Higher levels of zinc excreted in urine may signal an elevated risk of developing peripheral artery disease, one of the most disabling circulatory conditions in older adults, according to a new analysis from the Strong Heart Study, a long-running cohort of American Indian communities in the United States. Researchers report that participants with higher baseline urinary zinc concentrations were more likely to develop peripheral artery disease over a decade of follow-up, and were also more likely to undergo diabetes-related amputations, with the association appearing strongest among people living with diabetes.
The study drew on the Strong Heart Study, a large population-based prospective cohort established to investigate cardiovascular disease and its risk factors among American Indian communities in Arizona, Oklahoma, North Dakota and South Dakota. Between 1989 and 1992, the study recruited 4,549 men and women aged 45 to 74 from 13 communities; after one community withdrew, 3,517 participants remained eligible, and retention across the first three study visits was about 90 percent.
Peripheral artery disease is a progressive condition caused by arterial occlusion in the lower extremities that can produce chronic pain and functional impairment. Roughly 11 percent of patients with clinical disease go on to develop chronic limb-threatening ischemia, which can result in ischemic ulceration and amputation. Type 2 diabetes is an established risk factor for the disease’s incidence and progression: people with a diabetes diagnosis face a two- to fourfold increase in incidence and are more likely to suffer complications including amputations. American Indian and Alaskan Native adults carry the highest prevalence of both diabetes and peripheral artery disease of any racial or ethnic group in the United States, with a documented twofold higher prevalence of the disease compared with White populations, making this population especially important for understanding the condition’s early markers.
Zinc itself is an essential micronutrient with antioxidant and anti-inflammatory properties, obtained mostly through the diet. It plays a direct role in pancreatic function: zinc is a component of the insulin complex and directly modulates insulin storage and release, and it also serves as a cofactor for enzymes such as superoxide dismutase, a key regulator of oxidative stress. Previous studies have linked higher urinary zinc levels to increased risk of cardiometabolic diseases including diabetes, coronary artery calcification and cardiovascular disease events. Urinary zinc can reflect early cardiometabolic dysregulation and loss of the body’s zinc reserves in addition to dietary intake, yet few studies had examined whether the biomarker relates to peripheral artery disease or diabetes-related amputations.
To address that gap, the researchers analyzed 2,045 participants free of peripheral artery disease and 2,180 participants free of amputation at baseline, the 1989 to 1991 examination. Participants averaged 56 years of age and 61 percent were women. Morning spot urine samples collected during a standardized clinical examination were frozen within one to two hours, shipped on dry ice and stored at minus 70 degrees Celsius for up to 18 years before metal concentrations were measured by inductively coupled plasma-mass spectrometry at the Trace Element Laboratory at Graz University in Austria. No samples fell below the 10 micrograms per liter detection limit for zinc. Urinary zinc levels were divided by creatinine to account for urine dilution and expressed in micrograms per gram creatinine.
During follow-up through the study’s second visit in 1993 to 1995 and third visit in 1997 to 1999, spanning roughly 10 years, 344 participants developed peripheral artery disease and 23 underwent diabetes-related amputations. The disease was determined by measuring the ankle-brachial index, the ratio of blood pressure at the ankle to blood pressure in the arm, using a hand-held Doppler device; cases included either an index below 0.9, indicating arterial disease, or above 1.4, indicating noncompressible disease due to vessel calcification. Amputation status, location and participant-reported cause were assessed by clinical staff during physical examinations, and only amputations attributed to diabetes were counted. Participants who developed the disease or underwent amputations had higher baseline urinary zinc levels than those who did not experience either event.
In logistic regression models adjusted for age, sex, study region, body mass index, smoking, alcohol use, kidney function, cholesterol measures and hypertension, the odds of developing peripheral artery disease rose 29 percent per interquartile-range increment in baseline urinary zinc, with an odds ratio of 1.29 and a 95 percent confidence interval of 1.10 to 1.51. For diabetes-related amputation, the corresponding odds ratio was 2.36, with a confidence interval of 1.43 to 3.90, meaning the odds of amputation were more than doubled across the same span of urinary zinc levels.
The picture grew more complicated when the researchers accounted for diabetes. Adding baseline diabetes status to the model attenuated the disease association to an odds ratio of 1.16, with a confidence interval spanning 0.98 to 1.38, no longer statistically significant. Further adjustment for fasting plasma glucose, a proxy for diabetes control, weakened it further to 1.09, and reduced the amputation estimate to 1.39 with a confidence interval of 0.76 to 2.54. Yet stratified analyses revealed a striking pattern: among participants with diabetes at baseline, the association between urinary zinc and incident disease remained significant after adjustment for cardiovascular risk factors, with an odds ratio of 1.43 and a confidence interval of 1.11 to 1.86, and an interaction p-value of 0.017. Among participants without diabetes, the association was not statistically significant. No significant subgroup differences emerged by smoking status, age category, sex or education level, and no subgroup analysis was performed for amputation because of the limited number of events.
The attenuation after adjusting for fasting plasma glucose suggests that urinary zinc and blood glucose are tightly connected. Previous studies have documented lower urinary zinc levels in type 2 diabetes patients with good glycemic control compared with those with poor control, and a recent Strong Heart Study analysis found an increased risk of type 2 diabetes among participants diabetes-free at baseline, with a hazard ratio of 1.21 per interquartile-range increase in urinary zinc. Two studies in the Multi-Ethnic Study of Atherosclerosis similarly linked urinary zinc to greater progression of coronary artery calcification, an indicator of arterial injury, and to increased risk of cardiovascular disease events. The authors propose several mechanisms: dysregulation of zinc’s role in insulin storage may release zinc from the intracellular compartment in early disease stages, and osmotic diuresis in diabetes can enhance urinary zinc excretion. Zinc dysregulation may also contribute to oxidative stress and inflammation, key factors in the onset and progression of peripheral artery disease.
The researchers caution that the study has limitations. Some event misclassification may have occurred because not all individuals had complete measurements at both follow-up visits, though this is likely small and non-differential. The absolute number of amputation events was small, limiting subgroup analyses, and classification of amputations as diabetes-related relied on participant-reported information, introducing potential recall bias. The study relied on a single urine biomarker for zinc, did not measure oxidative stress or inflammation biomarkers, and assessed fasting glucose and zinc at the same timepoint, preventing formal mediation analyses. Dietary zinc and supplement use information was limited, though prior studies suggest a low correlation between zinc intake and urinary zinc variability. Atherosclerotic and noncompressible forms of the disease were also grouped together.
Subject of Research: Prospective associations between urinary zinc levels and incident peripheral artery disease and diabetes-related amputation in the Strong Heart Study cohort of American Indian adults
Article Title: Associations of urinary zinc with incident peripheral artery disease and amputation in the Strong Heart Study
Article References: Howlett, C., Ravalli, F., Bhatt, K., Fabsitz, R. R., Tellez-Plaza, M., Umans, J. G., Goessler, W., Grau-Perez, M., Devereux, R. B., Navas-Acien, A., & Martinez-Morata, I. (2025). Associations of urinary zinc with incident peripheral artery disease and amputation in the Strong Heart Study. Discover Endocrinology and Metabolism, 1(1), Article 9. https://doi.org/10.1007/s44417-025-00005-0
Image Credits: AI Generated
DOI: 10.1007/s44417-025-00005-0
Keywords: urinary zinc, peripheral artery disease, amputation, diabetes, Strong Heart Study, American Indian adults, ankle-brachial index, fasting plasma glucose, cardiometabolic disease, epidemiology, cohort study, zinc metabolism
News Source: Ophelia Keating. (October 30, 2026). Higher Urinary Zinc Linked to Raised Peripheral Artery Disease Risk in American Indian Adults. Scienmag.
