Interstitial Fluid Glucose Levels Research Articles

Fully integrated wearable microneedle biosensing platform for wide-range and real-time continuous glucose monitoring

Wearable microneedle sensors for continuous glucose monitoring (CGM) have great potential for clinical impact by allowing access to large data sets to provide individualized treatment plans. To date, their development has been challenged by the accurate wide linear range tracking of interstitial fluid (ISF) glucose (Glu) levels. Here, we present a CGM platform consisting of a three-electrode microneedle electrochemical biosensor and a fully integrated radio-chemical analysis system. The long-term performance of the robust CGM on diabetic rats was achieved by electrodepositing Prussian blue (PB), and crosslinking glucose oxidase (GOx) and chitosan to form a 3D network using glutaraldehyde (GA). After redox by GOx, PB rapidly decomposes hydrogen peroxide and mediates charge transfer, while the 3D network and graphite powder provide enrichment and release sites for Glu and catalytic products, enabling a sensing range of 0.25–35 mM. Microneedle CGM has high sensitivity, good stability, and anti-interference ability. In diabetic rats, CGM can accurately monitor Glu levels in the ISF in real-time, which are highly consistent with levels measured by commercial Glu meters. These results indicate the feasibility and application prospects of the PB-based CGM for the clinical management of diabetes. Statement of SignificanceThis study addresses the challenge of continuous glucose monitoring system design where the narrow linear range of sensing due to the miniaturization of sensors fails to meet the monitoring needs of clinical diabetic patients. This was achieved by utilizing a three-dimensional network of glutaraldehyde cross-linked glucose oxidase and chitosan. The unique topology of the 3D network provides a large number of sites for glucose enrichment and anchors the enzyme to the sensing medium and the conductive substrate through covalent bonding, successfully blocking the escape of the enzyme and the sensing medium and shortening the electron transfer and transmission path.

Swellable colorimetric microneedles for glucose detection based on glucose oxidase-like gold nanoparticles

BackgroundRegular blood glucose monitoring is very important for diabetic patients. The composition of skin interstitial fluid (ISF) is similar to that of blood, which can be used for daily blood sugar detection and disease care. However, most methods of ISF extraction have complicated steps, may cause skin damage, and can only extract a limited amount of ISF, resulting in low detection efficiency. Therefore, it is very necessary to develop a detection method that can not only extract a large amount of ISF safely, efficiently, and conveniently, but also realize rapid detection of glucose level in ISF. ResultsHere, we developed a gold nanoparticle (AuNP)-based swellable colorimetric MN patch with minimally invasive sampling function and real-time ISF glucose analysis ability. The MN patch could quickly absorb a large amount of skin ISF, and 60.2 mg of ISF was extracted within 10 min in vitro. It was divided into two layers: the tip layer was embedded with AuNPs with glucose oxidase (GOx)-like activity, which catalyzed the oxidation of glucose extracted from ISF and produced hydrogen peroxide (H2O2); horseradish peroxidase (HRP) encapsulated in the backing layer catalyzed the oxidation of 3, 3′, 5, 5′-tetramethylbenzidine (TMB) by H2O2 to produce oxTMB, which led to a visible color shift in the backing layer. The ISF glucose level was judged by naked eyes and further quantified by color analysis with Image J software. As a result, the colorimetric MN patch successfully identified the normal blood sugar and hyperglycemia state in vivo. SignificanceThe colorimetric MN patch combined in-situ colorimetric sensing based on AuNP nanozyme with MN patch, which detected glucose level without blood drawing, increasing patients’ compliance and reducing detection steps and time. Compared with the detection methods based on natural nanozymes, our method had better stability and sensitivity to complex environments (extreme pH and high temperature, etc.) in actual detection.

Porous Colorimetric Microneedles for Minimally Invasive Rapid Glucose Sampling and Sensing in Skin Interstitial Fluid.

Though monitoring blood glucose (BG) is indispensable for regulating diabetes, the frequent pricking of the finger by the commonly used fingertip blood collection causes discomfort and poses an infection risk. Since glucose levels in skin interstitial fluid (ISF) correlate with blood glucose levels, monitoring glucose in the skin ISF can be a viable alternative. With this rationale, the present study developed a biocompatible porous microneedle capable of rapid sampling, sensing, and glucose analysis in ISF in a minimally invasive manner, which can improve patient compliance and detection efficiency. The microneedles contain glucose oxidase (GOx) and horseradish peroxidase (HRP), and a colorimetric sensing layer containing 3,3',5,5'-tetramethylbenzidine (TMB) is on the back of the microneedles. After penetrating rat skin, porous microneedles harvest ISF rapidly and smoothly via capillary action, triggering the production of hydrogen peroxide (H2O2) from glucose. In the presence of H2O2, HRP reacts with TMB contained in the filter paper on the back of microneedles, causing an easily visible color shift. Further, a smartphone analysis of the images quickly quantifies glucose levels in the 50-400 mg/dL range using the correlation between color intensity and glucose concentration. The developed microneedle-based sensing technique with minimally invasive sampling will have great implications for point-of-care clinical diagnosis and diabetic health management.

Ethanol exposure alters Alzheimer's-related pathology, behavior, and metabolism in APP/PS1 mice

Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-β (Aβ)-related pathology, metabolism, and behavior. Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol drinking APP/PS1 mice also exhibited deficits in nest building, a metric of self-care, as well as increased locomotor activity and central zone exploration in an open field test. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates Aβ in the hippocampal interstitial fluid (ISF). Acute ethanol transiently increased hippocampal ISF glucose levels, suggesting that ethanol directly affects cerebral metabolism. Acute ethanol also selectively increased ISF Aβ40, but not ISF Aβ42, levels during withdrawal. Lastly, chronic ethanol drinking increased N-methyl-d-aspartate receptor (NMDAR) and decreased γ-aminobutyric acid type-A receptor (GABAAR) mRNA levels, indicating a potential hyperexcitable shift in the brain's excitatory/inhibitory (E/I) balance. Collectively, these experiments suggest that ethanol may increase Aβ deposition by disrupting metabolism and the brain's E/I balance. Furthermore, this study provides evidence that a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.

Effects of different temperatures of carbohydrate-protein-containing drinks on gastric emptying rate after exercise in healthy young men: randomized crossover trial

BackgroundThe present study examined the effects of different temperatures of carbohydrate-protein-containing drinks after exercise on the subsequent gastric emptying rate in healthy young men.MethodsTwelve healthy young men completed two, 1-day trials in random order. In both trials, the participants completed intermittent cycling exercise for 20 min, consisting of a 120% heart rate peak for 20 s, followed by 25 W for 40 s. Participants consumed 400 mL of carbohydrate-protein-containing drink (0.85 MJ) at 4 °C (EX + 4 °C) or 60 °C (EX + 60 °C) over a 5-min period after exercise. The participants sat on a chair for 2.5 h to measure their gastric emptying rate using the 13C-sodium acetate breath test. Subjective feelings of gastrointestinal discomfort and appetite were measured using a visual analog scale. Interstitial fluid glucose levels after drinking were measured using a continuous glucose-monitoring device.ResultsThe percentage excretion of 13CO2 tended to be higher at EX + 60 °C than at EX + 4 °C from the start of the test until 30 min after drink ingestion (5.7 ± 0.5 vs. 6.5 ± 0.4%dose/h for the EX + 4 °C and EX + 60 °C trials, respectively; effect sizes [ES] = 0.277, p = 0.065). The time of maximum 13CO2 emissions per hour (Tmax-calc) and the time of half 13CO2 emissions per hour (T1/2) did not differ between trials. Subjective gastrointestinal discomfort was lower at EX + 60 °C compared to EX + 4 °C (ES = 0.328, p = 0.041). There were no significant differences in interstitial fluid glucose levels between the different temperatures of carbohydrate-protein-containing drinks after exercise (p = 0.698).ConclusionsConsumption of warm carbohydrate-protein-containing drinks after exercise may accelerate gastric emptying in the very early phase and may reduce gastric discomfort.Trial registrationUniversity Hospital Medical Information Network, UMIN000045626. Registered on June 10, 2021.

Pre-cooling with ingesting a high-carbohydrate ice slurry on thermoregulatory responses and subcutaneous interstitial fluid glucose during heat exposure

The purpose of this study was to compare the effects of ingesting ice slurries with two different carbohydrate contents on body temperatures and the subcutaneous interstitial fluid glucose level during heat exposure. Seven physically active men underwent one of three interventions: the ingestion of 7.5 g/kg of a control beverage (CON: 26°C), a normal-carbohydrate ice slurry (NCIS: −1°C), or a high-carbohydrate ice slurry (HCIS: −5°C). The participants were monitored for a 120-min period that included 10 min of rest, 25 min of exposure to the experimental cooling intervention (during which the beverage was ingested), and 85 min of seated rest in a climate chamber (36°C, 50% relative humidity). The rectal temperature in the HCIS and NCIS trials was lower than that in the CON trial from 40 to 75 min. The infrared tympanic temperature was also lower in the HCIS and NCIS trials than in the CON trial from 20 to 50 min, whereas the deep thigh or mean skin temperatures were not significantly different among the three groups. From 90 to 120 min, the subcutaneous interstitial fluid glucose level in the NCIS trial was lower than that at 65 min; however, reductions were not seen in the HCIS and CON trials. These findings suggest that both HCIS ingestion and conventional NCIS ingestion were effective cooling strategies for reducing thermal strain, while HCIS ingestion may also enable a higher subcutaneous interstitial fluid glucose level to be maintained, ensuring an adequate supply of required muscle substrates.

Glucose Prediction using Wide-Deep LSTM Network for Accurate Insulin Dosing in Artificial Pancreas.

Closed-loop diabetes management has been shown to indicate improved glycaemic control and better compliance over open loop diabetes management. Currently, commercially available diabetes management devices rely on continuous glucose monitoring (CGM) sensors which monitor glucose levels from the interstitial fluid (ISF). As there exists a physiological delay between the blood glucose levels compared to the ISF glucose levels, it is crucial to predict or forecast glucose levels, in order to prevent hyperglycaemic events due to delayed insulin dosing. Accuracy of the forecast also needs to be optimum such that overdosing on insulin does not lead to hypoglycaemia. In this paper, we describe a novel Long Short Term Memory (LSTM) network which follows a wide and deep approach for different features to deliver an accurate glucose prediction output. It achieved a Mean Absolute Relative Difference (MARD) of 2.61 and Root Mean Squared Error (MSE) of 5.04. Clinical relevance- This work is relevant for closed-loop diabetes management devices, which are currently being used to manage Type 1 Diabetes (T1D).

Changes in glycaemic control of oral anti-diabetic medications assessed by continuous glucose monitors among patients with type 2 diabetes: a protocol of network meta-analysis

BackgroundContinuous glucose monitors (CGMs) can measure interstitial fluid glucose levels to provide comprehensive real-time glucose profile among people with type 2 diabetes. These can accurately detect glucose levels, hyperglycaemia and hypoglycaemia events compared with conventional self-monitoring. Increased application of CGMs provides a valuable opportunity to evaluate glucose control on oral anti-diabetic medications. This review will compare the efficacy and safety of oral anti-diabetic medications among patients with type 2 diabetes, evaluated by CGM.MethodsThe following databases will be searched: Cochrane Library, PubMed, EMBASE, CINAHL, PsycINFO, Scopus and grey literature (ClinicalTrials.gov, PsycEXTRA, ProQuest Dissertations, Google Scholar and Theses Global) for the identification of studies. The review will include and summarise evidence from randomised clinical trials that use CGMs for blood glucose management in adults (aged ≥ 18 years), published in English between January 2000 and May 2021 without any restrictions of countries. Reference list of all selected articles will independently be screened to identify additional studies left out in the initial search. Primary outcomes will be HbA1c (≤ 7.0%), time spent with hypoglycaemia (< 70 mg/dl) or hyperglycaemia (≥ 180 mg/dl). Secondary outcomes will be change in weight, blood pressure and related comorbidities (cardiovascular mortality, heart failure events, myocardial infarction and stroke). Study selection, data extraction and quality assessment will be conducted independently by at least two reviewers. A third reviewer will determine and resolve discrepancies. At least two independent reviewers will cross-check data synthesis. The quality of evidence of the review will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Tool.DiscussionThe review is anticipated to provide up to date evidence for further studies and clinic practices regarding glycaemic control, hypoglycaemia, and hyperglycaemia issues. The results will be published in a peer-reviewed journal.Trial registrationPROSPERO CRD42020188399.

High incidence of undetected low sensor glucose events among elderly patients with type 2 diabetes more than a decade on after the ACCORD study

Objective Hypoglycaemia leads to significant morbidity and impacts negatively on quality-of-life, especially in elderly people with increased frailty. The aims of this study were to determine the prevalence of low interstitial fluid glucose (IFG) in patients with tightly controlled type 2 diabetes (T2D), and to evaluate whether there were differences in burden of low IFG between sulphonylurea and insulin treated groups. Methods A Freestyle Libre-Pro sensor was used for sampling of the IFG continuously. Patients were blinded to the IFG levels. The sensor was returned to the investigators after a 2-week period and the data were downloaded for analysis. Results There was a total of 69 patients (median age 72 years (IQR = 69–74)) − 40 were sulfonylurea-treated and 29 insulin-treated. In total, 781 low sensor glucose events (<4.0 mmol/L) were detected, of which 254 were very low sensor glucose events (<2.8 mmol/L). Twenty-six out of 29 insulin-treated (89.6%) and 36 out of 40 sulphonylurea-treated patients (90%) contributed to the 781 events of low sensor glucose. Twenty out of 29 insulin-treated (69%) and 26 out of 40 sulphonylurea-treated patients (65.0%) contributed to the 254 very low sensor glucose events. Only 9% of all events were identified by patients. Nocturnal events represented 55.8% of low sensor glucose events and 61.0% of very low sensor glucose events. At a cut-off of <2.8 mmol/L, it was found that the insulin group had a significantly greater number of such events as compared to the sulfonylurea group. Conclusions This study demonstrates that elderly patients with tightly-controlled T2D have a significant number of low sensor glucose events which go by undetected.

Physiological reconstruction of blood glucose level using CGMS-signals only

Patient with diabetes must regularly monitor blood glucose level. Drawing a blood sample is a painful and discomfort experience. Alternatively, the patient measures interstitial fluid glucose level with a sensor installed in subcutaneous tissue. Then, a model of glucose dynamics calculates blood glucose level from the sensor-measured, i.e., interstitial fluid glucose level of subcutaneous tissue. Interstitial fluid glucose level can significantly differ from blood glucose level. The sensor is either factory-calibrated, or the patient calibrates the sensor periodically by drawing blood samples, when glucose levels of both compartments are steady. In both cases, the sensor lifetime is limited up to 14 days. This is the present state of the art. With a physiological model, we would like to prolong the sensor lifetime with an adaptive approach, while requiring no additional blood sample. Prolonging sensor’s lifetime, while reducing the associated discomfort, would considerably improve patient’s quality of life. We demonstrate that it is possible to determine personalized model parameters from multiple CGMS-signals only, using an animal experiment with a hyperglycemic clamp. The experimenter injected separate glucose and insulin boluses to trigger rapid changes, on which we evaluated the ability to react to non-steady glucose levels in different compartments. With the proposed model, 70%, 80% and 95% of the calculated blood glucose levels had relative error less than or equal to 21.9%, 32.5% and 43.6% respectively. Without the model, accuracy of the sensor-estimated blood glucose level decreased to 39.4%, 49.9% and 99.0% relative errors. This confirms feasibility of the proposed method.

A novel interactive biosensor system for real-time remote stress response monitoring and visualization by using bi-directional data link

Modern aquaculture methods help fish get better potential in their growth and development. In the last decades, people have gained an interest in fish welfare aspects such as stress, which strongly affect fish performance. However, to grasp such a critical but complicated stress response is problematic easily affected by external factors. To this end, we developed a wireless biosensor system for fish stress monitoring. This system can monitor the glucose level (stress indicator) in fish eyeball scleral interstitial fluid using the proposed amperometry glucose biosensor based on glucose oxidase immobilized on the Pt–Ir electrode surface. In the presence of glucose, a typical catalytic oxidation current could be observed at +650 mV. Besides, the system shows the different stress statuses of fish by using a multi-color LED like a traffic light. The LED color-switching points, however, had to be manually calibrated. Besides, the process itself may induce stress to the fish. In this study, a novel interactive biosensor system that introduces bi-directional communication technology has been introduced. Datalink functions such as remote calibration and individual identification were advocated and checked. Also, some system characteristic evaluation tests were conducted in vitro and in vivo using Nile tilapia Oreochromis niloticus as test fish and got some satisfactory results. According to the results, we believe our proposed system could handle various stress monitoring intelligently with only some clicks on the software without unnecessarily handling the test fish.

Impact of Meal Timing on Postprandial Interstitial Fluid Glucose Levels in Young Japanese Females.

Flash glucose monitoring (FGM) provides continuous and accessible measurement of the interstitial fluid glucose (ISFG) level and this system is useful for understanding blood glucose fluctuations. We examined differences in postprandial ISFG after the main mealtimes (breakfast, lunch, and dinner) in healthy young Japanese females. Nine healthy young females (aged 21.5±0.6 y old) were enrolled in this study. ISFG was continuously measured by FGM. Participants ate the same meal three times a day consecutively, thereby satisfying their daily energy requirements. Postprandial ISFG fluctuations were evaluated for 4 h after each meal. There were no significant differences in ISFG before the 3 main meals. The postprandial ISFG peak was the lowest after breakfast, increasing in the order of lunch and then dinner. The area under the curve of the 4-h postprandial ISFG was higher after lunch and dinner than after breakfast. The results of this study suggest that postprandial ISFG differ depending on mealtimes in young Japanese females.

Novel glucose-responsive of the transparent nanofiber hydrogel patches as a wearable biosensor via electrospinning

Micro- and nanofiber (NF) hydrogels fabricated by electrospinning to typically exhibit outstanding high porosity and specific surface area under hydrated conditions. However, the high crystallinity of NFs limits the achievement of transparency via electrospinning. Transparent poly(vinyl alcohol)/β-cyclodextrin polymer NF hydrogels contacted with reverse iontophoresis electrodes were prepared for the development of a non-invasive continuous monitoring biosensor platform of interstitial fluid glucose levels reaching ~ 1 mM. We designed the PVA/BTCA/β-CD/GOx/AuNPs NF hydrogels, which exhibit flexibility, biocompatibility, excellent absorptivity (DI water: 21.9 ± 1.9, PBS: 41.91 ± 3.4), good mechanical properties (dried: 12.1 MPa, wetted: 5.33 MPa), and high enzyme activity of 76.3%. Owing to the unique features of PVA/β-CD/GOx containing AuNPs NF hydrogels, such as high permeability to bio-substrates and rapid electron transfer, our biosensors demonstrate excellent sensing performance with a wide linear range, high sensitivity(47.2 μA mM−1), low sensing limit (0.01 mM), and rapid response time (< 15 s). The results indicate that the PVA/BTCA/β-CD/GOx/AuNPs NF hydrogel patch sensor can measure the glucose concentration in human serum and holds massive potential for future clinical applications.

Enzyme-assisted glucose quantification for a painless Lab-on-PCB patch implementation

In the context of an integrated Lab-on-PCB wearable patch extracting interstitial fluid from the patient via integrated microneedles, the requirements from the integrated biosensing part are quite special compared to static glucose electrochemical biosensors. Hence, in this study, a fully PCB-integrated enzymatic glucose quantification Lab-on-Chip device is presented and evaluated considering these special requirements for such a patch implementation: a) range and limit of detection compatible with interstitial fluid glucose levels of diabetic patients and b) effect of sample flow rate on the biosensing platform performance. This work employs a chronoamperometric approach for glucose detection based on covalently immobilized glucose oxidase on PCB-integrated electrodes. The chronoamperometric measurements show that this platform exhibits μM range sensitivity, high specificity, and good reproducibility, and the assay can detect glucose from 10 μM to 9 mM with a lower limit of detection of 10 μM. The demonstrated detection range under continuous flow proved compatible with interstitial fluid glucose levels of diabetic patients. The sample-to-answer time of our Lab-on-PCB device is less than 1 min (sample delivery of few seconds and 20 s for electrochemical measurement), employing sample volumes of 50 μL in this instance. Increased flow rates substantially improve the platform sensitivity (1.1 μA/mM @0 μL/min to 6.2 μA/mM @10 μL/min), with the measured current increasing exponentially to the flow rate, as opposed to the theoretically expected much lower dependence. This work demonstrates the feasibility of Lab-on-PCB patches in terms of biosensing performance, paving the way for the first cost-effective, painless diabetes management microsystem.

Intranasal Insulin Treatment Attenuates Metabolic Distress and Early Brain Injury After Subarachnoid Hemorrhage in Mice

Intranasal administration of insulin to the brain bypasses the blood brain barrier (BBB) and can increase cerebral glucose uptake and prevent energy failure. Intranasal insulin treatment has shown neuroprotective effects in multiple central nervous system (CNS) lesions, but the effects of intranasal insulin on the metabolic and pathological process of subarachnoid hemorrhage (SAH) are not clear. This study is designed to explore the effects of intranasal insulin treatment on metabolic distress and early brain injury (EBI) after experimental SAH. SAH model was built by endovascular filament perforation method in adult male C57BL/6J mice, and then, insulin was administrated via intranasal route at 0, 24, and 48h post-SAH. EBI was assessed according to the neurological performance, BBB damage, brain edema, neuroinflammatory reaction, and neuronal apoptosis at each time point. To evaluate metabolic conditions, microdialysis was used to continuously monitor the real-time levels of glucose, pyruvate, and lactate in interstitial fluid (ISF) in living animals. The mRNA and protein expression of glucose transporter-1 and 3 (GLUT-1 and -3) were also tested by RT-PCR and Western blot in brain after SAH. Compared to vehicle, intranasal insulin treatment promoted the relative mRNA and protein levels of GLUT-1 in SAH brain (0.98 ± 0.020 vs 0.33 ± 0.016 at 24h, 0.91 ± 0.25 vs 0.21 ± 0.013 at 48h and 0.94 ± 0.025 vs 0.28 ± 0.015 at 72h in mRNA/0.96 ± 0.023 vs 0.36 ± 0.015 at 24h, 0.91 ± 0.022 vs 0.22 ± 0.011 at 48h and 0.95 ± 0.024 vs 0.27 ± 0.014 at 72h in protein, n = 8/Group, p < 0.001). Similar results were also observed in GLUT-3. Intranasal insulin reduced the lactate/pyruvate ratio (LPR) and increased ISF glucose level. It also improved neurological dysfunction, BBB damage, and brain edema and attenuated the levels of pro-inflammatory cytokines as well as neuronal apoptosis after SAH. The intranasal insulin treatment protects brain from EBI possibly via improving metabolic distress after SAH.

Comparing effects of continuous glucose monitoring systems (CGMs) and self-monitoring of blood glucose (SMBG) amongst adults with type 2 diabetes mellitus: a systematic review protocol

BackgroundContinuous glucose monitorings (CGMs) have been used to manage diabetes with reasonable glucose control amongst patients with type 2 diabetes (T2D) in recent decades. CGMs measure interstitial fluid glucose levels to provide information about glucose levels, which identify fluctuation that would not have been identified with conventional self-monitoring. Self-monitoring of blood glucose (SMBG) is a classical tool to measure glycaemic changes. However, the effectiveness of glucose control, hypoglycemia, weight change, quality of life and user satisfaction, are needed to evaluate and compare CGMs and SMBG amongst adults with T2D.MethodsThe review will compare the various forms of CGM systems (i.e flash CGM, real-time CGM, retrospective CGM) versus SMBG or usual intervention regarding diabetes management amongst adults with T2D. The following databases will be searched: Cochrane Library, PubMed, EMBASE, CINAHL, PsycINFO, Scopus and grey literature (ClinicalTrials.gov, PsycEXTRA, ProQuest Dissertations, Google Scholar and Theses Global) for the identification of studies. The studies involving adults (aged ≥ 18 years old) will be included. We will only include and summarise randomised clinical trials (RCTs) with respect to authors, publication type, year, status and type of devices. Studies published in English between February 2010 and March 2020, will be included as the field of CGMs amongst T2D patients has emerged over the last decade. Primary outcomes will be HbA1c (glycosylated haemoglobin level) (mmol/L), body weight (kg), time spent with hypoglycaemia (< 70 mg/dl) or hyperglycaemia (≥ 180 mg/dl), blood pressure (< 140/90 mmHg is considered as good management) and quality of life (understanding and feeling of living situation based on culture and value system). Secondary outcome measures will be user satisfaction (patient or treatment/intervention satisfaction or satisfaction scale) and barriers (physical and mental difficulties or issues). Study selection, data extraction and risk of bias assessment will be conducted independently by at least two reviewers. A third reviewer will determine and resolve discrepancies. Moreover, the quality of the evidence of the review will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation tool (GRADE).DiscussionThe review will synthesise evidence on the comparison between using CGMs and SMBG. The results will support researchers and health professionals to determine the most effective methods/technologies in the overall diabetes management.Systematic review registrationPROSPERO CRD42020149212

T4. SIGNIFICANT, PROLONGED HYPERGLYCEMIA IN AN 18-YEAR-OLD TYPE 1 DIABETIC PATIENT POST INITIATION OF ARIPIPRAZOLE: A CASE REPORT

BackgroundCurrent schizophrenia guidelines recommend that the choice of antipsychotic be made by the patient and physician together with a discussion of the likely benefits and side effects of each medication. Second-generation antipsychotics are commonly prescribed for the treatment of psychotic disorders, however metabolic adverse effects, such as hyperglycemia, are a potential complication of using this class of medications. Current sources indicate that the second-generation antipsychotic aripiprazole does not alter glucose homeostasis and confers low or no risk of developing diabetes. Below, the authors outline a case of significant, prolonged hyperglycemia secondary to the initiation of oral aripiprazole.MethodsSee Results.ResultsCase:An 18-year-old female was admitted involuntarily to hospital after she presented with suicidal ideation, ideas of reference, persecutory delusions and paranoia. She was reportedly a well-controlled Type 1 Diabetic prior to admission and her blood sugars were within normal limits for the first 9 days of hospitalization. Aripiprazole 10mg PO QAM was initiated to control symptoms. Within 9 hours of aripiprazole initiation, her blood sugars became unexpectedly and significantly elevated. After 5 days of therapy, aripiprazole was discontinued due to an inability to adequately control blood glucose. Diabetic ketoacidosis and pancreatitis were ruled out as laboratory results showed normal ketones, amylase and lipase. Blood glucose was taken via the Freestyle Libra device which measures interstitial fluid glucose levels and re-checked using the Accu-Chek Inform II monitor which is approved for use with capillary, venous, and arterial blood. Monitoring device malfunction was thereby ruled out as a cause. Diet and insulin administration techniques were closely monitored by nursing staff. Endocrinology and clinical dietary services were consulted. At their peak, blood sugars were as high as 25.9 mmol/L despite an increase in patient’s daily insulin (total bolus and basal) from 19 units/day to 132 units/day. Patient’s blood sugar and insulin requirements remained elevated over the next 17 days before gradually decreasing and returning to baseline.DiscussionIn this case, the authors are of the opinion that the patient experienced a severe idiosyncratic reaction to aripiprazole manifesting as severe hyperglycemia. Aripiprazole’s half-life of elimination is 75 hours, and dehydro-aripiprazole (Aripiprazole’s active metabolite) is 94 hours; the amount of time for the drug to be essentially removed from the body is 15.6 days and 19.6 days respectively (5 half-lives). This is consistent with the duration of time that passed before blood glucose levels normalized once aripiprazole was discontinued. The manufacturer of aripiprazole (Otsuka) has data regarding increases in blood glucose in adolescents. However, these increases are over a 26 week time frame, occurred in 1.9% of patients, and had a mean increase of 0.12mmol/L in their fasting glucose. This data, and the results of this case, therefore suggest that although increases of blood glucose while on aripiprazole tend to be rare and modest, there may be a subcategory of patients who develop severe hyperglycemia on this medication, and when this severe adverse effect is noted, the provocative agent should be promptly discontinued to reverse the effects.

MON-625 Utility of Continuous Glucose Monitoring in Children with Type 1 Diabetes: Is HbA1c Enough?

Introduction: Type 1 diabetes is an autoimmune condition resulting in insulin deficiency that requires daily insulin therapy and self-monitoring of blood glucose. Continuous glucose monitoring (CGM) systems allow for measurement of interstitial fluid glucose levels in a continuous fashion to identify variations and trends that are not feasible with conventional self-monitoring. Hemoglobin A1C (HbA1C) is the method used to assess adequate glycemic control and relates to future risk of developing complications. Current evidence has shown improvement in HbA1C with concomitant use of CGM in adults over 25 years of age with Type 1 diabetes, whereas studies in children and adolescents have failed to show this. However, it is important to note the limitations in HbA1C use as it is a marker of average blood glucose over 3 months but does not reflect glycemic variability. More recent data has suggested that factors such as time in range (TIR), which can be determined with CGM use, are also associated with decrease risk of diabetes complications. Methods: The goal of our study was to analyze the change in HbA1C levels after using a CGM (DEXCOM G4, G5, G6) over a 6-month period in pediatric patients with Type I diabetes. Two HBA1c levels 3 months apart from 92 patients were collected before using a CGM and two while using a CGM. Results were compared by using a dependent samples t-test. IBM SPSS 25.0 was used for data analysis. Results: Preliminary analysis indicates the average change in HBA1C among the patients (N=92) before (-0.08 ± 1.16) and while using the CGM (0.12 ± 1.00) was not significantly different (t (79) = -1.27, p = 0.21). The average change in HBA1C was also not significantly different (p>0.05) among the patients before and while using the CGM for gender (males and females), age groups (0-7 years, 8-14 years, and 15-24 years), and generations of DEXCOM used (G4, G5, and G6). Conclusion: As has been shown in other studies, we did not find a significant change in HbA1c after CGM use for 6 months in our patients. While HbA1C is a reflection of blood sugars over a 3-month period, it does not provide information about glycemic excursions. Metrics derived from CGM use, such as TIR, can provide actionable information which we did not address in our study. There have been reports of the association between TIR and long-term complications of diabetes. Most data comes from studies in adults and pediatric data is lacking. We propose that future studies must look into CGM metrics such as TIR to better define glycemic control in pediatric patients with diabetes mellitus.

Basics and use of continuous glucose monitoring (CGM) in diabetes therapy

Abstract Background For a long time, self-monitoring of blood glucose (SMBG) was widely viewed as the essential glucose measurement procedure in the therapy of insulin-treated people with diabetes. With increasing accuracy and simplified handling of continuous glucose monitoring (CGM) systems, this evolving technology challenges and at least partly replaces SMBG systems. Content Sensors of all currently available CGM systems measure glucose levels in the subcutaneous interstitial fluid for 6–14 days. The only available implantable sensor facilitates a measurement span of up to 6 months. Depending on the used system, glucose levels are either shown in real time (rtCGM systems) or after scanning (iscCGM systems). Functions such as alerts, alarms and trend arrows and data presentation encourage independent self-management of diabetes therapy. The high frequency of glucose data and the multitude of existing functions require an extensive training of people with diabetes and their caregivers. Summary CGM systems provide a much more detailed picture of glycemia in people with diabetes. Educated patients can use these data to react adequately to their glucose levels and therefore avoid hypoglycemic and hyperglycemic events. Studies showed that glycated hemoglobin (HbA1c) levels and hypoglycemic events can be significantly reduced by frequent use of CGM systems.

Protocol of a Prospective Observational Study on the Relationship Between Glucose Fluctuation and Cardiovascular Events in Patients with Type 2 Diabetes.

IntroductionA recent study demonstrated that large glucose fluctuations were associated with an increased incidence of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) and acute myocardial infarction. However, it is unknown whether glucose fluctuations are related to the incidence of CVD or the progression of atherosclerosis in patients with T2DM with no apparent history of CVD. In this protocol, we will be investigating the relationships of glucose fluctuations evaluated by continuous glucose monitoring (CGM) to the incidence of composite cardiovascular events and the progression of atherosclerosis in patients with T2DM who had no apparent history of CVD.MethodsThis is a prospective, multicenter, 5-year follow-up observational study. Between April 2018 and October 2019, 1000 participants are expected to be recruited at 34 medical institutions. CGM using FreeStyle Libre Pro is useful for evaluating glucose fluctuations by continuously monitoring glucose levels in interstitial fluid for up to 14 days. The primary study outcome is the relationship between fluctuations in glucose levels evaluated by CGM and the incidence of composite cardiovascular events. Secondary outcomes include the relationships of fluctuations in glucose levels evaluated by CGM to changes in carotid intima media thickness evaluated by echography or grayscale median (an index of tissue characteristics of the carotid wall), brachial–ankle pulse wave velocity, development or progression of diabetic retinopathy or nephropathy, quality-of-life-related diabetes therapy, quality of sleep, development of dementia, and autonomic nerve function.Planned OutcomeThis protocol is designed to investigate the relationship between glucose fluctuations and the incidence of composite cardiovascular events. We completed the registration of 1000 participants in March 2019. Thus, results will be available in 2024. We expect that evaluating glucose fluctuations will aid the identification of patients with a high probability of developing CVD.Trial RegistrationClinicalTrials.gov identifier, UMIN000032325.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-019-0665-8) contains supplementary material, which is available to authorized users.