This study is devoted to the development of novel glucose-responsive polymers that operate under physiological conditions (pH 7.4, 37 degrees C), aiming for future use in a self-regulated insulin delivery system to treat diabetes mellitus. The approach involves the use of a newly synthesized phenylborate derivative [4-(1,6-dioxo-2,5-diaza-7-oxamyl) phenylboronic acid, DDOPBA] possessing an appreciably low pK(a) ( approximately 7.8) as a glucose-sensing moiety, as well as the adoption of poly(N-isopropylmethacrylamide), PNIPMAAm, as the main chain that exhibits critical solution behavior in the range close to physiological temperature. Glucose- and pH-dependent changes in the critical solution behavior of the resultant copolymers were investigated at varying temperatures, revealing definite glucose sensitivities near the physiological conditions. Furthermore, DDOPBA moieties in the copolymers maintained constant apparent pK(a) values even when the temperature approaches the critical solution points of the main chain, indicating that spacing of the phenylborate moiety from the polymer backbone is a feasible way to minimize the microenvironment effect caused by a temperature-induced change in the hydration state of the polymer strands.