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Youth-onset type 2 diabetes mellitus: an urgent challenge

Nature Reviews Nephrology volume 19, pages 168–184 (2023)Cite this article

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Abstract

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

Key points

  • The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) are increasing worldwide; the disease has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected.

  • Important drivers of the epidemic of youth-onset T2DM include the increasing frequency, severity and earlier onset of childhood obesity, the increasing frequency of intrauterine exposure to diabetes, sedentary lifestyles, structural racism and other psychosocial factors.

  • Individuals who develop T2DM during childhood or adolescence often have a more aggressive clinical course than those with type 1 diabetes mellitus or those who develop T2DM in adulthood.

  • Youth-onset T2DM has a more extreme metabolic phenotype than adult-onset T2DM, with greater insulin resistance and more rapid deterioration of β-cell function; intermediate complications often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life.

  • Owing to limited efficacy and safety data, several drugs that are available for the treatment of adults with T2DM have not been approved for the treatment of youth, which reduces the options that are available to normalize glycaemia in these patients.

  • Managing youth-onset T2DM and mitigating the risk of microvascular and macrovascular complications require the development of more effective interventions as well as strategies to overcome barriers to adherence that are not typically encountered in adult patients.

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Fig. 1: Long-term complications of youth-onset T2DM.
Fig. 2: Odds of long-term complications in children and adolescents with T2DM versus those with T1DM.
Fig. 3: Potential mechanisms responsible for the aggressive clinical phenotype in youth-onset T2DM.
Fig. 4: Greater loss of β-cell function in youth-onset versus adult-onset T2DM.

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Acknowledgements

The authors’ work was supported in part by the Intramural Research Program of the NIDDK. P.B. receives salary and research support from NIDDK (R01 DK129211, R01 DK132399, R21 DK129720, K23 DK116720, UC DK114886 and P30 DK116073), NHLBI (R01 HL165433), JDRF (3-SRA-2022-1097-M-B, 3-SRA-2022-1243-M-B, 2-SRA-2019-845-S-B), Boettcher Foundation, AHA (20IPA35260142), Center for Women’s Health Research at University of Colorado, the Department of Paediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine. D.H.v.R. is supported by a senior fellowship of the Dutch Diabetes Foundation. K.J.N. receives salary and research support from NIDDK (R01 DK119450) and NHLBI (K24 HL145076, R01 HL165433). A.S.S. receives salary and research support from NIDDK (R01 DK119450), NHLBI (R01 HL157260) and NINDS (R01 NS125316). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Authors and Affiliations

  1. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Petter Bjornstad, Melanie Cree-Green & Kristen J. Nadeau

  2. Children’s Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

    Lily C. Chao

  3. Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada

    Allison B. Dart

  4. University of Saskatchewan College of Medicine, Saskatoon, Saskatchewan, Canada

    Malcolm King

  5. National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA

    Helen C. Looker & Robert G. Nelson

  6. Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia

    Dianna J. Magliano

  7. Monash University, School of Public Health and Preventive Medicine, Melbourne, Australia

    Dianna J. Magliano

  8. Paediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel

    Orit Pinhas-Hamiel

  9. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Orit Pinhas-Hamiel

  10. Cincinnati Children’s Hospital and The University of Cincinnati, Cincinnati, OH, USA

    Amy S. Shah

  11. Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands

    Daniel H. van Raalte

  12. Centers for Disease Control and Prevention, Atlanta, GA, USA

    Meda E. Pavkov

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Contributions

All authors researched data for the article, made substantial contributions to discussions of the content, wrote, reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Robert G. Nelson.

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Competing interests

P.B. has acted as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chem, Sanofi, Novo Nordisk, Horizon Pharma, XORTX. P.B. serves on the advisory boards of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and XORTX. D.H.v.R. has acted as a consultant and received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck and Sanofi, and received research operating funding from AstraZeneca, Boehringer Ingelheim–Eli Lilly Diabetes Alliance and Merck. The other authors declare no competing interests.

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Standardized mortality ratio

The ratio of the number of deaths observed in a population over a given period to the number that would be expected over the same period in the general population.

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Bjornstad, P., Chao, L.C., Cree-Green, M. et al. Youth-onset type 2 diabetes mellitus: an urgent challenge. Nat Rev Nephrol 19, 168–184 (2023). https://doi.org/10.1038/s41581-022-00645-1

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