Changes in Visceral and Subcutaneous Fat in Youth With Type 2 Diabetes in the TODAY Study

Abstract

Objective: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, metformin plus rosiglitazone (M + R) maintained glycemic control better than metformin alone (M) or metformin plus lifestyle (M + L) in youth with type 2 diabetes (T2D). We hypothesized that changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) would explain the differential treatment effects on glycemia.

Research design and methods: In 626 youth ages 11-17 years with T2D duration <2 years, VAT and SAT were estimated by DXA at baseline and at 6 and 24 months. Changes from baseline were analyzed in linear mixed models.

Results: Baseline mean age was 13.9 years, 66.4% were female, 72.2% were Hispanic/non-Hispanic black, and 20.3% were non-Hispanic white (NHW). Mean BMI was 33.7 kg/m2. VAT increased more in M + R (13.1%) than M + L (3.9%, P = 0.0006) or M (6.5%, P = 0.0146). SAT also increased more in M + R (13.3%) than in M + L (5.4%, P < 0.0001) or M (6.4%, P = 0.0005), indicating no significant fat redistribution in M + R. In NHWs, VAT increased more in M + R than M (P = 0.0192) and M + L (P = 0.0482) but did not explain the race-ethnicity differences in treatment effects on glycemic control among treatment groups. VAT and SAT increases correlated with higher HbA1c, lower insulin sensitivity, and lower oral disposition index (all P < 0.05), but associations did not differ by treatment group.

Conclusions: In contrast to the existing reports in adults with T2D, in TODAY, M + R resulted in the most VAT accumulation compared with M + L or M. Differential effects on depot-specific indirect measures of adiposity are unrelated to treatment effects in sustaining glycemic control. Additional studies are needed to understand the clinical markers of metabolic risk profile in youth with T2D on rosiglitazone.

Trial registration: ClinicalTrials.gov NCT00081328.

© 2019 by the American Diabetes Association.

Figures

Figure 1

Adjusted mean percent change from baseline in VAT mass and VAT:SAT ratio at months 6 and 24 by treatment group and race-ethnicity. Adjusted mean percent change from baseline for VAT mass in NHBs (A), Hispanics (B), and NHWs (C), and VAT:SAT ratio in NHBs (D), Hispanics (E), and NHWs (F) at months 6 and 24 by treatment. The three treatment groups are M, M + R, and M + L. P values were calculated from generalized linear mixed models that tested for pairwise treatment differences in the percent change from baseline during the first 2 years of the study as a function of time, study site (as a surrogate for DXA machine type), sex, age at baseline, height, treatment, and an interaction term for time by treatment. Significant treatment group differences for the 6- and 24-month percent changes from baseline are indicated within the figure.

Figure 2

Slopes of HbA1c, insulin sensitivity, β-cell function (as measured by C-peptide oDI), and HMWA versus change from baseline in VAT mass at months 6 and 24 by treatment group. Regression lines (slopes) of HbA1c (A and B), insulin sensitivity (C and D), C-peptide oDI (E and F), and HMWA (G and H) values at months 6 and 24 versus the respective change from baseline in VAT mass by treatment group. The three treatment groups are M, M + R, and M + L. P values were calculated from linear regression models testing for pairwise treatment differences in the slopes at months 6 and 24. Models were adjusted for study site (as surrogate for DXA machine type), sex, age at baseline, height, race-ethnicity, and treatment. Data are plotted on the original unit scale, but testing was performed on the log-transformed values of insulin sensitivity, C-peptide oDI, and HMWA because of lack of normality. Overall associations and significant P values for slope differences by treatment group are indicated within the figure.

Figure 2

Slopes of HbA1c, insulin sensitivity, β-cell function (as measured by C-peptide oDI), and HMWA versus change from baseline in VAT mass at months 6 and 24 by treatment group. Regression lines (slopes) of HbA1c (A and B), insulin sensitivity (C and D), C-peptide oDI (E and F), and HMWA (G and H) values at months 6 and 24 versus the respective change from baseline in VAT mass by treatment group. The three treatment groups are M, M + R, and M + L. P values were calculated from linear regression models testing for pairwise treatment differences in the slopes at months 6 and 24. Models were adjusted for study site (as surrogate for DXA machine type), sex, age at baseline, height, race-ethnicity, and treatment. Data are plotted on the original unit scale, but testing was performed on the log-transformed values of insulin sensitivity, C-peptide oDI, and HMWA because of lack of normality. Overall associations and significant P values for slope differences by treatment group are indicated within the figure.

Figure 3

Slopes of HbA1c, insulin sensitivity, β-cell function (as measured by C-peptide oDI), and HMWA versus change from baseline in SAT mass at months 6 and 24, by treatment group. Regression lines (slopes) of HbA1c (A and B), insulin sensitivity (C and D), C-peptide oDI (E and F), and HMWA (G and H) values at months 6 and 24 versus the respective change from baseline in SAT mass by treatment group. The three treatment groups are M, M + R, and M + L. P values were calculated from linear regression models testing for pairwise treatment differences in the slopes at months 6 and 24. Models were adjusted for study site (as surrogate for DXA machine type), sex, age at baseline, height, race-ethnicity, and treatment. Data are plotted on the original unit scale, but testing was performed on the log-transformed values of insulin sensitivity, C-peptide oDI, and HMWA because of lack of normality. Overall associations and significant P values for slope differences by treatment group are indicated within the figure.

Figure 3

Slopes of HbA1c, insulin sensitivity, β-cell function (as measured by C-peptide oDI), and HMWA versus change from baseline in SAT mass at months 6 and 24, by treatment group. Regression lines (slopes) of HbA1c (A and B), insulin sensitivity (C and D), C-peptide oDI (E and F), and HMWA (G and H) values at months 6 and 24 versus the respective change from baseline in SAT mass by treatment group. The three treatment groups are M, M + R, and M + L. P values were calculated from linear regression models testing for pairwise treatment differences in the slopes at months 6 and 24. Models were adjusted for study site (as surrogate for DXA machine type), sex, age at baseline, height, race-ethnicity, and treatment. Data are plotted on the original unit scale, but testing was performed on the log-transformed values of insulin sensitivity, C-peptide oDI, and HMWA because of lack of normality. Overall associations and significant P values for slope differences by treatment group are indicated within the figure.