The Relationship Between β-Cell Function and Glycated Hemoglobin: Results from the Veterans Administration Genetic Epidemiology Study

MUSTAFA KANAT DIEDRE WINNIER PHD LUKE NORTON PHD NAZIK ARAR CHRIS JENKINSON PHD RALPH A. DEFRONZO MUHAMMAD A. ABDUL-GHANI PHD OBJECTIVE-The study objective was to assess the relationship between b-cell function and HbA1c. RESEARCH DESIGN AND METHODS-A total of 522 Mexican American subjects participated in this study. Each subject received a 75-g oral glucose tolerance test (OGTT) after a 10- to 12-h overnight fast. Insulin sensitivity was assessed with the Matsuda index. Insulin secretory rate was quantitated from deconvolution of the plasma C-peptide concentration. b-Cell function was assessed with the insulin secretion/insulin resistance (IS/IR) (disposition) index and was related to the level of HbA1c. RESULTS-At HbA1c levels ,5.5%, both the Matsuda index of insulin sensitivity and IS/IR index were constant. However, as the HbA1c increased .5.5%, there was a precipitous decrease in both the Matsuda index and the IS/IR index. Subjects with HbA1c = 6.0-6.4% had a 44 and 74% decrease in the Matsuda index and the IS/IR index, respectively, compared with subjects with HbA1c ,5.5% (P , 0.01 for both indices). Subjects with normal glucose tolerance and HbA1c ,5.7% had b-cell function comparable to that of subjects with normal glucose tolerance with HbA1c = 5.7-6.4%. However, subjects with impaired fasting glucose or impaired glucose tolerance had a marked decrease in b-cell function independent of their HbA1c level. CONCLUSIONS-The results of the current study demonstrate that in Mexican Americans, as HbA1c increases .6.0%, both insulin sensitivity and b-cell function decrease markedly. Performing an OGTT is pivotal for accurate identification of subjects with impaired b-cell function. - I ciation (ADA) revised its criteria for the n 1997, the American Diabetes Assodiagnosis of type 2 diabetes and determined that subjects with fasting plasma glucose (FPG) .126 mg/dL and 2-h plasma glucose $200 mg/dL are considered to have type 2 diabetes (1). These cut points were chosen on the basis of the increased incidence of diabetic retinopathy rather than on the presence of metabolic abnormalities (i.e., insulin resistance and b-cell dysfunction) that are responsible for type 2 diabetes (1). Impaired b-cell function is the principal factor responsible for the development and progression of type 2 diabetes (2). In addition to b-cell dysfunction, subjects with type 2 diabetes manifest severe insulin resistance in skeletal muscle, liver, and adipocytes (36). Insulin resistance is the earliest metabolic abnormality detected in subjects destined to develop type 2 diabetes. In response to insulin resistance, the b-cell appropriately increases insulin secretion and normal glucose tolerance (NGT) is maintained. However, when b-cell failure ensues, glucose intolerance develops. Initially, this is manifest as impaired glucose tolerance (IGT) and subsequently as overt diabetes (1). Thus, impaired b-cell function is an essential condition in the development of type 2 diabetes (1). Although normal b-cell function is pivotal to the maintenance of NGT, c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c b-cell failure develops long before hyperglycemia becomes evident. Recent studies have demonstrated that the decrease in b-cell function begins in the range considered to be well within NGT according to the 1997 ADA criteria (710). Studies that have related b-cell function to FPG (7,8) and 2-h plasma glucose (9,10) concentrations reported that b-cell function progressively declined with the increase in both FPG and 2-h plasma glucose from the low normal range to the high normal range, to the impaired glucose tolerant and diabetic ranges. These results indicate that the decrease in b-cell function, which is the primary factor responsible for the deterioration of glucose tolerance, is a continuum with no threshold above which b-cell dysfunction develops. ADA recently changed the diagnostic criteria for type 2 diabetes to include individuals with HbA1c $6.5%; highrisk individuals are defined as having an HbA1c = 5.76.4% (11,12). No data are available relating the HbA1c to b-cell function. Therefore, the aim of the current study was to examine the relationship between b-cell function and HbA1c. RESEARCH DESIGN AND METHODS Subjects The participants in this study included 522 subjects of Mexican American descent who were part of the San Antonio Veterans Administration Genetic Epidemiology Study (5). In the Veterans Administration Genetic Epidemiology Study, Mexican American families with one diabetic and one nondiabetic parent and two siblings with type 2 diabetes were recruited through advertising within the medical center and in local newspapers. Subjects responding to the advertisement were screened with a 75-g oral glucose tolerance test (OGTT). All family members who responded to the advertisement and fulfilled the inclusion criteria agreed to participate in the study. This study reports on 522 subjects who were free of diabetes and received a 75-g OGTT and had NGT, IGT, impaired fasting glucose (IFG), or type 2 diabetes based on the 2003 glucose criteria established by ADA (13). None of the subjects with type 2 diabetes knew that he/she had diabetes, and type 2 diabetes was diagnosed for the first time with the OGTT. Thus, no type 2 diabetic subject in the study had used antidiabetic medications. All subjects had normal liver, cardiopulmonary, and kidney function as determined by medical history, physical examination, screening blood tests, electrocardiogram, and urinalysis. No subject with NGT, IFG, IGT, or type 2 diabetes was taking any medication known to affect glucose tolerance. Body weight was stable (62 kg) for at least 3 months before the study in all subjects. No subject participated in an excessively heavy exercise program. The study protocol was approved by the institutional review board of the University of Texas Health Science Center, San Antonio, and informed written consent was obtained from all subjects before their participation. All studies were performed at the General Clinical Research Center of the University of Texas Health Science Center at 0800 h after a 10- to 12-h overnight fast. OGTT Before the start of the OGTT, a small polyethylene catheter was placed into an antecubital vein, and blood samples were collected at 230, 215, 0, 15, 30, 45, 60, 75, 90, 105, and 120 min for the measurement of plasma glucose, C-peptide, and insulin concentrations. On the day of the OGTT, height, weight, and waist circumference were determined at the narrowest part of the torso, and a blood sample was obtained for HbA1c measurement. Analytic techniques Plasma glucose concentration was measured by the glucose oxidase reaction (Glucose Oxidase Analyzer, Beckman, Fullerton, CA). Plasma insulin and Cpeptide concentrations were measured by radioimmunoassay (Linco Research, St. Louis, MO). HbA1c was measured with high-performance liquid ch (...truncated)