Highlights
- Delayed puberty in male adolescents is associated with a significantly higher risk of developing type 2 diabetes by early adulthood.
- The hazard ratio for type 2 diabetes was 2.47 in those with delayed puberty, remaining at 1.37 even after adjusting for baseline body mass index (BMI).
- This nationwide study suggests that delayed pubertal onset is not merely a benign developmental variation but may serve as an early clinical marker for metabolic impairment.
The Rising Challenge of Early-Onset Metabolic Disease
The global incidence of type 2 diabetes (T2D) in young adults has been rising at an alarming rate, presenting a significant public health challenge. Unlike late-onset diabetes, early-onset T2D often follows a more aggressive clinical course, with a more rapid decline in beta-cell function and an earlier onset of microvascular and macrovascular complications. Identifying early-life predictors of this metabolic trajectory is essential for targeted prevention and intervention strategies. Puberty represents a critical developmental window characterized by profound physiological changes, including transient insulin resistance and shifts in body composition. While the relationship between precocious puberty and metabolic risk has been extensively studied, the long-term implications of delayed puberty—particularly in males—have remained poorly understood until recently.
Unveiling the Israeli Nationwide Cohort Study
A landmark study published in The Lancet Child & Adolescent Health has provided critical insights into this relationship. This nationwide, population-based, retrospective cohort study utilized data from the Israeli National Diabetes Registry (INDR) and medical assessments conducted by the Israeli Defense Forces. The study population included 964,108 male adolescents aged 16 to 19 years who underwent medical examinations between 1992 and 2015. These individuals were followed until the end of 2019, providing a cumulative follow-up of over 15 million person-years.
Methodological Rigor and Data Linkage
The strength of this study lies in its scale and the accuracy of its diagnostic criteria. Delayed puberty was diagnosed by board-certified pediatric endocrinologists based on standardized physical examinations and laboratory evaluations. To ensure the integrity of the findings, the researchers excluded individuals with pre-existing diabetes at baseline, those with hypogonadotropic hypogonadism (a specific medical cause for delayed puberty), and those with missing anthropometric data. Diabetes cases were identified through the INDR using stringent criteria: glycated hemoglobin (HbA1c) levels above 6.5%, repeated fasting glucose tests above 200 mg/dL, or the consistent purchase of glucose-lowering medications.
Key Findings: Quantifying the Metabolic Risk
The results of the analysis are striking. Among the nearly one million participants, 4,307 were diagnosed with delayed puberty. During the follow-up period, 2.6% of those with delayed puberty developed type 2 diabetes, compared to only 0.7% of those without the condition. The mean age at diabetes diagnosis was slightly earlier in the delayed puberty group (35.5 years) compared to the control group (36.8 years).
Statistical Significance and Hazard Ratios
The incidence rate of type 2 diabetes was 140.3 cases per 100,000 person-years in the delayed puberty group, versus 41.3 cases in the control group. Initial statistical models, which adjusted for age, education, socioeconomic status, and cognitive performance, revealed a hazard ratio (HR) of 2.47. This indicates that adolescents with delayed puberty were nearly two and a half times more likely to develop T2D than their peers with timely pubertal onset.
The Role of Body Mass Index
A critical question in metabolic research is whether these associations are simply a reflection of obesity. While the association was attenuated after adjusting for baseline BMI, it remained statistically significant with an HR of 1.37. This suggests that while weight contributes to the risk, it does not fully explain the link between delayed puberty and diabetes. The findings persisted across multiple sensitivity analyses, reinforcing the robustness of the association.
Mechanistic Insights and Biological Plausibility
The biological mechanisms linking delayed puberty to impaired glucose metabolism are likely multifactorial. Puberty is initiated by the activation of the hypothalamic-pituitary-gonadal (HPG) axis, which is closely intertwined with metabolic signals. For instance, leptin, a hormone produced by adipose tissue, plays a permissive role in pubertal onset. Delayed puberty may reflect a state of relative leptin resistance or other subtle neuroendocrine dysfunctions that also predispose individuals to metabolic syndrome.
Hormonal Interplay
Furthermore, the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis, which peaks during puberty, is essential for maintaining glucose homeostasis and muscle mass. A delay in the surge of these hormones may impact the development of lean body mass and insulin sensitivity during a formative period. Additionally, shared genetic factors—pleiotropy—might influence both the timing of puberty and the risk of metabolic disease, suggesting that some individuals are genetically predisposed to both delayed maturation and insulin resistance.
Clinical Implications: Moving Beyond a Benign Diagnosis
For decades, delayed puberty (particularly constitutional delay of growth and puberty) has been viewed by many clinicians as a benign variation of normal development—a ‘late bloomer’ phenomenon that eventually resolves without long-term consequences. However, this study challenges that paradigm. If delayed puberty is an early marker of metabolic vulnerability, it provides a unique opportunity for early intervention.
Recommendations for Practice
Clinicians should consider male adolescents with a history of delayed puberty as a group that may benefit from closer metabolic monitoring. This does not necessarily mean aggressive pharmacological intervention at age 17, but rather increased vigilance regarding lifestyle factors, weight management, and periodic screening of glycemic markers (such as HbA1c or fasting glucose) as these individuals transition into their 20s and 30s. Public health policies should also recognize the adolescent period as a critical window for identifying future cardiovascular and metabolic risks.
Study Strengths and Limitations
The primary strength of this research is its massive sample size and the use of a high-quality nationwide registry, which minimizes selection bias and provides high statistical power. The long-term follow-up into early adulthood is also a significant advantage. However, some limitations must be noted. The study focused exclusively on males, so the findings cannot be directly extrapolated to females. Additionally, while the study adjusted for baseline BMI, it did not have continuous data on weight changes throughout the follow-up period, which could further clarify the role of weight gain in early adulthood.
Conclusion
The Israeli nationwide cohort study provides compelling evidence that delayed puberty in male adolescents is a potent independent risk factor for early-onset type 2 diabetes. By identifying this association, the research shifts the clinical perspective on pubertal timing from a simple developmental milestone to a significant indicator of long-term health. As the medical community strives to curb the epidemic of early-onset diabetes, recognizing and monitoring these high-risk individuals could prove to be a vital component of preventive medicine.
References
Pinhas-Hamiel O, Simchoni M, Derazne E, Bendor CD, Tsur AM, Vinograd A, Lutski M, Zucker I, Singhal V, Gerstein HC, Afek A, Tirosh A, Twig G. Delayed puberty and early-onset type 2 diabetes risk: a nationwide cohort study of male adolescents in Israel. Lancet Child Adolesc Health. 2026 Feb;10(2):103-110. doi: 10.1016/S2352-4642(25)00333-5. PMID: 41513398.
