The Diabetes Control and Complications Trial emphasized the need to lower glycated hemoglobin (HbA1c) levels to decrease the risk of chronic complication of diabetes¹⁾. HbA1c is the gold standard marker of glycemic control and a useful tool in preventing diabetic complications and educating patients in the clinical setting.

However, HbA1c has a number of limitations. HbA1c is a mean value of glycemia over 2-3 months and cannot capture daily glucose fluctuations²⁾. It is also unable to distinguish between fasting plasma glucose and postprandial blood glucose (PBG)³⁾. Recently, it has been suggested that postprandial hyperglycemia and glycemic excursions contribute to the risk of long-term complications in diabetes, increasing their importance in diabetes management^4,5,6). Furthermore, HbA1c levels may be affected in patients with anemia, hemolysis, transfusion, renal disease, liver disease, alcoholism, drug use, and genetic hemoglobin abnormalities^7,8).

Wild et al.⁹⁾ estimated the prevalence of diabetes for all age groups to be 4.4% by 2030 and predicted that if the prevalence of obesity increased, the number of diabetics would be much higher than the estimated value. Thus, it is important to detect individuals with prediabetes who are at high-risk for type 2 diabetes mellitus (T2DM) and with undiagnosed diabetes, so that they receive appropriate early management¹⁰⁾.

The three major fundamental components of metabolic disturbances in diabetes are fasting hyperglycemia, postprandial hyperglycemia, and acute glucose fluctuations⁶⁾. According to previous studies, postprandial hyperglycemia and glycemic excursion are associated with cardiovascular disease^11,12,13). Frequent checking of self-monitored blood glucose (SMBG) levels was used to evaluate postprandial hyperglycemia and variation in blood glucose levels¹⁴⁾. However, this has limitations in reflecting glucose fluctuations precisely. Continuous glucose monitoring systems (CGMSs) are considered the gold standard for assessing glycemic excursion, but are quite expensive and invasive for wide application^14,15). The compound 1,5-anhydroglucitol (1,5-AG) is a glucose analog that declines in hyperglycemic subjects. Recent studies have shown that 1,5-AG is reflective of PBG, glucose excursions, and short-term glucose status^8,11,14). The Food and Drug Administration has recently validated 1,5-AG as a marker of short-term (2-3 weeks) glucose control status^2,16).

The purpose of this study was to assess the clinical utility of 1,5-AG in early diabetes detection in patients with prediabetes status by comparison with HbA1c in overweight and obese (OWOB) children.

1,5-AG is a six-carbon monosaccharide, the 1-deoxy form of glucose, that was first discovered in 1888^16,21). Because of its structural similarity to glucose, absorption of 1,5-AG is competitively inhibited by glucose in the proximal tubule if the renal threshold for glycosuria (generally>180 mg/dL in serum glucose) is reached^8,21), after which levels of 1,5-AG in serum decrease rapidly^8,21). Thus, patients with diabetes usually have markedly lower 1,5-AG levels than the healthy population²²⁾. The reported 1,5-AG range is quite wide, 0.49-110 µg/mL, and the intra- and interassay coefficients of variation are small²³⁾. The sensitivity and specificity of 1,5-AG has been reported as being superior to HbA1c and fructosamine, respectively, and is 84.2% and 93.1% when the cutoff of the 1,5-AG concentration is determined as 14 µg/mL^24,25).

The amount of 1,5-AG is generally maintained at approximately 500-1,000 mg in total²³⁾. This originates mainly from food (4.4 mg/day), whereas its biosynthesis only provides a small source (~0.5 mg/day)²⁶⁾; 1,5-AG is balanced by urinary excretion, and its renal reabsorption is ~99.9%¹⁶⁾. However, it can be affected by medications, diet, age, gender, race, and various pathological conditions (renal disease, liver disease, gastrectomy state, and cystic fibrosis)¹⁹⁾. 1,5-AG is derived mainly from food and is influenced by diet and some medications¹⁹⁾. The major food source is soy, and a small amount is included in rice, meat, fish, fruit, vegetable, tea, milk, and cheese²³⁾. A previous study showed that 1,5-AG decreased with aging in both sexes, and was higher in males than in females²⁷⁾; 1,5-AG was also significantly higher in Asian and African patients than in Caucasians^19,23).

1,5-AG is suitable for evaluating short-term glucose status, glucose excursions, and PBG and thus is suitable for use in monitoring strict glycemic control^19,28). Because postprandial hyperglycemia is a known risk factor for cardiovascular disease, control of PBG is an important target in glycemic control¹¹⁾. Stettler et al.²⁹⁾ showed that 1,5-AG was an optimal indicator of the 2-hour PBG value. According to Schindhelm et al.³⁰⁾, 1,5-AG was significantly inversely correlated with PBG, and the strongest association was seen in the second week, compared with HbA1c, which is considered to reflect mean glucose levels over the last 3 months. Sun et al.¹⁴⁾ analyzed the correlation between 1,5-AG and glycemic excursion, using CGMS, and 1,5-AG was more closely related to glycemic excursions than HbA1c. However, unlike SMBG or CGMS, 1,5-AG does not provide information about the peak timing of hyperglycemia¹⁹⁾. Besides, in some patients, there is a discordance between 1,5-AG and other glycemic markers; the reason for this discordance is presently unknown³¹⁾.

Recently, markedly increased T2DM, even in children, could lead to profound economic costs for diabetic care and managing complications related to diabetes, and the importance of identifying prediabetics has increased^9,32). Thus, today, early detection of prediabetes and appropriate intervention in early diabetes are very important in preventing the progress of diabetes³²⁾. Several prospective studies showed that 5-year cumulative incidence of diabetes was 12%-25% in subjects with HbA1c between 5.5% and 6%^33,34,35,36). Data from National Health and Nutrition Examination Survey indicated that the subjects with HbA1c between 5.5% and 6% were prone to impaired fasting glucose or IGT. Therefore, subjects with HbA1c between 5.5% and 6% should be initiated preventive intervention³⁷⁾. In this study, we decided a lower cutoff of HbA1c, 5.5%, for prediabetes.

In this study, we compared 1,5-AG with HbA1c, the "traditional" standard marker of glycemic control, in the OWOB and diabetes groups. The 1,5-AG levels were significantly inversely correlated with HbA1c 5.5%-8%. The 1,5-AG values of diabetes subjects overlapped with the OWOB group when HbA1c was ≤8%, whereas most of the poorly controlled diabetics (HbA1c>8%) had prominently low levels of 1,5-AG, and showed no correlation between 1,5-AG and HbA1c, and this result was consistent with a previous report on severely uncontrolled diabetes¹⁹⁾. According to this, 1,5 AG was a valuable index in prediabetic obese children and relatively well-controlled diabetic patients with HbA1c between 5.5% and 8%.

As mentioned earlier, 1,5-AG might be a more valuable marker of a detailed glucose status for the segment with HbA1c≤8%. This may imply that 1,5-AG better reflects glycemic changes of prediabetes than HbA1c. It was previously reported that serum 1,5-AG concentrations were lower in nondiabetic subjects with a family history of T2DM than in those with no family history³⁸⁾. The level of 1,5-AG, while maintained within the normal range, was decreased in IGT subjects³⁹⁾. The proportion of this reduction was correlated with the degree of glucose tolerance impairment. 1,5-AG precisely detected slight glycemic changes promptly, even in the near-normoglycemic range⁴⁰⁾. Also, HbA1c, fasting glucose, and 1,5-AG were reported as good predictive factors of T2DM in obese patients³²⁾. Among them, HbA1c and 1,5-AG were strong predictive variables of prediabetes just before T2DM in insulin-resistant obese patients³²⁾. Therefore, we suggested that the level of 1,5-AG could play a role in the continuum of diabetes in obese subject with a HbA1c level of less than 6.5% with glucose fluctuations and postprandial hyperglycemia.

1,5-AG is a valuable index in the HbA1c range 5.5%-8% and it might be considered as an early glycemic control index in obese patients with HbA1c levels of more than 5.5%., such as IGT or insulin-resistant obese children. Also, 1,5-AG level assessments should be stressed as a supplementary tool for better compliance as well as improvement of short-term glucose control in diabetes management in relatively well-controlled diabetes patients with an HbA1c level of less than 8%.

This study had several limitations. First, it is a retrospective study based on past medical records. Second, the small sample size and short follow-up durations of diabetes were additional limitations. Third, we could not examine patient glucose variability or peak glucose levels by CGMS or SMBG and were unable to include patients with large glucose variability. However, we did not select specific patients, thus more accurately reflecting a realistic diabetic population. Further studies are needed for 1,5-AG to be recognized as an early glycemic marker in prediabetes.