The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test: Forerunner of Heightened Glycemic Failure Rates and Accelerated Decline in β-Cell Function in TODAY

Abstract

Objective: Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose response curves have lower insulin sensitivity and impaired β-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in β-cell function.

Research design and methods: OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, insulin sensitivity (1/fasting insulin), C-peptide index (△C₃₀/△G₃₀), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]) were compared among the three groups.

Results: At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar insulin sensitivity but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus the biphasic group (39.1%) (P < 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in insulin sensitivity.

Conclusions: In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced β-cell function and foretells increased glycemic failure rates with accelerated deterioration in β-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00081328.

Figure 1

Survival curves and log-rank test results for freedom from glycemic failure in the TODAY study cohort by OGTT glucose response curve at baseline (A) and at month 6 (B). Data are shown for up to 48 months of follow-up (accounting for 95.7% of glycemic failure). Panel B excludes participants who failed to maintain glycemic control in the first 6 months of the study (n = 136 or 20.5%) or were lost to follow-up early and did not undergo an OGTT collected at month 6 (n = 2), resulting in a starting population of 524 youths free of glycemic failure at month 6.

Figure 2

Temporal patterns of insulin sensitivity (A), C-peptide index (B), and C-peptide oDI (C) in the three baseline OGTT glucose response curve groups. Data are reported as model-adjusted geometric mean ± SE asymmetric limits (obtained as exp [mean ± SE of log values]) over 48 months of follow-up in the TODAY study, analyzed using log-transformed values. P values refer to the overall effect of baseline OGTT glucose response curve in the longitudinal models, adjusted for treatment group, baseline age and BMI, and diabetes duration.