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.
Bingham, Coralie 1; Ellard, Sian 1; Nicholls, Anthony J. 2; Pennock, Charles A. 3; Allen, John 3; James, Alan J. 2; Satchell, Simon C. 2; Salzmann, Maurice B. 2; Hattersley, Andrew T. 1
[Miscellaneous Article] Diabetes. 50(9):2047-2052, September 2001.

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Hepatocyte nuclear factor-1[alpha] (HNF-1[alpha]) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1[alpha] 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-1[alpha] mutations. Sixteen amino acids were measured in urine samples from patients with HNF-1[alpha] 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-1[alpha] 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-1[alpha] 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-1[alpha] 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-1[alpha] 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.

(C) 2001 by the American Diabetes Association, Inc.