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

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 P 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.

[1]  A. Hattersley,et al.  Genetic cause of hyperglycaemia and response to treatment in diabetes , 2003, The Lancet.

[2]  S. Ellard,et al.  Heterogeneity in young adult onset diabetes: aetiology alters clinical characteristics , 2002, Diabetic medicine : a journal of the British Diabetic Association.

[3]  T. Hansen,et al.  The genetic abnormality in the beta cell determines the response to an oral glucose load , 2002, Diabetologia.

[4]  C. Holland,et al.  Dimeric inhibins in girls from birth to adulthood: relationship with age, pubertal stage, FSH and oestradiol , 2002, Clinical endocrinology.

[5]  C. Holland,et al.  Inhibin B in boys from birth to adulthood: relationship with age, pubertal stage, FSH and testosterone , 2002, Clinical endocrinology.

[6]  A. Hattersley,et al.  Different genes, different diabetes: lessons from maturity-onset diabetes of the young , 2002, Annals of medicine.

[7]  Á. Hreidarsson,et al.  MODY in Iceland is associated with mutations in HNF-1α and a novel mutation in NeuroD1 , 2001, Diabetologia.

[8]  G I Bell,et al.  Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. , 2001, The New England journal of medicine.

[9]  T. Frayling,et al.  beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. , 2001, Diabetes.

[10]  T. Frayling,et al.  beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. , 2001, Diabetes.

[11]  L. Groop,et al.  Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state , 2000, Diabetologia.

[12]  S. Ellard.  Hepatocyte nuclear factor 1 alpha (HNF‐1α) mutations in maturity‐onset diabetes of the young , 2000 .

[13]  P. Froguel,et al.  HNF1α controls renal glucose reabsorption in mouse and man , 2000 .

[14]  K. Clément,et al.  Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations. , 1999, European journal of endocrinology.

[15]  J. Levy,et al.  Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes , 1999, Diabetologia.

[16]  T. Frayling,et al.  Allelic drop-out in exon 2 of the hepatocyte nuclear factor-1alpha gene hinders the identification of mutations in three families with maturity-onset diabetes of the young. , 1999, Diabetes.

[17]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[18]  J. Levy,et al.  Correct Homeostasis Model Assessment (HOMA) Evaluation Uses the Computer Program , 1998, Diabetes Care.

[19]  P. Heinke,et al.  A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor‐1α (HNF‐1α) gene , 1998 .

[20]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[21]  A. Hattersley.  Erratum: Maturity‐onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med 1998; 15(1): 15‐24. , 1998 .

[22]  A. Hattersley,et al.  Maturity‐onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[23]  T. Frayling,et al.  Mutations in the Hepatocyte Nuclear Factor–1α Gene Are a Common Cause of Maturity-Onset Diabetes of the Young in the U.K. , 1997, Diabetes.

[24]  E. Lander,et al.  Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. , 1997, The Journal of clinical investigation.

[25]  T. Hansen,et al.  Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3) , 1996, Nature.

[26]  A. Hattersley,et al.  Altered Insulin Secretory Responses to Glucose in Diabetic and Nondiabetic Subjects With Mutations in the Diabetes Susceptibility Gene MODY3 on Chromosome 12 , 1996, Diabetes.

[27]  M. Yaniv,et al.  Hepatocyte Nuclear Factor 1 Inactivation Results in Hepatic Dysfunction, Phenylketonuria, and Renal Fanconi Syndrome , 1996, Cell.

[28]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[29]  R. Tattersall.  Mild familial diabetes with dominant inheritance. , 1974, The Quarterly journal of medicine.

[30]  T. Frayling,et al.  - Cell Genes and Diabetes : Quantitative and Qualitative Differences in the Pathophysiology of Hepatic Nuclear Factor-1 and Glucokinase Mutations , 2001 .

[31]  S. Ellard.  Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. , 2000, Human mutation.

[32]  P. Heinke,et al.  A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene. , 1998, Diabetic medicine : a journal of the British Diabetic Association.