Identifying monogenic forms of diabetes and assigning the subtypes correctly currently depends on recognizing a clinical phenotype and arranging confirmatory molecular testing. Additional biochemical tests that aid prioritization of cases for genetic testing would have great clinical utility.
1,5AG is an attractive candidate marker for HNF1A-MODY because it utilizes the known characteristic of low renal threshold for glucose seen in HNF1A
mutations. We confirm the previous finding (4
) that 1,5AG levels are lower in HNF1A-MODY than type 2 diabetes, but this difference is only apparent after adjustment for A1C. This is necessary because the lower A1C in our HNF1A-MODY group (7.2 vs. 7.8%, P
= 0.04) has the effect of diminishing the difference in unadjusted 1,5AG levels (the previous study was well matched at baseline for A1C). Adjusting for A1C increased the discriminative accuracy of 1,5AG to identify HNF1A-MODY from type 2 diabetes with the AUC of the ROC curve rising from 0.60 to 0.75. This is still of rather limited clinical utility (AUC of ≥0.8 representing a useful test) and would require further validation to design a suitable model that includes A1C. Ideally this validation would include more HNF1A-MODY cases with higher A1C, as we have limited data on A1C >9%. A further limitation for a role of 1,5AG in a diagnostic strategy to detect HNF1A-MODY is that we found no difference in 1,5AG levels between HNF1A-MODY and either form of autoimmune diabetes.
The most striking finding in our study was the higher 1,5AG levels in subjects with GCK-MODY compared with all other groups. This is likely to be explained by the known modest postchallenge glucose increment seen in those with GCK
). Postprandial glucose levels rarely rise high enough to cause glycosuria, resulting in levels of 1,5AG that are mainly within the normal range. Our ROC curve analyses result in promising estimates for the ability of 1,5AG to discriminate GCK-MODY from both type 2 diabetes and HNF1A-MODY.
Though 1,5AG levels are likely to be influenced by recent dietary intake, we made no attempt to adjust for this. The ROC curve results are reassuring that this test will perform well in routine clinical practice where prior dietary information is not likely to be available.
There are some limitations to extrapolating this finding to a general type 2 diabetes clinic population: The subjects in this study were selected for age of diagnosis ≤45 years, where the pretest probability of possessing a GCK
mutation is likely to be higher than in an unselected group of patients with type 2 diabetes (GCK
mutations in fasting hyperglycemia fall from a prevalence of 40% in children [19
] to ~1% in adults diagnosed over 50 years of age [20
]). In the <45 years of age range the likely prevalence of GCK
mutations is difficult to estimate but probably in the range of 3–5%.
We found that duration of diabetes did not have a significant effect on 1,5AG level; however, the type 2 diabetic patients on diet treatment had a higher 1,5AG than those on oral hyperglycemic agents or insulin. This suggests that postprandial glucose excursion is not normalized by treatment of diabetes. Therefore, we would predict that 1,5AG levels might be less useful in discriminating GCK-MODY from those with type 2 diabetes who are well-controlled on diet treatment.
There was very little overlap between the 1,5AG levels in our GCK-MODY and HNF1A-MODY groups. This discriminative performance benefits from the fact that two major characteristics of these subtypes of MODY (low renal threshold and low postchallenge increment) have opposite effects on 1,5AG levels and suggests 1,5AG analysis might have the most potential as a discriminative test between these two MODY subtypes. Currently patients suspected of having MODY are frequently selected for GCK
rather than HNF1A
mutation testing on the basis of the characteristic pattern seen on OGTTs: In GCK-MODY a mild fasting hyperglycemia with a modest 2-h increment (90th centile <4.6 mmol/l) is observed (12
), while in HNF1A-MODY FPG may be normal but with a high 2-h postchallenge level (mean >5 mmol/l) (18
Although an OGTT is quoted as the gold standard investigation (12
), it is time consuming, difficult to interpret in those on treatment, and has large day-to-day variability (21
). A 1,5AG measurement would in theory be a useful, more cost-effective, and practical alternative to an OGTT, as it reflects postprandial glucose excursion from a single nonfasting blood sample. OGTT data were not available on our GCK-MODY cases, so we were not able to directly assess the correlation with 2-h glucose. However, a relationship between 1,5AG levels and OGTT has been examined previously; in subjects with IGT 1,5AG levels were strongly correlated (r
= −0.8) with 2-h glucose levels, and this was greater than the correlation seen with FPG and the correlation between A1C and either fasting or 2-h values (22
). Similarly, 1,5AG levels showed good correlation with postprandial continuous glucose monitoring system readings (23
) and 2-h postprandial capillary measurements (24
). This supports the use of 1,5AG as a surrogate for postchallenge glucose and merits further validation in GCK-MODY.
In conclusion, we suggest future research should focus on the role of the 1,5AG level as a tool to differentiate MODY subtypes in those already suspected of having a monogenic form of diabetes.