A study recently published in Scientific Reports evaluated the relationship between age at diabetes diagnosis (ADD) and the development and progression of diabetic retinopathy (DR).
Give me some background.
The prevalence of DR increases with the duration of diabetes.
Case in point: Nearly all individuals with type 1 diabetes mellitus (T1DM) and the majority of individuals with type 2 DM (T2DM) develop DR within 20 years from disease onset.
- Recently: ADD has emerged as a potential factor influencing DR development, with previous studies demonstrating that patients with diabetes onset before 40 years of age had a 5.56 times higher risk of developing DR compared to those diagnosed at 60 years or older.
Now, talk about the study.
This study was completed in two phases:
- A cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) 2005-2008 database to evaluate the relationship between ADD and DR
- Mendelian randomization (MR) analysis of genome-wide association studies (GWAS) data from the UK Biobank to explore the causal genetic influence of ADD on DR
Note: MR is a method of assessing the causal effects of potential risk factors on health, social, and economic outcomes using genetic variants associated with specific exposures of interest.
Findings?
Cross-sectional analysis of the NHANES data (n = 877) demonstrated that the DR group had a significantly younger ADD compared to the DR-free group (47.08±13.91 vs. 53.10±12.60 years, P < 0.001).
Further: They found a significant inverse association between ADD and DR prevalence (odds ratio [OR] = 0.96, P < 0.001).
- Moreover: MR analysis further reinforced this inverse relationship (OR: 0.42, P = 0.003).
Anything else?
The investigators identified two peak ages of DR occurrence probability at 24.45 and 24.2 years.
In addition: Younger ADD was associated with increased DR severity across all clinical subtypes (P < 0.05).
Note: Subgroup analyses revealed that the protective effect of later ADD on DR occurrence only existed in specific demographic and clinical groups, such as:
- Non-insulin users
- Patients with clinical indicators within the normal range, such as:
- Systolic blood pressure (SBP)
- Diastolic blood pressure (DBP)
- Hemoglobin A1C (HbA1c)
- Urine albumin-creatinine ratio (UACR)
- Vitamin D
Explain why later ADD may impact DR severity.
The protective effect of later ADD on DR can be explained by four potential mechanisms:
- Individuals diagnosed with diabetes at a younger age may experience faster deterioration in β-cell function—causing prolonged periods of poor glycemic control, a well-known risk factor for DR
- Vascular endothelial growth factor (VEGF) levels have been shown to decrease with age—meaning younger patients may have a more robust response to VEGF, potentially accelerating retinal vascular complications
- Hormonal changes during puberty and adolescence may exacerbate the risk of complications in early-onset diabetes
- Younger patients with diabetes may have lower adherence to treatment regimens and poorer glycemic control
Expert opinion?
The study authors noted that the results of the analyses supported these mechanisms, as decreasing age of diabetes onset was associated with:
- Lower education levels
- Higher body mass index (BMI) and waist circumference
- Elevated HbA1c levels
- Longer diabetes duration
- Higher proportion of insulin use
- Increased energy intake
Moreover: HbA1c and insulin use significantly mediated the relationship between ADD and DR risk, with insulin showing a higher mediation effect.
- Meaning: This underscores the critical role of glycemic control and early insulin dependence in the development of DR among younger-onset diabetes patients.
Limitations?
These included:
- The cross-sectional study design limits the ability to identify causal relationships and a longitudinal understanding of DR development and progression
- The NHANES data was self-reported—potentially introducing recall bias, particularly regarding ADD
- MR analysis mitigates some biases, but relies on genetic assumptions that may not always hold, potentially introducing a new source of bias
- The MR analyses demonstrated significant heterogeneity, suggesting that the causal estimates should be interpreted with caution
- The study populations differed between the two phases of the study (NHANES representing the U.S. population and MR data representing largely European cohorts), limiting ethnic generalizability
Take home.
These findings indicate that older ADD was associated with a protective effect against the development and progression of DR.
- As such: This emphasizes the importance of heightened vigilance and more frequent screening for DR in patients diagnosed with diabetes at a young age.
So what are the next steps?
The authors noted that further research with larger-scale genetic data is required to address the heterogeneity in the MR analyses, while longitudinal cohort studies are crucial to elucidate the causal relationship between ADD and DR.
Notably: Particular attention should be given to increasing the sample size for patients diagnosed before 25 years of age, as this study had limited representation of this population.