Evaluation of subcutaneously-implanted glucose sensors for continuous glucose measurements in hyperglycemic pigs

BACKGROUND: Subcutaneously-implanted glucose sensors for continuous glucose monitoring have the potential to replace serial blood glucose measurements. The objective of the present study was to test whether continuous glucose measurements could be obtained with glucose sensors implanted in the subcutis of pigs. Moreover, the in vivo biocompatibility of the sensors was evaluated since an inflammatory reaction may lead to drift in sensor-signaling. MATERIALS AND METHODS: Two types of glucose sensor were implanted for 3 days in the subcutis of hyperglycemic pigs. The plasma glucose concentration was correlated to the sensor outputs, and tissue was sampled for histological evaluation. RESULTS: There was a good correlation between the interstitial fluid and blood glucose levels. However, there was a statistical significantly difference in linearity from days 0 and 1 to day 2 (p<0.001) and variations in the sensitivity and background current of individual sensors were observed over time. The tissue reaction caused by the sensors was a mild focal subacute fibrinous dermatitis. CONCLUSION: Continuous glucose measurement can be achieved by glucose sensors implanted in the subcutis of pigs. The observed drift in sensor signals over time may have been caused by heterophils, macrophages and/or fibrinogen at the tissue-sensor interface.     

Implantable closed-loop glucose-sensing and insulin delivery: the future for insulin pump therapy

Although subcutaneous insulin infusion from portable pumps is the current optimal therapy for type 1 diabetic patients, implantable pumps using the intraperitoneal route allow increased blood glucose stability and lowered incidence of severe hypoglycemia. Subcutaneously implanted enzymatic glucose sensors provide continuous interstitial glucose monitoring, but this may differ from the real-time blood glucose levels. Preliminary investigations of intravascular enzymatic sensors demonstrate their clinical acceptability and accuracy and the possibility of developing closed-loop insulin delivery by combination with implantable pumps.     

Implantable electrochemical sensors for biomedical and clinical applications: progress, problems, and future possibilities

Biosensors are of great interest for their ability to monitor clinically important analytes such as blood gases, electrolytes, and metabolites. A classic example is to monitor the dynamics of blood-glucose levels for treating diabetes. However, the current practice, based on a three decade old technology, requires a drop of blood on a test strip, which is in dire need of replacement. The increasing demands and interests in developing implantable glucose sensors for treating diabetes has led to notable progress in this area, and various electrochemical sensors have been developed for intravascular and subcutaneous applications. However, implantations are plagued by biofouling, tissue destruction and infection around the implanted sensors and the response signals must be interpreted in terms of blood or plasma concentrations for clinical utility, rather than tissue fluid levels. This review focuses on the potentials and pitfalls of implantable electrochemical sensors and presents our opinions about future possibilities of such implantable devices with respect to biocompatibility issues, long-term calibration, and other aging effects on the sensors.     

Extracorporeal determination of glucose, lactate and potassium with electrochemical biosensors

Glucose, lactate and potassium ions have been continuously measured in whole blood by using two extracorporeal electrochemical biosensors and a new flow through potassium electrode. For experiments involving the “glucose clamp”, lactate and potassium electrodes have been connected in series to an endocrine artificial pancreas “Betalike” properly modified. The same artificial pancreas has been used in experiments measuring the anaerobic threshold (AT) by continuous monitoring of lactate in athletes. In this case glucose and lactate sensors were connected in series for continuous measurement of both metabolites in blood in real time. The results are in agreement with the biochemical pathways involving such metabolises.     

SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus

The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of clinical trials. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials are crucial to determine whether the risk-benefit ratio will allow approval of this new class of drugs for the management of type 2 diabetes mellitus.     

老年高血压与糖代谢异常关系分析

目的：观察老年原发性高血压与糖代谢异常两者间相关关系。方法：随机选取了原发性高血压老年人与正常血压健康老年人各130例,分别纳为高血压组与对照组,均采静脉血检测各自空腹和餐后2h血糖水平,将结果进行比较。结果：高血压组无论空腹和餐后2h血糖均值均明显高于正常血压对照组（P〈0.05）,即使是在同为高血压组中,各时段内血糖均值3级〈2级〈1级亚组者,尤以餐后2h血糖升高为著。结论：与正常血压对照组健康老年人相比,高血压组老年人中伴有糖代谢异常者明显居多,且高血压病情越严重,则并存糖代谢异常也就越明显。     

The role of kidney in glucose homeostasis – SGLT2 inhibitors,a new approach in diabetes treatment

The role of the kidney in blood glucose-level regulation was until recently underestimated. Renal gluconeogenesis, renal glucose uptake and tubular glucose reabsorption are the three ways of renal involvement in glucose homeostasis. In the postabsorptive state, 20% of total glucose release is attributed to renal gluconeogenesis. Tubular glucose reabsorption is performed by the combined action of Na⁺/D-glucose SGLTs co-transporters and GLUT-facilitated diffusion glucose transporters. SGLT2 inhibitors are a new family of agents, which occlude the path of SGLT2 glucose reabsorption and cause glucosuria. Efficacy of SGLT2 inhibitors includes reduction of HbA1c, fasting and postprandial blood glucose level and slight body weight and systolic blood pressure decrease. The most common adverse events of them are genital mycotic and urinary tract infections. Dapagliflozin and canagliflozin are the first agents of this class, approved from the European Medicine Agency and FDA, respectively.     

Unrecognized hypoglycemia due to maltodextrin interference with bedside glucometry

Introduction

Glucometry is widely used to confirm or exclude hypoglycemia in patients with suggestive clinical findings. Nonglucose sugars may be detected by certain types of glucometers, causing false elevation of the glucometer analysis of the blood sugar. Since these other sugars are not functionally glucose and may even induce excess insulin release, clinical hypoglycemia may be missed.

Case Report

We report a 79-year-old man on enteral feeds containing maltodextrin, a glucose polymer, who had persistently high glucometer-measured blood glucose despite normal blood glucose measured by formal laboratory analysis.

Discussion

Excess insulin administration, based on the erroneous glucometer reading, may have caused unrecognized fatal clinical hypoglycemia. This has been reported following intravenous administration of related nonglucose sugars but not with enteral maltodextrin. Further study is required to confirm the effects of maltodextrin on glucometry.

Conclusion

False elevation of blood glucose measured on certain point-of-care glucometers can occur following the oral administration of maltodextrin.     

Glucokinase activators in diabetes management

Type 2 diabetes is a chronic metabolic disease that adversely affects both the quality and longevity of life. The disease is characterised by elevated blood glucose (hyperglycaemia) that is associated with microvascular complications and increased macrovascular risk. Existing oral agents, either alone or in combination, do not exhibit adequate or sustained glucose lowering efficacy in Type 2 diabetics. Consequently, there is an unmet medical need for improved antidiabetic agents which are both more effective at lowering glucose and which display sustained efficacy over a number of years. Such agents would allow present glycaemic treatment targets to be achieved with greater success. Glucokinase activators (GKAs) represent a novel class of glucose-lowering agents. Preclinical data supports the notion that these agents act to lower blood glucose through effects in both the liver and pancreas. It is predicted that this dual compartment mechanism of action of GKAs will translate to robust glucose lowering in diabetic patients. The potential benefits and risks associated with the pharmacological activation of glucokinase are evaluated. The status of GKAs in preclinical and clinical development is assessed are the future prospects of these agents.     

Clinical assessment of the accuracy of blood glucose measurement devices

Abstract

Objectives:

Blood glucose meters for patient self-measurement need to comply with the accuracy standards of the ISO 15197 guideline. We investigated the accuracy of the two new blood glucose meters BG*Star and iBG*Star (Sanofi-Aventis) in comparison to four other competitive devices (Accu-Chek Aviva, Roche Diagnostics; FreeStyle Freedom Lite, Abbott Medisense; Contour, Bayer; OneTouch Ultra 2, Lifescan) at different blood glucose ranges in a clinical setting with healthy subjects and patients with type 1 and type 2 diabetes. BGStar and iBGStar are employ dynamic electrochemistry, which is supposed to result in highly accurate results.     

Glucokinase activators in diabetes management

Type 2 diabetes is a chronic metabolic disease that adversely affects both the quality and longevity of life. The disease is characterised by elevated blood glucose (hyperglycaemia) that is associated with microvascular complications and increased macrovascular risk. Existing oral agents, either alone or in combination, do not exhibit adequate or sustained glucose lowering efficacy in Type 2 diabetics. Consequently, there is an unmet medical need for improved antidiabetic agents which are both more effective at lowering glucose and which display sustained efficacy over a number of years. Such agents would allow present glycaemic treatment targets to be achieved with greater success. Glucokinase activators (GKAs) represent a novel class of glucose-lowering agents. Preclinical data supports the notion that these agents act to lower blood glucose through effects in both the liver and pancreas. It is predicted that this dual compartment mechanism of action of GKAs will translate to robust glucose lowering in diabetic patients. The potential benefits and risks associated with the pharmacological activation of glucokinase are evaluated. The status of GKAs in preclinical and clinical development is assessed are the future prospects of these agents.     

血脑屏障上葡萄糖转运体1研究进展

葡萄糖是中枢神经系统主要的能源物质,葡萄糖转运体（glucose transporter proteins,GLUTs）家族是哺乳动物细胞葡萄糖转运的主要载体,目前发现有13个成员。基于序列的相似性和同源性,GLUTs家族分为三类,第一类：GLUT1~GLUT4,主要运输葡萄糖;第二类：GLUT5,GLUT7,GLUT9和GLUT11,主要转运果糖;第三类：GLUT6,GLUT8,GLUT10,GLUT12和HMIT,其功能尚不清楚。其中GLUT1以异构体的形式广泛存在于多种细胞,但45 000GLUT1是介导葡萄糖跨血脑屏障的主要转运体。一些中枢神经系统疾病使GLUT1表达和功能改变,从而使糖转运过程受到干扰或糖代谢功能障碍。近来研究显示,GLUT1能介导经糖基化修饰的前体药物跨膜运输,因此,靶向于葡萄糖转运体跨血脑屏障的运载方法将会引起研究者更广泛的关注。     

裂环环烯醚萜苷类化合物的药理作用研究进展

裂环环烯醚萜苷类化合物是一类具有保肝、降血糖、调血脂、抗炎、抗肿瘤和神经保护作用的天然活性分子。本文对龙胆苦苷、獐牙菜苷和獐牙菜苦苷3个代表化合物的药理作用进行了综述，以期为裂环环烯醚萜苷类化合物的进一步研究与开发奠定基础。     

Biosensor diagnosis of urinary tract infections: a path to better treatment?

Urinary tract infection (UTI) is among the most common bacterial infections and poses a significant healthcare burden. The standard culture-based diagnosis of UTI has a typical delay of two to three days. In the absence of definitive microbiological diagnosis at the point of care, physicians frequently initiate empirical broad-spectrum antibiotic treatment, and this has contributed to the emergence of resistant pathogens. Biosensors are emerging as a powerful diagnostic platform for infectious diseases. Paralleling how blood glucose sensors revolutionized the management of diabetes, and how pregnancy tests are now conducted in the home, biosensors are poised to improve UTI diagnosis significantly. Biosensors are amenable to integration with microfluidic technology for point-of-care (POC) applications. This review focuses on promising biosensor technology for UTI diagnosis, including pathogen identification and antimicrobial susceptibility testing, and hurdles to be surpassed in the translation of biosensor technology from bench to bedside.     

Pharmacokinetics and Efficacy of a Biweekly Dosage Formulation of Exenatide in Zucker Diabetic Fatty (ZDF) Rats

Purpose

To develop an improved sustained-release (SR) formulation of exenatide (a therapy for patients with type 2 diabetes mellitus) in a biweekly dosage form with therapeutic efficacy comparable to that achieved with twice-daily injections of the drug.

Methods

A SR formulation of exenatide, DA-3091, was prepared by single-emulsion solvent evaporation using poly(D,L-lactide-co-glycolide). Plasma exenatide, as well as plasma insulin, non-fasting blood glucose and HbA1c concentrations, and changes in food intake and body weight were evaluated in both Zucker diabetic fatty (ZDF) and ZDF lean control rats.

Results

After a single SC administration of DA-3091 (i.e., 2 mg/kg of exenatide), the plasma exenatide concentration increased and remained elevated in both groups. The concentrations of non-fasting blood glucose and HbA1c decreased significantly following a single SC injection of DA-3091 only in ZDF rats, indicating that the effects of exenatide are dependent on blood glucose concentration. On the other hand, both food intake and body weight gain were reduced in ZDF and ZDF lean control rats. A single injection of DA-3091 (i.e., 2 mg/kg of exenatide) lowered non-fasting blood glucose and HbA1c concentrations more effectively than 14 days of twice-daily administration of exenatide (i.e., 1.96 mg/kg of exenatide).

Conclusion

DA-3091 has the potential to be used safely and efficaciously in a biweekly dosing regimen.     

Closed-loop insulin delivery-the path to physiological glucose control

The development of an artificial pancreas for the treatment of insulin-dependent diabetes is a highly desired endeavor for patients, physicians, scientists, and engineers. Historical algorithms and recent progress in research and technology are reviewed in the present article, together with aspects of beta-cell physiology that lead to normal glucose tolerance. Algorithms are evaluated for their ability to deliver insulin as to recreate, as closely as possible, glucose and insulin profiles observed in healthy individuals. Emphasis is placed upon how the algorithms compare to the beta-cell's secretory response, specifically first-phase and second-phase insulin secretion. Experimental closed-loop data employing intravenous and subcutaneous glucose sensors and implanted and external insulin pumps (Medtronic MiniMed, Northridge CA) are presented.     

Empagliflozin for the treatment of Type 2 diabetes

Diabetes and its complications account for a significant healthcare burden. There is increasing prevalence of diabetes and newer drugs are being investigated to improve outcomes. Sodium–glucose cotransporter inhibitors (SGLT2 inhibitors) are a newer class of medications, which prevent renal reabsorption of glucose and hence help in glycaemic control without significant risk of hypoglycaemia. Two drugs, namely dapagliflozin and canagliflozin have gained approval and empagliflozin is one of the advanced agents of this class. Early trials with empagliflozin have shown a stable pharmacokinetic profile and pharmacodynamic effects with significant SGLT2 selectivity. Clinical trials have shown improvement in glycaemic control and other benefits including weight loss and lowering of blood pressure. Ongoing trials and surveillance will provide answers about cardiovascular benefits, risk of osteoporosis and cancer.     

Caffeine can decrease subjective energy depending on the vehicle with which it is consumed and when it is measured

Rationale

Energy drinks contain glucose and caffeine, although in the longer term both adversely influence blood glucose homeostasis, with the unconsidered potential to have adverse consequences for cognition and mood.

Objective

The objective of this study was to consider the influence on interstitial glucose levels, mood and cognition of drinks differing in their caffeine content and glycaemic load.

Methods

Ninety minutes after a standard breakfast, a yoghurt-, glucose- or water-based drink, with or without 80 mg of caffeine, was consumed.

Results

The consumption of caffeine negatively influenced glucose homeostasis: that is, irrespective of the vehicle, caffeine consumption resulted in elevated levels of blood glucose throughout the study. Thirty minutes after consuming caffeine and water, rather than water alone, greater subjective energy was reported. However, after 90 and 150 min, caffeine administered in water increased tiredness, hostility and confusion. In contrast, combining caffeine with a yoghurt-based drink increased energy, agreeableness and clearheadedness later in the morning. There were no effects of caffeine on ratings of mood when it was taken with glucose. Caffeine, irrespective of vehicle, resulted in better memory, quicker reaction times in the choice reaction time test and the working memory task, and better and quicker responses with the vigilance task.

Conclusion

Further research should consider how caffeine interacts with macronutrients and the timescale over which such effects occur.     

D‐420720, A novel orally active sulfonamide compound dipeptidyl peptidase IV inhibitor: structure and activity relationship of arylsulfonamide to dipeptidyl peptidase IV inhibition

Diabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP‐1 or GIP administration are short‐lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP‐IV). Therefore, DPP‐IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP‐IV‐specific inhibitor) indicates that DPP‐IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP‐IV inhibitors. Among these compounds, D‐420720 was a potent inhibitor (K_i=39 nM), with a selectivity of 9160‐fold over the DPP‐II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice. Drug Dev Res 69: 514–525, 2008. © 2008 Wiley‐Liss, Inc.     

SGLT2抑制剂引起酮症酸中毒的机制及处理

钠-葡萄糖协同转运蛋白-2（SGLT2）抑制剂是一类新型的降糖药物,通过抑制肾小管对葡萄糖的重吸收降低血糖。但临床中发现SGLT2抑制剂可导致血糖不明显升高的酮症酸中毒。本文就SGLT-2抑制剂引起酮症酸中毒的发生机制及处理措施进行了综述。