A study of urinary myo-inositol as a sensitive marker of glucose intolerance

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Abstract

Background: We assessed the possibility of using myo-inositol as a marker of glucose intolerance. Methods: We measured urinary myo-inositol enzymatically before and 2 h after a 75-g oral glucose tolerance test in 564 volunteers, who were divided into four groups [normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM)]. Furthermore, we classified NGT into NGT-A (2-h blood glucose <120 mg/dl and 2-h glucosuria <50 mg/dl) and NGT-B (remaining NGT subjects). We then compared Δmyo-inositol (myo-inositol/creatinine ratio: 2-h after glucose load—before load) of each group to investigate the relationship between glucose intolerance and Δmyo-inositol. Results: The glucose tolerance of NGT-B appeared to have deteriorated compared with NGT-A as determined by blood glucose, insulin, and glucosuria. There was very little effect of gender or age on Δmyo-inositol in NGT-A. Δmyo-inositol was significantly higher than that in NGT-A (0.5±7.1 mg/g Cr) not only in IFG (8.7±19.5 mg/g Cr, P<0.0001), IGT (14.8±22.9 mg/g Cr, P<0.0001) and DM (79.5±37.1 mg/g Cr, P<0.0001), but in NGT-B (7.4±12.7 mg/g Cr, P<0.0001). With 2 mg/g Cr as a tentative cut-off for Δmyo-inositol to detect NGT-A, sensitivity and specificity were 68% and 72%, respectively. Conclusions: The Δmyo-inositol can be use of a non-invasive and sensitive marker for glucose intolerance.

Introduction

According to reports by the World Health Organization (WHO) and the Centers for Disease Control and Prevention, the 135 million population of diabetics as of 1995 is expected to rise to 300 million by 2025. This has become a major social issue [1]. However, despite these alarming numbers, the actual number of diabetics who are properly treated is believed to be only one-third of the total number of cases. The remaining diabetics receive no treatment. An alarming number of diabetics are first diagnosed when they visit a medical institution for retinal hemorrhage or proteinurea. The prognosis of diabetic patients with complications is not good. Thus, it is important that diabetes mellitus be detected while it is in a mild stage.

There are numerous cases of impaired glucose tolerance (IGT) in which the post-loaded blood glucose level is high even though the fasting blood glucose value is <126 mg/dl. The risk in such cases of development of cardiovascular disease [2], arteriosclerosis [3] or diabetes [4], [5] is also high. According to a report by the Diabetes Prevention Program Research Group, by actively intervening in individual lifestyles in relation to IGT, the development of diabetes can be reduced to a considerable degree [6]. An oral glucose load or a meal challenge is important for detecting and controlling IGT, which indicates postprandial hyperglycemia.

To diagnose IGT or diabetes mellitus (DM), the blood glucose levels during fasting and 2 h after a glucose load are examined in the 75-g oral glucose tolerance test (75-g OGTT). According to the criteria for diagnosing diabetes mellitus supplied by the American Diabetes Association [7] and WHO [8], test subjects are divided into four groups (normal glucose tolerance (NGT), impaired fasting glucose (IFG), IGT, and DM). IFG and IGT are classified as borderline types based on the diabetes diagnostic criteria of the Japan Diabetes Society [9]. However, since the 75-g OGTT uses only fasting and 2-h post-loaded glucose levels as indicators and excludes the 30- to 90-min glucose level after a glucose load, cases with forms of temporary hyperglycemia such as oxyhyperglycemia may be overlooked. As a result, individuals with mild glucose intolerance might be judged to be NGT. This pathological significance of postprandial hyperglycemia has been a recent focus of attention [10], [11], [12].

To accurately determine the status of blood glucose after a glucose load, it is necessary to use a precise OGTT, in which one can collect a blood sample ≥4 times. Yet, if a precise OGTT is conducted as a routine test to screen for diabetes and glucose intolerance, it will be a major burden not only for health care professionals, but also for test subjects. It will also increase medical costs. Thus, medical institutions have sought convenient and useful diagnostic markers for the early detection of diabetes and glucose intolerance.

myo-Inositol is one form of inositol and is a cyclic d-glucose isomer. It is widely available in organisms unchanged or in the form of a component substance of phospholipid. myo-Inositol is an extremely stable circular alcohol and is supplied by food (1 g), either as free inositol, inositol-containing phospholipids or as phytic acid, and renal biosynthesis (2 g) every day. It is reabsorbed in the renal tubules, maintaining its blood concentration (Fig. 1) [13], [14]. In patients with diabetic complications or renal failure, metabolic disorders of myo-inositol are known to take place. In patients with severe diabetes [15], [16], [17] or kidney disease [18], blood and urinary myo-inositol levels are higher than in healthy individuals.

We previously suggested myo-inositol as a diagnostic marker for diabetes because urinary myo-inositol excretion at 2 h after 75-g OGTT in subjects with glucose intolerance such as IFG, IGT or DM were increased significantly compared to NGT [19]. It was possible to distinguish NGT from DM, IFG and IGT by examining the change in urinary myo-inositol excretion at 2 h after 75-g OGTT [19]. In this study, we first increased the number of cases of OGTT and classified subjects into NGT, IFG, IGT and DM based on the WHO criteria. Next, after further dividing the NGT group into two subgroups depending on either the 2-h post-load blood glucose level or 2-h post-loaded urinary glucose level, we compared the fluctuations in urinary myo-inositol of the respective groups.

The purposes of this study were to confirm significant increase in Δmyo-inositol (increase in urinary myo-inositol excretion before to after 75-g OGTT) not only in DM but also in IFG and IGT in comparison with NGT in 564 volunteers, to confirm the ability to detect NGT-B, which had been predicted to exhibit slight deterioration of glucose tolerance in NGT based on the WHO criteria by means of Δmyo-inositol, and to confirm gender and age effects on Δmyo-inositol in NGT-A patients whose glucose tolerance was assumed to be normal.

Section snippets

Samples

We conducted an OGTT on 564 volunteers who had agreed to participate in this study. They consisted of 343 males and 221 females 48.1±9.3 and 36.0±11.2 years, respectively (mean±S.D.). After fasting overnight, they underwent the 75-g OGTT. Blood and urine samples were collected during fasting and at 2 h after glucose load. Based on the blood glucose level and following the WHO criteria of 1998, we classified them into four groups (NGT, IFG, IGT and DM). Any NGT samples with a 2-h post-load

Clinical trials

Table 1 shows the characteristics of samples. NGT-B consisted of 59 samples that exceeded only the 2-h post-loaded blood glucose criteria, 11 samples that exceeded only the 2-h post-loaded urinary glucose criteria, and 17 samples that exceeded both criteria. Table 2 shows the background data for all of the groups. Although NGT-B, compared to NGT-A, exhibited no significant difference in either fasting insulin level or fasting urinary glucose level, it had significantly higher values than NGT-A

Discussion

In this study, three novel findings were obtained. First, this larger study of 564 cases verified our previous report's findings, confirming the relationship between degree of glucose tolerance and urinary myo-inositol level. Second, there was very little effect of gender or age on Δmyo-inositol in NGT-A subjects, whose glucose tolerance was assumed to be normal. Thus, in order to screen for individual whose glucose tolerance had deteriorated, as early as possible with Δmyo-inositol, neither

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