The Hidden Link Between PFAS and Diabetes Risk: Insights from a Comprehensive Systematic Review and Meta-Analysis

Per- and polyfluoroalkyl substances, commonly known as PFAS, have been called "forever chemicals" due to their persistence in the environment and in human bodies. These chemicals, widely used in products such as non-stick cookware, food packaging, firefighting foam, waterproof clothing, and cosmetics, have raised growing public health concerns. Recent scientific evidence suggests that PFAS exposure may influence metabolic health, particularly the risk of diabetes and related markers of glycemic control and insulin function.

A landmark study led by Sandra India Aldana and colleagues conducted a systematic review and meta-analysis of epidemiological research to investigate these associations. This analysis, encompassing 129 studies published through July 21, 2025, represents the most comprehensive synthesis of evidence linking PFAS exposure to diabetes risk and metabolic dysfunction to date.

What Are PFAS and Why Are They a Concern?

PFAS are a large group of over 10,000 synthetic chemicals used for their water- and stain-resistant properties. Unfortunately, these chemicals do not break down easily and can accumulate in the human body over time. The main exposure routes include ingestion of contaminated food and water, inhalation, and dermal absorption. Studies have found PFAS in nearly all populations globally, making understanding their health effects urgent.

PFAS have been identified as endocrine-disrupting chemicals, which can interfere with hormone signaling and metabolism. Animal studies suggest that PFAS may induce insulin resistance, dyslipidemia, and liver fat accumulation even at low exposure levels. Observational studies in humans have also linked PFAS exposure to metabolic syndrome components, further raising concerns about their potential role in diabetes development.

Understanding Diabetes and Its Key Biomarkers

Diabetes mellitus is a chronic disease characterized by elevated blood glucose due to insufficient insulin production or ineffective insulin use. It has three main forms:

• Type 1 diabetes (T1D): An autoimmune disease usually diagnosed in childhood, characterized by destruction of pancreatic β-cells and insulin deficiency.
• Type 2 diabetes (T2D): A condition marked by insulin resistance, most common in adults, accounting for over 90% of global diabetes cases.
• Gestational diabetes mellitus (GDM): Glucose intolerance that first occurs during pregnancy, affecting about 10% of pregnancies globally.

Key clinical markers used to assess diabetes risk include:

• HOMA-IR: Homeostatic Model Assessment of Insulin Resistance
• HOMA-β: Homeostatic Model Assessment of β-cell function
• Fasting insulin and glucose
• Hemoglobin A1c (HbA1c)

These biomarkers provide insight into the body’s ability to regulate glucose and secrete insulin, critical for early detection and management of diabetes.

The Study: Scope and Methods

Aldana and colleagues systematically searched PubMed/MEDLINE and Ovid/EMBASE for human observational studies investigating PFAS exposure and diabetes outcomes. The review included cross-sectional, case-control, nested case-control, retrospective, and prospective cohort studies. Studies that focused on experimental models or did not report quantitative outcomes were excluded.

In total, 129 studies from 17 countries were included, with the majority conducted in the United States and China. Sample sizes ranged from 40 participants to over 1.3 million. The studies analyzed 45 different PFAS, with the most common being PFOA, PFOS, PFHxS, PFNA, PFDA, and PFUnDA.

Random-effects meta-analyses were conducted on 79 studies, focusing on seven key diabetes outcomes: GDM, T2D, HOMA-IR, HOMA-β, fasting insulin, fasting glucose, and HbA1c. Associations were standardized across studies using log2-transformed PFAS exposure, allowing effect estimates to be expressed as the change in risk per doubling of PFAS levels. Risk of bias was evaluated using the Navigation Guide, and sensitivity analyses were conducted to ensure robustness.

Key Findings

PFAS and Gestational Diabetes

The most consistent finding across studies was that higher PFAS exposure was associated with increased odds of GDM. For example, prospective studies showed that doubling PFOS levels increased GDM odds by 13% [OR 1.13, 95% CI 1.01–1.26]. Other PFAS such as PFBS and 6:2 Cl-PFESA showed similar associations, while PFHpA showed a protective effect in some studies.

This suggests that pregnancy may represent a particularly vulnerable window for PFAS exposure, potentially due to interactions with thyroid hormone regulation, placental development, and energy homeostasis. Dysregulation of these pathways could increase insulin resistance and β-cell stress, contributing to hyperglycemia during pregnancy.

PFAS and Type 2 Diabetes

Evidence for associations between PFAS and T2D was less consistent. Prospective studies indicated a trend toward positive associations for PFOA, PFOS, and PFNA, but the results were not statistically significant. Cross-sectional studies showed mixed or null associations, likely reflecting differences in study design, exposure timing, and population characteristics.

PFAS and Insulin Resistance and β-cell Function

Meta-analyses revealed that PFAS exposure, particularly legacy PFAS, was positively associated with HOMA-IR and HOMA-β. For instance:

• PFOS was associated with increased HOMA-IR [β 0.06, 95% CI 0.01–0.12] and HOMA-β [β 5.93, 95% CI 1.72–10.2].
• PFNA was linked to higher fasting insulin [β 0.34 μU/mL, 95% CI 0.13–0.56].

These findings suggest that PFAS may disrupt both insulin sensitivity and secretion, potentially initiating early metabolic changes before the development of overt diabetes. Interestingly, some associations with fasting glucose and HbA1c were less consistent and primarily observed in studies with lower risk of bias.

PFAS Mixtures

A growing number of studies examined the combined effects of multiple PFAS or PFAS with other environmental chemicals. Exposure-mixture analyses indicated that legacy PFAS were the dominant contributors to associations with GDM and glucose metabolism markers. These findings highlight the importance of studying chemical mixtures rather than single compounds in isolation.

Biological Mechanisms

Several pathways may explain PFAS effects on glucose metabolism:

• Endocrine disruption: PFAS interfere with hormone signaling, including thyroid hormones, which regulate glucose homeostasis.
• PPAR pathways: PFAS can impair peroxisome proliferator-activated receptors (PPARα and PPARγ), affecting lipid metabolism and insulin sensitivity.
• β-cell stress: Increased HOMA-β may reflect early compensatory hypersecretion of insulin in response to PFAS-induced insulin resistance, potentially leading to β-cell failure over time.
• Oxidative stress and inflammation: PFAS can increase reactive oxygen species, promote adipogenesis, and alter energy homeostasis, contributing to metabolic dysfunction.

These mechanisms support the observed epidemiological associations between PFAS exposure and altered markers of glycemic control.

Implications for Public Health

The findings of Aldana et al. have important implications for public health and clinical practice:

1. Pregnancy care: Given the strong association between PFAS and GDM, clinicians may consider evaluating environmental chemical exposure histories in pre-conception and prenatal care, offering counseling on reducing PFAS exposure.
2. Policy interventions: Reducing environmental PFAS contamination through regulatory actions could mitigate metabolic health risks in the population.
3. Research priorities: There is a need for larger prospective studies that include emerging PFAS, examine early life exposure windows, and evaluate long-term diabetes risk, especially in underrepresented populations and low- and middle-income countries.

Limitations and Knowledge Gaps

While the review provides robust evidence for GDM and insulin markers, several limitations exist:

• Most studies were cross-sectional, limiting causal inference.
• Evidence for T1D is extremely limited, making it difficult to draw conclusions.
• Exposure assessment often focused on adult and prenatal periods, leaving childhood and adolescence underexplored.
• Few studies examined PFAS in low- and middle-income countries, despite rising diabetes prevalence.
• Residual confounding from diet, genetics, and other lifestyle factors may influence results.

Addressing these gaps is critical for understanding the full impact of PFAS on diabetes risk across the life course.

Conclusion

This systematic review and meta-analysis provides compelling evidence that PFAS exposure is associated with higher odds of gestational diabetes and alterations in insulin secretion and sensitivity. While evidence for type 2 and type 1 diabetes remains limited, the observed changes in key diabetes biomarkers highlight the potential metabolic effects of PFAS. The study underscores the need for further research into emerging PFAS, chemical mixtures, and vulnerable life stages, as well as public health interventions to reduce exposure.

Understanding and mitigating the metabolic risks posed by PFAS could play a critical role in addressing the global diabetes epidemic.

References

1. Aldana SI, Yu X, Yao M, et al. Associations of perfluoroalkyl and polyfluoroalkyl substances with markers of glycaemic control, insulin secretion and sensitivity, and diabetes risk: a systematic review and meta-analyses. eClinicalMedicine, Volume 0, Issue 0, 103747
2. National Institutes of Health. Environmental Health Perspectives on PFAS.
3. Centers for Disease Control and Prevention. Diabetes Facts.
4. WHO. Global Report on Diabetes, 2022.

Disclaimer: This blog is for informational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified healthcare provider regarding any questions about medical conditions or exposure risks.