Special Issue "Glucose Sensors"

Abstract: Blood glucose monitoring has been established as a valuable tool in the management of diabetes. Since maintaining normal blood glucose levels is recommended, a series of suitable glucose biosensors have been developed. During the last 50 years, glucose biosensor technology including point-of-care devices, continuous glucose monitoring systems and noninvasive glucose monitoring systems has been significantly improved. However, there continues to be several challenges related to the achievement of accurate and reliable glucose monitoring. Further technical improvements in glucose biosensors, standardization of the analytical goals for their performance, and continuously assessing and training lay users are required. This article reviews the brief history, basic principles, analytical performance, and the present status of glucose biosensors in the clinical practice.

Abstract: In recent years there has been considerable interest in the study of glucose-induced dielectric property variations of human tissues as a possible approach for non-invasive glycaemia monitoring. We have developed an electromagnetic sensor, and we tested in vitro its ability to estimate variations in glucose concentration of different solutions with similarities to blood (sodium chloride and Ringer-lactate solutions), differing though in the lack of any cellular components. The sensor was able to detect the effect of glucose variations over a wide range of concentrations (~78–5,000 mg/dL), with a sensitivity of ~0.22 mV/(mg/dL). Our proposed system may thus be useful in a new approach for non-invasive and non-contact glucose monitoring.

Abstract: PAS kinase is an evolutionarily conserved nutrient responsive protein kinase that regulates glucose homeostasis. Mammalian PAS kinase is activated by glucose in pancreatic beta cells, and knockout mice are protected from obesity, liver triglyceride accumulation, and insulin resistance when fed a high-fat diet. Yeast PAS kinase is regulated by both carbon source and cell integrity stress and stimulates the partitioning of glucose toward structural carbohydrate biosynthesis. In our current model for PAS kinase regulation, a small molecule metabolite binds the sensory PAS domain and activates the enzyme. Although bona fide PAS kinase substrates are scarce, in vitro substrate searches provide putative targets for exploration.

Abstract: We have developed a package for disposable glucose sensor chips using Parylene encapsulation of a glucose oxidase solution in the liquid phase and a cover structure made of an ultraviolet (UV) curable adhesive. Parylene was directly deposited onto a small volume (1 μL) of glucose oxidase solution through chemical vapor deposition. The cover and reaction chamber were constructed on Parylene film using a UV-curable adhesive and photolithography. The package was processed at room temperature to avoid denaturation of the glucose oxidase. The glucose oxidase solution was encapsulated and unsealed. Glucose sensing was demonstrated using standard amperometric detection at glucose concentrations between 0.1 and 100 mM, which covers the glucose concentration range of diabetic patients. Our proposed Parylene encapsulation and UV-adhesive cover form a liquid phase glucose-oxidase package that has the advantages of room temperature processing and direct liquid encapsulation of a small volume solution without use of conventional solidifying chemicals.

Abstract: Besides being the favorite carbon and energy source for the budding yeast Sacchromyces cerevisiae, glucose can act as a signaling molecule to regulate multiple aspects of yeast physiology. Yeast cells have evolved several mechanisms for monitoring the level of glucose in their habitat and respond quickly to frequent changes in the sugar availability in the environment: the cAMP/PKA pathways (with its two branches comprising Ras and the Gpr1/Gpa2 module), the Rgt2/Snf3-Rgt1 pathway and the main repression pathway involving the kinase Snf1. The cAMP/PKA pathway plays the prominent role in responding to changes in glucose availability and initiating the signaling processes that promote cell growth and division. Snf1 (the yeast homologous to mammalian AMP-activated protein kinase) is primarily required for the adaptation of yeast cell to glucose limitation and for growth on alternative carbon source, but it is also involved in the cellular response to various environmental stresses. The Rgt2/Snf3-Rgt1 pathway regulates the expression of genes required for glucose uptake. Many interconnections exist between the diverse glucose sensing systems, which enables yeast cells to fine tune cell growth, cell cycle and their coordination in response to nutritional changes.

Abstract: A novel potential treatment technique applied to a glucose biosensor that is based on pyrroloquinoline quinone (PQQ)-dependent glucose dehydrogenase (GDH) and chromium hexacyanoferrate (CrHCF) incorporated into a platinum (Pt) electrode was demonstrated. CrHCF, serving as a mediator, was electrochemically deposited on the Pt electrode as ascertained by CV, SEM, FTIR and XPS measurements. The potential treatment of CrHCF, which converts Fe(II) to Fe(III), enables the glucose detection. The amperometric measurement linearity of the biosensor was up to 20 mM (R = 0.9923), and the detection sensitivity was 199.94 nA/mM per cm². More importantly, this biosensor remained stable for >270 days.

Abstract: The availability of continuous glucose monitoring (CGM) sensors allows development of new strategies for the treatment of diabetes. In particular, from an on-line perspective, CGM sensors can become “smart” by providing them with algorithms able to generate alerts when glucose concentration is predicted to exceed the normal range thresholds. To do so, at least four important aspects have to be considered and dealt with on-line. First, the CGM data must be accurately calibrated. Then, CGM data need to be filtered in order to enhance their signal-to-noise ratio (SNR). Thirdly, predictions of future glucose concentration should be generated with suitable modeling methodologies. Finally, generation of alerts should be done by minimizing the risk of detecting false and missing true events. For these four challenges, several techniques, with various degrees of sophistication, have been proposed in the literature and are critically reviewed in this paper.

Abstract: Glucose control is the cornerstone of Diabetes Mellitus (DM) treatment. Although self-regulation using capillary glycemia (SRCG) still remains the best procedure in clinical practice, continuous glucose monitoring systems (CGM) offer the possibility of continuous and dynamic assessment of interstitial glucose concentration. CGM systems have the potential to improve glycemic control while decreasing the incidence of hypoglycemia but the efficiency, compared with SRCG, is still debated. CGM systems have the greatest potential value in patients with hypoglycemic unawareness and in controlling daily fluctuations in blood glucose. The implementation of continuous monitoring in the standard clinical setting has not yet been established but a new generation of open and close loop subcutaneous insulin infusion devices are emerging making insulin treatment and glycemic control more reliable.Glucose control is the cornerstone of Diabetes Mellitus (DM) treatment. Although self-regulation using capillary glycemia (SRCG) still remains the best procedure in clinical practice, continuous glucose monitoring systems (CGM) offer the possibility of continuous and dynamic assessment of interstitial glucose concentration. CGM systems have the potential to improve glycemic control while decreasing the incidence of hypoglycemia but the efficiency, compared with SRCG, is still debated. CGM systems have the greatest potential value in patients with hypoglycemic unawareness and in controlling daily fluctuations in blood glucose. The implementation of continuous monitoring in the standard clinical setting has not yet been established but a new generation of open and close loop subcutaneous insulin infusion devices are emerging making insulin treatment and glycemic control more reliable.

Abstract: The objective of this study was to evaluate the acute response of Sencil^TM, a fiber-optic sensor, in point accuracy for glucose monitoring in vivo on healthy dogs under anesthesia.  A total of four dogs with clinically normal glycemia were implanted with one sensor each in the chest region to measure the interstitial glucose concentration during the ovariohysterectomy procedure. The data was acquired every 10 seconds after initiation, and was compared to the concentration of venous plasma glucose sampled during the surgery procedures for accuracy of agreement analysis. In the four trials with a range of 71–297 mg/dL plasma glucose, the collected 21 pairs of ISF readings from the Sencil^TM and the plasma reference showed superior dispersion of residue values than the conventional system, and a linear correlation (the Pearson correlation coefficient is 0.9288 and the y-intercept is 14.22 mg/dL). The MAD (17.6 mg/dL) and RMAD (16.16%) of Sencil^TM measurements were in the comparable range of the conventional system. The Clarke error grid analysis indicated that 100% of the paired points were in the clinically acceptable zone A (61.9%) and B (38.1%).

Abstract: In 1962, Clark and Lyons proposed incorporating the enzyme glucose oxidase in the construction of an electrochemical sensor for glucose in blood plasma. In their application, Clark and Lyons describe an electrode in which a membrane permeable to glucose traps a small volume of solution containing the enzyme adjacent to a pH electrode, and the presence of glucose is detected by the change in the electrode potential that occurs when glucose reacts with the enzyme in this volume of solution. Although described nearly 50 years ago, this seminal development provides the general structure for constructing electrochemical glucose sensors that is still used today. Despite the maturity of the field, new developments that explore solutions to the fundamental limitations of electrochemical glucose sensors continue to emerge. Here we discuss two developments of the last 15 years; confining the enzyme and a redox mediator to a very thin molecular films at electrode surfaces by electrostatic assembly, and the use of electrodes modified by carbon nanotubes (CNTs) to leverage the electrocatalytic effect of the CNTs to reduce the oxidation overpotential of the electrode reaction or for the direct electron transport to the enzyme.

Abstract: Neurons whose activity is regulated by glucose are found in a number of brain regions. Glucose-excited (GE) neurons increase while glucose-inhibited (GI) neurons decrease their action potential frequency as interstitial brain glucose levels increase. We hypothesize that these neurons evolved to sense and respond to severe energy deficit (e.g., fasting) that threatens the brains glucose supply. During modern times, they are also important for the restoration of blood glucose levels following insulin-induced hypoglycemia. Our data suggest that impaired glucose sensing by hypothalamic glucose sensing neurons may contribute to the syndrome known as hypoglycemia-associated autonomic failure in which the mechanisms which restore euglycemia following hypoglycemia become impaired. On the other hand, increased responses of glucose sensing neurons to glucose deficit may play a role in the development of Type 2 Diabetes Mellitus and obesity. This review will discuss the mechanisms by which glucose sensing neurons sense changes in interstitial glucose and explore the roles of these specialized glucose sensors in glucose and energy homeostasis.

Abstract: Evaluation of metabolic control of diabetic people has been classically performed measuring glucose concentrations in blood samples. Due to the potential improvement it offers in diabetes care, continuous glucose monitoring (CGM) in the subcutaneous tissue is gaining popularity among both patients and physicians. However, devices for CGM measure glucose concentration in compartments other than blood, usually the interstitial space. This means that CGM need calibration against blood glucose values, and the accuracy of the estimation of blood glucose will also depend on the calibration algorithm. The complexity of the relationship between glucose dynamics in blood and the interstitial space, contrasts with the simplistic approach of calibration algorithms currently implemented in commercial CGM devices, translating in suboptimal accuracy. The present review will analyze the issue of calibration algorithms for CGM, focusing exclusively on the commercially available glucose sensors.