Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on β-Cell Function: Comparison of Responses In Youth And Adults

Abstract

β-Cell dysfunction is central to the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes. Compared with adults, youth have hyperresponsive β-cells and their decline in β-cell function appears to be more rapid. However, there are no direct comparisons of β-cell responses to pharmacological intervention between the two age-groups. The Restoring Insulin Secretion (RISE) Adult Medication Study and the RISE Pediatric Medication Study compared interventions to improve or preserve β-cell function. Obese youth (n = 91) and adults (n = 132) with IGT or recently diagnosed type 2 diabetes were randomized to 3 months of insulin glargine followed by 9 months of metformin, or 12 months of metformin. Hyperglycemic clamps conducted at baseline, after 12 months of medication, and 3 months after medication withdrawal assessed β-cell function as steady-state and maximal C-peptide responses adjusted for insulin sensitivity. Temporal changes in β-cell function were distinctly different. In youth, β-cell function deteriorated during treatment and after treatment withdrawal, with no differences between treatment groups. In adults, β-cell function improved during treatment, but this was not sustained after treatment withdrawal. The difference in β-cell function outcomes in response to medications in youth versus adults supports a more adverse trajectory of β-cell deterioration in youth.

Trial registration: ClinicalTrials.gov NCT01779362 NCT01779375.

Figure 1

Glucose and C-peptide concentrations during the hyperglycemic clamp. Glucose and C-peptide concentrations from the hyperglycemic clamps at baseline, after 12 months of treatment (Month 12), and 3 months after discontinuing the intervention (Month 15). The goal steady-state glucose targets were 11.1 mmol/L between 90 and 120 min and >25 mmol/L at 150 min. Data are displayed as mean ± SEM.

Figure 2

Vector plots illustrating the treatment effects on concurrent model-based changes from baseline to 12 and 15 months in hyperglycemic clamp–derived insulin sensitivity and β-cell responses in youth and adults. The figures depict the relationships in youth (A, C, and E) and adults (B, D, and F) of the two coprimary outcomes and secondary outcome: hyperglycemic clamp–derived β-cell responses (steady-state C-peptide, ACPRmax, and ACPRg), each paired with M/I, at baseline, 12 months, and 15 months, in green for the insulin glargine followed by metformin and in brown for metformin alone. The black line depicts the joint relationship between β-cell response and M/I at baseline for the full cohort within each study, with the mean value at baseline for the full cohort indicated by the black box with a 0. The dotted lines to boxes at months 12 and 15 show the trajectory of values from baseline to 12 months of intervention and then to 3 months after discontinuation of the intervention (15 months). Values above the black line represent improved β-cell function; values below the line represent poorer β-cell function. The ellipses depict the 95% confidence bands around the points at months 12 and 15.

Figure 3

Comparison of percent changes from baseline to 12 and 15 months in hyperglycemic clamp–derived insulin sensitivity and β-cell measures in youth vs. adults. Shown in shades of green are data from the insulin glargine followed by metformin arm (dark green, adults; light green, youth). Shades of brown are data from the metformin alone arm (dark brown, adults; light brown, youth). The bars indicate 95% CI.

Figure 4

Comparison in the temporal changes in BMI and HbA_1c from baseline in youth vs. adults. Shown in shades of green are data from the insulin glargine followed by metformin arm (dark green, adults; light green, youth). Shades of brown are data from the metformin alone arm (dark brown, adults; light brown, youth). The bars indicate 95% CI. The asterisks represent visits where changes were significantly different in youth vs. adults (P < 0.05).