The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1 alpha mutations is a feature of all patients with diabetes and is associated with glucosuria

Hepatocyte nuclear factor-1 alpha (HNF-1 alpha) mutations are the most comm on cause of maturity-onset diabetes of the young. HNF-1 alpha homozygous kn ockout mice exhibit a renal Fanconi syndrome with glucosuria and generalize d aminoaciduria in addition to diabetes. We investigated glucosuria and ami noaciduria in patients with HNF-1 alpha mutations. Sixteen amino acids were measured in urine samples from patients with HNF-1 alpha mutations, age-ma tched nondiabetic control subjects, and age-matched type I diabetic patient s, type 2 diabetic patients, and patients with diabetes and chronic renal f ailure. The HNF-1 alpha patients had glucosuria at lower glycemic control ( as shown by HbA(1c)) than type 1 and type 2 diabetic patients, consistent w ith a lower renal glucose threshold. The HNF-1 alpha patients had a general ized aminoaciduria with elevated levels of 14 of 16 amino acids and an incr eased 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. Ami noaciduria was not associated with microalbuminuria or proteinuria but was associated with glucosuria (1.00 glucosuria vs. 0.19 no glucosuria; P = 0.0 02). In type 1 diabetic patients, urine samples taken on the same day showe d significantly more aminoaciduria when glucosuria was present compared wit h when it was absent (P < 0.01). In conclusion, HNF-1<alpha> mutation carri ers have a mutation-specific defect of proximal tubular glucose transport, resulting in increased glucosuria. In contrast, the generalized aminoacidur ia seen in patients with HNF-1 alpha mutations is a general feature of pati ents 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.