A LOW RENAL THRESHOLD FOR GLUCOSE IN DIABETIC-PATIENTS WITH A MUTATION IN THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA (HNF-1-ALPHA) GENE

One form of maturity-onset diabetes of the young, Type 3 (MODY3), resu lts from mutations in the gene coding for hepatocyte nuclear factor-1 alpha (HNF-1 alpha), a transcription factor first described in the liv er. MODY3 is characterized by a defective glucose-stimulated insulin s ecretion. Earlier observations of glycosuria with normal blood glucose levels in some MODY families suggest an additional renal manifestatio n of the respective genetic defect. We measured the renal threshold fo r glucose in five diabetic carriers of a missense mutation (Arg 272 Hi s) in HNF-1 alpha and, for comparison, in eight Type 1 diabetic patien ts, applying a non-invasive protocol of frequent parallel blood and ur ine sampling during a in blood glucose levels. We found that the mean renal threshold for glucose was lowered in the HNF-1 alpha diabetic pa tients compared to those with Type 1 diabetes (6.5 +/- 0.9 mmol l(-1) vs 10.7 +/- 0.5 mmol l(-1); p < 0.01). This lowered glucose threshold might be an indication of an extra-pancreatic effect of HNF-1 alpha ge ne mutations in humans. Defects in HNF-1 alpha may lead to an altered tubular glucose reabsorption, possibly due to decreased expression of the renal glucose transporter proteins involved in reabsorption of glu cose from the urine. (C) 1998 John Wiley & Sons, Ltd.