The incidence, prevalence, mortality, and health expenditure associated with diabetes continue to grow, despite efforts. The use of multianalyte sensors, which detect glucose as well as key analytes such as ketones, lactate, insulin, uric acid, and electrolytes, may provide additional information to guide earlier identification and management of diabetes and its complications. We undertook a narrative review using a systematic approach in May 2023, with a bridge search undertaken in April 2024. Four biomedical databases were searched: MEDLINE (Ovid), Embase, Emcare, and Cochrane Library. Searches for gray literature were conducted on ClinicalTrials.gov, Google Scholar, and websites of relevant organizations. Included studies incorporated articles on multianalyte sensors in diabetes and single-analyte sensors proposing integration into multianalyte diabetes management, with no limits placed on publication date and study design. Data were screened and extracted using CovidenceTM software. Overall, 11 articles were included, of which 7 involved multianalyte sensors (involving glucose and other analytes) and 4 single-analyte sensors (measuring non-glucose substances for proposed future integration into multianalyte systems). Analytes examined were ketones (n = 3), lactate (n = 4), uric acid (n = 3), insulin (n = 1), and potassium (n = 1). Results demonstrated that in vitro and in vivo measurements of multi- and single-analyte sensors accurately and reliably corresponded with human capillary and serum samples. While the literature on this topic is sparse, our review demonstrated that measurement of glucose and other analytes can be feasibly undertaken using multi- and single-analyte sensors. More studies in humans are needed to establish clinical utility in diabetes self-management and assist with technological improvements.

Ketone bodies (KBs), especially β-hydroxybutyrate (BHB), have gained tremendous attention as potential biomarkers as their presence in bodily fluids is closely associated with health and wellness. While a variety of blood fingerstick test strips are available for self-testing of BHB, there are major needs for wearable devices capable of continuously tracking changing BHB concentrations. To address these needs, we present here the first demonstration of a wearable microneedle-based continuous ketone monitoring (CKM) in human interstitial fluid (ISF) and illustrate its ability to closely follow the intake of ketone drinks. To ensure highly stable and selective continuous detection of ISF BHB, the new enzymatic microneedle BHB sensor relies on a gold-coated platinum working electrode modified with a reagent layer containing toluidine blue O (TBO) redox mediator, β-hydroxybutyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) cofactor, along with carbon nanotubes (CNTs), chitosan (Chit), and a poly(vinyl chloride) (PVC) outer protective layer. The skin-worn microneedle sensing device operates with a miniaturized electrochemical analyzer connected wirelessly to a mobile electronic device for capturing, processing, and displaying the data. Cytotoxicity and skin penetration studies indicate the absence of potential harmful effects. A pilot study involving multiple human subjects evaluated continuous BHB monitoring in human ISF, against gold standard BHB meter measurements, revealing the close correlation between the two methods. Such microneedle-based CKM offers considerable promise for dynamic BHB tracking toward the management of diabetic ketoacidosis and personal nutrition and wellness.

Diabetic ketoacidosis (DKA) is a life-threatening complication, which is most common in individuals with type 1 diabetes (T1D) and is a significant risk for morbidity and mortality, and it is an economic burden on individuals, health care systems, and payers. Younger children, minority ethnic groups, and those with limited insurance are at the greatest risk for presentation of DKA at T1D diagnosis. Although monitoring ketone levels is an essential part of acute illness management and for both early detection and prevention of a DKA episode, studies have reported poor adherence to ketone monitoring. Ketone monitoring is particularly important for patients treated with sodium glucose cotransporter 2 inhibitor (SGLT2i) medications, in which DKA can present with only moderately elevated glucose levels, referred to as euglycemic DKA (euDKA). A majority of people with T1D and many with type 2 diabetes (T2D), particularly those using insulin therapy, are using continuous glucose monitoring (CGM) as their preferred method for measurement and management of glycemia. These devices provide a continuous stream of glucose data that enables users to take immediate action to mitigate and/or prevent severe hyperglycemic or hypoglycemic events. An international consensus of leading diabetes experts has recommended the development of continuous ketone monitoring systems, ideally a system that combines CGM technology with measurement of 3-β-OHB into a single sensor. In this narrative review of current literature, we report on the prevalence and burden of DKA, examine challenges to detecting and diagnosing this condition, and discuss a new monitoring option for DKA prevention.

The feasibility of measuring β-hydroxybutyrate in ISF using a continuous ketone monitoring (CKM) sensor using a single calibration without further adjustments over 14 days is described.
A CKM sensor was developed using wired enzyme technology with β-hydroxybutyrate dehydrogenase chemistry. In vitro characterization of the sensor was performed in phosphate buffered saline at 37°C. In vivo performance was evaluated in 12 healthy participants on low carbohydrate diets, who wore 3 ketone sensors on the back of their upper arms to continuously measure ketone levels over 14 days. Reference capillary ketone measurements were performed using Precision Xtra® test strips at least 8 times a day.
The sensor is stable over 14 days and has a linear response over the 0-8 mM range. The operational stability of the sensor is very good with a 2.1% signal change over 14 days. The first human study of the CKM sensor demonstrated that the sensor can continuously track ketones well through the entire 14 days of wear. The performance with a single retrospective calibration of the sensor showed 82.4% of data pairs within 0.225 mM/20% and 91.4% within 0.3 mM/30% of the capillary ketone reference (presented as mM at <1.5 mM and as percentage at or above 1.5 mM). This suggests that the sensor can be used with a single calibration for the 14 days of use.
Measuring ketones in ISF using a continuous ketone sensor is feasible. Additional studies are required to evaluate the performance in intended patient populations, including conditions of ketosis and diabetic ketoacidosis.