MASLD Increases Risk of Youth-Onset Type 2 Diabetes in Children with Obesity

Resthie Putri, MD

Credit: Karolinska Institutet

New research is calling attention to an increased risk of youth-onset type 2 diabetes in pediatric patients with both metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity.¹

Study results showed children with both obesity and MASLD had a greater risk of youth-onset type 2 diabetes than pediatric patients with obesity alone and general population comparators, attributed to MASLD’s synergistic interaction with intermediate hyperglycemia. However, an optimal response to obesity treatment was found to reduce type 2 diabetes risk, regardless of the presence of MASLD.¹

“A bidirectional association between MASLD, whose previous terminology was nonalcoholic fatty liver disease, and type 2 diabetes has been shown, particularly in adults,” Resthie Putri, MD, a PhD student in the department of clinical science, intervention and technology at Karolinska Institutet, and colleagues wrote.¹ “To which extent the association can be inferred to the pediatric population is precarious because the phenotypes of pediatric MASLD and type 2 diabetes differ from the adult types. Moreover, whether MASLD in pediatric obesity adds excess risk for type 2 diabetes remains unclear.”

MASLD is the leading cause of liver disease among pediatric patients. It affects up to 38% of children with obesity in the US, although not all children with MASLD have obesity. Although the exact cause of youth-onset diabetes is unknown, overweight/obesity and metabolic syndrome are widely recognized as risk factors predisposing children to type 2 diabetes.^2,3

To assess the association between MASLD in pediatric obesity and youth-onset type 2 diabetes, investigators conducted a nationwide cohort study using data from the Swedish Childhood Obesity Treatment Register Barnobesitas Registret i Sverige (BORIS) 1999–2020 linked with national registers. Children with overweight or obesity who were 9-18 years of age and free from type 2 diabetes at baseline were included in the study and matched in a 1:5 ratio to the general population based on sex, birth year, and residential area.¹

Investigators applied 2 approaches for identifying MASLD. The first was based on ALT levels in outpatient obesity care recorded in the BORIS register. The second used ICD-10 diagnosis codes for MASLD recorded in the Patient Register.¹

Participants were monitored from the index date until type 2 diabetes was detected, they reached 30 years of age, death, emigration, or end of follow-up (July 2023), whichever occurred first.¹

In total, investigators included 10,346 children with overweight or obesity and 59,336 matched controls. After excluding those with type 2 diabetes prior to obesity treatment, a total of 1102 patients with both obesity and MASLD were identified.¹

After a median follow-up of 8.1 years, the median age at type 2 diabetes diagnosis was 16.9 years in the obesity cohort and 22.8 years in the general population comparators. Investigators noted the greatest incidence rate (IR) of type 2 diabetes was found in patients with overweight or obesity and MASLD (IR, 131.1 per 10,000 P-Y; 95% CI, 109.4–157.0), observing the greatest cumulative incidence at age 30 in those with obesity and MASLD (22.7%) followed by those with obesity alone (9.9%) and the controls (0.7%).¹

Upon analysis, in the obesity cohort, MASLD was associated with an increased risk of type 2 diabetes (hazard ratio [HR], 2.71; 95% CI, 2.14–3.43), independent of sex, age, degree of obesity, intermediate hyperglycemia, and parental type 2 diabetes. Of note, the association was most prominent during adolescence (HR, 3.99; 95% CI, 2.99–5.32) and diminished in adulthood (HR, 1.28; 95% CI, 0.79–2.07).¹

Further analysis revealed that compared with patients with obesity alone, patients with both MASLD and intermediate hyperglycemia were at the greatest risk of developing type 2 diabetes (HR, 9.04; 95% CI, 6.38-12.79), followed by MASLD (HR, 2.16; 95% CI, 1.63-2.87) and intermediate hyperglycemia (HR, 1.79; 95% CI, 1.22–2.60). Investigators observed a synergistic effect between MASLD and intermediate hyperglycemia (Relative excess risk due to interaction, 6.09; 95% CI, 3.10-9.07; and synergy index, 4.12; 95% CI, 2.39 –7.10; P <.001).¹

Investigators additionally assessed the effect of obesity treatment on the risk for type 2 diabetes in a subgroup of the obesity cohort undergoing 6 months of obesity treatment. Of note, the new generation of antiobesity drugs was not approved for adolescents in Sweden during the study period, so no patients received pharmacological treatment for obesity.¹

In this subpopulation, the median treatment duration was 17.3 months. Every 0.1-unit decrease in BMI standard deviation score was associated with a relative risk reduction for type 2 diabetes of 9% (adjusted HR, 0.91; 95% CI 0.88–0.93). Additionally, an optimal response to obesity treatment was associated with a relative risk reduction of ≥ 43% (adjusted HR, 0.23; 95% CI, 0.09–0.57).¹

Investigators acknowledged multiple limitations to these findings, including the potential for exposure misclassification; the lack of histopathology and imaging data to assess the spectrum of MASLD; the use of diagnosis codes and antidiabetes medications from national registers to identify patients with type 2 diabetes; the possibility of detection bias in the obesity treatment subgroup; and the inability to account for genes related to MASLD and youth-onset type 2 diabetes.¹

“Children with obesity and MASLD, based on ALT or diagnosis code, have a higher risk for developing youth-onset type 2 diabetes compared with their peers with obesity alone and the general population comparators,” investigators concluded.¹ “MASLD interacts synergistically with intermediate hyperglycemia to dramatically increase the risk for type 2 diabetes. An optimal response in pediatric obesity treatment reduces the risk, regardless of MASLD.”

References

1. ^{Putri RR, Casswall T, Danielsson P, et al. Steatotic Liver Disease in Pediatric Obesity and Increased Risk for Youth-Onset Type 2 Diabetes. Diabetes Care 2024. https://doi.org/10.2337/dc24-1236}
2. ^{Mayo Clinic. Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). October 4, 2023. Accessed October 14, 2024. https://www.mayoclinic.org/medical-professionals/pediatrics/news/pediatric-metabolic-dysfunction-associated-steatotic-liver-disease-masld-formerly-known-as-nonalcoholic-fatty-liver-disease-nafld/mac-20555493}
3. ^{Mayo Clinic. Type 2 diabetes in children. November 18, 2023. Accessed October 14, 2024. https://www.mayoclinic.org/diseases-conditions/type-2-diabetes-in-children/symptoms-causes/syc-20355318}