Differential loss of β-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study

Abstract

Aims: To compare OGTT-derived estimates of β-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE.

Methods: Youth (n = 89) and adults (n = 132) were randomized to 3 months glargine followed by 9 months metformin (G/M) or 12 months metformin (MET). Insulin sensitivity and β-cell responses were estimated from 3-hour OGTTs over 21 months. Linear mixed models tested for differences by time and age group within each treatment arm.

Results: After treatment withdrawal, HbA1c increased in both youth and adults with a larger net increase in G/M youth vs. adults at 21 months. Among youth, β-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, β-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline β-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms.

Conclusions: After treatment withdrawal youth demonstrated progressive decline in β-cell function after stopping treatment with either G/M or MET. In contrast, β-cell function in adults remained stable despite an increase in HbA1c over time. ClinicalTrials.gov Identifier: NCT01779375 and NCT01779362 at clinical trials.gov.

Keywords: Impaired glucose tolerance; Insulin secretion; Metformin; Type 2 diabetes; Youth; β-cell function.

Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [KJM is currently employed by Eli Lilly and Co. No other potential conflicts of interest relevant to this article were reported.]

Copyright © 2021 Elsevier B.V. All rights reserved.

Figures

Figure 1.

Consort Diagram

Figure 2.

Changes from baseline over time are depicted for each treatment arm for HbA1c (A and B), iAUCg (C and D), OGIS (E and F) and 1/FI (G and H). Youth (blue) and Adults (red) in the Glargine/Metformin arm are depicted in panels A, C, E and G and those in the Metformin arm in panels B, D, F and H. All values are model estimates and 95% CI after adjustment for race, sex, BMI, and baseline glucose tolerance category. Significant differences in changes in measures between youth and adults are denoted by an *. iAUCg = incremental area under the curve for glucose, OGIS = oral glucose insulin sensitivity, 1/FI = 1/fasting insulin.

Figure 3.

Changes from baseline over time are depicted for each treatment arm for each β-cell function measure derived from modelling. Youth (blue) and Adults (red) treated with Glargine/Metformin are depicted in panels A, C, G and E and those in the Metformin arm in panels B, D, F and H. All values are model estimates with 95% CI after adjustment for race, sex, BMI, baseline glucose tolerance category and time-varying OGIS, and additionally adjusted with time-varying iAUCg for tISR only. Significant differences in changes in measures between youth and adults are denoted by an *. ISR = insulin secretion rate, OGIS = oral glucose insulin sensitivity.

Figure 4.

Changes from baseline over time are depicted for each treatment arm for each β-cell function measure calculated from the OGTT. Youth (blue) and Adults (red) treated with Glargine/Metformin are depicted in panels A, C, E, G and I and those in the Metformin arm in panels B, D, F, H and J. All values are model estimates with 95% CI after adjustment for race, sex, BMI, baseline glucose tolerance category and time-varying 1/FI (except for insulin DI model).Significant differences in changes in measures between youth and adults are denoted by an *. 1/FI = 1/fasting insulin, DI = disposition index, IGI = insulinogenic index, CPI = C-peptide index, iAUC = incremental area under the curve for insulin (i), C-peptide (cp) and glucose (g).