Noninvasive Interstitial Glucose Estimation Using Wearables and Machine Learning in Healthy Individuals and Individuals With Obesity: Observational Cohort Study

Abstract Background Continuous glucose monitoring (CGM) can facilitate weight management and lower the risk of metabolic diseases by providing real-time feedback on glycemic responses, thereby enabling more informed lifestyle decisions. However, current CGM systems remain constrained by invasiveness, cost, and short sensor lifespan, limiting their practicality for guiding individualized postprandial low-glycemic diets. Objective Extending earlier proof-of-concept findings, this study aimed to validate an interstitial glucose (IG) machine learning algorithm in real-world environments using multimodal, continuous data collected from wearable sensors and smartwatches. In the long term, we aim to embed a noninvasive, sensor-based algorithm for estimating tissue glucose within mobile health apps and postprandial low-glycemic diet frameworks to enable scalable, personalized prevention strategies. Methods We conducted a 2-week study phase during which participants continuously wore 2 noninvasive sensor devices: a scientific sensor wristband (Empatica EmbracePlus) and a commercially available smartwatch (Fitbit Sense 2). As a reference measurement, an invasive CGM sensor (Abbott FreeStyle Libre 3) measured IG levels. For metabolic characterization, 1-point fasting blood and urine samples were collected, and deep phenotyping using state-of-the-art nuclear magnetic resonance spectroscopy and bioelectrical impedance analysis was performed. For participants with overweight and obesity, clinical standard parameters focusing on glucose metabolism were analyzed. Results A total of 74 participants, 34 (46%) healthy controls and 40 (54%) metabolically at-risk (MR) individuals, simultaneously used an invasive CGM device together with 2 noninvasive wristbands over 2 weeks. Healthy controls were characterized by a mean age of 24.53 (SD 3.68) years and a mean BMI of 22.36 (SD 2.16) kg/m². In contrast, the MR cohort had a mean age of 55.38 (SD 15.08) years and a mean BMI of 35.38 (SD 4.91) kg/m². Furthermore, the MR cohort showed elevated fasting glucose levels (mean 107.56, SD 19.26 mg/dL), hemoglobin A 1c levels (mean 5.67%, SD 0.63%), and an increased homeostatic model assessment of insulin resistance index (mean 4.34, SD 3.49), indicating a disturbed glucose metabolism. The proposed long short-term memory network based on feature vectors obtained the best IG prediction performance, with an average root-mean-squared error of 21.04 (SD 8.32) mg/dL and 98.3% of predictions in zones A and B of the Clarke error grid analysis, representing a high level of predictive accuracy. In addition, based on data from a smartwatch, we achieved a comparable average root-mean-squared error of 23.49 (SD 11.46) mg/dL for the overall cohort. Conclusions This study demonstrates that IG levels can be predicted from multimodal, noninvasive wearable sensor data using a machine learning approach under real-world conditions. While further validation in larger and more diverse cohorts is warranted, this approach represents a promising step toward accessible, personalized glycemic monitoring and dietary guidance as a preventive tool in mobile health apps.