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Metformin, an oral anti-diabetic drug, is currently being investigated for its anti-aging properties and has also been used as adjunct therapy in cancer. Cancer is a disease of aging. Type 2 diabetes is also prevalent in older adults. We wanted to test the hypothesis that metformin could protect normal cells during chemotherapy treatment under different glucose conditions. We used C2C12 myoblast cells to study cellular bioenergetics, variations in gene expressions, and biochemical alterations induced by metformin and pegylated liposomal doxorubicin (L-Doxo) under low glucose (2.7 mM or 50 mg/dL) and normal physiologic glucose (5.5 mM, or 100 mg/dL) conditions. Using confocal microscopy, we noted that treatment of C2C12 cells with 30 µg/mL L-Doxo under low glucose and normal physiologic glucose conditions induced cellular defects. Furthermore, L-Doxo treatment dysregulated the expression of mitochondrial fission and fusion genes, which may influence transformation of the network’s connectivity. L-Doxo treatment significantly reduced mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). However, pre-treatment with 100 nM metformin provided protection against L-Doxo-induced damage and increased cell viability and ATP levels in cells even under low glucose conditions. Our data provide further evidence by which low dose metformin exerts protective effects against L-Doxo, a chemotherapeutic drug, under low glucose conditions. Metformin appears to act via AMPKα, Raptor, and SRF, and has significant cellular protective effects that may be useful in cancer and/or aging.

Activation of “suspend before low” in the Medtronic PLGM algorithm stops insulin delivery when sensor glucose (SG) is predicted to reach or fall below a preset low glucose limit in 30min. Basal insulin delivery automatically resumes once the algorithm detects an increasing SG trend. We evaluated the “suspend before low” feature of the MiniMed™ 670G with SmartGuard™ technology in children with T1D. Participants (N=105, aged 7-13 years) underwent an overnight in-clinic evaluation. Hypoglycemia was defined as 2 or more consecutive events of YSI or fingerstick blood glucose reference values ≤65 mg/dL (≤3.6 mmol/L). Children had exercise in the afternoon, no increase in basal insulin delivery, and were not in Auto Mode. Of the 1experiments, there were 79 with PLGM activation. Hypoglycemia was prevented 79.7% of the time (63/79). Mean duration of a suspension was 85.6±32.4min. The Table shows mean reference glucose values with respect to the start of automated insulin suspension and resumption, as well as 2 and 4 hours after insulin resumption. Rates of change (ROC) at insulin suspension and resumption start are also shown. All were evaluated by TDD and duration of diabetes, and stratified in quartiles. The “suspend before low” feature of the MiniMed™ 670G system reduced hypoglycemia events without rebound hyperglycemia in children with T1D regardless of TDD or duration of diabetes. Disclosure D.I. Shulman: Other Relationship; Self; Novo Nordisk Inc.. Research Support; Self; Medtronic MiniMed, Inc.. Board Member; Self; Pediatric Endocrine Society. Research Support; Self; Versartis, Inc. M.A. Wood: Research Support; Self; Medtronic MiniMed, Inc. G.P. Forlenza: Advisory Panel; Self; Dexcom, Inc.. Research Support; Self; Medtronic, Tandem Diabetes Care, Inc., Insulet Corporation, Dexcom, Inc., Novo Nordisk Inc., Bigfoot Biomedical. B. Buckingham: Advisory Panel; Self; Novo Nordisk Inc., ConvaTec Inc.. Research Support; Self; Medtronic, Insulet Corporation, Dexcom, Inc., Tandem Diabetes Care, Inc.. Consultant; Self; Tandem Diabetes Care, Inc., Becton, Dickinson and Company. T.S. Bailey: Research Support; Self; Abbott. Consultant; Self; Abbott. Speaker's Bureau; Self; Abbott. Research Support; Self; Ambra BioScience, Ascensia Diabetes Care, Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Calibra Medical. Consultant; Self; Calibra Medical. Research Support; Self; Companion Medical, Dexcom, Inc., Glooko, Inc., GlySens Incorporated, Lexicon Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Medtronic MiniMed, Inc.. Speaker's Bureau; Self; Medtronic MiniMed, Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Senseonics. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Versartis, Inc., Xeris Pharmaceuticals, Inc., MannKind Corporation. T.L. Cordero: Employee; Self; Medtronic. B.W. Bode: Research Support; Self; Abbott. Advisory Panel; Self; ADOCIA. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk Inc., Diasome Pharmaceuticals, Inc., Sanofi US, Eli Lilly and Company, MannKind Corporation, Dexcom, Inc., OmniPod, Senseonics. X. Chen: Employee; Self; Medtronic. J. Shin: Employee; Self; Medtronic.

Aim: To study the efficacy of the Medtronic MiniMed 640G insulin pump (CSII with Suspend before low (Predictive Low-Glucose Management [PLGM]) on glycemic control in patients with diabetes mellitus type 1 (DMT1) at baseline, after the first trimester and after 18 months’ use. Patients/Methods: Thirteen patients with DMT1 participated who were on PLGM system (Minimed 640G system-Medtronic), 8 females, age 45.8±12.5 years, DM duration 28.1±8.5 years and PLGM duration 17.5±7.4 months. HbA1c, anthropometric measurements and medical history were recorded at baseline, after 3 months and after 18 months’ use of the PLGM system. The continuous glucose measurements (CGM) data of the last two weeks of each interval were downloaded using the software Carelink Pro and Personal. Results: The glycemic control after using PLGM system was significantly better compared with baseline at 3 and 18 months’ use (HbA1c 7.2±0.7% vs. 6.6±0.5 vs. 6.7±0.5, p=0.006). There was an improvement at first trimester compared with baseline (HbA1c 6.6±0.5 vs. 7.2±0.7, p=0.027) and at 18 months’ use compared with baseline (HbA1c 6.7±0.5 vs. 7.2±0.7, p=0.046). There was no difference in glycemic control between 3 and 18 months’ use. There was no difference of time duration < 3.9 mmol/l (min/day), hypoglycemic episodes and AUC < 3.9 mmol/l compared with baseline at 3 and 18 months’ use. There was a reduction of the time duration > 9.9 mmol/l (min/day) between baseline and after 18 months’ use (3281.3±2175.9 vs. 1891.6±555.7, p=0.037). Hyperglycemic events were reduced significantly after 18 months compared to baseline (median 28.5, interquartile range (IQR) 14 vs. median 39.5, IQR 19, p=0.045). Conclusion: Patients with DMT1 using CSII with PLGM system for 18 months improved their glycemic control due to the reduction of hyperglycemic fluctuation. Glycemic control improved after 3 months and that improvement persisted for 18 months of follow-up. Disclosure T. Didandelos: None. P. Giannoulaki: None. E. Karlafti: None. E. Kotzakioulafi: None. Z. Kontoninas: None. K. Tziomalos: None. A.I. Hatzitolios: None.

The Medtronic GuardianTM Connect continuous glucose monitoring (CGM) system, with predictive high and low glucose alerts, allows users to view sensor glucose (SG) data on a smartphone that notifies them 10-60 minutes before an excursion. The rates of alerts and outcomes of users on the GuardianTM Connect system were evaluated. We identified 2,541 users with >5 days of SG data in the CareLinkTM database from Jan 2, 2017-Sep 5, 2017 (data collected Jan 2, 2017-Dec 14, 2017). Excursions were identified when SG values were beyond the users’ preset SG threshold limit for ≥15 min. As a control, alerts were simulated during user alert-disabled periods to compare excursion frequency. Excursion durations following the alert times were segmented into avoided, ≤20min, 20-60 min, and >60min. Simulated SG limits were 202mg/dL (11.2mmol/L) for high and 70mg/dL (3.9mmol/L) for low. Simulated predictive times before excursions were 12.5min for high and 17.5min for low. The Table shows percentages of each alert resulting in an excursion. Users who enabled predictive alerts avoided 60% of low and 39% of high events. The percentage point improvement for excursions avoided was 28% and 31% following predicted low and high alerts vs. control. Stand alone CGM technology, like the GuardianTM Connect system, with predictive alerts are useful for tracking SG and enabling timely actions that help avoid high and low excursions. Disclosure O. Cohen: Employee; Self; Medtronic. S. Abraham: None. C.M. McMahon: Employee; Self; Medtronic MiniMed, Inc.. P. Agrawal: None. R. Vigersky: Employee; Self; Medtronic MiniMed, Inc..

A tear glucose (TG) sensor with an integrated tear sampler can provide a noninvasive method for calibrating the continuous TG contact lens and monitoring glucose. Expanding from previous work, an improved TG sensor that implements dried reagents, genetically modified glucose dehydrogenase (GDH), and a tear sampler was developed and compared against the TG sensor prepared with commercial GDH. It was found that neither sensor was affected by the tear interferents: ascorbic acid, acetaminophen, and uric acid. The sensor prepared with commercial GDH generated higher current. This suggests that using enzymes with lower Km may be advantageous when operating in low glucose environments like tears. The improved TG sensor also demonstrated the potential of integrating Schirmer’s test strip as a tear sampler for self-monitoring of TG.

In 2013, Ly et al published a study in JAMA reporting a massive reduction in the frequency of severe hypoglycemic events when the patients used sensor augmented insulin pump therapy with low glucose suspense. The data of this study were reanalyzed by the IQWiG when this German institute started its evaluation of the evidence for continuous glucose monitoring (CGM) usage. The IQWiG came to a contrary conclusion than the authors of the Ly study. Decisive for this was the statistical analysis of the Ly study that led the IQWiG to evaluate this result as a lack of evidence for the superiority of CGM (plus pump) for preventing hypoglycemia. In this commentary, a direct English translation of the IQWiG analysis is provided to enable the reader to come to his or her own conclusion about this study.

Aims: To investigate the effects of a newly developed color-coded educational glucose control instruction (COLOR), combined with a color-displayed glucose meter on changes in type-2 diabetes patient’s behavior and their HbA1c levels. Material and Methods: Patients using a COLOR-self-monitoring of blood glucose (SMBG) method were instructed to record daily blood glucose levels with red (high glucose ≥ 180 mg/dL) or blue (low glucose ≤ 70 mg/dL) colored circles on their SMBG notebooks according to the colors displayed on the glucose meter. Results: COLOR-SMBG showed an improved the actual behavior modification scores by 14% compared to Conventional group at 1-month follow-up (p < 0.05). The mean HbA1c levels of COLOR-SMBG significantly decreased at 2 months (0.14% ± 0.28%, p < 0.01), 4 months (0.31% ± 0.48%, p = 0.05), and 6 months (0.39% ± 0.49%, p = 0.01) follow-up. Conclusions: The results suggest for the first time the usefulness of the instructional intervention using COLOR-SMBG for patients with type 2 diabetes. This trial was registered with UMIN (No. UMIN000011767).

We describe a man who developed pleural effusion with Pasteurella multocida, and review the reported literature concerning this entity. We identified 21 such cases, including our own. Most patients with P. multocida pleural effusions are immunocompromised and/or have significant co-morbidities. These effusions are typically complicated parapneumonic effusions that are grossly purulent (87%) with a low pleural fluid pH (mean 6.8), high protein (mean 4.8 g/dl) and high LDH (mean 1911 U/L) and low glucose (28.6 mg/dl). Pleural fluid drainage with tube thoracostomy was required in the majority (62%) of cases.

Achieving optimal transfection efficiency is the most critical step in overcoming the primary obstacle to success in nonviral-mediated gene therapy. Several transfection parameters were being examined including the effects of different types of transfection media, glucose concentration, reporter DNA concentration, and incubation time in lipotransfectant. Efficiency of transfection obtained was highest for Opti-MEM I (29 ± 2.28%; p = 0.001) followed by M199 (24 ± 1.54%; p = 0.009), both of which performed significantly better than DMEM (14 ± 0.28%) as a transfection medium. The rate of transfection was affected by glucose levels in only DMEM with higher efficiency achieved using low glucose containing DMEM (17 ± 0.38%) than its counterpart. Furthermore, transfection rate and cell viability were severely hampered by lengthened exposure to transfection complexes, leading to an overall mean efficiency of 5 ± 0.87%. However, doubling the DNA content in the transfection mixture did not significantly change the mean rate of transfection in M199 medium (24 ± 1.54% to 27 ± 1.54%; p = 0.273). The overall range of mean efficiency acquired with our protocol under different transfection conditions was between 14% and 29%. Hopefully results from this study will further potential success in nonviral-mediated gene transfer.

This paper presents a technique for accurate measurement of small capacitive changes. This is based on selecting the most linear part of the curve obtained by charging the capacitor undergoing changes through a known resistor value. This measurement is part of the design of a system for measuring blood glucose content non-invasively. The technique is based on measuring ultra-low low glucose levels in the blood as capacitive changes converted into RC timing constant optimized using a circuit set to trigger at an appropriate time activating a counter. The measured data is captured instant later, selecting the most linear part of the charging curve. The results so obtained are compared with the ones obtained through RC-timing standard procedure. The technique reported is with a remarkable low error of about 2.25% as against 11.78% by the standard RC-timing technique.

Predictive low glucose management (PLGM) may help prevent hypoglycemia by stopping insulin pump delivery based on predicted sensor glucose values.Hypoglycemic challenges were simulated using the Food and Drug Administration-accepted glucose simulator with 100 virtual patients. PLGM was then tested with a system composed of a Paradigm(®) insulin pump (Medtronic, Northridge, CA), an Enlite™ glucose sensor (Medtronic), and a BlackBerry(®) (Waterloo, ON, Canada)-based controller. Subjects (n=22) on continuous subcutaneous insulin infusion (five females, 17 males; median [range] age, 15 [range, 14-20] years; median [range] diabetes duration, 7 [2-14] years; median [range] glycated hemoglobin, 8.0% [6.7-10.4%]) exercised until the PLGM system suspended insulin delivery or until the reference blood glucose value (HemoCue(®); HemoCue GmbH, Großostheim, Germany) reached the predictive suspension threshold setting.PLGM reduced hypoglycemia (70 mg/dL) in silico by 26.7% compared with no insulin suspension, as opposed to a 5.3% reduction in hypoglycemia with use of low glucose suspend (LGS). The median duration of hypoglycemia (time spent70 mg/dL) with PLGM was significantly less than with LGS (58 min vs. 101 min, respectively; P0.001). In the clinical trial the hypoglycemic threshold during exercise was reached in 73% of the patients, and hypoglycemia was prevented in 80% of the successful experiments. The mean (±SD) sensor glucose at predictive suspension was 92±7 mg/dL, resulting in a postsuspension nadir (by HemoCue) of 77±22 mg/dL. The suspension lasted for 90±35 (range, 30-120) min, resulting in a sensor glucose level at insulin resumption of 97±19 mg/dL.In silico modeling and early feasibility data demonstrate that PLGM may further reduce the severity of hypoglycemia beyond that already established for algorithms that use a threshold-based suspension.

A decrease in blood glucose is a frequent and dangerous violation of the most important part of homeostasis - energy. The high frequency of hypoglycemia is explained by a pathogenetic relationship with many diseases and syndromes, as well as the important role of hypoglycemia as a physiological regulator of energy metabolism. The danger of hypoglycemia is that glucose is actually the only source of energy for nerve structures and a lack of glucose could lead to their damage. In addition, deep hypoglycemia and low glucose concentration in brain cells could lead to cerebral edema. Analyzes of the respectful literature for a 20-year period, as well as my own clinical experience, including the work as an endocrinologist surgeon. The article presents the definitions of hypoglycemia, the typology of the syndrome in terms of causes, development mechanisms and clinical forms, also issues of the clinic and laboratory diagnostics are defined. Algorithms for the treatment of hypoglycemic coma and pathogenetic diagnosis of the main variants of hypoglycemia are proposed. Hypoglycemic syndrome [HS] and hypoglycemic coma [HC] are frequent clinical and laboratory paroxysms, especially among patients with diabetes mellitus. These conditions are of great danger to the health and even to the lives of patients, and require quick, qualified help.

Input from continuous glucose monitors (CGMs) is a critical component of artificial pancreas (AP) systems, but CGM performance issues continue to limit progress in AP research. While G4 PLATINUM has been integrated into AP systems around the world and used in many successful AP controller feasibility studies, this system was designed to address the needs of ambulatory CGM users as an adjunctive use system. Dexcom and the University of Padova have developed an advanced CGM, called G4AP, to specifically address the heightened performance requirements for future AP studies. The G4AP employs the same sensor and transmitter as the G4 PLATINUM but contains updated denoising and calibration algorithms for improved accuracy and reliability. These algorithms were applied to raw data from an existing G4 PLATINUM clinical study using a simulated prospective procedure. The results show that mean absolute relative difference (MARD) compared with venous plasma glucose was improved from 13.2% with the G4 PLATINUM to 11.7% with the G4AP. Accuracy improvements were seen over all days of sensor wear and across the plasma glucose range (40–400 mg/dl). The greatest improvements occurred in the low glucose range (40–80 mg/dl), in euglycemia (80–120 mg/dl), and on the first day of sensor use. The percentage of sensors with a MARD

The purpose of this study was to design and evaluate a safety system for the artificial pancreas device system (APDS). Safe operation of the APDS is a critical task, where the safety system is engaged only as needed to ensure reliable operation without positive feedback to the controller.The Health Monitoring System (HMS) was designed as a modular system to ensure the safety of the APDS and the user. It was designed using a large set of ambulatory data and evaluated in silico by inducing hypoglycemia with a missed meal [bolus for a 65 g carbohydrate (CHO) meal] and administering rescue CHOs per HMS alerting. The HMS was validated in-clinic with a real-life challenge of a subject who overdosed insulin prior to admission.The HMS was evaluated for clinical use with a 15 min prediction horizon. Retrospectively, 93.5% of episodes were detected with 2.9 false alarms per day. During in silico evaluation, the HMS reduced the time spent70 mg/dl from 15% to 3%. When the HMS was first tested in-clinic, the subject overdosed ~3 U of insulin prior to her arrival to a closed-loop session (against protocol). The controller reduced insulin delivery, and the HMS gave four alerts that were successfully received via clinical software and text and multimedia messages. Even with insulin reduction and CHO supplements, hypoglycemia was unavoidable but manageable due to the HMS, confirming that a safety system to detect adverse events is an essential part of the APDS.The ability of the HMS to be an effective alert system that provides a safety layer to the APDS controller has been demonstrated in a clinical setting.

Recent scientific explorations in search of novel sources for autologous transplantation transpired an alternative source of MSCs (mesenchymal stem cells) derived from omentum fat. The scarcity of experimental evidences probing into the biosafety concerns of omentum fat-derived MSC under prolonged culture conditions limits its applicability as an efficient tool in regenerative medicine. This study, thus, aims to optimize human omentum fat-derived MSC in four different media [DMEM (Dulbecco's modified Eagle's medium) LG (low glucose), DMEM KO (knock out), α-MEM (α-minimal essential media) and DMEM F12] in the facets of phenotypic characterization, growth kinetics, differentiation and karyotyping under prolonged culture. The cells exhibited a similarity in expression profile for the majority of markers with evidential variations in certain markers. The relevance of omentum fat-derived MSCs became evident from its triumphant differentiation potential and karyotypic stability substantiated even at later passage. The results obtained from growth curve and PDT (population doubling time) lead to optimization of appropriate media for omentum fat-derived stem cell research, thereby bringing omentum fat into the forefront of regenerative medicine.

Sensor-augmented pumps, which consist of a pump and a continuous glucose monitoring system, offer considerable therapeutic opportunities, despite requiring close attention in the early phase of their use. The aim of this paper is to provide recommendations on the use of a predictive low glucose management (PLGM) system (Minimed 640G™, Medtronic, Northridge, CA, USA) in adolescents with type 1 diabetes either at the start of therapy or during follow-up. Sound clinical recommendations on PLGM are of increasing importance since several recent papers have reported significant clinical improvements in patients with PLGM, especially in adults. These recommendations are based on the experience of a group of pediatric endocrinologists who collaborated to closely and intensively study the on-boarding of adolescent patients with type 1 diabetes on automated systems to gain first-hand experience and peer-to-peer insights in a unique free-living environment. The suggestions provided here are indicative, so can be adapted to the individual realities and experiences of different diabetes centers. However, we believe that close adherence to the proposed scheme is likely to increase the chances of improving the clinical and metabolic outcomes of patients treated with this therapy.

Fear of hypoglycemia is a major concern for many patients with type 1 diabetes and affects patient decisions for use of an artificial pancreas system. We propose an alternative way for prevention of hypoglycemia by issuing predictive hypoglycemia alarms and encouraging patients to consume carbohydrates in a timely manner. The algorithm has been tested on 6 subjects (3 males and 3 females, age 24.2 ± 4.5 years, weight 79.2 ± 16.2 kg, height 172.7 ± 9.4 cm, HbA1C 7.3 ± 0.48%, duration of diabetes 209.2 ± 87.9 months) over 3-day closed-loop clinical experiments as part of a multivariable artificial pancreas control system. Over 6 three-day clinical experiments, there were only 5 real hypoglycemia episodes, of which only 1 hypoglycemia episode occurred due to being missed by the proposed algorithm. The average hypoglycemia alarms per day and per subject was 3. Average glucose value when the first alarms were triggered was recorded to be 117 ± 30.6 mg/dl. Average carbohydrate consumption per alarm was 14 ± 7.8 grams. Our results have shown that most low glucose concentrations can be predicted in advance and the glucose levels can be raised back to the desired levels by consuming an appropriate amount of carbohydrate. The proposed algorithm is able to prevent most hypoglycemic events by suggesting appropriate levels of carbohydrate consumption before the actual occurrence of hypoglycemia.

Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction. NEW & NOTEWORTHY Acute low-glucose exposure induces mitochondrial fragmentation in endothelial cells via Drp1 and is associated with impaired endothelial function in human arterioles. Targeting of Drp1 prevents fragmentation, improves vasofunction, and may provide a therapeutic target for improving cardiovascular complications among diabetics. Listen to this article’s corresponding podcast @ http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/ .

Glucose entropy was inversely correlated with insulin resistance in a series of non-diabetic individuals with low glucose variability. In long-standing type 1 diabetes, the inverse correlation between glucose entropy and insulin resistance is preserved, as lower glucose entropy is associated with higher BMI.

The participation of the carotid body (CB) in glucose homeostasis and evidence obtained in simplified cultured CB slices or dissociated cells have led to the proposal that CB chemoreceptor cells are glucoreceptors. However, data generated in intact, freshly excised organs deny CB chemoreceptor cells' glucosensing properties. The physiological significance of the contention has prompted the present study, performed in a newly developed preparation of the intact CB organ in culture that maintains chemoreceptor cells' microenvironment. Chemoreceptor cells of intact CBs in culture retained their capacity to store, synthesize, and secrete catecholamine in response to hypoxia for at least 6 days. Aglycemia did not elicit neurosecretion in dissociated chemoreceptor cells or in intact CB in culture, but potentiated hypoxia-elicited neurosecretion, exclusively, in 1-day-old intact CB cultures and dissociated chemoreceptor cells cultured for 24 h. In fura 2-loaded cells, aglycemia (but not 1 mM) caused a slow Ca(2+)-dependent and nifedipine-insensitive increase in fluorescence at 340- to 380-nm wavelength emission ratio and augmented the fluorescent signal elicited by hypoxia. Association of nifedipine and KBR7943 (a Na(+)/Ca(2+) exchanger inhibitor) completely abolished the aglycemic Ca(2+) response. We conclude that chemoreceptor cells are not sensitive to hypoglycemia. We hypothesize that cultured chemoreceptor cells become transiently more dependent on glycolysis. Consequently, aglycemia would partially inhibit the Na(+)/K(+) pump, causing an increase in intracellular Na(+) concentration, and a reversal of Na(+)/Ca(2+) exchanger. This would slowly increase intracellular Ca(2+) concentration and cause the potentiation of the hypoxic responses. We discuss the nature of the signals detected by chemoreceptor cells for the CB to achieve its glycemic homeostatic role., The work was supported by Grants BFU2007–61848 (Departmento Governmental de Investigaciónes Cientificas y Técnológicas) and Centro de Investigación Biomédica en Red CB06/06/0050 (FISS-ICiii).

Introduction: Intensive glucose control in patients with Type 2 Diabetes Mellitus has resulted in increased incidence of hypoglycemia, often with elevated risk of adverse cardiovascular events. Studies of endothelial cells (ECs) and human arterioles exposed to a low glucose (LG) environment suggest the risk is mediated through a dysfunctional endothelium, characterized by greater reactive oxygen species (ROS) production and decreased nitric oxide (NO). Hypothesis: We propose that LG-induced endothelial dysfunction is driven by an imbalance in the fission/fusion process of mitochondrial networks within ECs. Methods: Human ECs were used to quantify mitochondrial fission and evaluate Mdivi-1, a fission inhibitor, following incubation in either LG (40 mg/dL) or normal glucose (NG, 90 mg/dL) physiologic environments for 2 hours. Similarly, human subcutaneous adipose arterioles subjected to either LG or NG, were used to detect ROS with MitoSOX and NO with DAF-2DA, ±Mdivi-1. Arteriole vasoactivity was measured ±Mdivi-1 in a dose-response manner to acetylcholine (Ach). This experiment was repeated employing siRNA to knockdown expression of the primary fission protein, Drp1. Results: More mitochondrial fragmentation was observed in ECs exposed to LG (LG vs NG: 3.2±0.6 vs 2.4 ±0.5, P-7 to 10 -5 M, P-7 to 10 -5 M, P Conclusion: Human arterioles exposed to LG conditions exhibit a decrease in NO, increased ROS and an impaired vasodilatory response correlating with dynamic mitochondrial changes. The role of the mitochondria in LG-induced endothelial dysfunction appears to be rooted in an increased mitochondrial fission response.

The market for glucoamylase is large and very competitive and the production process has been optimized through several decades. So far a thorough characterization of the process has not been published, but previous academic reports suggest that the process suffers from severe byproduct formation. In this study we have carried out a thorough characterization of a process as close as possible to the industrial reality. The results show that the oxygen-limited phases of the process have the highest glucoamylase yields on carbon and that the byproducts are efficiently reused in late phases of the process. An alternative process with low glucose concentration show that high osmolarity is beneficial for the process, and we conclude that oxygen limitation, high osmolarity, and the associated byproduct metabolism are important for the efficiency of the process.

To investigate the effect of media on mouse follicular development and oocyte maturation in vitro, we compared eight culture media. Early preantral follicles were mechanically dissected from the ovaries of 14-day-old mice and cultured for 10 days. The tested media were: α-MEM, D-MEM/F-12, D-MEM with high glucose (4.5 g/L) (D-MEM[H]) or low glucose (1 g/L) (D-MEM[L]), Weymouth, M199, IMDM, and RPMI1640. All of the media were supplemented with 5% FBS, ITS, 100 mlU/ ml rhFSH, 1 mlU/ml rhLH and, 0.5% gentamicin. Compared to the other media (P < 0.05), a higher percentage of follicles survived and antral-like cavity formation was seen after 10 days of culture when the follicles were cultured in α-MEM, Waymouth, D-MEM/F-12, or D-MEM(L). Among the four media with higher follicle survival, the oocyte diameter on day 10 of culture was largest in α-MEM and smallest in Waymouth. The highest percentages of MII oocytes were obtained when follicles were cultured in α-MEM, D-MEM(L), and D-MEM/F-12. In contrast...

Background: The evaluation of continuous glucose monitor (CGM) alert performance should reflect patient use in real time. By evaluating alerts as real-time events, their ability to both detect and predict low and high blood glucose (BG) events can be examined. Method: True alerts (TA) were defined as a CGM alert occurring within ± 30 minutes from the beginning of a low or a high BG event. The TA time to detection was calculated as [time of CGM alert] – [beginning of event]. False alerts (FA) were defined as a BG event outside of the alert zone within ± 30 minutes from a CGM alert. Analysis was performed comparing DexCom™ SEVEN ® PLUS CGM data to BG measured with a laboratory analyzer. Results: Of 49 low glucose events (BG ≤70 mg/dl), with the CGM alert set to 90 mg/dl, the TA rate was 91.8%. For 50% of TAs, the CGM alert preceded the event by at least 21 minutes. The FA rate was 25.0%. Similar results were found for high alerts. Conclusion: Continuous glucose monitor alerts are capable of both detecting and predicting low and high BG events. The setting of alerts entails a trade-off between predictive ability and FA rate. Realistic analysis of this trade-off will guide patients in the effective utilization of CGM.

Blood glucose regulation is of a great concern for insulin-dependant patients with excessive glucose in blood (hyperglycaemia), or low glucose profile (hypoglycaemia) due to excess insulin delivery. Both conditions can cause dangerous complications for diabetic patients, and hence glucose regulation in blood is of prime importance. Insulin pumps are used to deliver insulin in small quantities, allowing the glucose level to remain as close as possible to that of non-diabetics (near 100 mg dl(-1)). Different control techniques are used to maintain the glucose level and most of them depend on an exact mathematical or empirical model of insulin-glucose interaction. Recently, we have proposed different controllers that are based on fuzzy logic and so do not use mathematical modelling, which in general is nonlinear, complex and suffers from uncertainties. PI fuzzy controllers are physically related to classical PI and PID controllers, which are extremely popular. The parameter settings of classical and fuzzy logic controllers are based on deep common physical background. In this manuscript, a comparative study is proposed to evaluate the use of fuzzy logic controllers over other conventional controllers such as PI and PID controllers to maintain the blood glucose level within a normoglycaemic average especially when a diabetic patient is subjected to different conditions.

During screening for asymptomatic bacteriuria with the hypoglucosuria test, the urine from a seven-year-old girl showed low glucose values, but negative conventional cultures. Heavy growth of l-forms of Escherichia coli, unaccompanied by growth of the classical bacterial form, was obtained on two occasions. The girl had no symptoms, no past history of urinary tract infection, and had never been treated with antibiotics. Shortly afterwards she presented symptoms suggestive of urinary tract infection, accompanied on this occasion by growth of classical E. coli. The finding of subnormal, fasting urinary glucose levels in combination with negative conventional cultures may indicate a latent infection due to l-forms.

Blood sugar levels in 228 EDTA-treated venous blood samples were measured in the laboratory by a new test-strip (Visidex) and the hexokinase reference method. There was good agreement between the two, with a linear correlation of r = 0.92 and a regression line with a slope of 0.98. 97.8% of all values deviated by less than one concentration range from the reference values. At low glucose concentrations the median of the absolute differences between the two methods was 9.5 mg/dl. Over the whole concentration range of 20-800 mg/dl the mean deviation from the reference values was between 14.4 and 32.6 mg/dl. The results indicate that the Visidex test-strip method is suitable for the visual estimation of blood sugar values.

Interactions between advanced glycation endproducts (AGE) and the receptor for AGE (RAGE) have been implicated in the development of diabetic vascular complications. RAGE has two N-glycosylation sites in and near the AGE-binding domain, and G82S mutation in the second N-glycosylation motif was recently reported in human. In this study, we examined whether de-N-glycosylation or G82S of RAGE affect its ability to bind AGE and cellular response to AGE. Recombinant wild-type, de-N-glycosylation and G82S RAGE proteins were produced in COS-7 cells, purified and assayed for ligand-binding abilities. De-N-glycosylation at N81 and G82S mutation decreased Kd for glycolaldehyde-derived AGE to three orders of magnitude lower levels compared with wild-type. AGE-induced upregulation of VEGF mRNA was significantly augmented in endothelial cell-derived ECV304 cells expressing de-N-glycosylated and G82S RAGE when compared with wild-type expressor. Exposure to low glucose resulted in the appearance of RAGE proteins of deglycosylated size in wild-type RAGE-expressing cells and significantly enhanced glycolaldehyde-derived AGE-induced VEGF mRNA expression. De-N-glycosylation or G82S mutation of RAGE increases affinity for AGE ligands, and may sensitize cells or conditions with it to AGE.

Catastrophic longitudinal myelitis is an extremely rare neurologic manifestation of collagen vascular disease, described heretofore in 11 cases of SLE and 1 of Sjogren's Syndrome. This report documents markedly abnormal and worsening CSF findings on sequential CSF examinations over a period of three days (WBC >1500 cells/μL, >80% neutrophils, markedly elevated protein, and extremely low glucose levels) in the absence of infection. These abnormalities cleared rapidly with institution of immunosuppressive therapy so that a third CSF exam done within three days revealed almost complete normalization of CSF values. These findings suggest that in some cases of CLM a strong inflammatory component may be present, while in others, other pathogenic factors may predominate. Lupus (2007) 16, 823—826.

Investigation of the effects of low glucose concentrations on the oxygen consumption rates of intervertebral disc cells.To determine the oxygen consumption rate of porcine anulus fibrosus (AF) cells at different glucose concentrations and to examine the differences in the oxygen consumption rate between AF and nucleus pulposus (NP) cells at different glucose levels.Poor nutrient supply has been suggested as a potential mechanism for degeneration of the intervertebral disc (IVD). Distribution of nutrients in the IVD is strongly dependent on transport properties of the tissue and cellular metabolic rates. Previous studies have shown dependence of oxygen consumption rate of IVD cells on oxygen tension, pH levels, and glucose levels outside the physiologic range. However, the oxygen consumption rate of AF cells at in vivo glucose levels has not been investigated.IVD cells were isolated from the outer AF and NP of 4- to 5-month-old porcine lumbar discs. The changes in oxygen tension were recorded when cells were cultured in sealed metabolism chamber. The oxygen consumption rate of cells was determined by theoretical curve fitting using the Michaelis-Menten equation.The outer AF cells cultured in high glucose medium (25 mmol/L) exhibited the lowest oxygen consumption rate, whereas no significant differences in oxygen consumption rates were found among outer AF cells cultured at physiologic glucose levels (i.e., 1 mmol/L, 2.5 mmol/L, 5 mmol/L). The oxygen consumption rate of NP cells was significantly greater than that of outer AF cells.Since the oxygen consumption rates determined in this study are comparable to the findings in the literature, this study has developed a new alternative method for determining oxygen consumption rate. The oxygen consumption rates of IVD cells reported in this study will be valuable for theoretically predicting local oxygen concentrations in IVD, which can provide a better understanding of transport of oxygen in the discs.

The aim of the present study was to investigate whether low glucose and pH level, which are usually measured in complicated pleural effusions, alter the electrochemical function of healthy human parietal pleura. Parietal pleural pieces were stripped from 66 patients during thoracic surgery and were mounted in Ussing chambers. Krebs’ solutions containing different glucose levels (0, 40 and 100 mg) and balanced at different pH levels (7.4, 7.3 and 7.2) were added to the pleural cavity surface of the pieces. Transmesothelial potential difference was measured at various time-points as an electrophysiological variable and transmesothelial resistance ( R TM ) was calculated using Ohm9s law. When normal-glucose Krebs at pH 7.45 was used, R TM remained unchanged over time, but when low-glucose Krebs was used, R TM decreased. Krebs without glucose caused the greatest decrease in R TM . Use of low-pH Krebs decreased R TM . The lower the pH of the Krebs, the faster the decrease in R TM and the greater the effect. The decrease in R TM was greater with low-pH than with low-glucose Krebs. Low glucose and low pH caused an additive decrease in R TM . Low glucose concentration and low pH cause alteration of the electrochemical function of human parietal pleura and could act as agents that lead to further exudate progression.

Accuracy of continuous glucose monitoring (CGM) devices in hypoglycemia has been a widely reported shortcoming of this technology. We report the accuracy in hypoglycemia of a new version of the Dexcom (San Diego, CA) G4 Platinum CGM system (software 505) and present results regarding the optimum setting of CGM hypoglycemic alerts.CGM values were compared with YSI analyzer (YSI Life Sciences, Yellow Springs, OH) measurements every 15 min. We reviewed the accuracy of the CGM system in the hypoglycemic range using standard metrics. We analyzed the time required for the CGM system to detect biochemical hypoglycemia (70 mg/dL) compared with the YSI with alert settings at 70 mg/dL and 80 mg/dL. We also analyzed the time between the YSI value crossing 55 mg/dL, defined as the threshold for cognitive impairment due to hypoglycemia, and when the CGM system alerted for hypoglycemia.The mean absolute difference for a glucose level of less than 70 mg/dL was 6 mg/dL. Ninety-six percent of CGM values were within 20 mg/dL of the YSI values between 40 and 80 mg/dL. When the CGM hypoglycemic alert was set at 80 mg/dL, the device provided an alert for biochemical hypoglycemia within 10 min in 95% of instances and at least a 10-min advance warning before the cognitive impairment threshold in 91% of instances in the study.Use of an 80 mg/dL threshold setting for hypoglycemic alerts on the G4 Platinum (software 505) may provide patients with timely warning of hypoglycemia before the onset of cognitive impairment, enabling them to treat themselves for hypoglycemia with fast-acting carbohydrates and prevent neuroglycopenia associated with very low glucose levels.

Background The impact of a low-glucose peritoneal dialysis (PD) regimen on biomarkers of peritoneal inflammation, fibrosis and membrane integrity remains to be investigated. Methods In a randomized, prospective study, 80 incident PD patients received either a low-glucose regimen comprising Physioneal (P), Extraneal (E) and Nutrineal (N) (Baxter Healthcare Corporation, Deerfield, IL, USA) (PEN group), or Dianeal (control group) for 12 months, after which both groups continued with Dianeal dialysis for 6 months. Serum and dialysate levels of vascular endothelial growth factor (VEGF), decorin, hepatocyte growth factor (HGF), interleukin-6 (IL-6), macrophage migration inhibitory factor (MIF), hyaluronan (HA), adiponectin, solubleintracellular adhesion molecule (s-ICAM), vascular cell adhesion molecule-1 (VCAM-1) and P-selectin, and dialysate cancer antigen 125 (CA125), were measured after 12 and 18 months. This paper focuses on results after 12 months, when patients in the PEN group changed to glucose-based PD fluid (PDF). Results At the end of 12 months, effluent dialysate levels of CA125, decorin, HGF, IL-6, adiponectin and adhesion molecules were significantly higher in the PEN group compared to controls, but all decreased after patients switched to glucose-based PDF. Macrophage migration inhibitory factor level was lower in the PEN group but increased after changing to glucose-based PDF and was similar to controls at 18 months. Serum adiponectin level was higher in the PEN group at 12 months, but was similar in the 2 groups at 18 months. Body weight, residual renal function, ultrafiltration volume and total Kt/V did not differ between both groups. Dialysate-to-plasma creatinine ratio at 4 h was higher in the PEN group at 12 months and remained so after switching to glucose-based PDF. Conclusion Changes in the biomarkers suggest that the PEN PD regimen may be associated with better preservation of peritoneal membrane integrity and reduced systemic vascular endothelial injury.

Taurine has beneficial effects in many pathological conditions. However, we have recently found in mice that high doses of taurine combined with ethanol can be lethal. Measurements of blood glucose in adult and old mice indicate that one possible mechanism of this toxicity might be hypoglycemia. We focused here mainly on effects of taurine and ethanol co-administration on blood glucose in 7-day-old mice and compared the results to data obtained from adult and old mice. We applied non-lethal (2 g/kg + 5 g/kg), sub-lethal (4 g/kg + 5 g/kg) and lethal (6 g/kg + 5 g/kg) doses of taurine and ethanol to 7-day-old mice and measured their blood glucose near death. Taurine alone reduced blood glucose but not to a hazardous level. Co-administration of taurine and ethanol lowered blood glucose levels in a dose-dependent manner. The lethal combination of taurine and ethanol reduced blood glucose to approximately one half, from 8–10 to 4–6 mmol/l, at all ages. However, 25 % of 7-day-old and 40 % of elderly mice treated with taurine and ethanol showed a dramatic drop in blood glucose to 2–3 mmol/l, which may be lethal. Hypoglycemia may thus be a single cause of death, but other mechanisms of toxicity prevail because 100 % of animals died after lethal doses of taurine and ethanol, but only 25–40 % of them had dangerously low glucose levels.

2-Deoxyglucose (2-DG), a non-metabolizable glucose analogue, blocks glycolysis and inhibits protein glycosylation. It has been tested in multiple studies for possible application as an anticancer or antiviral therapeutic. The inhibitory effect of 2-DG on ATP generation made it a good candidate molecule as a calorie restriction mimetic as well. Furthermore, 2-DG has been utilized in numerous studies to simulate a condition of glucose starvation. Because 2-DG disrupts glucose metabolism, protein glycosylation, and ER quality control at the same time, a cellular or pathologic outcome could be easily misinterpreted without clear understanding of 2-DG's effect on each of these aspects. However, the effect of 2-DG on protein glycosylation has rarely been investigated. A recent study suggested that 2-DG causes hyperGlcNAcylation of proteins, while low glucose supply causes hypoGlcNAcylation. In certain aspects of cellular physiology, this difference could be disregarded, but in others, this may possibly cause totally different outcomes.

Science Skills include observing skills with all the senses, using tools and materials, planned the exThis study aims to investigate the influence of variations in the concentration and dipping time of lactic acid to glucose and organoleptic sweet potato (Ipomoea batatas). The research method using completely randomized design (CRD) with factorial 3x3 and three replications. The first factor is the variation of concentration (K) include 1%, 1.5%, 2%, both long immersion factor (L) includes 60 minutes, 90 minutes, 120 minutes. Collecting data by calculating the glucose level using titration method using Na2S2O3 and organoleptic tests include color, smell, texture and level of preference to the 15 panelists using the enclosed questionnaire. Analysis of data using analysis of variance (ANOVA) two paths through SPSS version 17.0 with a significance level of 0.05, then when will significantly dilanjutkanuji LSD or LSD. The analysis showed variation in the concentration effect on glucose levels (P = 0.000

In this study, the system of electrodialysis fermentation (EDF) was improved by a glucose concentration controller (GC controller) which could control glucose concentration stable and low in fermentation broth. Under the control of the GC controller, there were little inhibitory effects of the end product and substrate on bacteria so as to result in high activity of bacteria and, further, in high productivity of lactic acid. Moreover, the low glucose concentration in the fermentation broth brought about little glucose leakage to the recovery solution and hence high yield of lactic acid. Compared with the EDFs carried out in the previous studies, the continuous EDF with a glucose concentration controller (CEDF with GC controller) was higher in productivity, yield and conversion ratio of lactic acid, indicating that it was a system more efficient to produce lactic acid.

Energetic costs of fighting, such as high lactate or low glucose, have been shown in a range of species to correlate with the decisions made by each opponent, particularly the decision by one opponent, the ‘loser’, to end the fight by ‘giving up’. Studies based on complete fights of differing duration, however, do not provide information on the changes in the physiological correlates of fighting that may take place during the course of the encounter, or how these changes may influence the capability and decisions of the contestants. We interrupted fights between hermit crabs, Pagurus bernhardus, at specific points, and related energy status to the preceding activities. Costs rose quickly with a rapid accumulation of lactic acid in attackers and declining muscular glycogen in defenders. Changes in physiological status appeared much earlier than the changes in behaviour that they may have caused. Furthermore, some physiological changes might have been an effect, rather than the cause, of fight decisions.

This prospective study of 15 dogs evaluated biochemical parameters in abdominal effusions of neoplastic and nonneoplastic origin in an attempt to identify markers for malignant effusions. Dogs in the neoplastic group had statistically significant lower glucose concentrations (mean, 72.6 mg/dL versus 110.0 mg/dL; P=0.0431) and higher lactate levels (mean, 3.81 mmol/L versus 1.68 mmol/L; P=0.0377) in their abdominal fluid than did dogs in the nonneoplastic group, indicating that low glucose and high lactate in abdominal effusions may be markers for neoplasia.

We have developed a range of disposable and colorless tear glucose sensing contact lenses, using off-the-shelf lenses embedded with new water soluble, highly fluorescent and glucose sensitive boronic acid containing fluorophores. The new lenses are readily able to track tear glucose levels and therefore blood glucose levels, which are ideally suited for potential use by diabetics. The fluorescence responses from the lenses can be monitored using simple excitation and emission detection devices. The novelty of our approach is two fold. Firstly, the notion of sensing extremely low glucose concentrations in tears, which track blood levels, by our contact lens approach, and secondly, the unique compatibility of our new glucose signaling probes with the internal mildly acidic contact lens environment. The new lenses are therefore ideal for the non-invasive and continuous monitoring of tear glucose, with about 15-min response time, and a measured shelf life in excess of 3 months. In this review article, we show that fluorescence based signaling using plastic disposable lenses, which have already been industrially optimized with regard to vision correction and oxygen/analyte permeability etc, may a notable alternative to invasive and random finger pricking, the most widely used glucose monitoring technology by diabetics.