Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure

Abstract

Objective: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and β-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and β-cell function in MODY vs. non-MODY obese youth at randomization and over time.

Methods: Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and β-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA).

Results: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. β-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth.

Conclusions: In TODAY, β-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.

Keywords: MODY; glycemic control; insulin secretion; insulin sensitivity; type 2 diabetes; youth.

Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

FIGURE 1

OGTT plasma glucose (A-C), C-peptide (D-F), and insulin concentrations (G-I) at randomization, and 6 and 24 months of follow-up, in non-MODY, HNF-MODY and GCK-MODY youth.*Data are mean ± SE (upper or lower bars only to minimize crowding by error bars and enhance figure clarity). P values refer to an overall difference between the three MODY groups at each time point (ie, testing whether the three curves overlap), in unadjusted generalized linear mixed models using log transformed values. Sample sizes (based on complete non-missing records) for the three groups at each time point (randomization, month 6, and month 24) were as follows: non-MODY (n = 406, n = 359, n = 264), HNF-MODY (n = 12, n = 8, n = 5) and GCK-MODY (n = 7, n = 7, n = 7). OGTT, oral glucose tolerance test; GCK, glucokinase; HNF, hepatocyte nuclear factor; MODY, maturity onset diabetes of youth

FIGURE 2

Temporal patterns of insulin sensitivity A, C-peptide index B, and C-peptide oDI C, in non-MODY, HNF-MODY, and GCK-MODY youth. *Data are reported as model-adjusted geometric mean ± SE asymmetric limits, obtained as exp(mean ± SE of log values) over 24 months of follow-up in TODAY, analyzed using log-transformed values. P-values refer to an overall difference over time between the three MODY groups, in generalized linear mixed models adjusted for randomized treatment group, sex, race/ethnicity, and BMIz. GCK, glucokinase; HNF, hepatocyte nuclear factor; MODY, maturity onset diabetes of youth; oDI, oral disposition index; TODAY, type 2 diabetes in adolescents and youth