In vivo molecular sensing in diabetes mellitus: an implantable glucose sensor with direct electron transfer

Abstract

Miniature, amperometric glucose sensors were constructed for implantation in the subcutaneous tissue of normal and insulin-dependent diabetic subjects. To minimise dependence on fluctuating tissue oxygen tension, we employed the technology of mediated electron transfer, with 1,1'-dimethylferrocene acting as the redox shuttle between immobilized glucose oxidase and a platinum base electrode. In 6 normal subjects, the subcutaneous sensor responses mirrored the simultaneously-measured changes in blood glucose concentration after a 75 g oral glucose load and after intravenous injection of 0.15 U/kg short-acting insulin, though increases and decreases in the sensor output were slower than the glycaemic changes. The mean peak delay in sensor response after the oral glucose was 40 min (range 0-45 min) and the delay in the hypoglycaemic nadir was 4 min (range 0-15 min). In 5 insulin-dependent diabetic subjects, spontaneous and induced hypoglycaemia was detectable by the implanted sensor. In addition, marked and frequent oscillations in the sensor current occurred in several normal and diabetic individuals as the blood glucose fell below about 1.9 mmol/l. These oscillations were present in a diabetic subject who had lost adrenergic warning symptoms to hypoglycaemia. Continuous metabolic monitoring in diabetes, particularly the detection of hypoglycaemia, may be possible with implanted sensors based on this technology.

Use of continuous glucose monitoring in normoglycemic, insulin-resistant women

“…Kulcu et al (2003) replicated these Wndings in diabetic (type 1 and type 2) humans to demonstrate that as venous glucose concentrations increased, the change in interstitial glucose was less than that in venous glucose. In six normoglycemic, healthy individuals, Pickup et al (1989) reported similar changes in interstitial and venous glucose concentrations after a 75 g glucose load; however the increase in interstitial glucose concentrations lagged behind that of venous measures. Cartee et al (1989) reported during exercise, interstitial glucose concentrations in rats decreased more quickly It must be noted that in one participant, the interstitial glucose AUC was dramatically lower compared to venous AUC during the OGTT.…”

“…The venous to interstitial glucose gradient can vary from 20% (Claremont et al 1986) to 101% (Bolinder et al 1992). In addition, time delays in the rise or fall of interstitial glucose concentrations can be as much as 45 min (Pickup et al 1989;PfeiVer et al 1993). Many of these discrepancies could potentially be the result of measuring interstitial glucose during non steady-state conditions.…”

“…Numerous studies have assessed changes in interstitial glucose concentration by: glucose administration into the peritoneal cavity (rat experiments) (Thome-Duret et al 1996), during an OGTT (trials in nondiabetic human participants) (Pickup et al 1989), or during a glucose clamp (trials in diabetic patients) (Schmidt et al 1993). Yet, the relationship between venous and interstitial glucose concentrations is unclear.…”

Measurement and modeling of the transient difference between blood and subcutaneous glucose concentrations in the rat after injection of insulin

“…Blood glucose concentrations are well correlated with subcutaneous glucose concentrations at steady-state (1)(2)(3)(4)(5). When the blood glucose concentration increases rapidly (3,4,(6)(7)(8)(9) or decreases (7,9,10) there is, however, a time lag, resulting in a transient difference between the blood and subcutaneous glucose concentrations. With recently developed 5 ϫ 10 Ϫ4 cm 2 active area, Ͻ150-sec response time flexible glucose electrodes, small enough to be implanted not only subcutaneously but also in the jugular vein of rats, it became possible to continuously and simultaneously track the two concentrations and to better time resolve them (11,12).…”

Recent Advances in Continuous Glucose Monitoring: Biocompatibility of Glucose Sensors for Implantation in Subcutis

“…In conclusion, the major drawback of subcutaneously implanted electrochemical sensors is the bioinstability with unpredictable drift and reproducibility of sensor measurements. 13,20,43,45,46 The bioinstability is partly explained by the sensor design, but obviously is also affected by the subcutaneous inflammatory reaction to implanted sensors. Suggested causes of the observed bioinstability have been attributed to protein/cellular biofouling in or on the membrane, tissue interferents affecting the electrode, enzymatic dysfunction, or unstable levels of oxygen.…”