{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:44:33Z","timestamp":1793400273953,"version":"4.5.0"},"reference-count":28,"publisher":"American Diabetes Association","issue":"7","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,7,1]]},"abstract":"<jats:p>OBJECTIVE\u2014Patients with diabetes due to hepatocyte nuclear factor (HNF)-1\u03b1 mutations have \u03b2-cell deficiency, insulin sensitivity, altered proinsulin levels, and a low renal threshold for glucose. It is uncertain how many of these features precede the development of diabetes. The aim of our study was to test for these characteristics in young nondiabetic HNF-1\u03b1 mutation carriers.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing.<\/jats:p>\n               <jats:p>RESULTS\u2014HNF-1\u03b1 mutations were found in 20 offspring, 7 with diabetes and 13 without diabetes. The 13 nondiabetic mutation carriers were compared with 27 family control subjects, who were matched for age, sex, and BMI. There was marked \u03b2-cell deficiency with reduced insulinogenic index (53.5 [31.5\u201390.9] vs. 226.0 [126.0\u2013407.1], SD [range], P &amp;lt; 0.001) and area under the curve for insulin (P &amp;lt; 0.001). Insulin sensitivity was increased in mutation carriers (homeostatic model assessment of insulin sensitivity 144.6 [82.7\u2013252.7] vs. 100 [66.9\u2013149.4], P = 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects (P = 0.0034). Those with glycosuria had peak glucose values that were higher than the mutations carriers without glycosuria (range 8.1\u201311.8 vs. 6.2\u20138.4 mmol\/l, P = 0.002). The seven subjects with diabetes all showed glycosuria.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014We conclude that marked \u03b2-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1\u03b1 mutation carriers. The presence of glycosuria post\u2013glucose load could be used to screen children of mutation carriers as it occurs in all mutation carriers with a peak glucose in the oral glucose tolerance test &amp;gt;8.4 mmol\/l.<\/jats:p>","DOI":"10.2337\/diacare.28.7.1751","type":"journal-article","created":{"date-parts":[[2007,3,5]],"date-time":"2007-03-05T22:51:27Z","timestamp":1173135087000},"page":"1751-1756","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":104,"title":["\u03b2-Cell Dysfunction, Insulin Sensitivity, and Glycosuria Precede Diabetes in Hepatocyte Nuclear Factor-1\u03b1 Mutation Carriers"],"prefix":"10.2337","volume":"28","author":[{"given":"Amanda","family":"Stride","sequence":"first","affiliation":[{"name":"Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, Devon, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Ellard","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, Devon, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penny","family":"Clark","sequence":"additional","affiliation":[{"name":"Regional Endocrine Laboratory, University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynette","family":"Shakespeare","sequence":"additional","affiliation":[{"name":"Regional Endocrine Laboratory, University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Salzmann","sequence":"additional","affiliation":[{"name":"Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Shepherd","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, Devon, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T.","family":"Hattersley","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, Devon, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031218310985700_R1","doi-asserted-by":"crossref","unstructured":"Stride A, Hattersley AT: Different genes, different diabetes: lessons from maturity-onset diabetes of the young. 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Diabet Med\u200815: 15\u201324, 1998","DOI":"10.1002\/(SICI)1096-9136(199801)15:1<15::AID-DIA562>3.0.CO;2-M"},{"key":"2022031218310985700_R8","doi-asserted-by":"crossref","unstructured":"Byrne MM, Sturis J, Menzel S, Yamagata K, Fajans SS, Dronsfield MJ, Bain SC, Hattersley AT, Velho G, Froguel P, Bell GI, Polonsky KS: Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes\u200845: 1503\u20131510, 1996","DOI":"10.2337\/diabetes.45.11.1503"},{"key":"2022031218310985700_R9","doi-asserted-by":"crossref","unstructured":"Lehto M, Tuomi T, Mahtani MM, Widen E, Forsblom C, Sarelin L, Gullstrom M, Isomaa B, Lehtovirta M, Hyrkko A, Kanninen T, Orho M, Manley S, Turner RC, Brettin T, Kirby A, Thomas J, Duyk G, Lander E, Taskinen M-R, Groop L: Characterization of the MODY3 phenotype: early-onset diabetes caused by an insulin secretion defect. 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Q J Med\u200843: 339\u2013357, 1974"},{"key":"2022031218310985700_R15","doi-asserted-by":"crossref","unstructured":"Ellard S: Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Hum Mutat\u200816: 377\u2013385, 2000","DOI":"10.1002\/1098-1004(200011)16:5<377::AID-HUMU1>3.0.CO;2-2"},{"key":"2022031218310985700_R16","doi-asserted-by":"crossref","unstructured":"Menzel R, Kaisaki PJ, Rjasanowski I, Heinke P, Kerner W, Menzel S: A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene. Diabet Med\u200815: 816\u2013820, 1998","DOI":"10.1002\/(SICI)1096-9136(199810)15:10<816::AID-DIA714>3.0.CO;2-P"},{"key":"2022031218310985700_R17","doi-asserted-by":"crossref","unstructured":"Pontoglio M, Prie D, Cheret C, Doyen A, Lero C, Froguel P, Velho G, Yaniv M, Friedlander G: HNF1 alpha controls renal glucose reabsorption in mouse and man. 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