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Andrew T Hattersley - One of the best experts on this subject based on the ideXlab platform.

  • management of sulfonylurea treated monogenic diabetes in pregnancy implications of placental glibenclamide transfer
    Diabetic Medicine, 2017
    Co-Authors: Maggie Shepherd, Adam Brook, Ali J Chakera, Andrew T Hattersley
    Abstract:

    The optimum treatment for HNF1A/HNF4A maturity-onset diabetes of the young and ATP-sensitive potassium (KATP ) channel neonatal diabetes, outside pregnancy, is sulfonylureas, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, but recent data have established that glibenclamide crosses the placenta and increases risk of macrosomia and neonatal hypoglycaemia. This raises questions about its use in pregnancy. We review the available evidence and make recommendations for the management of monogenic diabetes in pregnancy. Due to the risk of stimulating increased insulin secretion in utero, we recommend that in women with HNF1A/ HNF4A maturity-onset diabetes of the young, those with good glycaemic control who are on a sulfonylurea per conception either transfer to insulin before conception (at the risk of a short-term deterioration of glycaemic control) or continue with sulfonylurea (glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. Early delivery is needed if the fetus inherits an HNF4A mutation from either parent because increased insulin secretion results in ~800-g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post-delivery. If the fetus inherits a KATP neonatal diabetes mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by ~900 g. Treating the mother with glibenclamide in the third trimester treats the affected fetus in utero, normalising fetal growth, but is not desirable, especially in the high doses used in this condition, if the fetus is unaffected. Prospective studies of pregnancy in monogenic diabetes are needed.

  • Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes
    Pediatric diabetes, 2013
    Co-Authors: Roopa Kanakatti Shankar, Sian Ellard, Andrew T Hattersley, Debra A. Standiford, Catherine Pihoker, Lisa K. Gilliam, Lawrence M. Dolan
    Abstract:

    Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.

  • Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
    Clinica chimica acta; international journal of clinical chemistry, 2012
    Co-Authors: Tim J Mcdonald, Sian Ellard, Beverley M. Shields, Katharine R. Owen, Magdalena Szopa, Gaya Thanabalasingham, Maciej T. Malecki, Jane Mceneny, Ewan R Pearson, Andrew T Hattersley
    Abstract:

    The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. Copyright © 2012 Elsevier B.V. All rights reserved.

  • Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
    Clinica Chimica Acta, 2012
    Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Katharine R. Owen, Magdalena Szopa, Gaya Thanabalasingham, Maciej T. Malecki, Jane Mceneny, Ewan R Pearson, Andrew T Hattersley
    Abstract:

    Abstract Introduction The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. Methods 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. Results 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. Conclusion The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.

  • high sensitivity crp discriminates HNF1A mody from other subtypes of diabetes
    Diabetes Care, 2011
    Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Andrew T Hattersley
    Abstract:

    OBJECTIVE Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α ( HNF1A ) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS hs-CRP levels were assessed in 750 patients (220 HNF1A , 245 GCK , 54 HNF4-α [ HNF4A ], 21 HNF1-β ( HNF1B ), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS hs-CRP was lower in HNF1A-MODY (median interquartile [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (median [IQR] 1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (median [IQR] 1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (median [IQR] 1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (median [IQR] 0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (median [IQR] 0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under curve = 0.84). CONCLUSIONS hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.

Sian Ellard - One of the best experts on this subject based on the ideXlab platform.

  • prevalence characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A hnf4a and glucokinase results from the search for diabetes in youth
    The Journal of Clinical Endocrinology and Metabolism, 2013
    Co-Authors: Catherine Pihoker, Sian Ellard, Lisa K. Gilliam, Lawrence M. Dolan, Dana Dabelea, Cralen Davis, Carla J Greenbaum, Giuseppina Imperatore, Jean M Lawrence, Santica M Marcovina
    Abstract:

    Aims: Our study aims were to determine the frequency of MODY mutations (HNF1A, HNF4A, glucokinase) in a diverse population of youth with diabetes and to assess how well clinical features identify youth with maturity-onset diabetes of the young (MODY). Methods: The SEARCH for Diabetes in Youth study is a US multicenter, population-based study of youth with diabetes diagnosed at age younger than 20 years. We sequenced genomic DNA for mutations in the HNF1A, HNF4A, and glucokinase genes in 586 participants enrolled in SEARCH between 2001 and 2006. Selection criteria included diabetes autoantibody negativity and fasting C-peptide levels of 0.8 ng/mL or greater. Results: We identified a mutation in one of three MODY genes in 47 participants, or 8.0% of the tested sample, for a prevalence of at least 1.2% in the pediatric diabetes population. Of these, only 3 had a clinical diagnosis of MODY, and the majority was treated with insulin. Compared with the MODY-negative group, MODY-positive participants had lower F...

  • Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes
    Pediatric diabetes, 2013
    Co-Authors: Roopa Kanakatti Shankar, Sian Ellard, Andrew T Hattersley, Debra A. Standiford, Catherine Pihoker, Lisa K. Gilliam, Lawrence M. Dolan
    Abstract:

    Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.

  • systematic assessment of etiology in adults with a clinical diagnosis of young onset type 2 diabetes is a successful strategy for identifying maturity onset diabetes of the young
    Diabetes Care, 2012
    Co-Authors: G Thanabalasingham, Sian Ellard, Aparna Pal, Mary Selwood, Christina Dudley, Karen Fisher, Polly J Bingley, Andrew Farmer, Mark I Mccarthy, Katharine R. Owen
    Abstract:

    OBJECTIVE Misdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young adult-onset type 1 and type 2 diabetes by extending genetic testing beyond current guidelines. RESEARCH DESIGN AND METHODS Individuals were selected for diagnostic sequencing if they displayed features atypical for their diagnostic label. From 247 case subjects with clinically labeled type 1 diabetes, we sequenced hepatocyte nuclear factor 1 α ( HNF1A ) and hepatocyte nuclear factor 4 ( HNF4A ) in 20 with residual β-cell function ≥3 years from diagnosis (random or glucagon-stimulated C-peptide ≥0.2 nmol/L). From 322 with clinically labeled type 2 diabetes, we sequenced HNF1A and HNF4A in 80 with diabetes diagnosed ≤30 years and/or diabetes diagnosed ≤45 years without metabolic syndrome. We also sequenced the glucokinase ( GCK ) in 40 subjects with mild fasting hyperglycemia. RESULTS In the type 1 diabetic group, two HNF1A mutations were found (0.8% prevalence). In type 2 diabetic subjects, 10 HNF1A , two HNF4A , and one GCK mutation were identified (4.0%). Only 47% of MODY case subjects identified met current guidelines for diagnostic sequencing. Follow-up revealed a further 12 mutation carriers among relatives. Twenty-seven percent of newly identified MODY subjects changed treatment, all with improved glycemic control (HbA 1c 8.8 vs. 7.3% at 3 months; P = 0.02). CONCLUSIONS The systematic use of widened diagnostic testing criteria doubled the numbers of MODY case subjects identified compared with current clinical practice. The yield was greatest in young adult-onset type 2 diabetes. We recommend that all patients diagnosed before age 30 and with presence of C-peptide at 3 years duration are considered for molecular diagnostic analysis.

  • Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
    Clinica chimica acta; international journal of clinical chemistry, 2012
    Co-Authors: Tim J Mcdonald, Sian Ellard, Beverley M. Shields, Katharine R. Owen, Magdalena Szopa, Gaya Thanabalasingham, Maciej T. Malecki, Jane Mceneny, Ewan R Pearson, Andrew T Hattersley
    Abstract:

    The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. Copyright © 2012 Elsevier B.V. All rights reserved.

  • Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
    Clinica Chimica Acta, 2012
    Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Katharine R. Owen, Magdalena Szopa, Gaya Thanabalasingham, Maciej T. Malecki, Jane Mceneny, Ewan R Pearson, Andrew T Hattersley
    Abstract:

    Abstract Introduction The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. Methods 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. Results 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. Conclusion The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.

Katharine R. Owen - One of the best experts on this subject based on the ideXlab platform.

  • Altered cortisol metabolism in individuals with HNF1A‐MODY
    Clinical endocrinology, 2020
    Co-Authors: Agata Juszczak, Mark I Mccarthy, Lorna C Gilligan, Beverly A. Hughes, Zaki Hassan-smith, Wiebke Arlt, Jeremy W. Tomlinson, Katharine R. Owen
    Abstract:

    Objective and context Maturity onset diabetes of the young due to variants in HNF1A (HNF1A-MODY) is the most common form of monogenic diabetes. Individuals with HNF1A-MODY usually have a lean phenotype which contrasts with type 2 diabetes (T2DM). Data from hepatocytes derived from HNF1A knock-out mice demonstrated dysregulation of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regulates glucocorticoid availability and action in target tissues, together with 11β-HSD2 and steroid A-ring reductases, 5α- and 5β-reductase. We proposed that altered glucocorticoid metabolism might underpin some of the phenotypic differences between patients with HNF1A-MODY and those with T2DM. Design A retrospective matched cohort study. Patients and measurements 24-hours urine steroid metabolome profiling was carried out by gas chromatography-mass spectrometry in 35 subjects with HNF1A-MODY, 35 individuals with T2DM and 35 healthy controls matched for age, sex and BMI. The steroid metabolites were expressed as μg/L in all groups and measured in mid-morning urine in diabetic subjects and 24-hour urine collection in healthy controls. Hence, only ratios were compared not the individual steroids. Established ratios of glucocorticoid metabolites were used to estimate 11β-HSD1/2 and 5α- and 5β-reductase activities. Results While 11β-HSD1 activity was similar in all groups, 11β-HSD2 activity was significantly lower in subjects with HNF1A-MODY and T2DM than in healthy controls. The ratio of 5β- to 5α-metabolites of cortisol was higher in subjects with HNF1A-MODY than in T2DM and healthy controls, probably due to increased activity of the 5β-reductase (AKR1D1) in HNF1A-MODY. Conclusions This is the first report of steroid metabolites in HNF1A-MODY. We have identified distinct differences in steroid metabolism pathways in subjects with HNF1A-MODY that have the potential to alter steroid hormone availability. Further studies are required to explore whether these changes link to phenotype.

  • systematic assessment of etiology in adults with a clinical diagnosis of young onset type 2 diabetes is a successful strategy for identifying maturity onset diabetes of the young
    Diabetes Care, 2012
    Co-Authors: G Thanabalasingham, Sian Ellard, Aparna Pal, Mary Selwood, Christina Dudley, Karen Fisher, Polly J Bingley, Andrew Farmer, Mark I Mccarthy, Katharine R. Owen
    Abstract:

    OBJECTIVE Misdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young adult-onset type 1 and type 2 diabetes by extending genetic testing beyond current guidelines. RESEARCH DESIGN AND METHODS Individuals were selected for diagnostic sequencing if they displayed features atypical for their diagnostic label. From 247 case subjects with clinically labeled type 1 diabetes, we sequenced hepatocyte nuclear factor 1 α ( HNF1A ) and hepatocyte nuclear factor 4 ( HNF4A ) in 20 with residual β-cell function ≥3 years from diagnosis (random or glucagon-stimulated C-peptide ≥0.2 nmol/L). From 322 with clinically labeled type 2 diabetes, we sequenced HNF1A and HNF4A in 80 with diabetes diagnosed ≤30 years and/or diabetes diagnosed ≤45 years without metabolic syndrome. We also sequenced the glucokinase ( GCK ) in 40 subjects with mild fasting hyperglycemia. RESULTS In the type 1 diabetic group, two HNF1A mutations were found (0.8% prevalence). In type 2 diabetic subjects, 10 HNF1A , two HNF4A , and one GCK mutation were identified (4.0%). Only 47% of MODY case subjects identified met current guidelines for diagnostic sequencing. Follow-up revealed a further 12 mutation carriers among relatives. Twenty-seven percent of newly identified MODY subjects changed treatment, all with improved glycemic control (HbA 1c 8.8 vs. 7.3% at 3 months; P = 0.02). CONCLUSIONS The systematic use of widened diagnostic testing criteria doubled the numbers of MODY case subjects identified compared with current clinical practice. The yield was greatest in young adult-onset type 2 diabetes. We recommend that all patients diagnosed before age 30 and with presence of C-peptide at 3 years duration are considered for molecular diagnostic analysis.

  • Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
    Clinica chimica acta; international journal of clinical chemistry, 2012
    Co-Authors: Tim J Mcdonald, Sian Ellard, Beverley M. Shields, Katharine R. Owen, Magdalena Szopa, Gaya Thanabalasingham, Maciej T. Malecki, Jane Mceneny, Ewan R Pearson, Andrew T Hattersley
    Abstract:

    The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. Copyright © 2012 Elsevier B.V. All rights reserved.

  • Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
    Clinica Chimica Acta, 2012
    Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Katharine R. Owen, Magdalena Szopa, Gaya Thanabalasingham, Maciej T. Malecki, Jane Mceneny, Ewan R Pearson, Andrew T Hattersley
    Abstract:

    Abstract Introduction The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. Methods 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. Results 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. Conclusion The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.

  • high sensitivity crp discriminates HNF1A mody from other subtypes of diabetes
    Diabetes Care, 2011
    Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Andrew T Hattersley
    Abstract:

    OBJECTIVE Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α ( HNF1A ) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS hs-CRP levels were assessed in 750 patients (220 HNF1A , 245 GCK , 54 HNF4-α [ HNF4A ], 21 HNF1-β ( HNF1B ), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS hs-CRP was lower in HNF1A-MODY (median interquartile [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (median [IQR] 1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (median [IQR] 1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (median [IQR] 1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (median [IQR] 0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (median [IQR] 0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under curve = 0.84). CONCLUSIONS hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.

Guang Wan - One of the best experts on this subject based on the ideXlab platform.

  • Upregulation of lncRNA HNF1A-AS1 promotes cell proliferation and metastasis in osteosarcoma through activation of the Wnt/β-catenin signaling pathway.
    American journal of translational research, 2016
    Co-Authors: Hongxing Zhao, Wengen Hou, Jingang Tao, Yilei Zhao, Guang Wan
    Abstract:

    HNF1A-antisense 1 (HNF1A-AS1), a long non-coding RNA (lncRNA), is associated with metastasis and is an independent prognostic factor for lung cancer. Recent studies demonstrated that HNF1A-AS1 play important roles in cacinogenesis. However, the exact effects and molecular mechanisms of HNF1A-AS1 in osteosarcoma (OS) progression is still unclear. In the present study, we found that HNF1A-AS1 was markedly up-regulated in OS tissues compared to their adjacent non-tumor tissues. HNF1A-AS1 expression levels were positively associated with the clinical stage, distant metastasis, and reduced overall survival of OS patients. In addition, knockdown HNF1A-AS1 expression inhibited cell proliferation, metastasis and influences the activity of the Wnt/β-catenin pathway in OS cells. Wnt/β-catenin pathway activator (LiCl) rescued the anticancer effect of knockdown HNF1A-AS1 expression in OS cells. In conclusion, our study demonstrated that HNF1A-AS1 promoted the progression of OS via regulating the activity of the Wnt/β-catenin pathway, indicating that HNF1A-AS1 might be a potential target for the treatment of OS.

  • upregulation of lncrna HNF1A as1 promotes cell proliferation and metastasis in osteosarcoma through activation of the wnt β catenin signaling pathway
    American Journal of Translational Research, 2016
    Co-Authors: Hongxing Zhao, Wengen Hou, Jingang Tao, Yilei Zhao, Guang Wan
    Abstract:

    HNF1A-antisense 1 (HNF1A-AS1), a long non-coding RNA (lncRNA), is associated with metastasis and is an independent prognostic factor for lung cancer. Recent studies demonstrated that HNF1A-AS1 play important roles in cacinogenesis. However, the exact effects and molecular mechanisms of HNF1A-AS1 in osteosarcoma (OS) progression is still unclear. In the present study, we found that HNF1A-AS1 was markedly up-regulated in OS tissues compared to their adjacent non-tumor tissues. HNF1A-AS1 expression levels were positively associated with the clinical stage, distant metastasis, and reduced overall survival of OS patients. In addition, knockdown HNF1A-AS1 expression inhibited cell proliferation, metastasis and influences the activity of the Wnt/β-catenin pathway in OS cells. Wnt/β-catenin pathway activator (LiCl) rescued the anticancer effect of knockdown HNF1A-AS1 expression in OS cells. In conclusion, our study demonstrated that HNF1A-AS1 promoted the progression of OS via regulating the activity of the Wnt/β-catenin pathway, indicating that HNF1A-AS1 might be a potential target for the treatment of OS.

Anna L. Gloyn - One of the best experts on this subject based on the ideXlab platform.

  • Mutations in HNF1A result in marked alterations of plasma glycan profile.
    Diabetes, 2012
    Co-Authors: Gaya Thanabalasingham, Anna L. Gloyn, Jennifer E. Huffman, Jayesh J. Kattla, Mislav Novokmet, Igor Rudan, Caroline Hayward, Barbara Adamczyk, Rebecca M. Reynolds, Ana Muzinic
    Abstract:

    A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.

  • high sensitivity crp discriminates HNF1A mody from other subtypes of diabetes
    Diabetes Care, 2011
    Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Andrew T Hattersley
    Abstract:

    OBJECTIVE Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α ( HNF1A ) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS hs-CRP levels were assessed in 750 patients (220 HNF1A , 245 GCK , 54 HNF4-α [ HNF4A ], 21 HNF1-β ( HNF1B ), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS hs-CRP was lower in HNF1A-MODY (median interquartile [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (median [IQR] 1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (median [IQR] 1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (median [IQR] 1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (median [IQR] 0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (median [IQR] 0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under curve = 0.84). CONCLUSIONS hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.

  • High-Sensitivity CRP Discriminates HNF1A-MODY From Other Subtypes of Diabetes
    Diabetes care, 2011
    Co-Authors: Timothy J. Mcdonald, Sian Ellard, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Andrew T Hattersley
    Abstract:

    OBJECTIVE Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α ( HNF1A ) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS hs-CRP levels were assessed in 750 patients (220 HNF1A , 245 GCK , 54 HNF4-α [ HNF4A ], 21 HNF1-β ( HNF1B ), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS hs-CRP was lower in HNF1A-MODY (median interquartile [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (median [IQR] 1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (median [IQR] 1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (median [IQR] 1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (median [IQR] 0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (median [IQR] 0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP

  • assessment of high sensitivity c reactive protein levels as diagnostic discriminator of maturity onset diabetes of the young due to HNF1A mutations
    Diabetes Care, 2010
    Co-Authors: Katharine R. Owen, Tim James, G Thanabalasingham, Andrew Farmer, Mark I Mccarthy, Fredrik Karpe, Anna L. Gloyn
    Abstract:

    OBJECTIVE Despite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A ( HNF1A ) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY). RESEARCH DESIGN AND METHODS Serum hs-CRP was measured in subjects with HNF1A-MODY ( n = 31), autoimmune diabetes ( n = 316), type 2 diabetes ( n = 240), and glucokinase (GCK) MODY ( n = 24) and in nondiabetic individuals ( n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded ∼11% of subjects in whom the single available hs-CRP measurement was >10 mg/l. RESULTS Geometric mean (SD range) hs-CRP levels were significantly lower ( P ≤ 0.009) for HNF1A-MODY individuals, 0.20 (0.03–1.14) mg/l, than for any other group: autoimmune diabetes 0.58 (0.10–2.75) mg/l, type 2 diabetes 1.33 (0.28–6.14) mg/l, GCK-MODY 1.01 (0.19–5.33) mg/l, and nondiabetic 0.48 (0.10–2.42) mg/l. The ROC-derived C-statistic for discriminating HNF1A-MODY and type 2 diabetes was 0.8. Measurement of hs-CRP, either alone or in combination with current diagnostic criteria, was superior to current diagnostic criteria alone. Sensitivity and specificity for the combined criteria approached 80%. CONCLUSIONS Serum hs-CRP levels are markedly lower in HNF1A-MODY than in other forms of diabetes. hs-CRP has potential as a widely available, cost-effective screening test to support more precise targeting of MODY diagnostic testing.

  • Species-specific differences in the expression of the HNF1A, HNF1B and HNF4A genes.
    PloS one, 2009
    Co-Authors: Lorna W. Harries, James Brown, Anna L. Gloyn
    Abstract:

    Background: The HNF1A, HNF1B and HNF4A genes are part of an autoregulatory network in mammalian pancreas, liver, kidney and gut. The layout of this network appears to be similar in rodents and humans, but inactivation of HNF1A, HNF1B or HNF4A genes in animal models cause divergent phenotypes to those seen in man. We hypothesised that some differences may arise from variation in the expression profile of alternatively processed isoforms between species. Methodology/Principal Findings: We measured the expression of the major isoforms of the HNF1A, HNF1B and HNF4A genes in human and rodent pancreas, islet, liver and kidney by isoform-specific quantitative real-time PCR and compared their expression by the comparative Ct (??Ct) method. We found major changes in the expression profiles of the HNF genes between humans and rodents. The principal difference lies in the expression of the HNF1A gene, which exists as three isoforms in man, but as a single isoform only in rodents. More subtle changes were to the balance of HNF1B and HNF4A isoforms between species; the repressor isoform HNF1B(C) comprised only 6% in human islets compared with 24–26% in rodents (p = 0.006) whereas HNF4A9 comprised 22% of HNF4A expression in human pancreas but only 11% in rodents (p = 0.001). Conclusions/Significance: The differences we note in the isoform-specific expression of the human and rodent HNF1A, HNF1B and HNF4A genes may impact on the absolute activity of these genes, and therefore on the activity of the pancreatic transcription factor network as a whole. We conclude that alterations to expression of HNF isoforms may underlie some of the phenotypic variation caused by mutations in these genes.