BMI, Sedentary Habits and HbA1c Flag Hidden Nerve Damage in Diabetes

Nearly eight in ten patients with type 2 diabetes attending a tertiary clinic in Zanzibar showed signs of cardiac autonomic neuropathy, a serious but often underdiagnosed complication that impairs the autonomic nerves controlling heart rate and blood vessels. In a hospital-based cross-sectional study of 364 adults treated at the Mnazi Mmoja Hospital diabetic clinic, 291 patients, or 79.9 percent, tested positive for some degree of autonomic dysfunction using standardized Ewing cardiovascular reflex tests. Most of these cases were early stage: 220 patients, or 60.4 percent of the full cohort, had early CAN, 65 patients, or 17.9 percent, had definite CAN, and only 6 patients, or 1.6 percent, had severe CAN. The findings, published in Cardiovascular Diabetology – Endocrinology Reports, point to body mass index, sedentary lifestyle and elevated HbA1c as factors linked to the condition in this population.

The study team, led by Hassan Thabit Haji and Fredirick L. Mashili with colleagues at Muhimbili University of Health and Allied Sciences and collaborating institutions, enrolled participants between December 20th, 2023, and March 20th, 2024. Eligible patients were aged 18 or older, permanent residents of Zanzibar, had a confirmed diagnosis of type 2 diabetes, and were taking at least one prescribed anti-diabetic medication. People with serious comorbid conditions such as chronic kidney disease or severe liver disease were excluded because those illnesses can independently affect autonomic nervous system function and could confound the assessment of diabetes-related nerve damage. Pregnant women and women less than 12 weeks postpartum were also excluded. Participants were selected through systematic random sampling, and the sample size was calculated with a standard formula for prevalence studies using a 5 percent margin of error and a 5 percent significance level, with an additional 5 percent added to account for potential non-response.

Diagnosing cardiac autonomic neuropathy requires more than a routine checkup. The researchers used an automated device, the Cardiac Autonomic Neuropathy System Analyzer CAN 504, to run six standard Ewing non-invasive tests based on multi-parameter electrocardiography. Before testing, patients fasted for 12 hours and avoided antidepressants, neuroleptics, caffeine, nicotine, antihistamines, alcohol and smoking. The tests took place in a quiet room held at a constant temperature of 22 to 24 degrees Celsius, with a two-minute rest after each test to allow heart rate stabilization. The battery included measurement of resting heart rate, the heart rate response to deep breathing at six breaths per minute, the lying-to-standing 30–15 ratio, the Valsalva maneuver performed at 40 mmHg for 15 seconds, postural hypotension assessed after standing, and the blood pressure response to sustained handgrip at 30 percent of maximum voluntary contraction. Each test contributed points to a composite score: a total of 0 indicated absent CAN, 0.5 to 1.5 points indicated early CAN, 2 to 3 points indicated definite CAN, and scores of 3.5 or above indicated severe CAN.

The cohort was predominantly female, with 243 of 364 participants, or 66.8 percent, and had a mean age of 56 years with a standard deviation of 10.9 years. Most participants fell in the 40 to 60 year age band, at 55.5 percent, followed by those older than 60 at 36.8 percent and those younger than 40 at 7.7 percent. The mean body mass index was 28.3 kilograms per square meter with a standard deviation of 6.4, and the distribution leaned heavily toward excess weight: 36.0 percent of participants were overweight, 32.1 percent had obesity, 28.9 percent had normal weight, and 3.0 percent were underweight. Physical inactivity was nearly universal, with 98.1 percent of participants classified as sedentary according to the World Health Organization guideline of fewer than 600 metabolic equivalent task minutes per week, and the median sedentary time was 45 minutes with an interquartile range of 30.0 to 60.0. The mean HbA1c was 7.3 percent with a standard deviation of 2.8, and 53.3 percent of participants had abnormal values at or above the 6.5 percent threshold recommended by the American Diabetes Association.

To identify which characteristics were independently associated with CAN, the researchers used modified Poisson regression models with robust variance, analyzing the data in STATA version 18. All variables included in the univariable analyses were retained in the multivariable models based on a priori considerations guided by existing literature and biological relevance, a strategy the authors say allowed proper adjustment for potential confounding. Three factors emerged as statistically significant. Patients with normal body mass index had a lower risk of CAN, with an adjusted prevalence ratio of 0.86 and a 95 percent confidence interval of 0.76 to 0.99, at a p value of 0.036. Patients with a sedentary lifestyle had a higher risk, with an adjusted prevalence ratio of 1.00 and a 95 percent confidence interval of 1.00 to 1.00, at a p value of 0.002. Elevated HbA1c levels were also associated with higher risk, with an adjusted prevalence ratio of 1.01 and a 95 percent confidence interval of 1.00 to 1.03, at a p value of 0.013.

The bivariate patterns echoed these signals. The highest prevalence of CAN appeared among participants aged 40 to 60 years at 82.2 percent, compared with 77.6 percent among those older than 60 and 75.0 percent among those younger than 40, although the age difference was not statistically significant at a p value of 0.470. Overweight participants showed the highest proportion of CAN at 85.5 percent, while those with normal BMI had the lowest at 74.3 percent, a difference that also fell short of significance at a p value of 0.123. The starkest contrast involved physical activity: inactive patients had a CAN prevalence of 81.2 percent compared with just 14.3 percent among active individuals, a difference that was highly significant at a p value below 0.001. Higher CAN proportions were also observed among patients with abnormal HbA1c, at 82.0 percent versus 77.6 percent for those with normal values, but this difference was not statistically significant at a p value of 0.305.

The 79.9 percent prevalence sits above figures reported elsewhere in Africa, including 44.3 percent in South-East Nigeria and 52.2 percent in Uganda, but below the 89 percent reported in Sudan. The authors attribute part of this elevation to the tertiary care setting, which likely included patients with longer diabetes duration and a higher burden of risk factors, and to the use of sensitive diagnostic methods capable of detecting early or subclinical cases. Among people with type 2 diabetes generally, published prevalence estimates range from 25 to 75 percent depending on diagnostic criteria and study population, so the Zanzibar cohort, drawn from the main tertiary referral hospital receiving patients from all districts across Unguja and Pemba islands, represents a particularly high-risk group rather than a community sample.

The biological plausibility behind the BMI finding draws on a growing body of work on fat distribution and autonomic function. Increased adiposity promotes inflammation, oxidative stress and endothelial dysfunction, all of which contribute to autonomic nerve damage. Studies have linked visceral and ectopic fat to impaired cardiovascular reflexes and reductions in heart rate variability in type 2 diabetes, although one research group reported that ectopic fat was associated with CAN only in autoimmune diabetes, suggesting differences in fat distribution and metabolic mechanisms across diabetes types. Interventional evidence further suggests that improving metabolic dysfunction, including insulin resistance and body weight, may enhance autonomic regulation. Notably, the Zanzibar team measured waist and hip circumferences but did not include them in the final analysis, so the role of central adiposity could not be fully evaluated.

On the glycemic side, the association between elevated HbA1c and CAN aligns with landmark trials such as the Diabetes Control and Complications Trial and the EURODIAB Prospective Complications Study, which identified chronic hyperglycemia as a major driver of diabetic neuropathies. Beyond average HbA1c, other studies have shown that greater HbA1c variability independently predicts increased CAN severity, and research on glycemic variability and so-called metabolic memory suggests that autonomic damage can persist even after HbA1c normalization. Persistent hyperglycemia, rather than intermittent hypoglycemia, appears to be the principal contributor to CAN in diabetes patients. Physical inactivity, meanwhile, is known to impair autonomic balance by increasing sympathetic activity and reducing parasympathetic tone, and systematic reviews show that aerobic exercise improves heart rate variability and autonomic function in patients with type 2 diabetes.

The authors are careful about what this cross-sectional study can and cannot show. The design precludes causal inference, physical activity was self-reported and may be subject to recall bias, and although participants with known cardiovascular comorbidities were excluded, unmeasured factors such as medication use and hypertension severity may have influenced the observed associations. The absence of a non-diabetic control group further limits causal attribution. Even so, the team argues that the sheer burden of CAN, with nearly 80 percent of clinic patients affected and most cases caught at an early stage, makes a case for routine non-invasive autonomic function screening at secondary and tertiary levels of care, particularly for patients with elevated BMI, sedentary lifestyles and abnormal HbA1c. Early identification, they note, can lead to tailored therapeutic strategies that may slow the progression of cardiovascular complications, and future longitudinal studies are needed to clarify the causal relationships these cross-sectional associations only hint at.

Subject of Research: Prevalence and predictors of cardiac autonomic neuropathy among type 2 diabetes patients in Zanzibar

Article Title: Body mass index, sedentary lifestyle, and HbA1c predict cardiac autonomic neuropathy in type 2 diabetes

Article References: Haji, H. T., Ali, R. M., Khamis, A. G., Ebrahim, A., Muya, M. R., Ramaiya, K., & Mashili, F. L. (2026). Body mass index, sedentary lifestyle, and HbA1c predict cardiac autonomic neuropathy in type 2 diabetes. Cardiovascular Diabetology – Endocrinology Reports, 12(1), Article 44. https://doi.org/10.1186/s40842-026-00308-1

Image Credits: AI Generated

DOI: 10.1186/s40842-026-00308-1

Keywords: cardiac autonomic neuropathy, type 2 diabetes, HbA1c, body mass index, sedentary lifestyle, Zanzibar, Ewing cardiovascular reflex tests, cross-sectional study, autonomic dysfunction, tertiary diabetes clinic, prevalence, glycemic control