Introduction
The global burden of diabetes was estimated to be 463 million people in 2019 and is steadily rising.1 The key pathomechanisms of type 2 diabetes are impaired insulin sensitivity combined with a progressive loss of pancreatic beta-cell function. Longitudinal studies have shown that beta-cell function is altered many years before the diabetes diagnosis.2 With the increasing recognition of disease heterogeneity, insulin secretion has been used as a key feature in the subclassification of pre-diabetes and diabetes.3 In one recent work, adult-onset diabetes has been classified into five clusters, each of which features different pathophysiologic phenotypes and distinct patterns of complication.4 In this approach, a reliable measurement of insulin secretion is important to differentiate insulinopenic and hyperinsulinemic diabetes endotypes. In pre-diabetes subphenotyping, adequate methods for measurement of insulin secretion are similarly important for capturing key differences between pre-diabetes subphenotypes.
In healthy individuals, insulin is secreted in a biphasic manner in response to an increase in arterial glucose concentration. The first phase lasts approximately 10 min, and the second phase reaches a plateau after 2–3 hours, provided glucose is continuously elevated, in an experimental setting.5 In type 2 diabetes, the first phase of insulin secretion is impaired or even absent and the second phase is decreased.6 The first phase of insulin secretion is frequently used in pathophysiological studies of type 2 diabetes and the prediction of type 1 diabetes.7 Homeostatic model assessment and beta cell function (HOMA-beta) is used to estimate insulin secretion for the classification of diabetes and can have importance in clinical settings for optimizing diabetes treatment.
There are numerous methods to assess first-phase secretion; of these the hyperglycemic clamp (HGC) test and intravenous glucose tolerance test (IVGTT) are referred to as the gold standards.8 Gold-standard methods are used in smaller populations for an accurate measurement of secretion, often in combination with an examination of insulin resistance in the same protocol. The HGC test allows assessment of both first-phase and second-phase insulin secretion, whereas the IVGTT is a reference test only for first-phase insulin secretion.
During the HGC test, a glucose bolus is given to quickly raise glucose levels to a fixed hyperglycemic target value, usually 125 mg/dL (6.9 mmol/L) above basal level.9 The elevated plasma glucose concentration is then maintained by continuous glucose infusion. Blood samples are taken frequently using a catheter to measure blood glucose, and the glucose infusion is adjusted as necessary. The first phase of insulin secretion is calculated from insulin levels during the first 8–10 min, and the second phase is calculated as the mean insulin value after the initial secretion peak.9
When performing an IVGTT, only one glucose bolus is given intravenously, and blood samples are collected for 3–4 hours. The most commonly used parameter is acute insulin response (AIR), which is the mean insulin concentration above basal levels during the first peak.10
The two reference methods are used to calculate the first phase of insulin secretion in similar ways and research settings. During the HGC test an amount of glucose, which is based on the participant’s level of glucose, is given to raise insulin secretion. In an IVGTT the bolus given is fixed. The difference between the reference methods is more evident in the second phase when an infusion of glucose is used in the HGC test. In both methods, the first phase is calculated from the insulin levels during the first minutes. Because both reference methods measure insulin secretion as a response to intravenous glucose administration, they cannot assess all aspects of physiological insulin secretion when food is consumed. Both reference methods are also time-consuming to perform. Therefore, several surrogate measures have been developed for broader use. Surrogate measures are used in a wide range of epidemiological studies wherein associations between insulin secretion and conditions related to diabetes are investigated. Since the oral glucose tolerance test (OGTT) is frequently used for the classification and diagnosis of diabetes and pre-diabetes, the additional blood samples taken to calculate a surrogate measure of insulin secretion are relatively inexpensive and time-efficient to collect.
The most frequently used surrogate measures of insulin secretion are based on the OGTT, which is performed after an overnight fast. Subjects are given an oral load of 75 mg glucose, which triggers insulin secretion.8 Plasma insulin or C-peptide and glucose levels are measured at baseline and repeatedly for at least 120 min.
HOMA-beta is based on a fasting blood sample and assesses insulin secretion by calculating the ratio of insulin concentration to glucose concentration minus 3.5 mmol/L.8
Although there are numerous surrogate indices for the first phase of insulin secretion, no systematic review has summarized the validation studies of surrogate indices. This study investigated the diagnostic accuracy of surrogate measures by assessing the correlation between first-phase insulin secretion calculated using surrogate methods and the reference methods IVGTT and HGC. This was undertaken to help researchers decide which surrogate measure to use for larger studies.