Discussion
Prediabetes is one of the strongest clinical risk factors for diabetes and vascular disease. In prediabetes and the early stages of diabetes, fasting glucose and HbA1c are often highly correlated, reflecting basal hepatic glucose output in the fasting state. The 75 g OGTT provides important, additional, diagnostic information by challenging insulin–glucose homeostasis with conditions that simulate the usual postprandial state, in which there is induction of insulin secretion, insulin-stimulated glucose uptake by skeletal muscle and other tissues, and suppression of hepatic glucose production. As such, the OGTT can uncover defective glucose regulation that is not observed in the fasting state. Consistent with this, up to 40% of individuals with abnormal 2 h OGTT glucose values have normal fasting glucose levels.29 Hence, fasting blood glucose and HbA1c values are not adequate substitutes for the OGTT. Nevertheless, the OGTT is not routinely administered in most clinical practice settings, in part due to the time and technical effort it requires.
Recent studies are revealing that there is more to be learned from an OGTT than 2 h glucose values, which primarily reflect the rate of glucose clearance as a function of peripheral insulin resistance. Pancreatic β-cell dysfunction, the more proximal cause of diabetes, is directly reflected in impaired early-phase insulin response, and thus steeper early rises in glucose values during the first hour of the OGTT. Consistent with this, it has been demonstrated in two large prospective studies that the 1 h postload plasma glucose value obtained during the 75 g OGTT is a strong, independent predictor of risk for diabetes, even in individuals with normal (ie, not prediabetic or diabetic) fasting or 2 h glucose levels (normal glucose tolerance; NGT).30 In the San Antonio Heart Study and the Botnia Study, baseline 1 h glucose levels predicted diabetes incidence better than did either fasting or 2 h glucose, and were strongly associated with indices of β-cell function and insulin resistance.21 ,31 ,32
Cross-sectional data from several recent studies have reinforced the clinical importance of elevated 1 h glucose levels in individuals with otherwise normal glucose regulation. For example, among the 39% of patients with NGT in the GENFIEV study, an elevated 1 h glucose level predicted β-cell dysfunction, insulin resistance, and increased numbers of cardiovascular risk factors such as dyslipidemia and elevated blood pressure.33 Others have shown that patients with NGT and elevated 1 h glucose levels have features of insulin resistance or impaired β-cell function by diverse measures: acute insulin response and disposition index (calculated from the frequently sampled intravenous glucose tolerance test (IVGTT)), decreased glucose disposal on hyperinsulinemic–euglycemic clamp, elevated markers of chronic inflammation (hsCRP and fibrinogen), and increased levels of hepatic transaminases.34–37 Moreover, increased 1 h glucose predicts increased cardiovascular risk. In patients with hypertensive NGT, elevated 1 h glucose levels are associated with higher blood pressure, increased vascular stiffness, and left ventricular hypertrophy.38 ,39 Thus, elevated 1 h postload glucose may represent a unique ‘subclinical’ form of hyperglycemia that is not accounted for in current models for clinical detection of prediabetes or diabetes, but which plays an important role in the pathophysiology of diabetes and diabetes-related cardiovascular complications.
In the present study, we found that fasting serum levels of α-HB predicted insulin resistance, impaired insulin secretion kinetics, and abnormal glucose regulation during the 75 g OGTT—in particular, elevated 1 h post-load plasma glucose levels. Importantly, the predictive ability of α-HB for 1 h postload glucose levels is observed even in individuals with ostensibly normal insulin–glucose homeostasis by other standard clinical criteria. These findings indicate that α-HB has clinical utility for predicting subclinical hyperglycemia, even under conditions where other commonly used indicators of impaired insulin–glucose homeostasis are ostensibly normal. This suggests that measurement of serum α-HB could provide a rapid, inexpensive screening tool for detecting early, subclinical stages of the disease process leading to prediabetes/diabetes. In addition, measurement of α-HB in conjunction with fasting plasma glucose and HbA1c could enhance the ability to detect hyperglycemia that might otherwise only be apparent by OGTT testing in diabetic and non-diabetic individuals.
Our findings are consistent with prior observations that elevated serum α-HB levels can identify individuals with impaired insulin–glucose homeostasis, and further indicate that this relationship is independent of BMI and other traditional diabetes risk factors. In the present study, no differences between α-HB tertiles were observed for age, gender, BMI, or HbA1c. α-HB was also shown to be independent of other novel biomarkers of diabetes risk such as L-GPC. The observation that α-HB does not associate with other traditional factors associated with diabetes risk but is associated with elevated 1 h glucose in the OGTT suggests it has truly independent value in identifying patients at risk for developing diabetes.
The results of the present study suggest that elevated serum α-HB is associated with delayed insulin secretory kinetics and insufficient insulin secretion during the OGTT, as differences were observed in the early rise in insulin levels during the OGTT and the OGTT-derived version of the disposition index. These findings are consistent with prior observations that serum α-HB correlates inversely with indices of β-cell function during OGTT in the RISC and Botnia study cohorts.19 The importance of interpreting estimates of β-cell function within the context of prevailing insulin resistance has been well established, as insulin resistance is normally compensated for by increased insulin secretion.40 In the present study, a direct estimate of insulin secretion during the OGTT, AUCinsulin/glucose, trended lower according to α-HB tertile, though did not achieve statistical significance (similar to AUCc-peptide/glucose, data not shown). However, when adjusted for insulin resistance, the observed deficits were striking. It should be noted that the original formulation of the disposition index as reported by Kahn et al41 utilized an estimate of insulin secretion obtained over only the first 8 min of an IVGTT, which was relatively independent of the estimate of insulin sensitivity obtained over the next few hours. However, when the same insulin excursion is used in the estimate of insulin secretion and insulin resistance, as in the OGTT-derived version of the disposition index used here, interpretation becomes more complicated. Additional experiments investigating α-HB utilizing an IVGTT protocol will be helpful in this regard.
In conclusion, we report the discovery that elevated α-HB is strongly predictive of abnormal 1 h postload plasma glucose levels and decreased insulin secretion in the spectrum of clinic patients undergoing OGTT for evaluation of suspected metabolic risk. In addition, we confirm prior reports that serum α-HB is associated with insulin resistance based on 2 h OGTT glucose levels. Remarkably, we find that α-HB is highly predictive of OGTT glucose responses, and calculated indices of insulin sensitivity and β-cell function—even among a subset of patients selected for having ostensibly normal indicators of insulin–glucose homeostasis. Hence, α-HB may have broad applications as a tool for detecting states of subclinical hyperglycemia, insulin resistance, and β-cell dysfunction that could indicate increased risk for diabetes and cardiovascular disease.