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The Generalized Aminoaciduria Seen in Patients with Hepatocyte Nuclear Factor-1 Mutations Is a Feature of All Patients with Diab

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The Generalized Aminoaciduria Seen in Patients with Hepatocyte Nuclear Factor-1 Mutations Is a Feature of All Patients with Diab The Generalized Aminoaciduria Seen in Patients With Hepatocyte Nuclear Factor-1␣ Mutations Is a Feature of All Patients With Diabetes and Is Associated With Glucosuria Coralie Bingham,1 Sian Ellard,1 Anthony J. Nicholls,2 Charles A. Pennock,3 John Allen,3 Alan J. James,2 Simon C. Satchell,2 Maurice B. Salzmann,2 and Andrew T. Hattersley1 Hepatocyte nuclear factor-1␣ (HNF-1␣) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1␣ homozygous knockout mice exhibit a epatocyte nuclear factor-1␣ (HNF-1␣) is a mem- renal Fanconi syndrome with glucosuria and general- ber of the homeodomain-containing superfam- ized aminoaciduria in addition to diabetes. We investi- ily of transcription factors (1–4). These factors gated glucosuria and aminoaciduria in patients with have a role in the tissue-specific regulation of HNF-1␣ mutations. Sixteen amino acids were measured H gene expression in a number of tissues, including liver, in urine samples from patients with HNF-1␣ mutations, kidney, intestine, and pancreatic islets (5). Heterozygous age-matched nondiabetic control subjects, and age- ␣ matched type 1 diabetic patients, type 2 diabetic pa- mutations in the gene encoding HNF-1 are the most tients, and patients with diabetes and chronic renal common cause of maturity-onset diabetes of the young failure. The HNF-1␣ patients had glucosuria at lower (MODY) (6). MODY is a subgroup of type 2 diabetes glycemic control (as shown by HbA1c) than type 1 and characterized by autosomal dominant inheritance and a type 2 diabetic patients, consistent with a lower renal young age of onset (7). glucose threshold. The HNF-1␣ patients had a general- The HNF-1␣ gene is expressed in the kidney. In situ ized aminoaciduria with elevated levels of 14 of 16 hybridization experiments in developing rat kidney have amino acids and an increased mean Z score for all amino shown that HNF-1␣ is first expressed at 15–16 days post acids compared with control subjects (0.66 vs. 0.00; P < 0.0005). Generalized aminoaciduria was also present in coitum, the postinductory phase, in the s-shaped structure type 1 diabetic (Z score, 0.80; P < 0.0001), type 2 diabetic in cells committed to tubular differentiation (5). In the (Z score, 0.71; P < 0.0002), and chronic renal failure (Z newborn rat kidney, HNF-1␣ is present in the proximal score, 0.65; P < 0.01) patients. Aminoaciduria was not convoluted tubule, distal convoluted tubule, and loop of associated with microalbuminuria or proteinuria but was Henle but not in the collecting ducts (5). associated with glucosuria (1.00 glucosuria vs. 0.19 no The HNF-1␣ knockout mouse has a severe renal Fan- ؍ glucosuria; P 0.002). In type 1 diabetic patients, urine coni syndrome with polyuria (85% body wt/day), glucos- samples taken on the same day showed significantly more aminoaciduria when glucosuria was present com- uria, increased renal fractional excretion of 24 amino pared with when it was absent (P < 0.01). In conclusion, acids, and phosphaturia caused by renal proximal tubular HNF-1␣ mutation carriers have a mutation-specific dysfunction (8). The defect in renal proximal tubular glu- defect of proximal tubular glucose transport, resulting cose resorption in the HNF-1␣ knockout mouse is caused in increased glucosuria. In contrast, the generalized by a significant reduction in expression of the high-capacity/ aminoaciduria seen in patients with HNF-1␣ mutations is low-affinity sodium-glucose transporter-2 (SGLT-2) (9). a general feature of patients with diabetes and glucosuria. In humans, there is evidence to support a specific Glucose may depolarize and dissipate the electrical gradi- alteration in renal glucose handling. In the early descrip- ent of the sodium-dependent amino acid transporters in the proximal renal tubule, causing a reduction in amino tions of MODY, a reduced renal glucose threshold was acid resorption.Diabetes 50:2047–2052, 2001 noticed to be a phenotypic marker in some families (10). Some of these families have been subsequently found to have mutations in the HNF-1␣ gene (11). A low renal From the 1Department of Vascular Medicine and Diabetes Research, School of threshold for glucose has been found in small studies of Postgraduate Medicine and Health Sciences, University of Exeter, Devon, individuals with HNF-1␣ mutations (9,12). There has been U.K.; 2Royal Devon and Exeter Healthcare NHS Trust, Barrack Road, Exeter, no comprehensive study of aminoaciduria in individuals U.K.; and 3Lewis Laboratory, Southmead Hospital, Westbury-On-Trym, Bristol, U.K. with HNF-1␣ mutations, although in a preliminary study, Address correspondence and reprint requests to Prof. Andrew Hattersley, increased excretion of two amino acids, glycine and ala- Department of Diabetes and Vascular Medicine, School of Postgraduate ␣ Medicine and Health Sciences, Barrack Road, Exeter EX2 5AX, Devon, U.K. nine, was recorded in three individuals with HNF-1 mu- E-mail: [email protected]. tations (13). Received for publication 12 January 2001 and accepted in revised form Diabetic renal complications have been described in 21 May 2001. ␣ HNF-1␣, hepatocyte nuclear factor-1␣; MODY, maturity-onset diabetes of patients with HNF-1 mutations (14,15). As a feature of the young; SGLT-2, sodium-glucose transporter-2. diabetic nephropathy, microalbuminuria has been report- DIABETES, VOL. 50, SEPTEMBER 2001 2047 AMINOACIDURIA IN HNF-1␣ MUTATIONS TABLE 1 Clinical characteristics of the five groups of participants Mean age Mean age of at diagnosis Mean duration participants with diabetes of diabetes Mean HbA1c Group n (years) (years) (years) (%) Treatment HNF-1␣ 50 45.3 Ϯ 2.6 24.8 Ϯ 2.2 22.6 Ϯ 2.3 6.1 Ϯ 0.2 Insulin (15), OHA (23), diet (12) Type 1 diabetes 25 45.9 Ϯ 3.8 25.2 Ϯ 3.6 20.7 Ϯ 3.2 8.4 Ϯ 0.4 Insulin (25) Type 2 diabetes 25 61.6 Ϯ 2.3 52.6 Ϯ 2.0 9.0 Ϯ 1.3 7.6 Ϯ 0.3 Insulin (9), OHA (9), insulin and OHA (5), diet (2) CRF and diabetes 10 (5 type 1, 59.9 Ϯ 5.5 39.4 Ϯ 7.6 20.5 Ϯ 5.3 NA Insulin (8), diet (2) 5 type 2) Control subjects 50 45.4 Ϯ 2.6 NA NA 4.4 Ϯ 0.1 NA Data are means Ϯ SE. CRF, chronic renal failure; OHA, oral hypoglycemic agent; NA, not applicable. ␣ ␣ ed in 19% of HNF-1 patients (15). As in type 1 and type 2 for a given level of HbA1c in HNF-1 mutation carriers or diabetes, glycemic control is the best predictor of the de- in the combined type 1 and type 2 diabetic group is shown velopment of microalbuminuria in individuals with HNF-1␣ in Fig. 1. Glucosuria was more likely in the HNF-1␣ mutations, as this is a microvascular complication of hyper- participants at almost all levels of glycemia. In patients ␣ glycemia rather than a direct result of the mutation (15). with an HbA1c below 6.9%, 63% of the 30 HNF-1 partici- We hypothesized that aminoaciduria is a specific phe- pants and 36% of the 14 type 1 and type 2 diabetic notypic feature of individuals with HNF-1␣ mutations as a participants had glucosuria (P ϭ 0.043, one-tailed ␹2 test). result of a direct mutational effect that alters amino acid These results indirectly support that the glucose renal transport. We aimed to test this hypothesis and to study threshold is lower in HNF-1␣ mutation carriers compared whether aminoaciduria is a more generalized feature of with type 1 and type 2 diabetic patients. type 1 and type 2 diabetes. If aminoaciduria is specific to Urine amino acid concentrations were elevated in individuals with HNF-1␣ mutations, then it could be used as participants with HNF-1␣ mutations compared with a phenotypic marker before confirmatory genetic testing. control subjects. The results of the individual amino acid concentrations in participants with HNF-1␣ and non- RESEARCH DESIGN AND METHODS diabetic control subjects are shown in Table 2. For 14 of Participants. A total of 50 people with HNF-1␣ mutations were recruited the 16 amino acids, concentrations were higher in the from the U.K. MODY collection, and 50 age-matched normal (nonmutation HNF-1␣ participants compared with the nondiabetic con- carriers) control subjects were recruited from MODY families. Further control trol subjects; for 6 amino acids, statistical significance were recruited from diabetes hospital subjects and renal clinics: 25 partici- pants with type 1 diabetes (age and diabetes duration matched to the HNF-1␣ was reached after Bonferroni correction for performing patients), 25 participants with type 2 diabetes, and 10 participants with 16 analyses. An elevation of urinary amino acid concen- diabetes and non–dialysis-dependent chronic renal failure. The clinical char- tration in the HNF-1␣ participants was seen in all of the acteristics of the participants are shown in Table 1. basic (n ϭ 4) and neutral (n ϭ 11) amino acids except for Laboratory assays. Early morning urine samples were taken from all participants except for the renal failure patients, who gave random samples. valine, which was significantly lower. The only acidic The urine pH and glucose level was tested using BM-Test-7 strips (Boehringer amino acid measured, aspartate, showed a significantly Mannheim). Glucosuria was detected using these strips at a concentration of lower urinary level in the HNF-1␣ participants than in the Ն2.8 mmol/l. Urine albumin and creatinine concentrations were measured control subjects (P Ͻ 0.0001). The mean combined Z score using a Bayer Technicon opeRA analyzer, and albumin/creatinine ratios were calculated.
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