The dramatic increase in incidence of diabetes (1) has prompted efforts to identify individuals who have milder glucose intolerance, because early management with lifestyle change and/or medication can delay progression to diabetes with its attendant morbidity, mortality, and cost (2). It has long been recognized that impaired glucose tolerance (IGT) is a diabetes precursor, but recognition of IGT requires oral glucose tolerance tests (OGTTs), which many health care providers are reluctant to order (3). As a more convenient alternative, the American Diabetes Association has emphasized screening by measurement of fasting plasma glucose (FPG) and lowered the cutoff for abnormal FPG progressively from 140 to 125 to 110 mg/dl. However, compared with IGT, an impaired fasting glucose (IFG) cutoff of 110 mg/dl provided good specificity but reduced sensitivity for detecting risk of developing diabetes (46).

To obtain increased sensitivity, the American Diabetes Association recently lowered the cutoff for IFG from 110 to 100 mg/dl (7), and application of this cutoff has increased the number of Americans thought to have “pre-diabetes” to 41 million (8). Although such individuals are considered candidates for management aimed at decreasing their risk of progressing to diabetes (9), the metabolic and cardiovascular risks of individuals with very modest abnormalities in FPG are not well understood. In this study, we compared measures of risk in individuals with fasting glucose 100–109 mg/dl (IFG100) with those with fasting glucose 110–125 mg/dl (IFG110).

The study was approved by the Emory University Institutional Review Board and involved 550 adult volunteer subjects who were not known to have diabetes and were in general good health (had not needed to miss work during the previous week). As part of the Screening for Impaired Glucose Tolerance (SIGT) study, standard 75-g OGTTs were performed in the morning after an overnight fast, and fasting blood and urine samples were obtained for measurement of biomarkers. Normal glucose tolerance (NGT) was characterized by fasting glucose <100 mg/dl and 2-h glucose <140 mg/dl, IGT by 2-h glucose 140–199 mg/dl, diabetes by 2-h glucose ≥200 mg/dl, and IFG as described above; 13 subjects with fasting glucose >125 mg/dl were excluded from analysis because they could not be included in the IFG categories. Plasma glucose and other biomarkers were measured in the Clinical Laboratory at Grady Memorial Hospital using the Beckman LX-20 (Beckman, Brea, CA). Biomarkers were expressed relative to the upper quintile (high) of values of the 368 subjects with NGT. The “metabolic syndrome” was examined as defined by both International Diabetes Federation (10) and National Cholesterol Education Program (NCEP) (11) criteria. Statistical analyses were conducted using S-Plus, version 6 (Insightful, Seattle, WA), and Stata, version 7 (Stata, College Station, TX).

Clinical demographics were similar in 95 subjects with IFG100 compared with 41 subjects with IFG110, respectively: age 50 vs. 51 years, BMI 32.2 vs. 33.8 kg/m2, female 44 vs. 46%, and black 36 vs. 41% (all P = NS). Relative to NGT, IFG100 and IFG110 were associated with (“conferred”) significant (Fig. 1) but comparable risk of the metabolic syndrome by International Diabetes Federation criteria (odds ratio ([OR] 7.10 [95% CI 4.39–11.46] vs. 10.33 [4.87–21.88]), but IFG110 conferred greater risk by NCEP criteria (5.86 [3.66–9.37] for IFG100 vs. 17.25 [7.58–39.14] for IFG110; P = 0.025). There were also only minor differences in risk for elevated C-reactive protein (1.27 [0.76–2.12] vs. 1.54 [0.77–3.09]) and alanine aminotransferase (4.03 [2.55–6.38] vs. 2.87 [1.52–5.41]). However, only IFG110 increased the risk for high urine albumin-to-creatinine ratio (0.59 [0.32–1.08] for IFG100 vs. 2.05 [1.05–4.02] for IFG 110) and LDL cholesterol >130 mg/dl (0.99 [0.61–1.58] vs. 2.42 [1.28–4.56]) (both P < 0.03 for IFG100 vs. IFG110).

In contrast, there was a more dramatic difference in risk of postchallenge glucose intolerance (IGT or diabetes). The risk conferred by IFG100 was 2.53 (1.55–4.13), while the risk for IFG110 was 11.54 (5.78–23.02) (P = 0.0004). In multivariable analyses adjusting for age, race, sex, and BMI, the risk of glucose intolerance was OR 3.22 (95% CI 1.84–5.66) for IFG100 vs. 13.14 (6.12–28.23) for IFG110 (P = 0.001).

The present studies demonstrate that although pre-diabetes, characterized as IFG100 and IFG110, identifies individuals with similar demographics, IFG110 carries increased risk of the metabolic syndrome by NCEP criteria, LDL cholesterol >130 mg/dl, and high urine albumin-to-creatinine ratio, and IFG110 is much more likely to confer risk of postchallenge hyperglycemia. It has previously been reported that individuals with progressive elevation in FPG are more likely to have IGT or diabetes (9). However, we are not aware of previous comparisons of the risks in individuals added by inclusion under “newer” criteria (IFG100) versus the risks conferred by the “older” criteria (IFG110).

Recognition of pre-diabetes is important to identify individuals who have risks that can be modified to improve outcomes. The Baltimore Longitudinal Study of Aging has shown that mortality is increased in men by levels of FPG >110 mg/dl and/or 2-h OGTT glucose levels >140 mg/dl, even after adjustment for the presence of other risk factors (12), and mortality was also independently increased by the presence of postchallenge hyperglycemia in men in the Whitehall Study (13) and in both men and women in the DECODE (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe) study (14). Although it is not yet established in randomized controlled trials that mortality and/or cardiovascular events can be decreased in individuals with such mild hyperglycemia by interventions other than treatment with acarbose (15), the hypothesis is being tested in ongoing studies with rosiglitazone, nateglinide, ramipril, and valsartan. Moreover, several different studies have shown that lifestyle change and/or medication can reduce progression from IGT to diabetes (2,1618), and such interventions appear to be cost-effective (19). Such considerations indicate that identification of pre-diabetes should be a national priority.

The present study demonstrates that it is particularly important to follow recognition of IFG110 with additional diagnostic and therapeutic strategies. Since IGT and diabetes are associated with increased mortality (above), detection of IFG110 should also prompt consideration of further evaluation by OGTT.

This work was supported in part by grants DK07298, DK062668, RR017643, DK066204, and RR00039.

Parts of this study will be presented in abstract form at the 66th annual meeting of the American Diabetes Association, Washington, DC, 9–13 June 2006.

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W.S.W. and P.K. are currently affiliated with Christiana Hospital, Newark, Delaware.

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