The Generalized Aminoaciduria Seen in Patients With Hepatocyte Nuclear Factor-1α Mutations Is a Feature of All Patients With Diabetes and Is Associated With Glucosuria
Author:
Bingham Coralie1, Ellard Sian1, Nicholls Anthony J.2, Pennock Charles A.3, Allen John3, James Alan J.2, Satchell Simon C.2, Salzmann Maurice B.2, Hattersley Andrew T.1
Affiliation:
1. Department of Vascular Medicine and Diabetes Research, School of Postgraduate Medicine and Health Sciences, University of Exeter, Devon, U.K. 2. Royal Devon and Exeter Healthcare NHS Trust, Barrack Road, Exeter, U.K. 3. Lewis Laboratory, Southmead Hospital, Westbury-On-Trym, Bristol, U.K.
Abstract
Hepatocyte nuclear factor-1α (HNF-1α) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1α 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-1α mutations. Sixteen amino acids were measured in urine samples from patients with HNF-1α 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-1α 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-1α 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-1α 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-1α 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.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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