Diabetic ketoacidosis (DKA) is a life-threatening complication which can arise in individuals with insulin deficiency. The American Diabetes Association has stated that blood testing methods for the quantification of D-β-hydroxybutyrate (abbreviated BHB) would be desirable for the diagnosis and monitoring of ketoacidosis, which occurs predominantly in type 1 diabetic patients. To realize a tool which can predict DKA, accurate and dynamic information is needed about the blood ketone concentration of a patient and their “ketone variability.” Thus, there is a great push to develop continuous ketone monitoring (CKM) technologies for the prevention of DKA. Currently available measurement systems for BHB are limited by the nature of BHB dehydrogenase enzymes. Unlike the enzymes used in systems for continuous glucose monitoring (CGM), BHB dehydrogenases are NAD dependent, which makes them difficult to configure for continuous operation. In this study, we report the development a continuous ketone monitoring system that uses a novel binding protein as its primary biorecognition element. The protein undergoes conformational change after binding to BHB which can be leveraged to create signal change. The reversibility of this interaction makes a binding protein-based sensor an innovative solution for CKM which circumvents the technological challenge of using an NAD dependent enzyme. First, we undertook a thorough screening of candidate binding proteins and tested their ability to bind BHB through intrinsic fluorescence measurements. Then, we transitioned to preparing a ketone sensor electrochemically; by immobilizing redox probe modified binding proteins on the surface of gold electrodes, we were able to interrogate their conformational change in the presence of BHB. In the future, we hope a BHB sensing system based on this principle can be easily integrated with current, commercially available CGM systems for the realization of a readily accessible CGM/CKM system.

Development of an electrochemical continuous ketone monitoring system using a binding protein as a novel biosensing molecule

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