Glucoregulatory function among African Americans and European Americans with normal or pre-diabetic hemoglobin A1c levels

Abstract

Objective

A hemoglobin (Hb) A1c range of 5.7%–6.4% has been recommended for the diagnosis of prediabetes. To determine the significance of such “prediabetic” HbA1c levels, we compared glucoregulatory function in persons with HbA1c levels of 5.7%–6.4% and those with HbA1c < 5.7%.

Methods

We studied 280 nondiabetic adults (142 black, 138 white; mean (± SD) age 44.2 ± 10.6 years). Each subject underwent clinical assessment, blood sampling for HbA1c measurement, and a 75-g oral glucose tolerance test at baseline. Additional assessments during subsequent outpatient visits included insulin sensitivity, using homeostasis model assessment (HOMA)-IR and the hyperinsulinemic euglycemic clamp; insulin secretion, using HOMA-B and frequently samples intravenous glucose tolerance test (FSIVGTT) and disposition index (DI); and measurement of fat mass, using DXA.

Results

Compared to subjects with HbA1c < 5.7%, persons with HbA1c levels of 5.7%–6.4% were older, and had higher body mass index (BMI) and insulin secretion but similar insulin sensitivity. When the two groups were matched in age and BMI, persons with HbA1c 5.7%–6.4% were indistinguishable from those with HbA1c < 5.7% with regard to all measures of glycemia and glucoregulatory function.

Conclusions

Unlike glucose-defined prediabetes status, an HbA1c range of 5.7%–6.4% does not reliably identify individuals with impaired insulin action or secretion, the classical defects underlying the pathophysiology of prediabetes. Thus, HbA1c cannot validly replace blood glucose measurement in the diagnosis of prediabetes. If utilized as a screening test due to convenience, aberrant HbA1c values should be corroborated with blood glucose measurement before therapeutic intervention.

Introduction

Since 2009, several organizations have recommended the use of glycated hemoglobin (HbA1c) levels for the diagnosis of diabetes and prediabetes [1], [2], [3]. Currently, diabetes can be diagnosed if the HbA1c level is confirmed to be 6.5% or greater, and prediabetes (or “high risk for diabetes”) is diagnosed if the HbA1c falls within the range of 5.7%–6.4% [4]. Traditionally, the diagnosis of diabetes has been based on measurement of fasting plasma glucose (FPG, > 126 mg/dl or 7.0 mmol/l) or the standard 75-g oral glucose tolerance test (OGTT) (2-h plasma glucose{2hPG} > 200 mg/dl or 11.1 mmol/l) [5], [6]. Similarly, the traditional diagnosis of pre-diabetes has relied on measurement of FPG (impaired fasting glucose{IFG}, 100–125 mg/dl or 5.6–6.9 mmol/l) [6] or OGTT (impaired glucose tolerance {IGT}, 2hPG 140–199 mg/dl or 7.8–11.0 mmol/dl) [7].

HbA1c is a minor hemoglobin variant that results from nonenzymatic amino-terminal glycosylation of the β-chain of the hemoglobin molecule [8]. The observation that HbA1c levels are correlated with average blood glucose levels over the preceding 3 months led to the use of HbA1c as “gold standard” measure of glycemic control in people with diabetes and a prognosticator of vascular complications of diabetes in landmark studies [8], [9], [10], [11]. The advantages of HbA1c as a clinical test include its obvious role as a measure of chronic rather than acute glycemic burden, the lack of requirement for fasting specimens, preanalytical sample stability, and greater measurement precision, among others [1], [12]. These advantages make the HbA1c test a valuable tool for monitoring glycemic control in established patients with diabetes. However, there is less experience with measurement of HbA1c in nondiabetic persons, and the utility of the test as a valid indicator of early dysglycemia is yet to be established. In the present study, we aimed to determine the metabolic significance of HbA1c-defined prediabetes status by comparing markers of glucoregulatory function in nondiabetic persons whose HbA1c levels fall either within or below 5.7%–6.4% for diagnosis of prediabetes.