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Metabolic Syndrome/Insulin Resistance Syndrome/Pre-Diabetes

β-Cell Dysfunction, Insulin Sensitivity, and Glycosuria Precede Diabetes in Hepatocyte Nuclear Factor-1α Mutation Carriers

  1. Amanda Stride, MRCP1,
  2. Sian Ellard, PHD1,
  3. Penny Clark, PHD2,
  4. Lynette Shakespeare, PHD2,
  5. Maurice Salzmann, FRCPATH3,
  6. Maggie Shepherd, PHD1 and
  7. Andrew T. Hattersley, DM1
  1. 1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, Devon, U.K
  2. 2Regional Endocrine Laboratory, University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, U.K
  3. 3Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, U.K
  1. Address correspondence and reprint requests to Professor Andrew Hattersley, Peninsula Medical School, the Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, Devon, U.K. E-mail: a.t.hattersley{at}ex.ac.uk
Diabetes Care 2005 Jul; 28(7): 1751-1756. https://doi.org/10.2337/diacare.28.7.1751
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Abstract

OBJECTIVE—Patients with diabetes due to hepatocyte nuclear factor (HNF)-1α mutations have β-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-1α mutation carriers.

RESEARCH DESIGN AND METHODS—A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing.

RESULTS—HNF-1α 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 β-cell deficiency with reduced insulinogenic index (53.5 [31.5–90.9] vs. 226.0 [126.0–407.1], SD [range], P < 0.001) and area under the curve for insulin (P < 0.001). Insulin sensitivity was increased in mutation carriers (homeostatic model assessment of insulin sensitivity 144.6 [82.7–252.7] vs. 100 [66.9–149.4], 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 8.1–11.8 vs. 6.2–8.4 mmol/l, P = 0.002). The seven subjects with diabetes all showed glycosuria.

CONCLUSIONS—We conclude that marked β-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1α mutation carriers. The presence of glycosuria post–glucose 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 >8.4 mmol/l.

  • AUC, area under the curve
  • FPG, fasting plasma glucose
  • HNF, hepatocyte nuclear factor
  • HOMA, homeostatic model assessment
  • IGT, impaired glucose tolerance
  • MODY, maturity-onset diabetes of the young
  • NGT, normal glucose tolerance
  • OGTT, oral glucose tolerance test

Footnotes

  • A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted March 22, 2005.
    • Received December 6, 2004.
  • DIABETES CARE
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Diabetes Care: 28 (7)

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July 2005, 28(7)
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β-Cell Dysfunction, Insulin Sensitivity, and Glycosuria Precede Diabetes in Hepatocyte Nuclear Factor-1α Mutation Carriers
Amanda Stride, Sian Ellard, Penny Clark, Lynette Shakespeare, Maurice Salzmann, Maggie Shepherd, Andrew T. Hattersley
Diabetes Care Jul 2005, 28 (7) 1751-1756; DOI: 10.2337/diacare.28.7.1751

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β-Cell Dysfunction, Insulin Sensitivity, and Glycosuria Precede Diabetes in Hepatocyte Nuclear Factor-1α Mutation Carriers
Amanda Stride, Sian Ellard, Penny Clark, Lynette Shakespeare, Maurice Salzmann, Maggie Shepherd, Andrew T. Hattersley
Diabetes Care Jul 2005, 28 (7) 1751-1756; DOI: 10.2337/diacare.28.7.1751
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