DOI: 10.2337/db07-0634. Common Variants of the Novel Type 2 Diabetes Genes<i>CDKAL1</i>and<i>HHEX/IDE</i>Are Associated With Decreased Pancreatic β-Cell Function

Common Variants of the Novel Type 2 Diabetes GenesCDKAL1andHHEX/IDEAre Associated With Decreased Pancreatic β-Cell Function

10.2337/db07-0634

Crossref journal-article

American Diabetes Association

Diabetes (1167)

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, CDKN2A/CDKN2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of β-cell function and whole-body insulin sensitivity.RESEARCH DESIGN AND METHODS— A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of β-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (M/I) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center.RESULTS— CDKAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic β-cell glucose sensitivity (P = 9.86 × 10−5 and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity.CONCLUSIONS— CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic β-cell function, including decreased β-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity.

Bibliography

Pascoe, L., Tura, A., Patel, S. K., Ibrahim, I. M., Ferrannini, E., Zeggini, E., Weedon, M. N., Mari, A., Hattersley, A. T., McCarthy, M. I., Frayling, T. M., & Walker, M. (2007). Common Variants of the Novel Type 2 Diabetes GenesCDKAL1andHHEX/IDEAre Associated With Decreased Pancreatic Î²-Cell Function. Diabetes, 56(12), 3101â3104.

Authors 13

Laura Pascoe (first)
Andrea Tura (additional)
Sheila K. Patel (additional)
Ibrahim M. Ibrahim (additional)
Ele Ferrannini (additional)
Eleftheria Zeggini (additional)
Michael N. Weedon (additional)
Andrea Mari (additional)
Andrew T. Hattersley (additional)
Mark I. McCarthy (additional)
Timothy M. Frayling (additional)
Mark Walker (additional)
(additional)

References 17 Referenced 209

Sladek R, Rocheleau G, Rung J, et al.: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885,2007 (10.1038/nature05616)
Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al.: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770–775,2007 (10.1038/ng2043)
Zeggini E, Weedon MN, Lindgren CM, et al.:Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341,2007 (10.1126/science.1142364)
Scott LJ, Mohlke KL, Bonnycastle LL, et al.: A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345,2007
Diabetes Research Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for Biomedical Research: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336,2007
Frayling TM, Timpson NJ, Weedon MN, et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894,2007
Hills SA, Balkau B, Coppack SW, et al.: The EGIR-RISC study (the European Group for the study of Insulin Resistance: Relationship between Insulin Senstivity and Cardiovascular disease risk). 1. Methodology and objectives. Diabetologia 47:566–570,2004 (10.1007/s00125-004-1335-5)
Wareham NJ, Phillips DI, Byrne CD, et al.: The 30 minute insulin incremental response in an oral glucose tolerance test as a measure of insulin secretion. Diabet Med 12:931,1995 (10.1111/j.1464-5491.1995.tb00399.x)
Van Cauter E, Mestrez F, Sturis J, et al.: Estimation of insulin secretion rates from C-peptide levels: comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 41:368–377,1992 (10.2337/diabetes.41.3.368)
Walker M, Mari A, Jayapaul MK, et al.: Impaired β cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects. Diabetologia 48:2470–2476,2005 (10.1007/s00125-005-0004-7)
Mari A, Schmitz O, Gastaldelli A, et al.: Meal and oral glucose tests for assessment of β-cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 283:E1159–E1166,2002 (10.1152/ajpendo.00093.2002)
Mari A, Pacini G, Murphy E, et al.: A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 24:539–548,2001 (10.2337/diacare.24.3.539)
Yen CJ, Beamer BA, Negri C, et al.: Molecular scanning of the human peroxisome proliferator activated receptor γ (hPPARγ) gene in diabetic caucasians: identification of a Pro12Ala PPARγ2 missense mutation. Biochem Biophys Res Commun 241:270–274,1997 (10.1006/bbrc.1997.7798)
Dudbridge F: Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121,2003 (10.1002/gepi.10252)
Deeb SS, Fajas L, Nemoto M, et al.: A Pro12Ala substiution in PPARγ2 aasociated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284–287,1998 (10.1038/3099)
Ek J, Andersen G, Urhammer SA, et al.: Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene in relation to insulin sensitivity among glucose tolerant Caucasians. Diabetologia 44:1170–1176,2001 (10.1007/s001250100629)
Bort R, Martinez-Barbera JP, Beddington RSP, et al.: Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development 131:797–806,2004 (10.1242/dev.00965)

Dates

Type	When
Created	17 years, 11 months ago (Sept. 5, 2007, 9:39 p.m.)
Deposited	2 years, 3 months ago (May 13, 2023, 9:42 p.m.)
Indexed	1 month, 2 weeks ago (July 14, 2025, 11:13 p.m.)
Issued	17 years, 8 months ago (Dec. 1, 2007)
Published	17 years, 8 months ago (Dec. 1, 2007)
Published Print	17 years, 8 months ago (Dec. 1, 2007)

Funders 0

None

BibTeX

@article{Pascoe_2007, title={Common Variants of the Novel Type 2 Diabetes GenesCDKAL1andHHEX/IDEAre Associated With Decreased Pancreatic β-Cell Function}, volume={56}, ISSN={1939-327X}, url={http://dx.doi.org/10.2337/db07-0634}, DOI={10.2337/db07-0634}, number={12}, journal={Diabetes}, publisher={American Diabetes Association}, author={Pascoe, Laura and Tura, Andrea and Patel, Sheila K. and Ibrahim, Ibrahim M. and Ferrannini, Ele and Zeggini, Eleftheria and Weedon, Michael N. and Mari, Andrea and Hattersley, Andrew T. and McCarthy, Mark I. and Frayling, Timothy M. and Walker, Mark}, year={2007}, month=dec, pages={3101–3104} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        15
      ]
    ],
    "date-time": "2025-07-15T03:13:28Z",
    "timestamp": 1752549208998
  },
  "reference-count": 17,
  "publisher": "American Diabetes Association",
  "issue": "12",
  "content-domain": {
    "domain": [
      "diabetesjournals.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2007,
        12,
        1
      ]
    ]
  },
  "abstract": "<jats:p>OBJECTIVE\u2014 Type 2 diabetes is characterized by impaired pancreatic \u03b2-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of \u03b2-cell function and whole-body insulin sensitivity.</jats:p><jats:p>RESEARCH DESIGN AND METHODS\u2014 A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of \u03b2-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (M/I) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center.</jats:p><jats:p>RESULTS\u2014\u2008CDKAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic \u03b2-cell glucose sensitivity (P = 9.86 \u00d7 10\u22125 and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity.</jats:p><jats:p>CONCLUSIONS\u2014\u2008CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic \u03b2-cell function, including decreased \u03b2-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity.</jats:p>",
  "DOI": "10.2337/db07-0634",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2007,
        9,
        6
      ]
    ],
    "date-time": "2007-09-06T01:39:49Z",
    "timestamp": 1189042789000
  },
  "page": "3101-3104",
  "update-policy": "http://dx.doi.org/10.2337/ada-journal-policies",
  "source": "Crossref",
  "is-referenced-by-count": 209,
  "title": "Common Variants of the Novel Type 2 Diabetes Genes<i>CDKAL1</i>and<i>HHEX/IDE</i>Are Associated With Decreased Pancreatic \u03b2-Cell Function",
  "prefix": "10.2337",
  "volume": "56",
  "author": [
    {
      "given": "Laura",
      "family": "Pascoe",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Diabetes Research Group, Newcastle University, Newcastle upon Tyne, U.K"
        }
      ]
    },
    {
      "given": "Andrea",
      "family": "Tura",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "CNR Institute of Biomedical Engineering, Padova, Italy"
        }
      ]
    },
    {
      "given": "Sheila K.",
      "family": "Patel",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Cardiovascular Research Group, Department of Medicine, University of Melbourne, Melbourne, Australia"
        }
      ]
    },
    {
      "given": "Ibrahim M.",
      "family": "Ibrahim",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Diabetes Research Group, Newcastle University, Newcastle upon Tyne, U.K"
        }
      ]
    },
    {
      "given": "Ele",
      "family": "Ferrannini",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "University of Pisa, School of Medicine, Pisa, Italy"
        }
      ]
    },
    {
      "given": "Eleftheria",
      "family": "Zeggini",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K"
        }
      ]
    },
    {
      "given": "Michael N.",
      "family": "Weedon",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Diabetes Genetics Group and Genetics of Complex Traits, Peninsula Medical School, Exeter, U.K"
        }
      ]
    },
    {
      "given": "Andrea",
      "family": "Mari",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "CNR Institute of Biomedical Engineering, Padova, Italy"
        }
      ]
    },
    {
      "given": "Andrew T.",
      "family": "Hattersley",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Diabetes Genetics Group and Genetics of Complex Traits, Peninsula Medical School, Exeter, U.K"
        }
      ]
    },
    {
      "given": "Mark I.",
      "family": "McCarthy",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K"
        }
      ]
    },
    {
      "given": "Timothy M.",
      "family": "Frayling",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Diabetes Genetics Group and Genetics of Complex Traits, Peninsula Medical School, Exeter, U.K"
        }
      ]
    },
    {
      "given": "Mark",
      "family": "Walker",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Diabetes Research Group, Newcastle University, Newcastle upon Tyne, U.K"
        }
      ]
    },
    {
      "name": "for the RISC Consortium and the U.K. Type 2 Diabetes Genetics Consortium",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "1167",
  "reference": [
    {
      "key": "2022031207551705400_R1",
      "doi-asserted-by": "crossref",
      "unstructured": "Sladek R, Rocheleau G, Rung J, et al.: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature\u2008445:881\u2013885,2007",
      "DOI": "10.1038/nature05616"
    },
    {
      "key": "2022031207551705400_R2",
      "doi-asserted-by": "crossref",
      "unstructured": "Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al.: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet\u200839:770\u2013775,2007",
      "DOI": "10.1038/ng2043"
    },
    {
      "key": "2022031207551705400_R3",
      "doi-asserted-by": "crossref",
      "unstructured": "Zeggini E, Weedon MN, Lindgren CM, et al.:Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science\u2008316:1336\u20131341,2007",
      "DOI": "10.1126/science.1142364"
    },
    {
      "key": "2022031207551705400_R4",
      "unstructured": "Scott LJ, Mohlke KL, Bonnycastle LL, et al.: A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science\u2008316:1341\u20131345,2007"
    },
    {
      "key": "2022031207551705400_R5",
      "unstructured": "Diabetes Research Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for Biomedical Research: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science\u2008316:1331\u20131336,2007"
    },
    {
      "key": "2022031207551705400_R6",
      "unstructured": "Frayling TM, Timpson NJ, Weedon MN, et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science\u2008316:889\u2013894,2007"
    },
    {
      "key": "2022031207551705400_R7",
      "doi-asserted-by": "crossref",
      "unstructured": "Hills SA, Balkau B, Coppack SW, et al.: The EGIR-RISC study (the European Group for the study of Insulin Resistance: Relationship between Insulin Senstivity and Cardiovascular disease risk). 1. Methodology and objectives. Diabetologia\u200847:566\u2013570,2004",
      "DOI": "10.1007/s00125-004-1335-5"
    },
    {
      "key": "2022031207551705400_R8",
      "doi-asserted-by": "crossref",
      "unstructured": "Wareham NJ, Phillips DI, Byrne CD, et al.: The 30 minute insulin incremental response in an oral glucose tolerance test as a measure of insulin secretion. Diabet Med\u200812:931,1995",
      "DOI": "10.1111/j.1464-5491.1995.tb00399.x"
    },
    {
      "key": "2022031207551705400_R9",
      "doi-asserted-by": "crossref",
      "unstructured": "Van Cauter E, Mestrez F, Sturis J, et al.: Estimation of insulin secretion rates from C-peptide levels: comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes\u200841:368\u2013377,1992",
      "DOI": "10.2337/diabetes.41.3.368"
    },
    {
      "key": "2022031207551705400_R10",
      "doi-asserted-by": "crossref",
      "unstructured": "Walker M, Mari A, Jayapaul MK, et al.: Impaired \u03b2 cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects. Diabetologia\u200848:2470\u20132476,2005",
      "DOI": "10.1007/s00125-005-0004-7"
    },
    {
      "key": "2022031207551705400_R11",
      "doi-asserted-by": "crossref",
      "unstructured": "Mari A, Schmitz O, Gastaldelli A, et al.: Meal and oral glucose tests for assessment of \u03b2-cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab\u2008283:E1159\u2013E1166,2002",
      "DOI": "10.1152/ajpendo.00093.2002"
    },
    {
      "key": "2022031207551705400_R12",
      "doi-asserted-by": "crossref",
      "unstructured": "Mari A, Pacini G, Murphy E, et al.: A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care\u200824:539\u2013548,2001",
      "DOI": "10.2337/diacare.24.3.539"
    },
    {
      "key": "2022031207551705400_R13",
      "doi-asserted-by": "crossref",
      "unstructured": "Yen CJ, Beamer BA, Negri C, et al.: Molecular scanning of the human peroxisome proliferator activated receptor \u03b3 (hPPAR\u03b3) gene in diabetic caucasians: identification of a Pro12Ala PPAR\u03b32 missense mutation. Biochem Biophys Res Commun\u2008241:270\u2013274,1997",
      "DOI": "10.1006/bbrc.1997.7798"
    },
    {
      "key": "2022031207551705400_R14",
      "doi-asserted-by": "crossref",
      "unstructured": "Dudbridge F: Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol\u200825:115\u2013121,2003",
      "DOI": "10.1002/gepi.10252"
    },
    {
      "key": "2022031207551705400_R15",
      "doi-asserted-by": "crossref",
      "unstructured": "Deeb SS, Fajas L, Nemoto M, et al.: A Pro12Ala substiution in PPAR\u03b32 aasociated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet\u200820:284\u2013287,1998",
      "DOI": "10.1038/3099"
    },
    {
      "key": "2022031207551705400_R16",
      "doi-asserted-by": "crossref",
      "unstructured": "Ek J, Andersen G, Urhammer SA, et al.: Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-\u03b32 (PPAR-\u03b32) gene in relation to insulin sensitivity among glucose tolerant Caucasians. Diabetologia\u200844:1170\u20131176,2001",
      "DOI": "10.1007/s001250100629"
    },
    {
      "key": "2022031207551705400_R17",
      "doi-asserted-by": "crossref",
      "unstructured": "Bort R, Martinez-Barbera JP, Beddington RSP, et al.: Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development\u2008131:797\u2013806,2004",
      "DOI": "10.1242/dev.00965"
    }
  ],
  "container-title": "Diabetes",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://journals.org/diabetes/diabetes/article-pdf/56/12/3101/386241/zdb01207003101.pdf",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "syndication"
    },
    {
      "URL": "https://diabetesjournals.org/diabetes/article-pdf/56/12/3101/386241/zdb01207003101.pdf",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        5,
        14
      ]
    ],
    "date-time": "2023-05-14T01:42:15Z",
    "timestamp": 1684028535000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://diabetesjournals.org/diabetes/article/56/12/3101/13019/Common-Variants-of-the-Novel-Type-2-Diabetes-Genes"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2007,
        12,
        1
      ]
    ]
  },
  "references-count": 17,
  "journal-issue": {
    "issue": "12",
    "published-print": {
      "date-parts": [
        [
          2007,
          12,
          1
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.2337/db07-0634",
  "relation": {},
  "ISSN": [
    "0012-1797",
    "1939-327X"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        2007,
        12,
        1
      ]
    ]
  }
}