The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1alpha mutations is a feature of all patients with diabetes and is associated with glucosuria.
Hepatocyte nuclear factor-1alpha (HNF-1alpha) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1alpha homozygous knockout mice exhibit a renal Fanconi syndrome with glucosuria and generalized aminoaciduria in addition to diabetes. We investigated glucosuria and aminoaciduria in patients with HNF-1alpha mutations. Sixteen amino acids were measured in urine samples from patients with HNF-1alpha mutations, age-matched nondiabetic control subjects, and age-matched type 1 diabetic patients, type 2 diabetic patients, and patients with diabetes and chronic renal failure. The HNF-1alpha patients had glucosuria at lower glycemic control (as shown by HbA1c) than type 1 and type 2 diabetic patients, consistent with a lower renal glucose threshold. The HNF-1alpha patients had a generalized aminoaciduria with elevated levels of 14 of 16 amino acids and an increased mean Z score for all amino acids compared with control subjects (0.66 vs. 0.00; P < 0.0005). Generalized aminoaciduria was also present in type 1 diabetic (Z score, 0.80; P < 0.0001), type 2 diabetic (Z score, 0.71; P < 0.0002), and chronic renal failure (Z score, 0.65; P < 0.01) patients. Aminoaciduria was not associated with microalbuminuria or proteinuria but was associated with glucosuria (1.00 glucosuria vs. 0.19 no glucosuria; P = 0.002). In type 1 diabetic patients, urine samples taken on the same day showed significantly more aminoaciduria when glucosuria was present compared with when it was absent (P < 0.01). In conclusion, HNF-1alpha mutation carriers have a mutation-specific defect of proximal tubular glucose transport, resulting in increased glucosuria. In contrast, the generalized aminoaciduria seen in patients with HNF-1alpha mutations is a general feature of patients with diabetes and glucosuria. Glucose may depolarize and dissipate the electrical gradient of the sodium-dependent amino acid transporters in the proximal renal tubule, causing a reduction in amino acid resorption.
Bingham
C
C
Department of Vascular Medicine and Diabetes Research, School of Postgraduate Medicine and Health Sciences, University of Exeter, Devon, UK.
Ellard
S
S
Nicholls
A J
AJ
Pennock
C A
CA
Allen
J
J
James
A J
AJ
Satchell
S C
SC
Salzmann
M B
MB
Hattersley
A T
AT
D000328:Adult; D000419:Albuminuria / Q000150:complications; D000596:Amino Acids / Q000652:urine*; D002940:Circadian Rhythm; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000652:urine*; D003924:Diabetes Mellitus, Type 2 / Q000652:urine*; D003928:Diabetic Nephropathies / Q000652:urine; D006442:Glycated Hemoglobin / Q000032:analysis; D006029:Glycosuria / Q000150:complications / Q000209:etiology*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007676:Kidney Failure, Chronic / Q000652:urine; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins; D009994:Osmolar Concentration; D011507:Proteinuria / Q000150:complications; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics*
D000596:Amino Acids; D004268:DNA-Binding Proteins; D006442:Glycated Hemoglobin; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D009687:Nuclear Proteins; D014157:Transcription Factors; C496487:HNF1A protein, human; C496495:HNF1B protein, human