Review of methods for measuring β-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium

Abstract

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β-cell function and changes in β-cell function in response to interventions. In the present paper, we review approaches for measurement of β-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure β-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in β-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine.

Trial registration: ClinicalTrials.gov NCT01779362 NCT01779375 NCT01763346.

Keywords: glucose metabolism; insulin resistance; insulin secretion; type 2 diabetes; β cell.

Figure 1.

The hyperbolic relationship between insulin sensitivity (SI) and the first phase (acute) insulin response to glucose (AIRglucose) (a) and the maximal acute insulin response to arginine (AIRmax) (b) in a cohort of healthy individuals. The solid line depicts the best-fit relationship (50th percentile), while the broken lines represent the 5th, 25th, 75th, and 95th percentiles. A reduction in insulin sensitivity, as measured by a decrease in Si, results in a compensatory reciprocal and proportionate increase in glucose-stimulated insulin secretion and an increase in maximal acute insulin response to arginine, the latter a measure of β-cell secretory capacity. (Copyright 1993 American Diabetes Association. From Reference [10] Reprinted with permission from The American Diabetes Association)

Figure 2.

Plasma insulin response to a 20g intravenous glucose bolus in NGT (a) and T2D (b). The first-phase insulin response is absent in the subjects with diabetes while the second-phase response is relatively preserved, with a delayed maximal insulin response. (Reprinted from Reference [98], with permission from Excerpta Medica Inc.)

Figure 3.

Comparison of the acute insulin response to a 5g intravenous L-arginine injection at different glucose levels in NGT participants compared with participants with T2D, with simiar age and body weight. (Reprinted with permission from Reference [39]).

Figure 4:

(A) DI in obese adolescents across the spectrum of glycemia. Letters indicate significant post hoc analyses (a: T2D vs. NGT; b: T2D vs. IFG; c: T2D vs. IGT; e: NGT vs. IFG/IGT; f: NGT vs. IGT). Adapted with permission from reference [99]. (B) Incretin effect in obese youth. Letters indicate significant post hoc analyses (a: NGT vs. IGT; b: NGT vs. T2D). Adapted with permission from reference [78].