al.
(author)
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Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets.
- 2013
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 56:5, s. 1036-1046
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: To date, the molecular function of most of the reported type 2 diabetes-associated loci remains unknown. The introduction or removal of cytosine-phosphate-guanine (CpG) dinucleotides, which are possible sites of DNA methylation, has been suggested as a potential mechanism through which single-nucleotide polymorphisms (SNPs) can affect gene function via epigenetics. The aim of this study was to examine if any of 40 SNPs previously associated with type 2 diabetes introduce or remove a CpG site and if these CpG-SNPs are associated with differential DNA methylation in pancreatic islets of 84 human donors. METHODS: DNA methylation was analysed using pyrosequencing. RESULTS: We found that 19 of 40 (48%) type 2 diabetes-associated SNPs introduce or remove a CpG site. Successful DNA methylation data were generated for 16 of these 19 CpG-SNP loci, representing the candidate genes TCF7L2, KCNQ1, PPARG, HHEX, CDKN2A, SLC30A8, DUSP9, CDKAL1, ADCY5, SRR, WFS1, IRS1, DUSP8, HMGA2, TSPAN8 and CHCHD9. All analysed CpG-SNPs were associated with differential DNA methylation of the CpG-SNP site in human islets. Moreover, six CpG-SNPs, representing TCF7L2, KCNQ1, CDKN2A, ADCY5, WFS1 and HMGA2, were also associated with DNA methylation of surrounding CpG sites. Some of the type 2 diabetes CpG-SNP sites that exhibit differential DNA methylation were further associated with gene expression, alternative splicing events determined by splice index, and hormone secretion in the human islets. The 19 type 2 diabetes-associated CpG-SNPs are in strong linkage disequilibrium (r (2) > 0.8) with a total of 295 SNPs, including 91 CpG-SNPs. CONCLUSIONS/INTERPRETATION: Our results suggest that the introduction or removal of a CpG site may be a molecular mechanism through which some of the type 2 diabetes SNPs affect gene function via differential DNA methylation and consequently contributes to the phenotype of the disease.
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| 6. |
- Ekelund, M., et al.
(author)
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Prediction of postpartum diabetes in women with gestational diabetes mellitus
- 2010
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:3, s. 452-457
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Journal article (peer-reviewed)abstract
- We studied the incidence of postpartum diabetes after gestational diabetes mellitus and investigated biochemical and clinical predictors of postpartum diabetes. We monitored 174 women with gestational diabetes by performing oral glucose tolerance tests during pregnancy as well as 1, 2 and 5 years postpartum. Women who developed impaired fasting glucose, impaired glucose tolerance or diabetes were compared with women who remained normoglycaemic at 5 years. Insulinogenic index, disposition index and HOMA-beta cell index were used to assess beta cell function; insulin resistance was estimated by HOMA index of insulin resistance. At 5 years postpartum, 30% of the women had developed diabetes and 51% some form of abnormal glucose tolerance. Women who developed diabetes had higher fasting glucose and HbA(1c) during pregnancy than those who remained normoglycaemic. They also had lower HOMA-beta cell index, insulinogenic index and disposition index than the normoglycaemic women. HbA(1c) and fasting glucose during pregnancy as well as the number of previous pregnancies and family history of diabetes were independent predictors of postpartum diabetes. HbA(1c) a parts per thousand yen4.7% (Swedish Mono S) or a parts per thousand yen5.7% (National Glycohemoglobin Standardization Program) and fasting blood glucose a parts per thousand yen5.2 mmol/l were associated with a four- to sixfold increased risk. Among women with gestational diabetes mellitus, those at risk of future diabetes can be identified by HbA(1c) and fasting glucose values in the upper normal range during pregnancy. A family history of diabetes and previous pregnancies further increase this risk.
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| 7. |
- Florez, J. C., et al.
(author)
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Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes
- 2007
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:6, s. 1209-1217
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Journal article (peer-reviewed)abstract
- Aims/hypothesis Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. Subjects and methods We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. Results In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p=0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p=0.059). The combined OR was 1.20 (p=0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. Conclusion/interpretation Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
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| 8. |
- Heni, Martin, et al.
(author)
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Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity
- 2016
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:12, s. 2622-2631
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. Methods: Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. Results: We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. Conclusions/interpretation: The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.
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| 9. |
- Holmkvist, Johan, et al.
(author)
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Common variants in HNF-1 alpha and risk of type 2 diabetes.
- 2006
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Oct 11, s. 2882-2891
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Journal article (peer-reviewed)abstract
- Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1 alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes. We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1 alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Certain combinations of the I27L and A98V polymorphisms in the HNF-1 alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n=2,293; p=0.003). In a new case-control (=1,511 and n=2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR)=1.5 (p=0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR=2.3, p=0.002). This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1 alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.
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| 10. |
- Holmkvist, Johan, et al.
(author)
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Polymorphisms in the gene encoding the voltage-dependent Ca(2+) channel Ca (V)2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion
- 2007
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:12, s. 2467-2475
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca(2+) channel Ca(V)2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. METHODS: Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case-control sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case-control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT. RESULTS: The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case-control sample [odds ratio (OR) 1.4, 95% CI 1.0-2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D (I)) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D (I) over time in the Botnia prospective cohort (p = 0.05). CONCLUSIONS/INTERPRETATION: We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.
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