the nationwide registry of mody has been established at the department of metabolic diseases , jagiellonian university medical college , krakow , poland . we contacted 47 adult subjects from this group , and 41 agreed to enter this study . the following exclusion criteria were used : pregnancy , liver cirrhosis , hypo- or hyperalimentation , steroid therapy , gastrectomy , and elevated serum creatinine level . based on these criteria , we excluded four patients because of increased serum creatinine concentration ( i.e. , > the number of patients with hnf-1 mody , with diabetes diagnosed according to world health organization criteria , was 33 , whereas 4 subjects were normoglycemic in the fasting condition and were classified as nondiabetic subjects , which is also supported by the fact that they all had a1c levels within the normal range ( < 6.0% ) . the first group , 47 apparently healthy control subjects who were normoglycemic in the fasting condition , contained spouses of patients with mody and volunteers from the medical personnel of the department of metabolic diseases . the second group included 43 patients with type 2 diabetes diagnosed at age 35 years for whom no insulin therapy was used for at least 2 years after diagnosis , ascertained as previously described ( 13 ) . the study protocol and informed consent procedures were approved by the ethics committee of jagiellonian university , medical college and were concordant with the declaration of helsinki . serum and edta - plasma were obtained by spinning at 3,500 rpm and stored at 80c . the 1,5-ag concentration was measured in edta - plasma samples with an enzymatic , colorimetric method using glycomark chemicals ( tomen america ) by nippon kayaku tokyo co. ( tokyo , japan ) ( 14 ) . fasting glucose levels were determined by an enzymatic technique ( automated analysis glucose god - pap method ; boehringer mannheim ) . comparisons were made with the  or fisher 's exact test , where applicable , for frequencies of qualitative traits . for quantitative traits , student 's t test or anova was used with the tukey post hoc test when data fit into a normal distribution . the data for which the kruskal - wallis test was significant were further analyzed with a nonparametric multiple comparison steel test . these predictors were included as covariates in a general linear model analysis performed in all study groups and in the diabetic groups . computations were performed with minitab 14.20 statistical software and the r language and environment , version 2.4.1 . 1,5-ag measurements as a biochemical test for hnf-1 mody , the test parameters were calculated and receiver operating characteristic ( roc ) curve analysis was performed with medcalc 9.3.8.0 statistical software . both diabetic groups were similar for traditional measures of metabolic control such as fasting glucose and a1c . they varied , however , for age , bmi , and diabetes duration , which is in line with the way both groups were defined . the mean 1,5-ag plasma concentration in the diabetic hnf-1 mutation carriers group was 5.9 g / ml ( median 2.6 g / ml , quartile deviation 4.3 ) , whereas in the type 2 diabetic group it was 11.0 g / ml ( 11.5 g / ml , 6.7 ) and in the nondiabetic control group it was 23.9 g / ml ( 24.5 g / ml , 4.9 ) . there was a highly significant difference between the mody group and the control group ( p < 0.00005 ) and between the mody and type 2 diabetic groups ( p = 0.003 ) . to justify application of a parametric approach in further analysis , the data were reevaluated with anova and the tukey test , results of which were also significant ( p < 0.00005 and p = 0.013 , respectively ) . in four hnf-1 normoglycemic mutation carriers , the mean 1,5-ag level was 21.1 g / ml ( range 16.732.9 g / ml ) and was not different from the level in the control group ( p = 0.32 ) . the mean age of the four subjects was 24.7 years , mean bmi was 21.0 kg / m , and mean a1c was 5.6% . the 1,5-ag concentration was lower in women than in men in the control group ( 21.5 vs. 27.7 g / ml , p = 0.003 ) , whereas there were no significant differences between sexes in the mody and type 2 diabetic groups ( p = 0.71 and p = 0.91 , respectively ) . in the mody group , the 1,5-ag level significantly correlated only with the a1c level (  = 0.72 , p < 0.0005 ) , whereas in the type 2 diabetic group there was significant correlation of the 1,5-ag level with a1c (  = 0.72 , p < 0.0005 ) and age of diabetes diagnosis (  = 0.36 , p = 0.018 ) . in multiple linear regression the a1c level remained the only significant predictor for 1,5-ag ( p < 0.0005 ) . in the nondiabetic control group , the 1,5-ag concentration significantly correlated with age (  = 0.52 , p < 0.0005 ) and bmi (  = 0.34 , p = 0.02 ) . in the multiple regression model , the general linear model for 1,5-ag concentration as a dependent variable was applied in the three study groups combined ( r = 52.1% ) . the differences in 1,5-ag level between the study groups remained significant ( p < 0.0005 ) , and age was a significant covariable ( p = 0.044 ) . in the diabetic study groups ( r = 53.2% ) , the general linear model revealed a significant difference in 1,5-ag level between type 2 diabetes and hnf-1 mody ( p = 0.006 ) , with a1c level as a significant covariable ( p < 0.0005 ) . the roc curve analysis was performed in diabetic patients : 33 with hnf-1 mody and 43 with type 2 diabetes . area under the roc curve ( auc ) was 0.732 ( 95% ci 0.6180.827 ) . the optimal sensitivity and specificity to test for mody were 72.7% ( 54.586.7% ) and 65.1% ( 49.179.0% ) , respectively , at a criterion of < 6.6 g / ml of plasma 1,5-ag . to further improve the parameters of the test , we performed additional analyses with a narrowed a1c range based on the plot showing relationships between a1c and 1,5-ag in diabetic groups ( fig . 1 ) . because type 2 diabetic patients with an a1c level > 9.0% had a very low 1,5-ag level , similar to subjects with hnf-1 mody , we first excluded all individuals with a1c above this value ( 5 patients with mody and 10 with type 2 diabetes , respectively ) . the auc was 0.823 ( 0.7040.909 ) , and optimal sensitivity and specificity at the criterion of < 6.6 g / ml 1,5-ag were 71.4% ( 51.386.7% ) and 84.85% ( 68.194.8% ) , respectively . additionally , we excluded 7 patients with mody and 13 with type 2 diabetes who had a1c < 6.5% because of a lack of correlation of 1,5-ag with a1c in both groups ( p = 0.34 for mody and p = 0.44 for type 2 diabetes ) . this exclusion improved the test specificity and resulted in the following parameters : auc 0.887 ( 0.7490.964 ) and optimal sensitivity at the criterion for mody of < 6.5 g / ml 1,5-ag 85.7% ( 63.696.8% ) and specificity 80.0% ( 56.394.1% ) . figure 2 shows this roc curve analysis in the group of patients with an a1c range between 6.5 and 9.0% . here we report for the first time the plasma 1,5-ag levels in patients with hnf-1 mody . we observed that the levels of 1,5-ag in this group were significantly lower than those in type 2 diabetic subjects with similar glycemic control as assessed by a1c levels and fasting glucose level . we were prompted to perform this study by an earlier description of decreased renal threshold and increased glycosuria in hnf-1 mutation carriers ( 9,10 ) . the major cause of low 1,5-ag levels in diabetic hnf-1 mutation carriers is , as in other diabetic patients , most likely its competition in the renal tubule with a large amount of glucose for the ag / fructose / mannose transporter ( 3 ) . however , in hnf-1 mutation carriers , the threshold for glucosuria is lower , and therefore the excessive glucose in the renal tubule would be expected to result in greater decrements in 1,5-ag . one can not rule out , however , that the additional mechanism associated with the impaired expression of this transporter is a direct result of a mutation in the hnf-1 gene encoding a transcription factor present in kidney . first , 1,5-ag measurements have limited usefulness in hnf-1 mody as a marker of metabolic control . there were already some groups of patients described for whom 1,5-ag should not be recommended as a diabetes control measure owing to a low renal threshold for glucose , such as pregnant women and patients with end - stage renal disease ( 7,8 ) , although some promising attempts of its use in gestational diabetes were described ( 15 ) . in addition , there were some efforts to use 1,5-ag as a screening tool in diabetes ( 16,17 ) . it should be emphasized , however , that no scientific diabetes organization recommended it for this purpose . if , however , 1,5-ag is accepted as a screening tool for diabetes at any time in the future , this should not include situations in which the renal threshold for glucose is altered , such as hnf-1 mody . at the same time , our observation points to 1,5-ag as a potential differential diagnosis biomarker for mody associated with hnf-1 mutations . the measurement of plasma 1,5-ag level seems to have high sensitivity and specificity to differentiate between hnf-1 mody and type 2 diabetes as long as a1c values are between 6.5 and 9.0% . it should be noted that most of the patients seen in everyday clinical practice fall into this range . our study should be perhaps criticized for dissecting the data to improve the roc curve and for choosing an arbitrary range of a1c for this analysis . as shown in fig . 1 , all individuals , mody patients , and type 2 diabetic subjects with a1c > 9.0% had very low 1,5-ag levels , probably due to a massive overload of renal tubules by glucose , and thus the marker is not specific in this range of a1c . the exclusion of subjects with low a1c values is justified by the fact that some degree of hyperglycemia is necessary to cause glycosuria and a subsequent fall in 1,5-ag level . the renal threshold in patients with hnf-1 mody was measured at a mean whole blood glucose level of 6.5 mmol / l ( the equivalent of 7.4 mmol / l in plasma ) ( 9,10 ) . in another study , during an oral glucose tolerance test , glycosuria was detected only in nondiabetic subjects with hnf-1 mutations and with impaired glucose tolerance ( 10 ) . an additional argument constitutes a lack of correlation between a1c and 1,5-ag levels among subjects with well - controlled diabetes in our study and in an earlier report ( 18 ) . nevertheless , the specific range of a1c for which 1,5-ag is a useful biomarker for differential diagnosis will require further confirmation . interestingly , all nondiabetic hnf-1 mutation carriers had levels of marker in the range of the 10th90th percentile of the control subjects , indicating that 1,5-ag measurement is not useful for predictive testing . lack of postprandial hyperglycemia data in the subjects examined is a limitation of our study . as a consequence , we can not entirely rule out the possibility that a higher degree of postprandial hyperglycemia in hnf-1 mody patients might have partially contributed to the observed large , almost twofold difference in 1,5-ag level between both diabetic groups . there are , however , important indirect arguments on the key effect of renal tubulopathy . first , it was shown in two other clinical groups , pregnant women and patients with end - stage renal disease , that the renal threshold for glucose , which is substantially different from normal , seriously influenced the circulating 1,5-ag level ( 7,8 ) . because renal tubulopathy in hnf-1 mody has been well documented previously ( 9,10 ) second , our diabetic study groups were not only identical for a1c but also very similar for fasting glucose . because the a1c level is influenced by both postprandial and fasting plasma glucose ( 19 ) , it is very unlikely that putative significantly higher postprandial hyperglycemia had a substantial , if any , contribution to this huge difference in the 1,5-ag level . were previously reported as having higher postchallenge hyperglycemia compared with glucokinase mutation carriers ( mody2 ) ( 20 ) . the latter group , however , is very specific and unusual , with its own very low postchallenge glucose increase ( 23 mmol at 2 h ) . no published data support a notion that hnf-1 mody is characterized by greater postprandial hyperglycemia than type 2 diabetes . previously , a particularly high effect of postprandial hyperglycemia ( as assessed by a continuous glucose - monitoring system ) on 1,5-ag level was described in a group of diabetic patients with moderately controlled diabetes ( with a1c < 8% ) ; most of these patients had type 1 diabetes , which is characterized by absolute insulin deficiency ( 6 ) . the phenomenon of a greater contribution of postprandial hyperglycemia to overall glycemic control in such patients with moderately controlled diabetes was described earlier ( 19 ) . the comparison done between our diabetic groups with respect to 1,5-ag level included patients with a variable degree of glycemic control and also those with a1c values > 8% ( > 30% of mody subjects ) , in whom the impact of fasting plasma glucose is larger . our study should also perhaps be criticized for choosing type 2 diabetic patients for the comparison , as their clinical characteristics were different from those of patients with hnf-1 mutations and , thus , some variables could have an impact on individual glucose profiles and therefore contribute to lower 1,5-ag despite seemingly equal a1c values . the carriers of hnf-4 ( mody1 ) seem to be the most appropriate for the comparison because of its clinical similarity to hnf-1 mody , relatively high frequency , and the lack of data on the altered glucose renal threshold ( 21,22 ) . however , the families from the polish nationwide registry of mody have not been systematically tested for mutations in this gene , and we do not have a cohort of an appropriate size in this ethnic group . a second group that might be considered for the comparison of 1,5-ag with the diabetic hnf-1 mutation carriers is type 1 diabetic patients . there are , however , already biomarkers available to differentiate between mody and type 1 diabetes , such as islet - specific antibodies and c - peptide . in addition , it is difficult to provide positive and negative predictive values for the test based on serum 1,5-ag measurements . it would require a different study design in which testing is prospective and would not , as in our study , involve testing two discrete groups . we believe that an application for 1,5-ag as a marker for differentiation between other mody subtypes or in young type 2 diabetic subjects will be found eventually . the relative prevalence of hnf-1 mody may constitute from one - third to two - thirds of families with early - onset autosomal dominant diabetes ( 23,24 ) and about 8% of young patients with type 2 diabetes ( 25 ) . finally , we should acknowledge that a relatively small number of hnf-1 mody patients were examined . first , as expected , the 1,5-ag concentration was strongly inversely correlated with the a1c level in diabetic patients from both groups . the influence of sex and age on 1,5-ag levels was observed previously in control subjects ( 14,18 ) but , as with our data , not in the diabetic study groups , as reported from other populations ( 18 ) . the creatinine level did not influence plasma 1,5-ag concentration in these study groups : all three groups had normal creatinine levels . the mean level of 1,5-ag in the control group was slightly higher than that in an american reference population ( 14 ) , which may be caused by different nutritional habits in the polish population , especially higher consumption of cereal food . in summary , we conclude that 1,5-ag may be a useful biomarker for the differential diagnosis of patients with hnf-1 mody with a specific range of a1c , although it requires further investigation in larger sets of patients and other diabetic groups , as well as direct assessment of the relative contribution of the low renal threshold for glucose and postprandial hyperglycemia . however , the clinical use of this particle in diabetic hnf-1 mutation carriers for metabolic control has substantial limitations .
objective1,5-anhydroglucitol ( 1,5-ag ) is a short - term marker of metabolic control in diabetes . 
 its renal loss is stimulated in hyperglycemic conditions by glycosuria , which results in a lowered plasma concentration . as a low renal threshold for glucose has been described in hepatocyte nuclear factor-1 ( hnf-1 ) maturity - onset diabetes of the young ( mody ) , the 1,5-ag level may be altered in these patients . 
 the purpose of this study was to assess the 1,5-ag levels in patients with hnf-1 mody and in type 2 diabetic subjects with a similar degree of metabolic control . 
 in addition , we aimed to evaluate this particle as a biomarker for hnf-1 mody.research design and methods  we included 33 diabetic patients from the polish nationwide registry of mody . 
 in addition , we examined 43 type 2 diabetic patients and 47 nondiabetic control subjects . 
 the 1,5-ag concentration was measured with an enzymatic assay ( glycomark ) . 
 receiver operating characteristic ( roc ) curve analysis was used to evaluate 1,5-ag as a screening marker for hnf-1 mody.resultsthe mean 1,5-ag plasma concentration in diabetic hnf-1 mutation carriers was 5.9 g / ml , and it was lower than that in type 2 diabetic patients ( 11.0 g / ml , p = 0.003 ) and in nondiabetic control subjects ( 23.9 g / ml , p < 0.00005 ) . the roc curve analysis revealed 85.7% sensitivity and 80.0% specificity of 1,5-ag in screening for hnf-1 mody at the criterion of < 6.5 g / ml in patients with an a1c level between 6.5 and 9.0%.conclusions1,5-ag may be a useful biomarker for differential diagnosis of patients with hnf-1 mody with a specific range of a1c , although this requires further investigation . 
 however , the clinical use of this particle in diabetic hnf-1 mutation carriers for metabolic control has substantial limitations .