One-Hour Postload Plasma Glucose Levels,a Predictor of Additional Risk for Diabetes: Prevalence,Mechanisms,and Associated Cardiovascular and Metabolic Risk Factors in Hispanics

Abstract

Objective:

The aim of this study was to determine the prevalence of and the mechanisms by which elevated glucose concentrations at 1-h after a glucose load, conferred increased risk for type 2 diabetes mellitus (T2DM). The study was conducted in subjects with glucose abnormalities (impaired fasting glucose [IFG], and impaired glucose tolerance [IGT]), as well as in normal fasting-normal tolerant subjects (NFG-NGT).

Method:

One-hour plasma glucose concentrations were measured as part of 0- to180-min oral glucose tolerance test (OGTT) performed in an unselected sample of 490 Latino-Hispanics. A cutoff of 154 mg/dL at 1-h during the OGTT was employed, because higher glucose levels define subjects at increased risk for T2DM. Surrogate markers of insulin sensitivity and release, and glucose and insulin time courses were measured. Obesity, cardiovascular risk factors, and presence of metabolic syndrome were also assessed.

Results:

One-hour plasma glucose concentrations above the cutoff (≥155 mg/dL) were found in 8.3% of NFG-NGT, 43% of IFG, 65% of IGT, and in 90% of IFG + IGT, and were associated with greater postload hyperglycemia (AUCG) and hyperinsulinemia (AUCI), and with reductions in indices of β-cell function (ΔI_0–30/ΔG_0–30, and ΔI_0–180/ΔG_0–180), insulin sensitivity [Matsuda index, homeostasis model assessment of insulin resistance (HOMA-IR)], and disposition index (Δ_0–30 I/Δ_0–30 G ÷ HOMA-I), markers of increased risk of T2DM. In addition, those with ≥155 mg/dL were older, more obese, had higher blood pressure, and higher prevalence of metabolic syndrome. These clinical and metabolic changes were characteristic of subjects with 1-h plasma glucose concentrations ≥155 mg/dL, irrespectively of whether they were classified as NFG-NGT, IFG, or IGT.

Conclusions:

One-hour postload plasma glucose levels ≥155 mg/dL identified a subgroup of subjects, which by current guidelines are classified as NFG-NGT, IFG, or IGT, but that are at a higher risk that their average group risk. Recognition and management of these subjects may reduce incidence of diabetes and cardiovascular events.

Introduction

I dentification of subjects at high risk for developing type 2 diabetes mellitus (T2DM) is required for early initiation of preventive treatment. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are glucose abnormalities known to be associated with a higher future risk of T2DM.¹ Diagnosis of IFG relies on presence of fasting plasma glucose concentrations (100–125 mg/dL), and diagnosis of IGT is based on 2-h plasma glucose levels (140–199 mg/dL) obtained after ingestion of 75 g of glucose.^2
–4 Mexican Americans and Caucasian subjects with IFG or IGT have a 2–3% average yearly conversion rates to T2DM, increasing to 10% in those with combined abnormalities (IFG + IGT).^5,6 Noteworthy, not only there are differences in risk among subjects with IFG or IGT, but also a significant number of subjects with normal fasting (<100 mg/dL) (NFG) and normal postload 2-h plasma glucose concentrations (<140 mg/dL) [normal glucose tolerance (NGT)] are at increased risk for T2DM.¹ Unfortunately, these individuals are not being identified by adhering to current guidelines.

Several efforts have been made to better predict the risk of developing T2DM.^{5

–15} Presence of plasma glucose concentrations of ≥155 mg/dL 1 h after the ingestion of 75 g of glucose, was recently found to confer an additional 2- and 3.5-fold increase risk of developing T2DM in subjects with IGT and IFG, respectively, and an additional 5-fold increase risk in NFG-NGT individuals.^5,6 Because of its clinical significance, we investigated how prevalent 1-h postload plasma glucose levels ≥155 mg/dL are in an unselected population, as well as in subjects with isolated IFG, isolated IGT, combined IFG-IGT, and in NFG-NGT individuals. To understand how it predicts increased risk for T2DM, we evaluated if 1-h postload plasma glucose levels ≥155 mg/dL were associated with a worse cardiovascular and metabolic profile (metabolic syndrome), and with defects in glucose disposition, insulin secretion, postload hyperinsulinemia, and in indices of increased risk of diabetes.^14,15 Additionally, we evaluated whether the clinical and laboratory characteristics of subjects with 1-h postload plasma glucose levels ≥155 mg/dL helped in predicting those that are at a higher risk of future T2DM. The study was conducted in an unselected sample of 490 subjects of Hispanic descent, an ethnic group in whom 1-h postload abnormalities have not been evaluated.

Research Design and Methods

The study was performed at the Center for the Detection of Silent Cardiovascular and Metabolic risk factors affiliated to the Clinical Pharmacology Unit at the Central University of Venezuela. A total of 490 apparently healthy subjects were screened for glucose abnormalities and cardiovascular and metabolic risk factors. Patients with known type 1 diabetes mellitus were excluded. None of the studied subjects was taking medications affecting glucose or insulin metabolism. The study was conducted in adherence to the Declaration of Helsinki, and the research protocol was approved by the institutional review board of the Central University Hospital serving the city of Caracas. All participants gave written informed consent. All applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research.

Complete history, physical examination, and laboratory investigations, including hematology, chemistry, fasting lipid panel, fasting and postload (75 gD glucose) glucose and insulin levels, liver function tests, and urinalysis were obtained. Blood pressure was measured with a standard mercury sphygmomanometer, and the cuff size was optimized for arm circumference. Heart rate was obtained from a 1-min pulse. Overall adiposity was assessed by body weight and body mass index (BMI). Waist circumference was measured in the standing position midway between the highest point of the iliac crest and the lowest point of the costal margin in the midaxillary line. All anthropometric measurements reflected the average of two measurements.

After at least 5 days of weight-maintaining diet, the fasting subjects underwent a 75-g oral glucose tolerance test (OGTT). Blood samples were obtained at baseline, 30, 60, 90, 120, and 180 min after the glucose ingestion. Patients were classified into groups based on the American Diabetes Association (ADA) and the World Health Organization (WHO)^2
–4 diagnostic criteria based on glucose levels: NGT (fasting <100 mg/dL and 2 h <140 mg/dL); isolated IFG (fasting 100–125 mg/dL and 2 h <140 mg/dL); isolated IGT (fasting <100 mg/dL and 2 h 140–199 mg/dL); and combined IFG/IGT (fasting 100–125 mg/dL and 2 h 140–199 mg/dL. T2DM was diagnosed with fasting glucose >125 mg/dL and/or 2-h postload glucose >199 mg/dL. All subjects were then classified based on 1-h postload plasma glucose concentrations, as those with less than 155 mg/dL and ≥155 mg/dL.

Homeostasis assessement model of insulin resistance (HOMA-IR), an index of hepatic insulin resistance, was calculated as (fasting insulin μUI/mL × glucose mmol/L)/22.5.¹⁰ The total insulin response (ΔInsulin_0–180/ΔGlucose_0-–180 ratio) and the early insulin response (ΔInsulin_0–30/ΔGlucose_0–30 ratio), also known as insulinogenic indices, were calculated.^11,12 The Matsuda index, an approximation of whole-body insulin sensitivity¹³ and the disposition index (Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR), a predictor of risk of diabetes,^14,15 were also determined.

Subjects were categorized as having the metabolic syndrome if they met at least three of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria: Waist circumference >102 cm (>40 in) in men and >88 cm (35 in) in women; triglycerides ≥150 mg/dL (≥1.7 mmol/L), high-density lipoprotein cholesterol (HDL-C) <40 mg/dL (<1.03 mmol/L) in men and <50 mg/dL (≥1.29 mmol/L) in women, blood pressure ≥130/≥85 mmHg or on antihypertensive medication, and fasting glucose ≥110 mg/dL (≥6.1 mmol/L).¹⁶

Blood samples for plasma glucose and insulin were obtained from an arm vein. Five-milliliter samples were collected in heparinized ice-cold tubes, mixed by gentle inversion, and immediately centrifuged at 4°C for 15 min. The plasma was divided in three aliquots, two of which were stored at −40°C for subsequent insulin assay, and the other immediately employed for glucose quantification. Plasma glucose was measured with an automated glucose analyzer (Beckman Instruments, Palo Alto, CA), employing a glucose oxidase technique. The assay was linear between 5 and 500 mg/dL of plasma glucose. The intraassay variation was of 1.7% and the interassay variation was of 2.2%. Plasma insulin was quantitated by radioimmunoassay solid-phase radioimmunoassay (Immulite^® 2000 Insulin, Diagnostic Products Corporation, Los Angeles, CA). Intra- and interassay variability values were 5.2% and 8.1%, respectively. The assay sensitivity was of 2 μUI/mL, and the antibody was 100% specific for insulin. The assay showed linearity up to 290 μUI/mL of plasma insulin.

Statistical analyses

Descriptive statistics were generated for the study population using means (and standard error of the mean [SEM]) for continuous variables and proportions (%) for dichotomous variables. The significance of mean differences was tested with analysis of variance (ANOVA). Differences between categorical variables were tested with the chi-squared test. Two-sample comparison for continuous variables was analyzed with the Student t-test or paired t-test with Bonferroni adjustment for repeated testing. Triglyceride levels were log-transformed for statistical analysis and back-transformed for reporting. Pearson correlation analysis was used to assess the relationships between continuous variables. Differences were considered significant at values of P < 0.05. All statistical analysis was performed with SPSS version 11.0 (SPSS Inc, Chicago, Ill).

Results

A total of 490 unselected subjects were evaluated. One-hour plasma glucose concentrations after a 75-g glucose oral load were measured as part of the 0–180 min OGTT. Values equal to or greater than 155 mg/dL, known to define increased risk for T2DM,^5,6 were found in 29% of the study subjects, or in 22% when excluding newly diagnosed diabetics. One-hour postload plasma glucose levels ≥155 mg/dL were associated with older age (50 ± 1 vs. 40 ± 0.7 years; P < 0.01); more obesity, and abdominal obesity (waist, 99.4 ± 1.2 vs. 90.8 ± 0.8 cm; P < 0.01), and higher systolic blood pressure/diastolic blood pressure (SBP/DBP) (127 ± 1.8/82 ± 1 mmHg vs. 119 ± 0.8/77 ± 0.6 mmHg; P < 0.01). A greater prevalence of metabolic syndrome was also observed in subjects with 1-h postload plasma glucose levels ≥155 mg/dL (39% vs. 17.3%; P < 0.001). Abdominal obesity and postload insulin concentrations best correlated with 1-h plasma glucose concentrations (r ² = 0.12 for waist and for 1-h insulin concentrations; P < 0.0001).

Impairments in postload glucose disposal were more pronounced than in fasting glucose. In fact, subjects with 1-h postload plasma glucose levels ≥155 mg/dL had largest reductions in indices of β-cell function (ΔI_0–30/ΔG_0–30: 1.06 ± 0.08 vs. 2.3 ± 0.3; P < 0.001) and in the disposition index (Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR: 0.41 vs. 0.78), than in the HOMA-IR (2.57 ± 0.1 vs. 2.91 ± 0.1; P < 0.01) and the Matsuda index (2.41 ± 0.08 vs. 3.0 ± 0.08; P < 0.01).

The prevalence of 1-h postload plasma glucose concentrations <155 mg/dL in subjects with predefined glucose abnormalities such as isolated IFG, isolated IGT, and combined IFG + IGT is shown on Table 1. One-hour plasma glucose concentrations >155 mg/dL were found in 43% of IFG, 65% of IGT, and in 90% of subjects with combined abnormalities. All subjects with newly diagnosed T2DM had 1-h plasma glucose concentrations above 155 mg/dL (Table 1).

Table 1.

Prevalence of Glucose Abnormalities in Subjects with 1-h Glucose Concentrations Lower and Higher than 155 mg/dL

	1-h < 155 mg/dL	1-h > 155 mg/dL (including T2DM)	1-h > 155 mg/dL (excluding T2DM)
N	351	139	106
NFG-NGT	302 (86 %)	25 (18.2%)	25 (23.5%)
IFG	32 (9.1 %)	24 (17.5%)	24 (22.6%)
IGT	13 (3.7 %)	24 (17.5%)	24 (22.6%)
IFG + IGT	4 (1.2 %)	33 (24%)	33 (31.1%)
DM	0	33 (24%)	0

Abbreviations: T2DM, type 2 diabetes mellitus (fasting plasma glucose concentrations ≥126 mg/dL and/or 2-h plasma glucose concentrations ≥200 mg/dL); N, number of subjects; NFG-NGT, normal fasting glucose (fasting plasma concentrations <100 mg/dL) and normal glucose tolerant (2-h plasma glucose concentrations 140–199 mg/dL); IFG, impaired fasting glucose (fasting glucose concentrations 100–125 mg/dL); IGT, impaired glucose tolerance (2-h plasma glucose concentrations 140–199 mg/dL); IFG + IGT, presence of combined glucose abnormalities in the same subject.

One-hour plasma glucose concentrations ≥155 mg/dL were encountered in 8.3% (25/106) NFG-NGT subjects. These NFG-NGT subjects were older, heavier, had larger waists and BMI, had higher blood pressure, and had a greater prevalence of metabolic syndrome (40% vs. 16.6%; P < 0.001) than those NFG-NGT with 1-h glucose <155 mg/dL (Table 2). In NFG-NGT, 1-h plasma glucose levels ≥155 mg/dL were associated with a 40–50% decrease in indices of early and total insulin secretion, and increases in the area under the curve (AUC) for plasma glucose and insulin concentrations (Table 2, Fig. 1). Plasma glucose and insulin C _max were also reached at later times in subjects with 1-h plasma glucose ≥155 mg/dL (Fig. 1). However, there were no significant differences in the fasting plasma levels of glucose, insulin, HDL-C, triglycerides, and in the HOMA-IR ratios in NFG-NGT with and without 1-h plasma glucose levels ≥155 mg/dL (Table 2). It was noteworthy that values for the disposition index and for markers of β-cell function in NFG-NGT with 1-h plasma glucose concentrations >155 mg/dL, were more impaired than those found in subjects with IFG, and comparable to those of IGT with 1-h levels <155 mg/dL (Tables 1 –3).

FIG. 1.

Plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) in normal fasting–normal tolerant subjects (NFG-NGT), subjects with impaired fasting glucose (IFG), and in subjects with impaired glucose tolerance (IGT), with 1-h postload values lower than 155 mg/dL and ≥155 mg/dL. Shown are mean values ≥standard error of the mean (SEM). Significant difference at (*) P < 0.01 and (**) P < 0.001.

Table 2.

Characteristics of Normal Fasting–Normal Flucose Tolerant Subjects with 1-h Postload Glucose Levels ≥155 mg/dL

NFG-NGT	1-h < 155 mg/dL	1-h ≥ 155 mg/dL
Number	302	25
Age (years)	39.4 ± 0.8	47 ± 2^*
Weight (kg)	74 ± 0.8	78 ± 3
Waist (cm)	90 ± 0.8	97 ± 3^*
WHR	0.87 ± 0.005	0.92 ± 0.02^*
BMI (kg/m²)	28.5 ± 0.3^*	29.2 ± 1^*
SBP/DBP (mmHg)	118 ± 0.9/76 ± 0.6	122 ± 3^/81 ± 2^
FPG (mg/dL)	85 ± 0.5	87 ± 1
FPI (μIU/mL)	13 ± 0.7	12 ± 1
2-h PG (mg/dL)	95 ± 1	121 ± 2^*
2-h PI (μIU/mL)	69 ± 3	116 ± 10^**
AUCG _0–180 (mg.dl^–1 · h^–1)	53 ± 2	123 ± 5^**
AUCI _0–180 (μIU · ml^–1 · h^–1)	161 ± 4	252 ± 20^*
AUCI _0–180 ÷ AUCG _0–180	3.03 ± 0.2	2.05 ± 0.15^*
Δ_0–30 I _÷ Δ_0–30 G	2.3 ± 0.3	1.3 ± 0.2^**
HOMA-IR	2.87 ± 0.1	2.66 ± 0.2
Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR	0.82 ± 0.08	0.49 ± 0.05^**
Matsuda index	3.42 ± 0.26	2.51 ± 0.22^*
HDL-C (mg/dL)	43 ± 0.8	47 ± 3
Triglyceride (mg/dL)	130 ± 4	141 ± 16

Disposition index, Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR. Significantly different from <155 mg/dL at (*) P < 0.05 and (**) P < 0.01.

Abbreviations: NFG, normal fasting glucose; NGT, normal glucose tolerant subjects were classified according to their 1-h postload plasma glucose levels in two groups, those with <155 mg/dL and those with ≥155 mg/dL (shown are mean values ± standard of the mean [SEM]); WHR, waist-to-hip ratio; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; FPI, fasting plasma insulin; 2-hr G, 2-h postload plasma glucose; 2-h I, 2-h postload plasma insulin; AUC-G and AUCI, incremental area under the curve for the glucose plasma and insulin concentrations following an oral glucose tolerance test (OGTT); HOMA-IR, fasting insulin μUI/ml × glucose mmol/L)/22.5; ΔI_0–30/ΔI_0–30, and ΔI_0–180(AUC)/ΔG_0–180(AUC), ratios for the increases in plasma insulin and glucose levels from fasting to 30 or 180 min during the OGTT (μIU/mL per mg/dL; HDL-C, high-density lipoprotein cholesterol.

Table 3.

Characteristics of Subjects with IFG with 1-h Postload Glucose Levels ≥155 mg/dL

IFG	1-h < 155 mg/dL	1-h ≥ 155 mg/dL
Number	32	24
Age (years)	42.5 ± 2	49.8 ± 2^**
Weight (kg)	76.6 ± 2.0	80.6 ± 2^*
Waist (cm)	94.9 ± 2	98.2 ± 3^*
WHR	0.89 ± 0.01	0.92 ± 0.01^*
BMI (kg/m²)	29.4 ± 0.8^*	30.3 ± 1
SBP/DBP (mmHg)	120 ± 2/78 ± 2	127 ± 3^/81 ± 2^
FPG (mg/dL)	105 ± 0.8	106 ± 1
FPI (μIU/mL)	13 ± 0.9	16.7 ± 2
2-h G (mg/dL)	114 ± 3	121 ± 2^*
2-h I (μIU/mL)	70 ± 4	94 ± 9^*
AUCG _0–180	56 ± 9	95 ± 5^**
AUCI _0–180	164 ± 11	218 ± 16^**
AUCI _0–180/AUCG _0–180	2.92 ± 0.2	2.30 ± 0.18^*
Δ_0–30 I/Δ_0–30 G	2.9 ± 0.2	1.15 ± 0.2^**
HOMA-IR	3.4 ± 0.2	4.2 ± 0.4
Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR	0.85 ± 0.01	0.26 ± 0.02^**
Matsuda index	2.88	2.00^*
HDL-C	44 ± 1	41 ± 2
Triglyceride	132 ± 10	150 ± 15

Subjects with IFG were classified according to their 1-h postload plasma glucose levels in two groups, those with <155 mg/dL and those with ≥155 mg/dL. Shown are mean values ± SEM.

Disposition index, Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR. Significantly different from <155 mg/dL at (*) P < 0.05, and (**) P < 0.01.

Abbreviations: IFG, impaired fasting glucose; WHR, waist-to-hip ratio; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; FPI, fasting plasma insulin; 2-hr G, 2-h postload plasma glucose; 2-h I, 2-h postload plasma insulin; AUCG and AUCI, incremental area under the curve for the glucose plasma and insulin concentrations following an oral glucose tolerance test (OGTT); HOMA-IR, (fasting insulin μUI/ml × glucose mmol/L)/22.5; ΔI_0–30/δI_0–30 and δI_0–180(AUC)/ΔG_0–180(AUC), ratios for the increases in plasma insulin and glucose levels from fasting to 30 or 180 min during the OGTT (μIU/mL per mg/dL; HDL-C, high-density lipoprotein cholesterol.

Similar to the NFG-NGT subjects, presence of 1-h plasma glucose levels ≥155 mg/dL in subjects with isolated fasting abnormalities (IFG) was also found associated with older age, greater body weight, more abdominal obesity, higher blood pressure, higher prevalence of metabolic syndrome, greater postload hyperglycemia and hyperinsulinemia, and lower ΔI_0–30/ΔG_0–30, ΔI_0–180/ΔG_0–180 ratios, Matsuda and disposition indices (Table 3, Fig. 1). However, the HOMA ratio was unchanged. The glucose load triggered higher insulin levels in subjects with ≥155 mg/dL; however, there were no differences in their time courses between both groups of subjects (Fig. 1).

Subjects with isolated IGT and 1-h plasma glucose levels ≥155 mg/dL were on average 4 years older, had higher blood pressure (+8 mmHg SBP and +6 mmHg DBP), 40% lower ΔI_0–30/ΔG_0–30 and disposition index values, and 30–40% greater glucose and insulin AUCs than subjects with isolated IGT and 1-h plasma glucose levels below 155 mg/dL (Table 4, Fig. 1). However, there were no differences in body weight, waist circumference, BMI, and HOMA-IR, or in fasting plasma glucose, insulin, HDL-C, and triglyceride concentrations between both groups of IGT (Table 4).

Table 4.

Characteristics of Subjects with IGT with 1-h Postload Glucose Levels ≥155 mg/dL

IGT	1-h < 155 mg/dL	1-h ≥ 155 mg/dL
N = 326	13	24
Age	48 ± 3	52 ± 1^*
Weight (kg)	77.7 ± 4.0	77.5 ± 2
Waist (cm)	99 ± 3	97.8 ± 2
WHR	0.90 ± 0.02	0.92 ± 0.01
BMI (kg/m²)	30.3 ± 1.5^*	29.8 ± 0.9
SBP/DBP	122 ± 3/77 ± 2	130 ± 3^/83 ± 2^
FPG	91 ± 2	92 ± 1
FPI	15 ± 2	14 ± 1
2-h G	149 ± 2	160 ± 2^*
2-h I	98 ± 9	121 ± 9^*
AUCG _0–180	103 ± 9	152 ± 5^**
AUCI _0–180	180 ± 16	240 ± 16^**
AUCI _0–180/AUCG _0–180	1.81 ± 0.1	1.61 ± 0.16
Δ_0–30 I/Δ_0–30 G	1.4 ± 0.2	0.8 ± 0.07^**
HOMA-IR	3.3 ± 0.3	3.2 ± 0.2
Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR	0.42 ± 0.03	0.25 ± 0.01^**
Matsuda index	2.75 ± 0.09	2.36 ± 0.1^*
HDL-C	40 ± 2	39 ± 2
Triglyceride	132 ± 12	155 ± 15

Subjects with impaired glucose tolerance (IGT) were classified according to their 1-h postload glucose levels in two groups, those with <155 mg/dL and those with >155 mg/dL. Shown are mean values ± standard error of the mean (SEM).

Ratios for ΔI_0–30/ΔI_0–30 and ΔI_0–180(AUC)/ΔG_0–180(AUC) for the increases in plasma insulin and glucose levels from fasting to 30 or 180 min during the oral glucose tolerance test (OGTT) (μIU/mL per mg/dL). Disposition index: Δ_0–30 I/Δ_0–30 G ÷ HOMA-IR. Significantly different from <155 mg/dL at (*) P < 0.05 and (**) P < 0.01.

Abbreviations: IGT, impaired glucose tolerance; WHR, waist-to-hip ratio; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; FPI, fasting plasma insulin; 2-hr G, 2-h postload plasma glucose; 2-h I, 2-h postload plasma insulin; AUCG and AUCI, incremental area under the curve for the glucose plasma and insulin concentrations following an oral glucose tolerance test (OGTT); HOMA-IR, (fasting insulin μUI/mL × glucose mmol/L)/22.5; HDL-C, high-density lipoprotein cholesterol.

Subjects with combined IFG and IGT, with and without 1-h plasma glucose levels ≥155 mg/dL were not evaluated because 90% of these subjects had 1-h levels above 155 mg/dL, and were thus at a very high risk (Table 1).

Discussion

Predicting future risk for T2DM is useful in initiating and designing early intervention strategies. Presence of fasting (IFG) and postload (IGT) glucose abnormalities, also known as prediabetes, mark increased risk for developing T2DM.^2,5,6 However, not all subjects with IFG or IGT are at the same risk,^2,5,6 and, in addition, some subjects diagnosed by ADA and WHO guidelines as NFG-NGT, may also be at increased risk for future T2DM.^1,2 Recent studies revealed that plasma glucose levels obtained 1-h after a glucose load (OGTT) are a better predictor of future T2DM than either fasting or 2-h postload glucose concentrations.^5,6 The 1-h measurement showed the maximal sensitivity and specificity to predict T2DM. These findings suggest that 1-h postoad glucose concentrations are of clinical value in identifying subjects with isolated IFG and isolated IGT, and more importantly, NFG-NGT that are at higher risk for developing T2DM.

Our study, conducted in an unselected sample of 490 Latino Hispanics, revealed that 1-h postload plasma glucose concentrations ≥155 mg/dL are present in nearly 30% of the subjects screened when including newly diagnosed type 2 diabetics, or in 22% of the subjects when excluding the diabetics. Although no data on prevalence have been reported previously, from the available data we estimated that the prevalence of 1-h postload plasma glucose concentrations ≥155 mg/dL ranged for nondiabetic subjects from 22% to 30% (present study and refs. 5 and 6). Expectedly, a greater prevalence was observed in subjects with fasting and/or postload glucose abnormalities, than in those with glucose levels within “normal” range (combined IFG-IGT > isolated IGT > isolated IFG >> NFG-NGT) (present study). In fact, the prevalence of 1-h postload levels ≥155 mg/dL in subjects with isolated IFG ranged from 34% to 58% (calculated from data on refs. 6 and 7 and present study), and for subjects with IGT it ranged from 65% in Hispanics (present study), 73% in Mexican Americans (estimated from ref 5), and to 81% in Caucasians (estimated from ref 6). Differences in ethnicity, sample selection criteria and size, gender distribution of the study sample, and duration of the underlying glucose abnormality may be partly responsible for the observed differences in prevalence. The higher prevalence of 1-h postload glucose concentrations ≥155 mg/dL in IGT than in IFG, may result from the fact that both 1-h ≥ 155 and 2-h > 140 mg/dL are mainly postload abnormalities, whereas, IFG is mostly an abnormality of fasting glucose.

We also observed that around 8% of Latino Hispanics, with otherwise normal fasting and 2-h postload plasma glucose concentrations according to ADA and WHO guidelines, had 1-h plasma glucose concentrations ≥155 mg/dL. For NFG-NGT Mexican Americans and Caucasians, the estimated prevalence of the 1-h glucose abnormality was of approximately 15% (calculated from data on refs. 5 and 6). It can be seen that NFG-NGT individuals with 1-h plasma glucose concentrations ≥155 mg/dL have surrogate markers of β-cell function and of diabetes risk predictability comparable to those of subjects with IFG and IGT (present study). These results further support the view that the presence of elevated 1-h plasma glucose concentrations places subjects with “normal fasting-normal 2-h postload glucose levels” at a much higher risk of developing T2DM. One findings support data from longitudinal studies indicating that 1-h plasma glucose levels ≥155 mg/dL in NFG-NGT places subjects at a high risk of future diabetes.^5,6 Importantly, these individuals have a much higher rate of metabolic syndrome (present study), which adds additional risk of developing diabetes.^5,6 These findings indicate that unless 1-h postload glucose levels are measured, approximately 1–1.5 out of each 10 subjects classified as NFG-NGT are not receiving preventive treatment because they are considered normoglycemic based on current guidelines. Similarly, nearly half of the subjects with IFG or IGT requiring more aggressive intervention are missing treatment if following current guidelines.

The reported superior risk-predictive value of 1-h plasma glucose concentrations during the OGTT seems to result from its very strong correlation with measures of hepatic and skeletal muscle insulin resistance and of β-cell function.^5,6 Skeletal muscle insulin resistance (not assessed in this study) plays a crucial role in the handling of plasma glucose after a glucose load.⁷ Therefore, increased 1-h plasma glucose levels after an oral glucose load would in theory identify subjects with greater degrees of combined skeletal and liver muscle insulin resistance and decreased β-cell function, as demonstrated by the abnormal values in HOMA-IR, the insulinogenic, the Matsuda, and the disposition indices (present study and refs. 13 –15,17). All three groups of subjects (NFG-IGT, IFG, and IGT) with 1-h postload plasma glucose concentrations >155 mg/dL had decreased Δ_0–30I/Δ_0–30G ratios, a surrogate marker of early insulin response, and of the Δ_0–180I/Δ_0–180G ratio, a surrogate marker of total insulin response to an oral glucose load (present study). In addition, the Matsuda index, a marker of whole-body insulin sensitivity,¹³ and the insulin secretion insulin–resistance index (IS/IR index), also known as the disposition index,^14,15,17 were markedly reduced in NFG-NGT, IFG, and IGT individuals with 1-h plasma glucose concentrations >155 mg/dL. These results support the view that 1-h plasma glucose levels ≥155 mg/dL is a strong predictor of risk of diabetes.

These results suggest that 1-h plasma glucose levels ≥155 mg/dL identify subjects with substantial impairment in insulin response to an oral glucose load. The larger and more sustained surges in hyperglycemia and hyperinsulinemia observed in these subjects may further deteriorate the already reduced β-cell function of individuals with IFG and IGT, placing them at a higher risk for T2DM. A similar situation may arise in NFG-NGT individuals with elevated 1-h plasma glucose concentrations. Interestingly, NFG-NGT with 1-h postload glucose levels ≥155 mg/dL had Δ_0–30I/Δ_0–30G and Δ_0–180I/Δ_0–180G ratios, and Matsuda and disposition indices close to those of unselected IGT. This may explain that NGT-NFG subjects with 1-h plasma glucose concentrations ≥155 mg/dL have a risk for T2DM comparable to those of unselected subjects with IFG or IGT.^5,6 However, for all three groups of subjects, 1-h postload glucose levels above 155 mg/dL, revealed presence of severe β-cell dysfunction and in insulin sensitivity, leading to hyperglycemia and hyperinsulinemia.

Abnormally elevated 1-h plasma glucose levels (≥155 mg/dL) may result from obesity and its associated metabolic, cardiovascular, and inflammatory deleterious actions, leading to insulin resistance and β-cell dysfunction, such as in the metabolic syndrome.^1

–4 In fact, for the three groups of subjects, NFG-NGT, IFG, and IGT, the presence of 1-h postload glucose concentrations >155 mg/dL identifies those with higher blood pressure, greater postload hyperglycemia and hyperinsulinemia, and more obesity. The stronger association of 1-h plasma glucose levels with waist circumference rather than with BMI or body weight suggests that abdominal obesity is more important than general obesity in the setting of the 1-h glucose abnormality. These factors may not only be responsible for the increased 1-h plasma glucose levels, but may also account for associated increased risk for developing T2DM.^5,6 Therefore, 1-h plasma glucose concentrations ≥155 mg/dL identify subjects with a worse cardiovascular and metabolic risk profile, irrespective of whether the subjects were NFG-NGT or had predefined fasting or postload glucose abnormalities. In addition to degree of abdominal obesity, older age and years of obesity, may also play an important role in determining the increase risk of future diabetes. In fact, for NFG-NGT, IFG and IGT, 1-h plasma glucose levels ≥155 mg/dL were found in subjects that were an average of 5–7 years older than those with 1-h plasma glucose levels of <155 mg/dL. The fact that indices of early insulin secretion were greatly reduced in subjects with elevated 1-h glucose levels suggests that these individuals have had prolonged stress to their pancreatic β-cells. Unfortunately, this cause-and-effect relationship cannot be confirmed because we did not collect data on years of obesity.

In summary, the worldwide increase in cost and in accessing adequate health care requires the availability of simpler, inexpensive, highly sensitive, and specific screening tests for disease diagnosis and decision making. One-hour plasma glucose concentrations ≥155 during an OGTT has been shown to better predict risk of T2DM than 2-h postload glucose levels. In this work, we report a high prevalence of the 1-h postload abnormality in Latino-Hispanics, and that this condition is associated with other risk factors such as obesity, high blood pressure, metabolic syndrome, and deterioration of the insulin response to oral glucose leading to postload hyperglycemia and hyperinsulinemia. Even if its prevalence is greater in subjects with predefined glucose abnormalities, it was found to be present in nearly 1 out of 10 subjects of Hispanic descent with normal fasting and 2-h postload plasma glucose levels (NFG-NGT). Therefore, 1-h postload plasma glucose levels ≥155 mg/dL identified subjects that by current guidelines are classified as NFG-NGT, IFG, or IGT, but that are at a higher risk than their average group risk. Recognition and management of these individuals may reduce incidence of diabetes and cardiovascular events.

Footnotes

Author Disclosure Statement

The authors have no relevant conflict of interest to disclose.

References

Unwin

, Shaw

, Zimmer

, Alberti

KGMM

. Impaired glucose tolerance and impaired fasting glycemia: The current status on definition and intervention. Diabet Med, 2002; 19:709–723.

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 1997; 20:1183–1197.

The Expert Committee on the Diagnostic and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnostic and Classification of Diabetes Mellitus. Diabetes Care, 2003; 26:3160–3167.

Abdul-Ghani

, Abdul-Ghani

, Ali

, Defronzo

. One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes. Diabetes Care, 2008; 31:1650–1655.

Abdul-Ghani

, Lyssenko

, Tuomi

, DeFronzo

, Groop

. Fasting versus postload plasma glucose concentration and the risk for future type 2 diabetes: Results from the Botnia Study. Diabetes Care, 2009; 32:281–286.

Abdul-Ghani

, Williams

, DeFronzo

, Stern

. Risk of progression to type 2 diabetes based on relationship between postload plasma glucose and fasting plasma glucose. Diabetes Care, 2006; 29:1613–1618.

Stern

, Williams

, Haffner

. Identification of persons at high risk for type 2 diabetes mellitus: Do we need the oral glucose tolerance test? Ann Intern Med, 2002; 136:575–581.

McNeely

, Boyko

, Leonetti

, Kahn

, Fujimoto

. Comparison of a clinical model, the oral glucose tolerance test and fasting glucose for prediction of type 2 diabetes in Japanese Americans. Diabetes Care, 2003; 26:758–763.

10.

Belfiore

, Iannello

, Camuto

, Fagone

, Cavaleri

. Insulin sensitivity of blood glucose versus insulin sensitivity of blood free fatty acids in normal, obese, and obese-diabetic subjects. Metabolism, 2001; 50:573–582.

11.

Hanson

, Pratley

, Bogardus

, Narayan

, Roumain

, Imperatore

, Fagot-Campagna

, Pettitt

, Bennett

, Knowler

. Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol, 2000; 151:190–198.

12.

Abdul-Ghani

, Matsuda

, Jani

, Jenkinson

, Coletta

, Kaku

, DeFronzo

. The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance. Am J Physiol Endocrinol Metab, 2008; 295:401–406.

13.

Matsuda

, DeFronzo

. Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care, 1999; 22:1462–1470.

14.

De Fronzo

, Abdul-Ghani

. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care, 2009; 32:e86–e88.

15.

Utzschneider

, Prigeon

, Faulenbach

, Tong

, Carr

, Boyko

, Leonetti

, McNeely

, Fujimoto

, Kahn

. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care, 2009; 32:335–341.

16.

National Cholesterol Education Program: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of the High Blood Cholesterol in Adults (ATP III)

JAMA, 2001; 285:2486–2497.

17.

Abdul-Ghani

, Williams

, DeFronzo

, Stern

. What is the best predictor of future type 2 diabetes? Diabetes Care, 2007; 30:1544–1548.