91 results on '"Hattersley, Andrew T."'
Search Results
2. Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach
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Perry, John R.B., McCarthy, Mark I., Hattersley, Andrew T., Zeggini, Eleftheria, Weedon, Michael N., and Frayling, Timothy M.
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Genetic research -- Genetic aspects ,Diabetes -- Research ,Genetic variation -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Research ,Genetic aspects - Abstract
OBJECTIVE--Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci. RESEARCH DESIGN AND METHODS--We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and BioCarta databases. RESULTS---After correcting for the number of pathways tested, we found no strong evidence for any pathway showing association with type 2 diabetes (top [P.sub.adj] = 0.31). The candidate WNT-signaling pathway ranked top (nominal P = 0.0007, excluding TCF7L2; P = 0.002), containing a number of promising single gene associations. These include CCND2 (rs11833537; P = 0.003), SMAD3 (rs7178347; P = 0.0006), and PRICKLE1 (rs1796390; P = 0.001), all expressed in the pancreas. CONCLUSIONS--Common variants involved in type 2 diabetes risk are likely to occur in or near genes in multiple pathways. Pathway-based approaches to genome-wide association data may be more successful for some complex traits than others, depending on the nature of the underlying disease physiology., Recent genome-wide association (GWA) studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. There are now 18 common variants with [...]
- Published
- 2009
3. Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data
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Timpson, Nicholas J., Lindgren, Cecilia M., Weedon, Michael N., Randall, Joshua, Ouwehand, Willem H., Strachan, David P., Rayner, N. William, Walker, Mark, Hitman, Graham A., Doney, Alex S.F., Palmer, Colin N.A., Morris, Andrew D., Hattersley, Andrew T., Zeggini, Eleftheria, Frayling, Timothy M., and McCarthy, Mark I.
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Obesity -- Complications and side effects -- Research -- Risk factors -- Genetic aspects ,Disease susceptibility -- Genetic aspects -- Research -- Complications and side effects -- Risk factors ,Type 2 diabetes -- Research -- Genetic aspects -- Risk factors -- Complications and side effects ,Health ,Complications and side effects ,Genetic aspects ,Research ,Risk factors - Abstract
OBJECTIVE--This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genomewide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS--We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into 'obese' and 'nonobese') according to median BMI (30.2 kg/[m.sup.2]). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS--In the 'obese-type 2 diabetes' scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 x [10.sup.-13]), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the 'nonobese' scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 x [10.sup.-14]). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: [P.sub.DIFF] = 1.4 x [10.sup.-7]; TCF7L2: [P.sub.DIFF] = 4.0 x [10.sup.-6]). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone ([RR.sub.obese] 1.08 [1.01-1.15]; [RR.sub.nonobese] 1.18 [1.10-1.27]: [P.sub.DIFF] = 0.04). CONCLUSIONS--This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes., Over the past year, the capacity to perform large-scale high-density genome-wide association (GWA) analyses has provided the first global view of the genetic etiology of type 2 diabetes, albeit one [...]
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- 2009
4. Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies
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Barroso, Ines, Luan, Jian'an, Wheeler, Eleanor, Whittaker, Pamela, Wasson, Jon, Zeggini, Eleftheria, Weedon, Michael N., Hunt, Sarah, Venkatesh, Ranganath, Frayling, Timothy M., Delgado, Marcos, Neuman, Rosalind J., Zhao, Jinghua, Sherva, Richard, Glaser, Benjamin, Walker, Mark, Hitman, Graham, McCarthy, Mark I., Hattersley, Andrew T., Permutt, M. Alan, Wareham, Nicholas J., and Deloukas, Panagiotis
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Gene mutations -- Research -- Genetic aspects ,Genotype -- Research -- Genetic aspects ,Type 2 diabetes -- Research -- Genetic aspects -- Risk factors ,Health ,Genetic aspects ,Research ,Risk factors - Abstract
OBJECTIVE--Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS--Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS--Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x [10.sup.-6]). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] ~1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]). CONCLUSIONS--These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations., The presence of type 2 diabetes susceptibility genes on chromosome 20 has been suggested by linkage scans in several populations. The 20q12-q13 region (Online Mendelian Inheritance in Man [OMIM] 603694) [...]
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- 2008
5. Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk
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Lango, Hana, Palmer, Colin N.A, Morris, Andrew D., Zeggini, Eleftheria, Hattersley, Andrew T., McCarthy, Mark I., Frayling, Timothy M., and Weedon, Michael N.
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Genotype -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Risk factors -- Research ,Health ,Research ,Genetic aspects ,Risk factors - Abstract
OBJECTIVES--Genome-wide association studies have dramatically increased the number of common genetic variants that are robustly associated with type 2 diabetes. A possible clinical use of this information is to identify individuals at high risk of developing the disease, so that preventative measures may be more effectively targeted. Here, we assess the ability of 18 confirmed type 2 diabetes variants to differentiate between type 2 diabetic case and control subjects. RESEARCH DESIGN AND METHODS--We assessed index single nucleotide polymorphisms (SNPs) for the 18 independent loci in 2,598 control subjects and 2,309 ease subjects from the Genetics of Diabetes Audit and Research Tayside Study. The discriminatory ability of the combined SNP information was assessed by grouping individuals based on number of risk alleles carried and determining relative odds of type 2 diabetes and by calculating the area under the receiver-operator characteristic curve (AUC). RESULTS--Individuals carrying more risk alleles had a higher risk of type 2 diabetes. For example, 1.296 of individuals with >24 risk alleles had an odds ratio of 4.2 (95% CI 2.11-8.56) against the 1.8% with 10-12 risk alleles. The AUC (a measure of discriminative accuracy) for these variants was 0.60. The AUC for age, BMI, and sex was 0.78, and adding the genetic risk variants only marginally increased this to 0.80. CONCLUSIONS--Currently, common risk variants for type 2 diabetes do not provide strong predictive value at a population level. However, the joint effect of risk variants identified subgroups of the population at substantially different risk of disease. Further studies are needed to assess whether individuals with extreme numbers of risk alleles may benefit from genetic testing., Recent genome-wide association (GWA) studies, which assay >300,000 single nucleotide polymorphisms (SNPs) across many thousands of individuals, have led to the discoveries of variants predisposing to many common complex diseases, [...]
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- 2008
6. Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts
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Harries, Lorna W., Sloman, Melissa J., Sellers, Elizabeth A.C., Hattersley, Andrew T., and Ellard, Sian
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Obesity -- Research -- Physiological aspects ,Diabetes -- Surveys -- Demographic aspects -- Research ,Genetic polymorphisms -- Research -- Physiological aspects -- Surveys ,RNA processing -- Research -- Physiological aspects -- Surveys ,Health ,Physiological aspects ,Research ,Surveys ,Demographic aspects - Abstract
OBJECTIVE--The G319S HNF1A variant is associated with an increased risk of type 2 diabetes in the Canadian Oji-Cree population. We hypothesized that the variant site at the 3' end of exon 4 might influence splicing and characterized mRNA transcripts to investigate the mutational mechanism underlying this susceptibility to diabetes. RESEARCH DESIGN AND METHODS--We established lymphoblastoid cell lines from a G319S homozygote and controls. HNF1A transcripts were characterized in the cell lines and pancreatic tissue by sequence analysis of RT-PCR products and quantification using real-time PCR. Susceptibility to mRNA surveillance was investigated using cycloheximide. RESULTS--Full-length G319S mRNA accounted for 24% of mRNA transcripts in the homozygous G319S cell line. A novel isoform lacking the terminal 12 bases of exon 4 was upregulated (55% of mRNA transcripts) compared with control cell lines (33%) and human pancreatic tissue (17%). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. Cycloheximide treatment increased the levels of both transcripts. CONCLUSIONS--The G319S variant results in the production of two abnormal transcripts and an alteration in the relative balance of normal splicing products. This is predicted to lead to a reduction in total HNF1A transcript levels, but residual hepatocyte nuclear factor-1α protein activity in G319S homozygotes may still reach up to 66% of normal levels. A combination of abnormal splicing and reduced activity of the G319S protein may explain the diabetes susceptibility., The Oji-Cree are an isolated population from North Central Canada who are among the most diabetes-prone subpopulations in the world; almost 40% of adults (1) and a high proportion of [...]
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- 2008
7. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations
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Kapoor, Ritika R., Locke, Jonathan, Colclough, Kevin, Wales, Jerry, Conn, Jennifer J., Hattersley, Andrew T., Ellard, Sian, and Hussain, Khalid
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Gene mutations -- Physiological aspects -- Research ,Metabolic diseases -- Complications and side effects -- Genetic aspects -- Research ,Hypoglycemia -- Risk factors -- Genetic aspects -- Research ,Transcription factors -- Physiological aspects -- Research ,Health ,Physiological aspects ,Complications and side effects ,Research ,Genetic aspects ,Risk factors - Abstract
OBJECTIVE--Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4α are known to cause maturity-onset diabetes of the young (MODY), which is characterized by autosomal-dominant inheritance and impaired gincose-stimulated insulin secretion from pancreatic β-cells. HNF-4[apha] has a key role in regulating the multiple transcriptional factor networks in the islet. Recently, heterozygous mutations in the HNF4A gene were reported to cause transient hyperinsulinemic hypoglycemia associated with macrosomia. RESEARCH DESIGN AND METHODS--Three infants presented with macrosomia and severe hypoglycemia with a positive family history of MODY. The hypoglycemia was confirmed to be due to hyperinsulinism, and all three patients required diazoxide therapy to maintain normoglycemia. Two of the three infants are still requiring diazoxide therapy at 8 and 18 months, whereas one of them had resolution of hyperinsulinemic hypoglycemia at 32 months of age. RESULTS--Sequencing of the HNF4A gene identified heterozygous mutations in all three families. In family 1, a frameshift mutation L330fsde117ins9 (c.987 1003dell7ins9; p.Leu330fs) was present in the proband; a mutation affecting the conserved A nucleotide of the intron 2 branch site (c.264-21A>G) was identified in the proband of family 2; and finally a nonsense mutation, Y16X (c.48C>G, p.Tyrl6X), was found in the proband of family 3. CONCLUSIONS--Heterozygous HNF4A mutations can therefore cause both transient and persistent hyperinsulinemic hypoglycemia associated with macrosomia. We recommend that macrosomic infants with transient or persistent hyperinsulinemic hypoglycemia should be screened for HNF4A mutations if there is a family history of youth-onset diabetes., Hyperinsulinemic hypoglycemia is characterized by the inappropriate secretion of insulin in relation to the blood glucose concentration and can be transient or persistent. Recent studies established that heterozygous mutations in [...]
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- 2008
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8. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR 1) mutations
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Rafiq, Meena, Flanagan, Sarah E., Patch, Ann-Marie, Shields, Beverley M., Ellard, Sian, and Hattersley, Andrew T.
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Medical research -- Genetic aspects ,Medicine, Experimental -- Genetic aspects ,Diabetes therapy -- Genetic aspects -- Research ,Diabetes -- Research -- Care and treatment -- Genetic aspects ,Insulin -- Research -- Genetic aspects ,Diabetics -- Care and treatment -- Genetic aspects ,Infants (Newborn) -- Care and treatment -- Genetic aspects ,Health ,Care and treatment ,Genetic aspects ,Research - Abstract
OBJECTIVE--Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K+ channel. Transfer from insulin to oral sulfonylureas in patients with neonatal [...]
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- 2008
9. Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic β-cell function
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Pascoe, Laura, Tura, Andrea, Patel, Sheila K., Ibrahim, Ibrahim M., Ferrannini, Ele, Zeggini, Eleftheria, Weedon, Michael N., Mari, Andrea, Hattersley, Andrew T., McCarthy, Mark I., Frayling, Timothy M., and Walker, Mark
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Pancreatic beta cells -- Health aspects -- Genetic aspects -- Research ,Allelomorphism -- Health aspects -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Risk factors -- Research ,Health ,Research ,Genetic aspects ,Risk factors ,Health aspects - Abstract
OBJECTIVE--Type 2 diabetes is characterized by impaired pancreatic β-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO, CDKAL1, [...]
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- 2007
10. Measurement of cord insulin and insulin-related peptides suggests that girls are more insulin resistant than boys at birth
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Shields, Beverley M., Knight, Bridget, Hopper, Heather, Hill, Anita, Powell, Roy J., Hattersley, Andrew T., and Clark, Penelope M.
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Insulin -- Research ,Peptides -- Research ,Health ,Research - Abstract
OBJECTIVE--We aimed to examine sex differences in insulin and insulin propeptide concentrations at birth using validated cord blood collection. RESEARCH DESIGN AND METHODS--We tested the impact on insulin and insulin [...]
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- 2007
11. Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study
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Pearson, Ewan R., Donnelly, Louise A., Kimber, Charlotte, Whitley, Adrian, Doney, Alex S.F., McCarthy, Mark I., Hattersley, Andrew T., Morris, Andrew D., and Palmer, Colin N.A.
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Hypoglycemic sulfonylureas -- Dosage and administration -- Research ,Sulfonylurea compounds -- Dosage and administration -- Research ,Type 2 diabetes -- Genetic aspects -- Drug therapy -- Research ,Health ,Drug therapy ,Genetic aspects ,Research ,Dosage and administration - Abstract
OBJECTIVE--There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) variants have been identified to be strongly associated with type 2 diabetes risk, probably due to decreased β-cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response. RESEARCH DESIGN AND METHODS--The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3-12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755). RESULTS--Carriers of the risk allele were less likely to respond to sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23-3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 [95% CI 1.21-3.86L P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C. CONCLUSIONS--TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes., Sulfonylureas are widely used to treat type 2 diabetes. There is considerable interindividual variation in the hypoglycemic response to sulfonylureas. Physiological studies have shown response is in part predicted by [...]
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- 2007
12. Mutations in ATP-sensitive [K.sup.+] channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood
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Flanagan, Sarah E., Patch, Ann-Marie, Mackay, Deborah J.G., Edghill, Emma L., Gloyn, Anna L., Robinson, David, Shield, Julian P.H., Temple, Karen, Ellard, Sian, and Hattersley, Andrew T.
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Gene mutations -- Research -- Genetic aspects ,Infants (Newborn) -- Diseases ,Diabetes in children -- Genetic aspects -- Causes of -- Research -- Diagnosis ,Health ,Diagnosis ,Genetic aspects ,Research ,Causes of - Abstract
Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For ~50% of patients, their diabetes will relapse in [...]
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- 2007
13. The impact of maternal glycemia and obesity on early postnatal growth in a nondiabetic caucasian population
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Knight, Bridget, Shields, Beverley M., Hill, Anita, Powell, Roy J., Wright, David, and Hattersley, Andrew T.
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Obesity -- Risk factors -- Research ,Glycemic index -- Health aspects -- Research ,Pregnant women -- Health aspects -- Research ,Health ,Research ,Risk factors ,Health aspects - Abstract
OBJECTIVE--Offspring of mothers with diabetes have increased birth weight and higher rates of obesity in early childhood. The relative role of maternal glycemia and maternal obesity is uncertain. We therefore [...]
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- 2007
14. Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9,518 subjects
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Owen, Katharine R., Groves, Christopher J., Hanson, Robert L., Knowler, William C., Shuldiner, Alan R., Elbein, Steven C., Mitchell, Braxton D., Froguel, Philippe, Ng, Maggie C.Y., Chan, Juliana C., Jia, Weiping, Deloukas, Panos, Hitman, Graham A., Walker, Mark, Frayling, Timothy M., Hattersley, Andrew T., Zeggini, Eleftheria, and McCarthy, Mark I.
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Genetic code -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Research ,Genetic aspects - Abstract
Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001)., Only a limited number of genes with reproducible evidence of association with type 2 diabetes have been described. One emerging theme is the frequency with which rare mutations in these [...]
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- 2007
15. Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes
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Winckler, Wendy, Weedon, Michael N., Graham, Robert R., McCarroll, Steven A., Purcell, Shaun, Almgren, Peter, Tuomi, Tiinamaija, Gaudet, Daniel, Bostrom, Kristina Bengtsson, Walker, Mark, Hitman, Graham, Hattersley, Andrew T., McCarthy, Mark I., Ardlie, Kristin G., Hirschhorn, Joel N., Daly, Mark J., Frayling, Timothy M., Groop, Leif, and Altshuler, David
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Pancreatic beta cells -- Research -- Health aspects ,Glucose metabolism -- Health aspects -- Genetic aspects -- Research ,Type 2 diabetes -- Genetic aspects -- Risk factors -- Research ,Health ,Research ,Genetic aspects ,Risk factors ,Health aspects - Abstract
An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value 15,000 samples. We combined these results with our previous studies on HNF4α and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes., Common human diseases, like diabetes, cancer, and heart disease, are heritable, and yet to date only a fraction of their genetic predisposition has been explained. Positional cloning using linkage analysis [...]
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- 2007
16. A Kir6.2 mutation causing neonatal diabetes impairs electrical activity and insulin secretion from INS-1 β-cells
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Tarasov, Andrei I., Welters, Hannah J., Senkel, Sabine, Ryffel, Gerhart U., Hattersley, Andrew T., Morgan, Noel G., and Ashcroft, Frances M.
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Adenosine triphosphate -- Research -- Genetic aspects -- Health aspects ,Pancreatic beta cells -- Health aspects -- Research ,Diabetes in children -- Genetic aspects -- Research ,Health ,Research ,Genetic aspects ,Health aspects - Abstract
ATP-sensitive [K.sup.+] channels ([K.sub.ATP] channels) couple β-cell metabolism to electrical activity and thereby play an essential role in the control of insulin secretion. Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of this channel, cause neonatal diabetes. We investigated the effect of the most common neonatal diabetes mutation (R201H) on β-cell electrical activity and insulin secretion by stable transfection in the INS-1 cell line. Expression was regulated by placing the gene under the control of a tetracycline promoter. Transfection with wildtype Kir6.2 had no effect on the ATP sensitivity of the [K.sub.ATP] channel, whole-cell [K.sub.ATP] current magnitude, or insulin secretion. However, induction of Kir6.2-R201H expression strongly reduced [K.sub.ATP] channel ATP sensitivity (the half-maximal inhibitory concentration increased from ~20 µmol/l to ~2 mmol/l), and the metabolic substrate methyl succinate failed to close [K.sub.ATP] channels or stimulate electrical activity and insulin secretion. Thus, these results directly demonstrate that Kir6.2 mutations prevent electrical activity and insulin release from INS-1 cells by increasing the [K.sub.ATP] current and hyperpolarizing the β-cell membrane. This is consistent with the ability of the R201H mutation to cause neonatal diabetes in patients. The relationship between [K.sub.ATP] current and the membrane potential reveals that very small changes in current amplitude are sufficient to prevent hormone secretion. Diabetes 55: 3075-3082, 2006, Neonatal diabetes is a rare inherited form of diabetes that manifests within the first 6 months of life (1,2). Approximately 50% of cases of neonatal diabetes result from heterozygous mutations [...]
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- 2006
17. Assessment of the role of common genetic variation in the transient neonatal diabetes mellitus (TNDM) region in type 2 diabetes: a comparative genomic and tagging single nucleotide polymorphism approach
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Gloyn, Anna L., Mackay, Deborah J.G., Weedon, Michael N., McCarthy, Mark I., Walker, Mark, Hitman, Graham, Knight, Bridget A., Owen, Katharine R., Hattersley, Andrew T., and Frayling, Timothy M.
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Adenosine triphosphate -- Research -- Genetic aspects ,Genetic variation -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Care and treatment -- Research ,Health ,Care and treatment ,Genetic aspects ,Research - Abstract
Recent evidence supports the strong overlap between genes implicated in monogenic diabetes and susceptibility to type 2 diabetes. Transient neonatal diabetes mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlapping genes in this region: the transcription factor zinc finger protein associated with cell cycle control and apoptosis (ZAC also known as PLAGL1) and HYMA1, which encodes an untranslated mRNA. Several type 2 diabetes linkage studies have reported linkage to chromosome 6q22-25. We hypothesized that common genetic variation at this TNDM region influences type 2 diabetes susceptibility. In addition to the coding regions, we used comparative genomic analysis to identify conserved noncoding regions, which were resequenced for single nucleotide polymorphism (SNP) discovery in 47 individuals. Twenty-six SNPs were identified. Fifteen tag SNPs (tSNPs) were successfully genotyped in a large case-control (n = 3,594) and family-based (n = 1,654) study. We did not find any evidence of association or overtransmission of any tSNP to affected offspring or of a parent-of-origin effect. Using a study sufficiently powered to detect odds ratios of, Type 2 diabetes is a polygenic disorder, and progress in unraveling its underlying molecular genetics has so far been modest. However, two types of study have yielded valuable insights. First, [...]
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- 2006
18. The variable number of tandem repeats upstream of the insulin gene is a susceptibility locus for latent autoimmune diabetes in adults
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Desai, Minal, Zeggini, Eleftheria, Horton, Virginia A., Owen, Katharine R., Hattersley, Andrew T., Levy, Jonathan C., Hitman, Graham A., Walker, Mark, Holman, Rury R., McCarthy, Mark I., and Clark, Anne
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Type 1 diabetes -- Genetic aspects -- Research ,Genetic variation -- Research -- Genetic aspects ,Autoimmune diseases -- Genetic aspects -- Research ,Health ,Genetic aspects ,Research - Abstract
The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at -23HphI (odds ratio [OR] 0.42 [95% CI 0.31-0.58], P = 2.4 x [10.sup.-8]), A allele at +1,404Fnu4HI (0.50 [0.36-0.70], P = 3.2 x [10.sup.-5]), and C allele at +3,580MspI (0.55 [0.35-0.85], P = 0.0046). As with type 1 diabetes, the -23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA. Diabetes 55:1890-1894, 2006, Latent autoimmune diabetes in adults (LADA) and type 1 (insulin dependent) diabetes are both characterized by islet autoimmunity, indicated by the presence of circulating islet autoantibodies. However, the later age [...]
- Published
- 2006
19. Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1[beta] and -1[alpha] mutations
- Author
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Brackenridge, Anna, Pearson, Ewan R., Shojaee-Moradie, Fariba, Hattersley, Andrew T., Russell-Jones, David, and Umpleby, A. Margot
- Subjects
Liver cells -- Research ,Diabetes -- Genetic aspects -- Research ,Insulin -- Research ,Health ,Research ,Genetic aspects - Abstract
Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1[alpha] and -1[beta] result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1[alpha] and -1[beta], HNF-1[beta] mutation carriers have hyperinsulinemia, whereas HNF-1[alpha] mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1[beta] mutation carriers are insulin resistant. The endogenous glucose production rate and rate of glucose uptake were measured with a two-step, low-dose (0.3 mU x [kg.sup.-1] x [min.sup.-1]) and high-dose (1.5 mU x [kg.sup.-1] x [min.sup.-1]) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-[sup.2][H.sub.2]]glucose, in six subjects with HNF-1[alpha] mutations, six subjects with HNF-1[beta] mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1[beta] subjects but was suppressed by 89% in HNF-1[alpha] subjects (P = 0.004) and 80% in control subjects (P < 0.001). Insulin-stimulated glucose uptake and suppression of lipolysis were similar in all groups at low- and high-dose insulin. Subjects with HNF-1[beta] mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1[beta] in the liver and possibly the kidney. This may be mediated through regulation by HNF-1[beta] of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK., Heterozygous mutations in hepatocyte nuclear factor (HNF)-1[alpha] and -1[beta] can cause maturity-onset diabetes of the young (MODY) (1,2). HNF-1[alpha] and -1[beta] are homeodomain-containing transcription factors that share >90% sequence homology [...]
- Published
- 2006
20. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy
- Author
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Hattersley, Andrew T. and Ashcroft, Frances M.
- Subjects
Infants (Newborn) -- Diseases ,Diabetes -- Research ,Health ,Care and treatment ,Research - Abstract
Closure of ATP-sensitive [K.sup.+] channels ([K.sub.ATP] channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic β-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in ~47% of patients diagnosed with permanent diabetes at transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated [K.sub.ATP] channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the [K.sub.ATP] channel., Neonatal diabetes diagnosed within the first 3 months of life is usually a single gene disorder associated with altered β-cell number or function. Transient neonatal diabetes resolves by a median [...]
- Published
- 2005
21. Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes.
- Author
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Hiller, Helmut, Beachy, Dawn E., Lebowitz, Joseph J., Engler, Stefanie, Mason, Justin R., Miller, Douglas R., Kusmarteva, Irina, Jacobsen, Laura M., Posgai, Amanda L., Khoshbouei, Habibeh, Oram, Richard A., Schatz, Desmond A., Hattersley, Andrew T., Bodenmiller, Bernd, Atkinson, Mark A., Nick, Harry S., Wasserfall, Clive H., and Lebowitz, Joeseph J
- Subjects
TYPE 1 diabetes ,GENE expression ,GENES ,ETIOLOGY of diabetes ,DIABETES ,PANCREAS ,AUTOANTIBODIES ,RESEARCH ,GENETIC mutation ,RESEARCH methodology ,RETROSPECTIVE studies ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,GENE expression profiling - Abstract
Type 1 diabetes (T1D) has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for T1D would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by nonredundant single-gene mutations. Using a "monogenetic transcriptomic strategy," we measured the expression of these genes in human T1D, autoantibody-positive (autoantibody+), and control pancreas tissues with real-time quantitative PCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression was visualized in situ with use of immunofluorescence, RNAscope, and confocal microscopy. Two dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with T1D versus unaffected control subjects. Six of these genes also saw dysregulation in pancreata from autoantibody+ individuals at increased risk for T1D. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in T1D pancreata, including three of the four eIF2α-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the T1D disease process and likely contribute to the disorder's pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
22. Reappearance of C-Peptide During the Third Trimester of Pregnancy in Type 1 Diabetes: Pancreatic Regeneration or Fetal Hyperinsulinism?
- Author
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Meek, Claire L., Oram, Richard A., McDonald, Timothy J., Feig, Denice S., Hattersley, Andrew T., Murphy, Helen R., and CONCEPTT Collaborative Group
- Subjects
THIRD trimester of pregnancy ,TYPE 1 diabetes ,C-peptide ,HYPERINSULINISM ,GESTATIONAL diabetes ,RESEARCH ,REGENERATION (Biology) ,BLOOD sugar monitoring ,RESEARCH methodology ,BLOOD sugar ,MEDICAL cooperation ,EVALUATION research ,PREGNANCY outcomes ,COMPARATIVE studies ,QUESTIONNAIRES ,RESEARCH funding - Abstract
Objective: We assessed longitudinal patterns of maternal C-peptide concentration to examine the hypothesis of β-cell regeneration in pregnancy with type 1 diabetes.Research Design and Methods: C-peptide was measured on maternal serum samples from 127 participants (12, 24, and 34 weeks) and cord blood during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT). C-peptide was measured using a highly sensitive direct and solid-phase competitive electrochemiluminescent immunoassay.Results: Three discrete patterns of maternal C-peptide trajectory were identified: pattern 1, undetectable throughout pregnancy, n = 74 (58%; maternal C-peptide <3 pmol/L); pattern 2, detectable at baseline, n = 22 (17%; maternal C-peptide 7-272 pmol/L at baseline); and pattern 3, undetectable maternal C-peptide at 12 and 24 weeks, which first became detectable at 34 weeks, n = 31 (24%; maternal C-peptide 4-26 pmol/L at 34 weeks). Baseline characteristics and third trimester glucose profiles of women with pattern 1 and pattern 3 C-peptide trajectories were similar, but women in pattern 3 had suboptimal glycemia (50% time above range) at 24 weeks' gestation. Offspring of women with pattern 3 C-peptide trajectories had elevated cord blood C-peptide (geometric mean 1,319 vs. 718 pmol/L; P = 0.007), increased rates of large for gestational age (90% vs. 60%; P = 0.002), neonatal hypoglycemia (42% vs. 14%; P = 0.001), and neonatal intensive care admission (45% vs. 23%; P = 0.023) compared with pattern 1 offspring.Conclusions: First maternal C-peptide appearance at 34 weeks was associated with midtrimester hyperglycemia, elevated cord blood C-peptide, and high rates of neonatal complications. This suggests transfer of C-peptide from fetal to maternal serum and is inconsistent with pregnancy-related β-cell regeneration. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
23. Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene
- Author
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Weedon, Michael N., Frayling, Timothy M., Shields, Beverley, Knight, Beatrice, Turner, Tina, Metcalf, Bradley S., Voss, Linda, Wilkin, Terence J., McCarthy, Anne, Ben-Shlomo, Yoav, Smith, George Davey, Ring, Sue, Jones, Richard, Golding, Jean, Byberg, Liisa, Mann, Vera, Axelsson, Tomas, Syvanen, Ann-Christine, Leon, David, and Hattersley, Andrew T.
- Subjects
European Association for the Study of Diabetes ,Polymorphism (Crystallography) -- Research ,Genetic research ,Birth weight -- Research ,Diabetes -- Research ,Birth size -- Research ,Health ,Research - Abstract
Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position -30 of the GCK β-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the A allele at GCK(-30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The A allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(-30) on birth weight using 2,689 mother/child pairs. The presence of the A allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an A allele at GCK(-30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight., In pancreatic β-cells and hepatocytes, glucokinase (GCK) catalyzes the first rate-limiting step in glucose metabolism. Its key regulatory role in the β-cell has led to it being described as the [...]
- Published
- 2005
24. Association studies of insulin receptor substrate 1 gene (IRS1) variants in type 2 diabetes samples enriched for family history and early age of onset
- Author
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Zeggini, Eleftheria, Parkinson, James, Halford, Stephanie, Owen, Katharine R., Frayling, Timothy M., Walker, Mark, Hitman, Graham A., Levy, Jonathan C., Sampson, Mike J., Feskens, Edith J.M., Hattersley, Andrew T., and McCarthy, Mark I.
- Subjects
Insulin -- Receptors ,Type 2 diabetes -- Risk factors -- Care and treatment -- Research ,Health ,Care and treatment ,Research ,Risk factors - Abstract
The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contributory role in type 2 diabetes susceptibility. Indeed, functional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies suggested that carriage of 971R was associated with a 25% increase in disease risk. However, this association has not been evaluated in large samples. The present study genotyped the P512A and G971R IRS1 variants in 971 U.K. type 2 diabetic subjects ascertained for strong family history and/or early onset, as well as 1,257 control subjects matched by ethnicity. There was no evidence for association with type 2 diabetes for either variant. (For example, the odds ratio [OR] for carriage of 971R was 1.11 [95% CI 0.86-1.44, P = 0.44].) An updated meta-analysis (31 studies: 5,104 case and 7,418 control subjects) remained significant for the G971R association (P = 0.025), albeit with a diminished OR (1.15 [95% CI 1.02-1.31]). Additional studies of IRS1 variation will be required to obtain a robust estimate of the overall contribution of IRS1 variation to type 2 diabetes susceptibility, but the current study suggests that previous studies have overestimated the magnitude of this effect., Abnormalities in both insulin secretion and action contribute to the development of type 2 diabetes (1). In the search for genetic variants underlying the familial aggregation of defective insulin action [...]
- Published
- 2004
25. Common variants of the hepatocyte nuclear factor-4α P2 promoter are associated with type 2 diabetes in the U.K. population
- Author
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Weedon, Michael N., Owen, Katharine R., Shields, Beverley, Hitman, Graham, Walker, Mark, McCarthy, Mark I., Love-Gregory, Latisha D., Permutt, M. Alan, Hattersley, Andrew T., and Frayling, Timothy M.
- Subjects
European Association for the Study of Diabetes -- Services ,Diagnosis ,Care and treatment ,Genetic aspects ,Research ,Services ,Type 2 diabetes -- Genetic aspects -- Diagnosis -- Care and treatment -- Research ,Hepatocytes -- Research -- Genetic aspects ,Liver cells -- Research -- Genetic aspects - Abstract
Hepatocyte nuclear factor (HNF)-4α is excellent type 2 diabetes candidate gene. It is part of a transcription factor network that is key for the development, differentiation, and function of the [...], Hepatocyte nuclear factor (HNF)-4α is part of a transcription factor network that is key for the development and function of the β-cell. Rare mutations in the HNF4α gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12-13.1 where the HNF4α gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12-13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02-1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12-13.1-linked cases. In conclusion, we have replicated the association of the HNF4α P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q.
- Published
- 2004
26. Activating mutations in the KCNJ11 gene encoding the ATP-sensitive [K.sup.+] channel subunit Kir6.2 are rare in clinically defined type 1 diabetes diagnosed before 2 years
- Author
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Edghill, Emma L., Gloyn, Anna L., Gillespie, Kathleen M., Lambert, A. Paul, Raymond, Neil T., Swift, Peter G., Ellard, Sian, Gale, Edwin A.M., and Hattersley, Andrew T.
- Subjects
Diagnosis ,Research ,Genetic aspects ,Diabetes mellitus -- Diagnosis -- Genetic aspects -- Research ,Genetic code -- Research -- Genetic aspects ,Gene mutation -- Research -- Genetic aspects ,Gene mutations -- Research -- Genetic aspects ,Diabetes -- Diagnosis -- Genetic aspects -- Research - Abstract
We have recently shown that heterozygous mutations in the Kir6.2 (KCNJ11) gene, on chromosome 11p15.1, accounts for approximately one-third of cases of permanent neonatal diabetes mellitus (PNDM) (1). The gene [...], We have recently shown that permanent neonatal diabetes can be caused by activating mutations in KCNJ11 that encode the Kir6.2 subunit of the β-cell ATP-sensitive [K.sup.+] channel. Some of these patients were diagnosed after 3 months of age and presented with ketoacidosis and marked hyperglycemia, which could have been diagnosed as type 1 diabetes. We hypothesized that KCNJ11 mutations could present clinically as type 1 diabetes. We screened the KCNJ11 gene for mutations in 77 U.K. type 1 diabetic subjects diagnosed under the age of 2 years. One patient was found to be heterozygous for the missense mutation R201C. She had low birth weight, was diagnosed at 5 weeks, and did not have a high risk predisposing HLA genotype. A novel variant, R176C, was identified in one diabetic subject but did not cosegregate with diabetes within the family. In conclusion, we have shown that heterozygous activating mutations in the KCNJ11 gene are a rare cause of clinically defined type 1 diabetes diagnosed before 2 years. Although activating KCNJ11 mutations are rare in patients diagnosed with type 1 diabetes, the identification of a KCNJ11 mutation may have important treatment implications.
- Published
- 2004
27. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy
- Author
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Sagen, Jorn V., Raeder, Helge, Hathout, Eba, Shehadeh, Naim, Gudmundsson, Kolbeinn, Baevre, Halvor, Abuelo, Dianne, Phornphutkul, Chanika, Molnes, Janne, Bell, Graeme I., Gloyn, Anna L., Hattersley, Andrew T., Molven, Anders, Sovik, Oddmund, and Njolstad, Pal R.
- Subjects
Gene mutations -- Research ,Diabetes -- Care and treatment -- Research ,Health ,Care and treatment ,Research - Abstract
Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2α kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive [K.sup.+] channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg x [kg.sup.-1] x [day.sup.-1], insulin was discontinued. Blood glucose did not deteriorate, and Hb[A.sub.1c] was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment., Neonatal diabetes may be defined as hyperglycemia diagnosed within the first 3 months of life (1). Transient neonatal diabetes is associated with abnormalities in chromosome 6 (2), whereas the permanent [...]
- Published
- 2004
28. Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients
- Author
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Vaxillaire, Martine, Populaire, Celine, Busiah, Kanetee, Cave, Helene, Gloyn, Anna L., Hattersley, Andrew T., Czernichow, Paul, Froguel, Philippe, and Polak, Michel
- Subjects
Diabetes -- Care and treatment -- Research ,Hyperglycemia -- Research -- Care and treatment ,Health ,Care and treatment ,Research - Abstract
Permanent neonatal diabetes (PND), requiring insulin within the first months of life, is unexplained at the molecular level in most cases. It has very recently been shown that heterozygous activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic ATP-sensitive [K.sup.+] channel involved in the regulation of insulin secretion, cause PND. In the present study, we screened the KCNJ11 gene for mutations in French patients with PND. Patients were recruited through the French network for the study of neonatal diabetes. Seventeen at-term babies with a median age at diagnosis of diabetes of 64 days (range 1-260) were included. We identified in nine patients seven heterozygous nonsynonymous mutations: three of them (V59M, R201C, and R201H) were already described, and the four novel mutations resulted in an amino acid change of Kir6.2 at positions F35L, G53N, E322K, and Y330C. More patients with a Kir6.2 mutation (six of nine) were reported to have a smaller birth weight than those without mutation (two of eight). Although Kir6.2 mutation carriers do not represent a phenotypically specific form of PND, an impaired function of Kir6.2 is associated with in utero insulin secretory insufficiency and growth retardation. In conclusion, we confirmed that Kir6.2 mutations are a common cause (53%) of PND in Caucasians., Neonatal diabetes, defined as insulin-requiring hyperglycemia within the first months of life, is a rare entity, with an estimated incidence of 1 in 400,000 neonates (1). In about one-half of [...]
- Published
- 2004
29. Contrasting diabetes phenotypes associated--with hepatocyte nuclear factor-1α and -1β mutations
- Author
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Pearson, Ewan R., Badman, Michael K., Lockwood, Christopher R., Clark, Penelope M., Ellard, Sian, Bingham, Coralie, and Hattersley, Andrew T.
- Subjects
Gene mutations -- Research -- Health aspects -- Genetic aspects ,Glucose tolerance tests -- Health aspects -- Research ,Diabetes -- Care and treatment -- Genetic aspects -- Research ,Phenotype -- Research -- Health aspects -- Genetic aspects ,Health ,Care and treatment ,Genetic aspects ,Research ,Health aspects - Abstract
OBJECTIVE--Mutations in the highly homologous transcription factors hepatocyte nuclear factor (HNF)-1α and -1β cause maturity-onset diabetes of the young types 3 and 5, respectively. Diabetes due to HNF-1α mutations is [...]
- Published
- 2004
30. A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity. (Genetics)
- Author
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Frayling, Timothy M., Lindgren, Cecilia M., Chevre, Jean Claude, Menzel, Stephan, Wishart, Marie, Benmezroua, Yamina, Brown, Alison, Evans, Julie C., Rao, Pamidghantam Subba, Dina, Christian, Lecoeur, Cecile, Kanninen, Timo, Almgren, Peter, Bulman, Michael P., Wang, Youxiang, Mills, James, Wright-Pascoe, Rosemarie, Mahtani, Melanie M., Prisco, Francesco, Costa, Angels, Cognet, Ignacio, Hansen, Torben, Pedersen, Oluf, Ellard, Sian, Tuomi, Tiinamaija, Groop, Leif C., Froguel, Philippe, Hattersley, Andrew T., and Vaxillaire, Martine
- Subjects
Familial diseases -- Research -- Genetic aspects ,Diabetes in children -- Genetic aspects -- Research ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Research ,Genetic aspects - Abstract
Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of β-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LeD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Oar results provide evidence for further heterogeneity in MODY., Maturity-onset diabetes of the young (MODY) is characterized by β-cell dysfunction, no requirement for insulin in the first years of the disease, an autosomal dominant mode of inheritance, and an [...]
- Published
- 2003
31. Identifying hepatic nuclear factor 1α mutations in children and young adults with a clinical diagnosis of type 1 diabetes. (Original Article: Epidemiology/Health Services/Psychosocial Research)
- Author
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Lambert, A. Paul, Ellard, Sian, Allen, Lisa I.S., Gallen, Ian W., Gillespie, Kathleen M., Bingley, Polly J., and Hattersley, Andrew T.
- Subjects
Gene mutations -- Analysis -- Research -- Genetic aspects ,Familial diseases -- Research -- Development and progression -- Genetic aspects ,Type 1 diabetes -- Development and progression -- Genetic aspects -- Research ,Health ,Analysis ,Development and progression ,Genetic aspects ,Research - Abstract
OBJECTIVE -- HNF-1α gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk [...]
- Published
- 2003
32. The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1α mutations is a feature of all patients with diabetes and is associated with glucosuria
- Author
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Bingham, Coralie, Ellard, Sian, Nicholls, Anthony J., Pennock, Charles A., Allen, John, James, Alan J., Satchell, Simon C., Salzmann, Maurice B., and Hattersley, Andrew T.
- Subjects
Gene mutations -- Evaluation -- Research -- Genetic aspects ,Liver cells -- Research -- Genetic aspects ,Aminoaciduria, Renal -- Research -- Genetic aspects ,Diabetics -- Genetic aspects -- Research ,Health ,Evaluation ,Genetic aspects ,Research - Abstract
Hepatocyte nuclear factor-1α (HNF-1α) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1α homozygous knockout mice exhibit a renal Fanconi syndrome with glucosuria and generalized aminoaciduria [...]
- Published
- 2001
33. Latent Autoimmune Diabetes of Adults (LADA) Is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes.
- Author
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Jones, Angus G., McDonald, Timothy J., Shields, Beverley M., Hagopian, William, and Hattersley, Andrew T.
- Subjects
TYPE 2 diabetes ,TYPE 1 diabetes ,MEDICAL personnel ,DIABETES ,ADULTS ,PROGNOSIS ,AUTOANTIBODIES ,RESEARCH ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,INSULIN ,COMPARATIVE studies ,RESEARCH funding - Abstract
Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes-associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test-islet autoantibody measurement-with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
34. Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress.
- Author
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Montaser, Hossam, Patel, Kashyap A., Balboa, Diego, Ibrahim, Hazem, Lithovius, Väinö, Näätänen, Anna, Chandra, Vikash, Demir, Korcan, Acar, Sezer, Ben-Omran, Tawfeg, Colclough, Kevin, Locke, Jonathan M., Wakeling, Matthew, Lindahl, Maria, Hattersley, Andrew T., Saarimäki-Vire, Jonna, and Otonkoski, Timo
- Subjects
ENDOPLASMIC reticulum ,HUMAN embryonic stem cells ,DIABETES in children ,ETIOLOGY of diabetes ,DIABETES ,NERVE growth factor ,FLOW cytometry ,RESEARCH ,GENETIC mutation ,IMMUNOHISTOCHEMISTRY ,WESTERN immunoblotting ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,ENZYME-linked immunosorbent assay ,RESEARCH funding ,POLYMERASE chain reaction ,GLUCOSE tolerance tests - Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse β-cells, its precise role in human β-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired β-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human β-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of β-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human β-cell function and demonstrate the crucial role of MANF in this process. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
35. Mutations in the hepatocyte nuclear factor-1α gene are a common cause of maturity-onset diabetes of the young in the U.K
- Author
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Frayling, Timothy M., Bulman, Michael P., Ellard, Sian, Appleton, Maggie, Dronsfield, Mark J., Mackie, Alasdair D.R., Baird, Joyce D., Kaisaki, Pamela J., Yamagata, Kazuya, Bell, Graeme I., Bain, Stephen C., and Hattersley, Andrew T.
- Subjects
Diabetes -- Research ,Children -- Health aspects ,Health ,Analysis ,Research - Abstract
Mutations in the hepatocyte nuclear factor-1α (HNF-1α) gene have recently been shown to cause maturity-onset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-1α gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (, NIDDM affects 2-6% of the world population and is a major cause of morbidity and mortality. Both genetic and nongenetic factors contribute to the development of this heterogeneous disorder. Maturity-onset [...]
- Published
- 1997
36. Type II diabetes: clinical aspects of molecular biological studies
- Author
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Turner, Robert C., Hattersley, Andrew T., Shaw, Joanne T.E., and Levy, Jonathan C.
- Subjects
Familial diseases -- Research -- Genetic aspects ,Molecular biology -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Research ,Genetic aspects - Abstract
Type II diabetes remains a genetic nightmare. The major problem is identifying suitable pedigrees, sib-pairs, and populations for study. Segregation analysis data suggest that type II diabetes is likely to [...]
- Published
- 1995
37. Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated Permanent Neonatal Diabetes.
- Author
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Bowman, Pamela, Mathews, Frances, Barbetti, Fabrizio, Shepherd, Maggie H., Sanchez, Janine, Piccini, Barbara, Beltrand, Jacques, Letourneau-Freiberg, Lisa R., Polak, Michel, Greeley, Siri Atma W., Rawlins, Eamon, Babiker, Tarig, Thomas, Nicholas J., De Franco, Elisa, Ellard, Sian, Flanagan, Sarah E., Hattersley, Andrew T., Mohsin, Fauzia, Cummings, Elizabeth, and LeGault, Laurent
- Subjects
METABOLIC regulation ,GLYCEMIC control ,ATTENTION-deficit hyperactivity disorder ,NEURODEVELOPMENTAL treatment ,DIABETES ,RESEARCH ,GENETIC mutation ,RESEARCH methodology ,POTASSIUM ,HYPOGLYCEMIC agents ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,RESEARCH funding ,LONGITUDINAL method - Abstract
Objective: ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM.Research Design and Methods: We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.Results: Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1-13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).Conclusions: Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
38. Distribution of type II diabetes in nuclear families
- Author
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Cook, Joanne T.E., Hattersley, Andrew T., Levy, Jonathan C., Patel, Pushpa, Wainscoat, James S., Hockaday, T. Derek R., and Turner, Robert C.
- Subjects
Familial diseases -- Research -- Genetic aspects ,Twins -- Research -- Diseases -- Genetic aspects ,Twin studies -- Research ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Diseases ,Genetic aspects ,Research - Abstract
Type II diabetes has a substantial genetic component, but the mode of inheritance and the molecular basis of this inheritance are uncertain. This study documents the familial distribution of the [...]
- Published
- 1993
39. Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study.
- Author
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Donnelly, Louise A., Dennis, John M., Coleman, Ruth L., Sattar, Naveed, Hattersley, Andrew T., Holman, Rury R., and Pearson, Ewan R.
- Subjects
TYPE 2 diabetes ,METFORMIN ,ANEMIA ,VITAMIN B12 ,FAILURE analysis ,RESEARCH ,CLINICAL trials ,CHAOS theory ,RESEARCH methodology ,ACQUISITION of data ,SULFONYLUREAS ,HYPOGLYCEMIC agents ,MEDICAL cooperation ,EVALUATION research ,INSULIN ,COMPARATIVE studies ,THIAZOLIDINEDIONES ,LONGITUDINAL method - Abstract
Objective: To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data.Research Design and Methods: Anemia was defined as a hemoglobin measure of <11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.Results: In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia.Conclusions: Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B12 deficiency alone. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
40. De Novo Mutations in Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.
- Author
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De Franco, Elisa, Caswell, Richard, Johnson, Matthew B., Wakeling, Matthew N., Amnon Zung, Vῦ Chí Dῦng, Cȃ Thi Bích Ngọc, Goonetilleke, Rajiv, Jury, Maritza Vivanco, El-Khateeb, Mohammed, Ellard, Sian, Flanagan, Sarah E., Ron, David, Hattersley, Andrew T., Zung, Amnon, Dũng, Vũ Chí, Bích Ngọc, Cấn Thị, and Vivanco Jury, Maritza
- Subjects
ETIOLOGY of diabetes ,HUMAN chromosome abnormality diagnosis ,CELLULAR control mechanisms ,NUCLEOTIDE sequencing ,GENETIC disorders ,PROTEIN metabolism ,COMPARATIVE studies ,COMPUTER simulation ,DIABETES ,LIVER diseases ,MATHEMATICAL models ,RESEARCH methodology ,MEDICAL cooperation ,GENETIC mutation ,PROTEINS ,RESEARCH ,PHYSIOLOGICAL stress ,DISEASE relapse ,THEORY ,EVALUATION research ,SEQUENCE analysis - Abstract
Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1's fundamental role within this pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
41. Can clinical features be used to differentiate type 1 from type 2 diabetes? A systematic review of the literature
- Author
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Shields, Beverley M, Peters, Jaime L, Cooper, Chris, Lowe, Jenny, Knight, Bridget A, Powell, Roy J, Jones, Angus, Hyde, Christopher J, and Hattersley, Andrew T
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Diagnosis, Differential ,Diabetes and Endocrinology ,Diabetes Mellitus, Type 1 ,Diabetes Mellitus, Type 2 ,Research ,Humans ,STATISTICS & RESEARCH METHODS - Abstract
Objective Clinicians predominantly use clinical features to differentiate type 1 from type 2 diabetes yet there are no evidence-based clinical criteria to aid classification of patients. Misclassification of diabetes is widespread (7–15% of cases), resulting in patients receiving inappropriate treatment. We sought to identify which clinical criteria could be used to discriminate type 1 and type 2 diabetes. Design Systematic review of all diagnostic accuracy studies published since 1979 using clinical criteria to predict insulin deficiency (measured by C-peptide). Data sources 14 databases including: MEDLINE, MEDLINE in Process and EMBASE. The search strategy took the form of: (terms for diabetes) AND (terms for C-Peptide). Eligibility criteria Diagnostic accuracy studies of any routinely available clinical predictors against a reference standard of insulin deficiency defined by cut-offs of C-peptide concentrations. No restrictions on race, age, language or country of origin. Results 10 917 abstracts were screened, and 231 full texts reviewed. 11 studies met inclusion criteria, but varied by age, race, year and proportion of participants who were C-peptide negative. Age at diagnosis was the most discriminatory feature in 7/9 studies where it was assessed, with optimal cut-offs (>70% mean sensitivity and specificity) across studies being
- Published
- 2015
42. Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated.
- Author
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Johnson, Matthew B., De Franco, Elisa, Greeley, Siri Atma W., Letourneau, Lisa R., Gillespie, Kathleen M., Wakeling, Matthew N., Ellard, Sian, Flanagan, Sarah E., Patel, Kashyap A., Hattersley, Andrew T., and International DS-PNDM Consortium
- Subjects
DOWN syndrome ,TRISOMY 18 syndrome ,TYPE 1 diabetes ,DIABETES in children ,PEOPLE with Down syndrome ,DIABETES ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,GENETIC mutation ,RESEARCH ,EVALUATION research ,SEQUENCE analysis ,DISEASE complications - Abstract
Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into β-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
43. Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype Is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.
- Author
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Yingjie Ji, Yiorkas, Andrianos M., Frau, Francesca, Mook-Kanamori, Dennis, Staiger, Harald, Thomas, E.Louise, Atabaki-Pasdar, Naeimeh, Campbell, Archie, Tyrrell, Jessica, Jones, Samuel E., Beaumont, Robin N., Wood, Andrew R., Tuke, Marcus A., Ruth, Katherine S., Mahajan, Anubha, Murray, Anna, Freathy, Rachel M., Weedon, Michael N., Hattersley, Andrew T., and Hayward, Caroline
- Subjects
TYPE 2 diabetes ,MAGNETIC resonance imaging ,FATTY liver ,HEART disease risk factors ,DIABETES risk factors ,HYPERTENSION ,ADIPOSE tissues ,ADIPOSE tissue physiology ,COMPARATIVE studies ,HEART diseases ,RESEARCH methodology ,MEDICAL cooperation ,OBESITY ,RESEARCH ,RESEARCH funding ,EVALUATION research ,WAIST-hip ratio ,SEQUENCE analysis - Abstract
Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
44. Sex and BMI Alter the Benefits and Risks of Sulfonylureas and Thiazolidinediones in Type 2 Diabetes: A Framework for Evaluating Stratification Using Routine Clinical and Individual Trial Data.
- Author
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Dennis, John M., Henley, William E., Weedon, Michael N., Lonergan, Mike, Rodgers, Lauren R., Jones, Angus G., Hamilton, William T., Sattar, Naveed, Janmohamed, Salim, Holman, Rury R., Pearson, Ewan R., Shields, Beverley M., Hattersley, Andrew T., and MASTERMIND Consortium
- Subjects
BLOOD sugar ,CLINICAL trials ,COMPARATIVE studies ,COST effectiveness ,HYPOGLYCEMIA ,HYPOGLYCEMIC agents ,RESEARCH methodology ,MEDICAL cooperation ,PRIMARY health care ,TYPE 2 diabetes ,RESEARCH ,RISK assessment ,SEX distribution ,EVALUATION research ,BODY mass index ,ACQUISITION of data ,SULFONYLUREAS ,METFORMIN ,THIAZOLIDINEDIONES ,ECONOMICS ,THERAPEUTICS - Abstract
Objective: The choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones.Research Design and Methods: We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2,725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2,222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1,977).Results: In CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups.Conclusions: Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
45. C-Peptide Decline in Type 1 Diabetes Has Two Phases: An Initial Exponential Fall and a Subsequent Stable Phase.
- Author
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Shields, Beverley M., McDonald, Timothy J., Oram, Richard, Hill, Anita, Hudson, Michelle, Leete, Pia, Pearson, Ewan R., Richardson, Sarah J., Morgan, Noel G., Hattersley, Andrew T., and TIGI Consortium
- Subjects
TYPE 1 diabetes ,C-peptide ,TREATMENT of diabetes ,CHRONIC diseases ,AUTOIMMUNITY ,DIAGNOSIS ,THERAPEUTICS ,BIOCHEMISTRY ,BLOOD testing ,COMPARATIVE studies ,LONGITUDINAL method ,PHENOMENOLOGY ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RESEARCH funding ,TIME ,EVALUATION research ,CROSS-sectional method ,DISEASE progression - Abstract
Objective: The decline in C-peptide in the 5 years after diagnosis of type 1 diabetes has been well studied, but little is known about the longer-term trajectory. We aimed to examine the association between log-transformed C-peptide levels and the duration of diabetes up to 40 years after diagnosis.Research Design and Methods: We assessed the pattern of association between urinary C-peptide/creatinine ratio (UCPCR) and duration of diabetes in cross-sectional data from 1,549 individuals with type 1 diabetes using nonlinear regression approaches. Findings were replicated in longitudinal follow-up data for both UCPCR (n = 161 individuals, 326 observations) and plasma C-peptide (n = 93 individuals, 473 observations).Results: We identified two clear phases of C-peptide decline: an initial exponential fall over 7 years (47% decrease/year [95% CI -51, -43]) followed by a stable period thereafter (+0.07%/year [-1.3, +1.5]). The two phases had similar durations and slopes in patients above and below the median age at diagnosis (10.8 years), although levels were lower in the younger patients irrespective of duration. Patterns were consistent in both longitudinal UCPCR (n = 162; ≤7 years duration: -48%/year [-55, -38]; >7 years duration -0.1% [-4.1, +3.9]) and plasma C-peptide (n = 93; >7 years duration only: -2.6% [-6.7, +1.5]).Conclusions: These data support two clear phases of C-peptide decline: an initial exponential fall over a 7-year period, followed by a prolonged stabilization where C-peptide levels no longer decline. Understanding the pathophysiological and immunological differences between these two phases will give crucial insights into understanding β-cell survival. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
46. Fetal Genotype and Maternal Glucose Have Independent and Additive Effects on Birth Weight.
- Author
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Hughes, Alice E., Nodzenski, Michael, Beaumont, Robin N., Talbot, Octavious, Shields, Beverley M., Scholtens, Denise M., Knight, Bridget A., Lowe Jr., William L., Hattersley, Andrew T., Freathy, Rachel M., and Lowe, William L Jr
- Subjects
FETAL development ,GENOTYPES ,BIRTH weight ,GLUCOSE ,MATERNAL health ,BLACK people ,BLOOD sugar ,C-peptide ,COMPARATIVE studies ,GESTATIONAL diabetes ,CORD blood ,HISPANIC Americans ,INSULIN ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RESEARCH funding ,WHITE people ,EVALUATION research ,FETAL macrosomia ,SEQUENCE analysis - Abstract
Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
47. Β-Cell Genes and Diabetes
- Author
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Frayling, Timothy M., Evans, Julie C., Bulman, Michael P., Pearson, Ewan, Allen, Lisa, Owen, Katharine, Bingham, Coralie, Hannemann, Michael, Shepherd, Maggie, Ellard, Sian, and Hattersley, Andrew T.
- Subjects
Diabetes -- Research ,Pancreatic beta cells -- Genetic aspects -- Research ,Genetic regulation -- Genetic aspects -- Research ,Genetic transcription -- Genetic aspects -- Research ,Type 2 diabetes -- Development and progression -- Research -- Genetic aspects ,Health ,Development and progression ,Research ,Genetic aspects - Abstract
Molecular and Clinical Characterization of Mutations in Transcription Factors Β-Cell transcription factor genes are important in the pathophysiology of the Β-cell, with mutations in hepatocyte nuclear factor (HNF)-1[Alpha], HNF-4[Alpha], insulin [...]
- Published
- 2001
48. Β-Cell Genes and Diabetes: Quantitative and Qualitative Differences in the Pathophysiology of Hepatic Nuclear Factor-1[Alpha] and Glucokinase Mutations
- Author
-
Pearson, Ewan R., Velho, Gilberto, Clark, Penny, Stride, Amanda, Shepherd, Maggie, Frayling, Timothy M., Bulman, Michael P., Ellard, Sian, Froguel, Phillipe, and Hattersley, Andrew T.
- Subjects
Diabetes -- Research ,Pancreatic beta cells -- Genetic aspects -- Research ,Diabetes in children -- Development and progression -- Research -- Genetic aspects ,Genetic regulation -- Genetic aspects -- Research ,Genetic transcription -- Genetic aspects -- Research ,Health ,Development and progression ,Genetic aspects ,Research - Abstract
Mutations in the Β-cell genes encoding the glycolytic enzyme glucokinase (GCK) and the transcription factor hepatocyte nuclear factor (HNF)-1[Alpha] are the most common causes of maturity-onset diabetes of the young [...]
- Published
- 2001
49. Analysis of Parent-Offspring Trios Provides Evidence for Linkage and Association Between the Insulin Gene and Type 2 Diabetes Mediated Exclusively Through Paternally Transmitted Class III Variable Number Tandem Repeat Alleles
- Author
-
Huxtable, Stewart J., Saker, Philip J., Haddad, Lema, Walker, Mark, Frayling, Timothy M., Levy, Jonathan C., Hitman, Graham A., O'Rahilly, Stephen, Hattersley, Andrew T., and McCarthy, Mark I.
- Subjects
Familial diseases -- Research -- Genetic aspects ,Type 1 diabetes -- Genetic aspects -- Research ,Disease susceptibility -- Genetic aspects -- Research ,Health ,Research ,Genetic aspects - Abstract
Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. [...]
- Published
- 2000
50. High-dose glibenclamide can replace insulin therapy despite transitory diarrhea in early-onset diabetes caused by a novel R201L Kir6.2 mutation
- Author
-
Codner, Ethel, Flanagan, Sarah, Ellard, Sian, Garcia, Hernan, and Hattersley, Andrew T.
- Subjects
Diabetes -- Drug therapy -- Research ,Glibenclamide -- Dosage and administration -- Research ,Insulin -- Dosage and administration -- Research ,Health ,Drug therapy ,Research ,Dosage and administration - Abstract
Recently, mutations in the gene KCNJ11 encoding the Kir 6.2 subunit of the ATP-sensitive [K.sup.+] channel ([K.sub.ATP] channel) have been described in patients with permanent neonatal diabetes (1). The [K.sub.ATP] [...]
- Published
- 2005
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