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

Pediatr Diabetes. 2020 Jun;21(4):575-585. doi: 10.1111/pedi.12998. Epub 2020 Mar 3.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Child
  • Combined Modality Therapy
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Diabetes Mellitus, Type 2* / physiopathology
  • Drug Therapy, Combination
  • Female
  • Glucokinase / genetics
  • Hepatocyte Nuclear Factor 4 / genetics
  • Humans
  • Insulin Resistance / physiology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Life Style
  • Longitudinal Studies
  • Male
  • Metformin / administration & dosage
  • Metformin / adverse effects
  • Mutation
  • Pediatric Obesity* / complications
  • Pediatric Obesity* / drug therapy
  • Pediatric Obesity* / metabolism
  • Pediatric Obesity* / physiopathology
  • Risk Reduction Behavior
  • Rosiglitazone / administration & dosage
  • Rosiglitazone / adverse effects


  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Rosiglitazone
  • Metformin
  • Glucokinase

Supplementary concepts

  • Mason-Type Diabetes