bluuebunny/crossref_metadata_2025 huggingface dataset:
Luseogliflozin Inhibits HIF-1α Expression in Renal Proximal Tubular Epithelial Cells
Authors: BESSHO RYOICHI , TAKIYAMA YUMI , OTA TSUGUHITO
Published: June 2018

Recent clinical trials have demonstrated the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy (DN). However, the mechanisms of SGLT2 inhibitors on prevention of DN have not been fully elucidated. Hypoxia-induced tubulointerstitial fibrosis is considered to be a common pathway for various progressive kidney diseases including DN. Hypoxia inducible factor (HIF)-1α plays an important role in these pathological processes. In this study, we assessed the effects of luseogliflozin, an SGLT2 inhibitor, on HIF-1α expression in both cultured human renal proximal tubular epithelial cells (HRPTECs) and kidney of diabetic mice. Hypoxia (1%O2 for 24h) markedly increased HIF-1α protein in HRPTEC, whereas luseogliflozin inhibited expression of hypoxia-induced HIF-1α protein. In addition, luseogliflozin inhibited mRNA expression for HIF-1α-targeted genes, PAI-1, VEGF and GLUT-1 under hypoxia. The inhibitors of mitochondrial respiratory complex I, rotenone or complex III, antimycin A equally suppressed hypoxia-induced HIF-1α expression. We next treated db/db mice with 15 mg/kg/day luseogliflozin for 8 weeks. Luseogliflozin administration lowered plasma glucose levels and decreased glomerular mesangial matrix expansion as well as glomerular and interstitial fibronectin accumulation in db/db mice. Electron microscopic study revealed that luseogliflozin attenuated the thickening of glomerular basement membrane in db/db mice. Intriguingly, luseogliflozin decreased the length of mitochondria in the renal proximal tubules of the S1 segment. Furthermore, luseogliflozin attenuated diabetes-induced HIF-1α accumulation in the kidney of db/db mice. These results suggest that luseogliflozin inhibits hypoxia-induced HIF-1α accumulation at least partly by suppressing mitochondrial respiration. SGLT2 inhibitors may protect diabetic kidney from hypoxia-induced renal fibrosis by attenuating the expression of HIF-1α and profibrotic molecules.

Disclosure

R. Bessho: None. Y. Takiyama: None. T. Ota: None.
Insulin Degludec/Insulin Aspart (IDegAsp) Twice Daily (BID) vs. Biphasic Insulin Aspart 30 (BIAsp 30) BID—A Randomized Trial in Chinese Patients with Type 2 Diabetes
Authors: YANG WENYING , MA JIANHUA , HONG TIANPEI , LIU MING , MIAO HENG , PENG YONGDE , WANG CHANGJIANG , XU XIANGJIN , YANG TAO , NIELSEN ANNE MOELLER , PAN LILI , LIU WEIHONG , WEIGANG ZHAO
Published: June 2018

IDegAsp is the first coformulation of long-acting basal (degludec) and bolus (IAsp) insulin with no need for re-suspension. This 26-week, phase 3, open-label, treat-to-target, 2:1, randomized trial assessed the efficacy and safety of IDegAsp BID vs. BIAsp 30 BID ±metformin in Chinese adults (N=541) with T2D inadequately controlled on pre-/self-mix or basal insulin ±metformin (NCT02762578). Hierarchical testing was used with non-inferiority of A1C change from baseline to week 26 as the primary endpoint and superiority for secondary endpoints. Non-inferiority of A1C change from baseline to week 26 and statistical superiority of IDegAsp BID vs. BIAsp 30 BID for change in fasting plasma glucose, nocturnal (00:01-05:59 hours inclusive) confirmed hypoglycemic and confirmed hypoglycemic episodes (severe or plasma glucose <56mg/dL with or without symptoms) was confirmed (Table). Significantly more patients reached A1C <7% without confirmed hypoglycemia with IDegAsp BID vs. BIAsp 30 BID by week 26. Daily insulin dose (U/kg [SD]) was lower in patients receiving IDegAsp BID vs. BIAsp 30 BID at week 26 (0.78 [0.35] vs. 0.95 [0.35]). No new safety signals were identified. These results demonstrate the efficacy and safety of IDegAsp in Chinese patients with T2D, confirming results from other international trials comparing the two treatment modalities (NCT02762578).

Disclosure

W. Yang: None. J. Ma: None. T. Hong: Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca. M. Liu: None. H. Miao: None. Y. Peng: None. C. Wang: None. X. Xu: None. T. Yang: None. A. Moeller Nielsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. L. Pan: Employee; Self; Novo Nordisk (China). W. Liu: Employee; Self; Novo Nordisk (China). Z. Weigang: None.
MiniMed™ Veo™ Insulin Pump Analysis for Real-World Nonadjunctive CGM Insights
Authors: JIANG BOYI , SOLEYMANI SADAF , VIGERSKY ROBERT , SULLIVAN ASHLEY , ZHONG YUXIANG , AGRAWAL PRATIK , KAUFMAN FRANCINE R.
Published: June 2018

To assess glycemic outcomes during non-adjunctive use of a Medtronic continuous glucose monitoring system, CareLink™ personal software data were analyzed after insulin bolus delivery to correct hyperglycemia.

Voluntarily uploaded data captured between January 1, 2015-August 12, 2016, from European users of the MiniMed™ Veo™ insulin pump with SmartGuard™ technology, were de-identified and analyzed. Non-adjunctive sensor glucose (SG) values were defined as manually-entered self-monitored blood glucose (SMBG) values that were within ±5mg/dL of the preceding SG value. Non-adjunct vs. adjunct performance of the system in frequent non-adjunct users (at least, 10% non-adjunct use) was evaluated based on the frequency of post-corrective bolus hypoglycemia (nadir) and hyperglycemia (peak) over the 4 hours following insulin bolus delivery. All statistics were conducted per patient and analyzed using Wilcoxon signed rank test.

Among 23,784 total users, 5,851 were identified as frequent non-adjunct users. Of the over 1.7 million corrective boluses evaluated, 32% met the non-adjunctive criteria. Outcomes results are presented in the Table below.

The frequency and severity of hypoglycemia and hyperglycemia, although lower statistically with non-adjunctive vs. adjunctive corrective bolus delivery, showed likely clinical equivalency.

Disclosure

B. Jiang: None. S. Soleymani: Employee; Self; Medtronic MiniMed, Inc. R. Vigersky: Employee; Self; Medtronic MiniMed, Inc.. A. Sullivan: None. Y. Zhong: None. P. Agrawal: None. F.R. Kaufman: Employee; Self; Medtronic.
Adults with Type 1 Diabetes (T1D) Using Continuous Glucose Monitoring (CGM) Report Disease Has Little Impact on Daily Functioning—T1D Exchange
Authors: FAN LUDI , GAREY COLLEEN , LIU JINGWEN , MITCHELL BETH , BISPHAM JEOFFREY , MCAULIFFE-FOGARTY ALICIA H.
Published: June 2018

Glycemic Variability (GV) and Treatment Satisfaction (TS) are not accurately reflected in HbA1c. This study explored GV measures and their effect on insulin TS, productivity and activity in a real-world population with T1D. This prospective survey was of 98 adults from the T1D Exchange online patient community. Surveys were completed and CGM data were downloaded at baseline and weekly thereafter for 4 weeks (week). The Insulin Treatment Satisfaction Questionnaire was done at week 4, and Work Productivity Impairment (WPI) and Activity Impairment (AI)-General Health Questionnaire were done weekly for 4 weeks. Linear regression and mixed models explored the relationship between GV and TS, and impairment, respectively. Overall mean age was 43 years (SD 15.3), mean years with T1D was 22 (SD 14.2), 68% were female, and mean self-reported most recent HbA1c was 6.8% (SD 0.8). Participants on insulin pump (n=86) and multiple daily injections (n=12) took an average of 47.7 Units (±35.8) and 39.3 Units (±23.1) of insulin, respectively. Markers of GV and patient reported measures are in Table. Of the 14 GV measures examined, CV and LBGI showed a positive association with insulin TS (p<.05). No GV measures significantly impacted WPI or AI. The adult population with T1D in this survey had high TS, and had low WPI and AI, despite overall moderate risk for hypoglycemia.

Disclosure

L. Fan: Employee; Self; Eli Lilly and Company. C. Garey: None. J. Liu: None. B. Mitchell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Bispham: None. A.H. McAuliffe-Fogarty: Advisory Panel; Self; Novo Nordisk Inc..
Adaptive Modeling of Glucose Measurements with Unannounced Meals and Exercise
Authors: HAJIZADEH IMAN , RASHID MUDASSIR , CINAR ALI
Published: June 2018

Reliable artificial pancreas (AP) systems require accurate models of the glucose-insulin dynamics in people with type 1 diabetes mellitus (T1DM). The realization of a fully automated AP system, however, is not possible with manual user entries for meals and exercise. To promote the development of automated AP systems without any user inputs, an adaptive and personalized data-driven model is developed that characterizes the evolving glycemic dynamics of individuals while explicitly considering the estimated effects of unknown disturbances such as meals and exercise. To achieve this adaptive and personalized modeling approach that best describes the glucose dynamics at any given instant without manual user input, we first quantify the effects of the unknown meals through adaptive estimates of time-varying parameters in dynamic physiological model. The evaluated meal effects are incorporated with plasma insulin concentration estimates and readily measured physiological data from noninvasive sensors, such as heart rate and energy expenditure, to determine the overall state of the individuals. The proposed modeling approach integrates first-principles physiological models and data-driven empirical techniques to determine an accurate and comprehensive perspective of the individual at any given time. Simulation case studies involving in silico subjects from the U.S. Food and Drug Administration approved University of Virginia/Padova metabolic simulator demonstrate the improvement in prediction ability of the proposed approach. The root-mean-square error and mean absolute error for 30-, 45-, and 60-min-ahead predictions are 15.61 and 8.98 mg/dL, 21.82 and 13.49 mg/dL, and 25.96 and 17.00 mg/dL, respectively. The accurate predictions of future glucose concentration measurements without requiring manual user inputs will enable fully-automated AP systems that perform efficiently by maintaining euglycemia and mitigating glucose excursions.

Disclosure

I. Hajizadeh: None. M. Rashid: None. A. Cinar: None.
Intermittently Scanned Continuous Glucose Monitoring (isCGM)—Examination in Pediatric Patients With and Without Ketoacidosis
Authors: BOU GABRIELA A. , WURM MICHAEL , HANSEN BARBARA C. , SCHWAB KARL OTFRIED
Published: June 2018

The isCGM (FreeStyle Libre “flash”) is approved in a number of countries for use in adults, but has had minimal study in pediatric groups and no reports of its use during ketoacidosis. This study in pediatric patients sought to compare paired samples from this isCGM to the Accucheck Aviva glucose monitor under conditions of varying glucose levels and varying degrees of ketoacidosis.

Twelve hyperglycemic T1D patients, ages 6-16 years, were studied with a minimum of 6 paired comparisons in each condition: 3 with ketoacidosis (pH 7.2-7.3) and one with severe ketoacidosis (pH <7.2), and all others nonketotic. Up to a 15% measurement difference between BG and tissue glucose measurements for BG > 100 mg/dL, or an absolute difference of 15 mg/dL for BG < 100 mg/dL, were considered within target range. Blood glucose levels ranged from 35 to 556 mg/dl (1.94-30.89 mmol/L) and pH levels 6.9 to 7.6. Mean absolute relative differences (MARD, isCGM vs. Accucheck paired measurements) were: 426 non-ketoacidotic with BG >100 mg/dL: MARD of 11.77% with 69.2% of values within a 15% difference; 96 non-ketoacidotic with BG < 100 mg/dL: MARD of 12.4% with 78.1% within 15%; 17 ketoacidotic with BG>100 mg/dL: MARD of 12.42% with 70.6% within 15%; and 6 severely ketoacidotic: MARD of 22.68% with 16.7% within 15%, constituting a major difference with severe ketoacidosis. Clarke Error Grid Analysis for results with non-ketoacidotic values with BG <=79 mg/dL: 93% in Zone A and 7% in Zone B; ketoacidotic values: 94.11% in Zone A and 5.88% in Zone B; and severely ketoacidotic values: 50% in Zone A and 50% in Zone B. Of the 545 paired comparisons obtained, only 17 were obtained during ketosis and 6 during severe ketoacidosis. These results show that this “flash” isCGM and BG measurements determined by Accucheck Aviva are highly concordant, however, the major differences observed during severe ketoacidosis urge caution in interpreting the blood glucose levels under this condition.

Disclosure

G.A. Bou: None. M. Wurm: None. B.C. Hansen: None. K. Schwab: None.
Use of the Tidepool Platform to Collect, Integrate, and Visualize Diabetes Device Data in a Pediatric Clinic Setting
Authors: WONG JENISE C. , IZADI ZARA , SCHROEDER SHANNON M. , NADER MARIE , MIN HYOJIN J. , NEINSTEIN AARON B. , ADI SALEH
Published: June 2018

Glucose meters, insulin pumps, and continuous glucose monitoring systems provide data needed for people with type 1 diabetes to modify insulin regimens, evaluate lifestyle changes, or troubleshoot unexpected glucose levels. Health care providers (HCPs) can use device-specific software to review data at patient visits, often using separate, proprietary applications for each device. Using mixed qualitative and quantitative methods, we examined the feasibility of using the Tidepool platform and web application to view diabetes data from multiple devices together, in a multidisciplinary pediatric diabetes center where it was standard practice to upload and view data using device-specific software for each patient visit. Participating HCPs (n=15) used the software with compatible devices in all patient visits for 6 months. To evaluate the effect of the application on workflow, registration desk activity and office visits were observed before and after introducing the software, and HCPs provided feedback by survey and focus groups. The time required to upload device data and the length of the office visit did not change. However, the number of times the provider referred to the device data with patients increased from a mean of 2.8 (±1.2) to 6.1 (±3.1) times per observed visit (p=0.0002). A significantly larger proportion of the children looked at the device data with the new application (61% at baseline vs. 94% at study end, p=0.015). HCPs liked the use of color to indicate glucose levels, the graphical web-based user interface, integration of the data in one application, and the ability to remotely access data via the web for telehealth. They found the application most useful for initiating patient conversations and education. Remaining challenges include the need for automated data upload and integration with electronic medical records. Future studies of HCP use of the application will focus on clinical outcomes and effects on patient engagement and self-management.

Disclosure

J.C. Wong: Research Support; Self; Dexcom, Inc.. Other Relationship; Self; Tidepool Project. Z. Izadi: None. S.M. Schroeder: None. M. Nader: None. H.J. Min: None. A.B. Neinstein: None. S. Adi: Stock/Shareholder; Spouse/Partner; Dexcom, Inc.. Speaker's Bureau; Self; Dexcom, Inc.. Board Member; Self; Tidepool Project. Other Relationship; Self; Novo Nordisk Inc..
Study of the Correlation between Tear Glucose Concentrations and Blood Glucose Concentrations
Authors: AIHARA MASAKAZU , KUBOTA NAOTO , KADOWAKI TAKASHI
Published: June 2018

To achieve intensive glucose control for avoiding diabetic complications, it is necessary for diabetic patients to measure their blood glucose levels frequently. However, all currently available methods for blood glucose monitoring, including the finger prick method, are invasive. One of the possible noninvasive glucose monitoring approaches is tear glucose monitoring. Previous studies have showed the correlations between blood and tear glucose concentrations. But these correlations were not accurate sufficiently because the methods for tear sample collection were not standardized. For clinical development of tear glucose monitoring as a tool for predicting the blood glucose concentrations, we recruited 10 nondiabetic subjects and 20 diabetic subjects, observed the daily blood and tear glucose dynamics using samples collected under the standardized method, and determined the correlation between the blood and tear glucose concentrations. Preprandial blood glucose levels of diabetic subjects were significantly higher than those of nondiabetic subjects (p < 0.001), and preprandial tear glucose levels of diabetic subjects had a higher tendency than those of nondiabetic subjects (p = 0.051). Two hours postprandial blood and tear glucose levels of diabetic subjects were significantly higher than those of nondiabetic subjects (p < 0.001, p < 0.05, respectively). The blood and tear glucose dynamics showed that the behavior of the tear glucose concentrations paralleled that of the blood glucose concentrations. A linear mixed model for diabetic subjects revealed the existence of a significant association between the blood glucose concentrations and tear glucose concentrations (p < 0.001), and the association consisted even after adjusting for HbA1c levels and conditions of meals.

In conclusion, tear glucose monitoring would be a tool for predicting the blood glucose levels noninvasively for various diabetic patients.

Disclosure

M. Aihara: None. N. Kubota: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.
A Novel, Nonenzymatic Strategy for Stable, Optical Glucose Detection in Small Volumes of Fluid
Authors: WANG BING , BAZAN GUILLERMO , PENNATHUR SUMITA , QUEENAN B.N. , SCIDA KAREN
Published: June 2018

The performance of any continuous glucose monitor (CGM) cannot exceed the performance of the underlying glucose sensor. Commercially available CGMs are built around the enzyme glucose oxidase. However, the performance of the enzyme is known to drift over time; accordingly, existing CGMs must be calibrated over periods of hours to days and replaced over periods of weeks. To overcome these fundamental limitations, we have developed a non-enzymatic glucose detection strategy that offers the promise of significantly improved stability and sensitivity. Specifically, we have designed and synthesized a water-soluble, molecular recognition element, which binds glucose with appropriate specificity and selectivity (Kd = 1.9 mM for glucose vs. Kd = 3.3 mM for fructose). The molecular recognition of glucose by our synthetic probes activates interactions between fluorescence-based reporters. Moreover, by coupling the recognition element with a light-harvesting molecular system with high optical cross-section, we are able to amplify optical signals that betray the presence of glucose, making it possible to carry out measurements in volumes as small as picoliters using off-the-shelf LEDs and photodetectors. Our detection platform also offers broad tunability: by altering the molecular recognition element and/or optical reporter we seek to achieve stable, optical detection of other sugars and biomarkers.

Disclosure

B. Wang: Research Support; Self; American Diabetes Association. G. Bazan: None. S. Pennathur: Stock/Shareholder; Self; Laxmi Therapeutic Devices. Research Support; Self; American Diabetes Association, JDRF. B. Queenan: Research Support; Self; American Diabetes Association. K. Scida: Research Support; Self; American Diabetes Association.
Costimulatory Molecules CD226 and TIGIT Impact CD8+ T-Cell Activity and Function during Type 1 Diabetes
Authors: YEH WEN-I , SEAY HOWARD , MATHEWS CLAYTON E. , BRUSKO TODD M.
Published: June 2018

Investigations into the pathogenesis of type 1 diabetes (T1D) implicate antigen interaction and co-stimulation as key pathways in disease development. A non-synonymous polymorphism in CD226 (rs763361), that encodes for a co-stimulatory molecule, has been linked to risk for T1D. The CD226 activating pathway is constrained by TIGIT, the high-affinity co-inhibitory receptor T cell immunoreceptor with Ig and ITIM domains, which competes with CD226 for ligands CD112/CD155. We have previously demonstrated that CD226 facilitates CD4+ T effector function, whereas TIGIT potentiates regulatory T (Treg) cell activity. Here, we report that both receptors impact CD8+ T cell pathogenesis. Both CD226 and TIGIT are upregulated upon human CD8+ T cell activation and are divergently expressed by memory CD8+ T cell subsets. These results support our finding in the positive correlation between age and CD226 or TIGIT expression (P=0.0002 and P<0.0001, respectively). Interestingly, TIGIT is co-expressed with the transcription factors T-bet and EOMES, whereas ∼80% of cytokine producing cells express CD226, demonstrating the coordinated expression of these factors with differentiated T cell lineages. We next sorted CD8+ T cells based on CD226 and TIGIT expression and assessed effector activity as well as gene expression profile following in vitro activation. Using a multiplex assay, we showed that CD226+ cells produced cytokines, chemokines, and cytolytic proteins (e.g., IFNγ, MIP-1α, granzyme B, and perforin) in a manner independent of TIGIT. Importantly, CD8+ T cell cytotoxicity to human β-cell line βLox5 that express high levels of ligands CD112 and CD155 is attenuated by blocking CD226 and enhanced by hindering TIGIT through a granzyme B dependent mechanism. These data support this co-stimulatory axis as a potential therapeutic pathway in T1D that could either attenuate CD226 co-stimulation of effector T cells, or inversely support tolerance induction by TIGIT signaling on Tregs.

Disclosure

W. Yeh: None. H. Seay: None. C.E. Mathews: None. T.M. Brusko: Stock/Shareholder; Self; OneVax, LLC. Advisory Panel; Self; Caladrius Biosciences, Inc.. Consultant; Self; Merck & Co., Inc., Sanofi-Aventis.
Preference Differences between Insulin Glargine and MK-1293 Pens among Patients with Diabetes and Certified Diabetes Educators
Authors: ALEMAYEHU BERHANU , DIBONAVENTURA MARCO , NGUYEN ALLISON M. , CRUTCHLOW MICHAEL
Published: June 2018

This study sought to develop and implement a usability/preference survey to compare the pen devices used with innovator insulin glargine and MK-1293 (Pen X). Type 1 and type 2 diabetes patients and certified diabetes educators (CDEs) in the U.S., Canada, and the UK were recruited from commercial panels. Several rounds of qualitative research with both groups were conducted to develop and refine the survey. Respondents were asked to perform two mock injections (into a cushion pad) for each of the two insulin pens. Pen order was randomized and after each set of injections, respondents completed the survey. Non-inferiority analyses were conducted to compare ratings of the pens as the primary analysis; two-tailed tests were also conducted. 296 respondents completed the study (177 patients and 119 CDEs). The mean age was 53.2 years for patients and 49.4 years for CDEs; 55.9% and 1.7% were male, respectively; 27.1% of patients were type 1 and 72.9% were type 2. Both patients (66.7%) and CDEs (58.0%) preferred Pen X overall. Individual ratings are reported in Table. The qualitative research results indicated our measure had appropriate content validity for assessing pen preferences. The main results suggested that the appearance and function of Pen X is non-inferior to the insulin glargine pen from the perspective of both patients and CDEs and, in many cases, superior.Table. Patients (N=177)CDEs (N=119)Rated insulin glargine pen higherRated both pens identicallyRated Pen X higherRated insulin glargine pen higherRated both pens identicallyRated Pen X higherOverall, this pen would be "easy to teach" my patients to use (CDEs only)------8.4%71.4%20.2%†Overall, this pen was “easy to learn” to use6.8%70.1%23.2%*12.6%67.2%20.2%†Selecting the correct dose each time with this pen was…(1=Difficult, 6=Easy)4.5%74.6%20.9%*8.4%69.7%21.8%*Pushing down the injection button/knob was…(1=Difficult, 6=Easy)8.5%57.6%33.9%*22.7%38.7%38.7%†The injection was smooth.13.6%57.6%28.8%*28.6%37.0%34.5%The instruction booklet is ‘user friendly’.4.0%34.5%61.6%*4.2%17.6%78.2%*Which pen would you prefer?21.5%11.9%66.7%*23.5%18.5%58.0%**p<.in non-inferiority and superiority analysis; †p<.only in non-inferiority analysis

Disclosure

B. Alemayehu: Employee; Self; Merck & Co., Inc. M. DiBonaventura: Employee; Self; Pfizer Inc.. Consultant; Self; Merck & Co., Inc. A.M. Nguyen: Employee; Self; Merck & Co., Inc. M. Crutchlow: Employee; Self; Merck & Co., Inc.. Consultant; Spouse/Partner; Novo Nordisk Inc., Zealand Pharma A/S, XOMA Corporation.
Decrease in Proportion of CD24hiCD38hi Beta Cells and Impairment of Their Regulatory Capacity in Type 1 Diabetes Patients
Authors: WANG YUESHU , WANG XING , QIN YAO , ZHANG MEI
Published: June 2018

Several studies have shown a subset of B cells play an important role in regulating the autoimmune response via the production of interleukin-10 known as B10 cells. However, the role of B10 cells in type 1 diabetes (T1D) and their relevance to the maintenance of peripheral tolerance in humans remains elusive. The aim of this study was to investigate the role of B10 cells in the pathogenesis of T1D. Peripheral mononuclear blood cells of 62 patients with T1D and 74 healthy volunteers were included. We showed that B10 cells in human peripheral blood belonged to a CD24hiCD38hi B cell subpopulation. Additionally, CD24hiCD38hi B cells from healthy individuals possessed regulatory capacity, inhibited IFN-γ, TNF-α and IL-17 production and promoted IL-4 production and Foxp3 expression of CD4+ T cells via an IL-10-dependent pathway. Compared with healthy controls, the proportion of B10 cells in patients with T1D was significantly lower (5.6±3.5% vs. 6.9±3.3%; P <0.05), produced less IL-10 (15.4±4.3% vs. 29.0±4.5%; P <0.001), and lacked the regulatory capacity. Pearson correlation analysis showed that the frequency of circulating B10 cells were negatively correlated with the frequency of CD4+IFN-γ+ and CD4+TNF-α+ T cells(r=-0.3and r=-0.360,P=0.037 and P=0.021, respectively), and positively correlated with the frequency of CD4+ CD25+ Foxp3+ T cells(r=0.018,P=0.001). There was also a negatively correlation between the frequency of circulating B10 cells and HbA1c(r=-0.339,P=0.010). These data provide direct evidence that there is a deficiency of circulating CD24hiCD38hi B cells in peripheral blood of patients with T1D, which might take part in the T1D immune imbalance, involved in the development of T1D.

Disclosure

Y. Wang: None. X. Wang: None. Y. Qin: None. M. Zhang: None.
Delivery of Low Basal Rates in Different Insulin Pumps—An Accuracy Evaluation
Authors: ZIEGLER RALPH , KAMECKE ULRIKE , WALDENMAIER DELIA , HAUG CORNELIA , FRECKMANN GUIDO
Published: June 2018

Insulin pumps are commonly used in the therapy of children with type 1 diabetes, among other reasons due to the flexible continuous delivery of low basal rates. The standard EN 60601-2-24 describes test settings and procedures for the evaluation of infusion pumps in general; however, no acceptance criteria related to insulin delivery accuracy are stipulated. Most manufacturers’ specifications are limited to the accuracy of basal rates ≥1 U/h, while far lower basal rates are common in children.

In this study, the accuracy of a 0.1 U/h basal rate delivery of different insulin pumps was evaluated in an experimental setting based on EN 60601-2-24. The insulin pumps Accu-Chek® Insight, Accu-Chek® Spirit Combo, Animas® Vibe®, MiniMed® 640G, Paradigm® Veo™ and mylife™ OmniPod® were tested with different infusion sets (IIS). Measurements were based on the determination of weight increase of water-filled, oil-covered beakers placed on balances into which insulin was delivered by the pumps. Pumps were installed outside of the balance with the infusion set or a steel pipe (for the patch pump), respectively, connected to the beaker. After priming, a basal rate of 0.1 U/h was run for 72 h while weight increases were recorded. Each combination of insulin pump and IIS was tested 9 times. The total and the mean delivery over 1-h windows were calculated.

Large differences in total delivery were observed between the tested systems (+4.1% to +24.4% of the expected). During the first 24 h, all deviations were >10% from the expected rate. Evaluation of 1-h windows showed that 31% to 80% of results were within ±15% of the weight increase expected with the set basal rate and large variations between the individual 1-h windows.

With the low basal rate tested in this study, delivery rates calculated from weight increases showed marked deviations from what was expected for this rate. When using insulin pumps in children with low insulin demands, it has to be considered that the basal rate might not be delivered as accurate and as consistent as expected.

Disclosure

R. Ziegler: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Sanofi-Aventis. Speaker's Bureau; Self; Animas Corporation. U. Kamecke: None. D. Waldenmaier: None. C. Haug: None. G. Freckmann: Speaker's Bureau; Self; Ascensia Diabetes Care. Research Support; Self; Ascensia Diabetes Care. Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Abbott, Novo Nordisk Inc.. Consultant; Self; Sensile Medical AG. Speaker's Bureau; Self; Ypsomed AG.
Meta-analysis vs. Single Trial (OpT2mise Study) Data to Assess Cost-Effectiveness of Simple CSII Devices in T2DM in the U.S.
Authors: WAHLQVIST PETER , WARNER JAY L. , PICKUP JOHN C.
Published: June 2018

Continuous subcutaneous insulin infusion (CSII) in T2DM improves HbA1c and reduces insulin dosage vs. multiple daily injections (MDI). However, for T2DM traditional CSII can be costly and overly sophisticated. Emerging evidence shows T2DM can be treated with limited numbers of fixed basal rates and simple bolusing (‘simple CSII’) e.g., PAQ®, a 3-day wearable device (CeQur Corporation, Marlborough, MA), as alternatives to traditional CSII. This analysis investigated cost-effectiveness in the U.S. of simple CSII vs. MDI in poorly controlled T2DM, assuming similar efficacy of traditional and simple CSII. The analysis used data from a systematic review of relationships between reduced HbA1c and increased life-expectancy and quality-adjusted life-years (QALYs). Relationships between baseline HbA1c and simple CSII vs. MDI HbA1c treatment difference were based on data from either a 5-trial meta-analysis or a large single trial (OpT2mise study). Incremental cost-effectiveness ratios of costs per QALY gained below 1xGDP per capita (2016: USD 57,467) were defined as ‘highly cost-effective’ and below 3xGDP as ‘cost-effective’. Using meta-analysis data, simple CSII devices can be cost-effective below a unit cost about $18, and below $26 per patient per day using OpT2mise data. In either case, simple CSII is potentially a highly cost-effective treatment option in poorly controlled T2DM.

Disclosure

P. Wahlqvist: Employee; Self; CeQur (Wales) Ltd. J.L. Warner: Employee; Self; CeQur Corporation. J.C. Pickup: Advisory Panel; Self; Medtronic, Roche Diabetes Care Health and Digital Solutions. Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions, CeQur Corporation. Consultant; Self; CeQur Corporation. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Medtronic. Speaker's Bureau; Self; Berlin-Chemie AG, Elsevier.
Characterization of T Cells Reactive to Hybrid Insulin Peptides in the Peripheral Blood of in Type 1 Diabetes Patients
Authors: BAKER ROCKY L. , DELONG THOMAS , GOTTLIEB PETER , HASKINS KATHRYN M.
Published: June 2018

We recently established, using the NOD mouse model, that hybrid insulin peptides (HIPs), formed spontaneously in islet beta-cells by fusion of insulin C-peptide fragments to peptides of Chromogranin A (ChgA) or Islet Amyloid Polypeptide (IAPP), are ligands for diabetogenic CD4 T cell clones. The goal of this study was to investigate whether HIP-reactive T cells were indicative of ongoing autoimmunity in human T1D patients.

To investigate their relevance to human disease, we used IFN-gamma ELISPOT to determine whether HIP-reactive T cells with an inflammatory phenotype were present in PBMCs of new onset T1D patients. We observed that PBMCs from new onset T1D patients responded to 8 of 16 HIPs tested and that nearly half of the patients tested responded to one or more HIPs.

We used a CFSE based assay to further characterize T cells reactive to HIP peptides. CD4+CFSEdimCD25+ T cells were sorted single into single wells using FACS and cloned. T cell clonality was confirmed using TCR deep sequencing and T cell reactivity to specific HIPs was confirmed by ELISA. A total of 6 T cell clones were isolated and show a variety of TCR usage. One T cell clone was isolated from the same patient on two different blood draws, indicating a high frequency of this T cell clone in the peripheral blood. While all the T cell clones isolated secreted IFN-gamma in response to HIPs, they also produced other inflammatory cytokines such as TNF-alpha and GM-CSF and reacted to HIPs in the low nanomolar range.

Our findings provide new evidence that HIP-reactive T cells are critical players in the pathogenesis of T1D and indicate that HIP-reactive T cells present in the peripheral blood can potentially serve as a biomarker of disease in a subset of patients.

Disclosure

R.L. Baker: None. T. Delong: None. P. Gottlieb: Advisory Panel; Self; Bristol-Myers Squibb Company. Research Support; Self; Caladrius Biosciences, Inc.. Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; ImmunoMolecular Therapeutics. Consultant; Self; Kamada. Research Support; Self; JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc., MacroGenics, Inc., Pfizer Inc.. Advisory Panel; Self; Viacyte, Inc.. Research Support; Self; GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.. K.M. Haskins: None.
Multiple Oral Insulin (ORMD-0801) Doses Elicit a Cumulative Effect on Glucose Control in T2DM Patients
Authors: ELDOR ROY , NEUTEL JOEL , HOMER KENNETH E. , KIDRON MIRIAM
Published: June 2018

Efforts to overcome the narrow therapeutic index of subcutaneously delivered insulin, have propelled the development of orally delivered alternatives. The enteric-coated ORMD-0801 oral insulin capsule has been shown to provide effective glucose control in both type 1 and type 2 diabetes patients. In this single-center, randomized, double-blind, placebo-controlled, three-way crossover study, 31 adult T2DM patients were treated with a placebo capsule during the first three days of three 1-week treatment periods, followed by five days of treatment with an oral placebo (n=31) or a 460 IU insulin capsule, delivered one (qd; n=20), two (bid; n=21) or three (tid; n=20) time per day. Run-in (Days 1-3) vs. treatment (Days 4-8) period continuous glucose monitoring (CGM) data were compared, as were pre- vs. post-treatment insulin and c-peptide levels. Patients were of a mean age of 57.5±7.8, and most were male (61.3%) and Caucasian (80.6%). Mean placebo-adjusted change from baseline in 24-hour glucose (all run-in days vs. all treatment days) ranged from -7.65 mg/dL for qd to -9.91 mg/dL for tid, with a more dramatic change observed in subjects with higher glucose (>190 mg/dL; n=17) at baseline (-12.44 mg/dL (qd) and -18.43 (tid)). Pre- vs. posttreatment and placebo vs. active treatment c-peptide and insulin ratios were similar across all regimens. ORMD-0801 was well tolerated and did not elicit any serious adverse effects. The vast majority of hyperglycemic events were recorded during placebo treatment (n=27), while hypoglycemic events were evenly distributed across treatment groups (≤5/group). Thus, multiple-dose ORMD-0801 regimens safely provide for improved glucose control, which is expected to be enhanced with more extended treatment. Its impact may be of particular benefit to patients uncontrolled by current drug regimens.

Disclosure

R. Eldor: Consultant; Self; Oramed Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Medtronic. J. Neutel: None. K.E. Homer: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc..
Impact of Switching from Twice-Daily Basal Insulin to Once-Daily Insulin Glargine 300 U/mL (Gla-300) in Patients with Type 1 Diabetes (T1DM)—Phase 4 OPTIMIZE Study, Belgian Cohort
Authors: MATHIEU CHANTAL , STELLA PETER , BRUHWYLER JACQUES , ALEXANDRE KATHY
Published: June 2018

The 28-week, prospective, multicenter, open-label OPTIMIZE study, conducted in Belgium and Canada, evaluated treatment optimization with once-daily (OD) Gla-300 in combination with a prandial rapid-acting insulin analog in adults with T1DM previously uncontrolled (HbA1c 8-10%) on twice-daily (BID) basal insulin as part of basal-bolus therapy.

The intent-to-treat (ITT) and safety populations of the Belgian cohort comprised 48 patients (52.1% women); mean (SD) age 51.7 (12.8) years and mean (SD) body mass index 28.2 (4.9) kg/m². Prior to the study, 37.5% were on insulin glargine 100 U/mL and 62.5% were on insulin detemir. There was a statistically significant reduction in HbA1c from baseline to month 6 (primary endpoint, p<0.0001). No significant changes were observed in basal or prandial insulin dose, or in total or nocturnal hypoglycemic event rates. Statistically significant improvements were seen in the Diabetes Treatment Satisfaction Questionnaire (DTSQ) total and perceived hyperglycemia scores (p<0.05) (Table), and in the patient satisfaction score for number of injections (p=0.004).

Switching from a BID basal insulin analog to OD Gla-300 in this challenging T1DM population was associated with a statistically significant improvement in HbA1c levels and better overall treatment satisfaction.

Disclosure

C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott. P. Stella: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Bruhwyler: Other Relationship; Self; Sanofi. K. Alexandre: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi.
Patient Input for Design of a Type 1 Diabetes (T1D) Decision Support Smartphone Application
Authors: WILSON LEAH M. , GABO VIRGINIA , TYLER NICHOLE S. , REDDY RAVI , JACOBS PETER G. , CASTLE JESSICA R.
Published: June 2018

The complexity of T1D results in inadequate glucose control for patients which can lead to acute and chronic complications. We are developing a decision support smartphone application (app) for patients using multiple daily injection (MDI) therapy and continuous glucose monitoring (CGM). This app will use glucose trends, insulin dosing, and physical activity to provide recommendations for titration of insulin dosing to improve glycemic control.

We performed an online survey of patients age 18-80 with T1D from a diabetes specialty clinic, targeting MDI users, to determine current needs and preferences of candidates for decision support tools. Twenty-seven respondents are included in the analysis: mean age of 39.4 years, 54% female, 17.5 years mean duration of T1D, 89% use MDI. A total of 41% of respondents used CGM 50-100% of the time with all checking their CGM >6 times per day. Over 90% use a smartphone, 88% have the phone with them 75-100% of the time. Only 19% used an app to calculate insulin doses, while 81% were interested in using an app to manage diabetes.

Participants wanted the following features in a decision support app: hypoglycemia avoidance (89%), insulin dose calculation (78%), behavioral change suggestions (74%), predicted glucose trends (70%), and insulin-on-board (70%). Many expressed low confidence in their ability to manage glucose during exercise (51%). Most respondents were interested in viewing predicted glucose trends prior to exercise (85%). Preferences about alerts to improve glucose control were varied with 44% saying they would be comfortable with 1-3 alerts per day. Preferences about alerts for predicted hypoglycemia were also varied; 11% would want to be alerted 5 minutes prior, 19% 15 minutes, 44% 30 minutes, and 26% >1 hour.

These survey results confirm the need for and interest in a smartphone-based decision support app that will assist with management of T1D. The results will enable intelligent app design to better meet the needs of end users.

Disclosure

L.M. Wilson: None. V. Gabo: None. N.S. Tyler: None. R. Reddy: None. P.G. Jacobs: Stock/Shareholder; Self; Pacific Diabetes Technologies. J.R. Castle: Consultant; Self; Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk Inc..
Late and Missed Meal Boluses with Multiple Daily Insulin Injections
Authors: NORLANDER LISA M. , ANDERSON STACEY , LEVY CAROL J. , EKHLASPOUR LAYA , LAM DAVID W. , HSU LIANA , LOEBNER SARAH E. , OGYAADU SELASSIE J. , O'MALLEY GRENYE , LEVISTER CAMILLA M. , BRETON MARC D. , BUCKINGHAM BRUCE
Published: June 2018

Background: Using sensor augmented pump data, late or missed meal boluses have shown a strong correlation with higher A1c levels, particularly in adolescents. With the Type Zero InControl Phone connected to a Dexcom G5 sensor and Novo insulin pens with memory and connectivity it is now possible to evaluate for late and missed meal boluses in MDI users.

Methods: For this study 326 days of CGM data were evaluated from 24 subjects (mean age 33, range 15-59 years). Seven days of data were analyzed on starting the system and 7 days 1 month later. Overall 1,173 meals were evaluated. Meals were determined by either the subject manually recording the meal, or if the CGM was >70 mg/dl and there was a >70 mg/dl rise within 2 hours. A late meal bolus was defined when the CGM increased >50 mg/dl from baseline prior to an insulin dose. A missed meal bolus was defined by no insulin dose within 2 hours from the start of the CGM rise.

Results: 27% (range 8 to 55%) of meals had either a late or missed meal boluses: 13% (range 2-30%) were late and 14% (range 2 to 38%) were missed. There was no correlation with age or gender. There was a positive correlation with the percentage of missed meal boluses and A1c levels (p=0.019), but no correlation with the percentage of late meal boluses and A1c levels. There were no significant differences in missed or late meal boluses when comparing the first week of use to using the system one month later.

Conclusion: The rate of late or missed meal boluses is high for both adults and adolescents using MDI therapy, and missed meal boluses correlated with higher A1c levels. Having this information may provide significant insight to patients and help clinicians provide advice to MDI patients.

Disclosure

L.M. Norlander: None. S. Anderson: Research Support; Self; Medtronic. Consultant; Self; Senseonics. C.J. Levy: Advisory Panel; Self; Medtronic MiniMed, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Dexcom, Inc.. L. Ekhlaspour: None. D.W. Lam: None. L. Hsu: None. S.E. Loebner: None. S.J. Ogyaadu: None. G. O'Malley: None. C.M. Levister: None. M.D. Breton: Stock/Shareholder; Self; TypeZero Technologies, Inc.. Speaker's Bureau; Self; Ascensia Diabetes Care. Consultant; Self; Sanofi. Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Dexcom, Inc., Ascensia Diabetes Care, Senseonics. 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.
Beta-Cell Function Improved in Insulin Deficient Type 2 Diabetics and Insulin Sensitivity Improved in Insulin-Resistant Type 2 Diabetics during Long-Term Insulin Pump Therapy
Authors: CHOI SOO BONG , HONG EUN SHIL , NOH YUN HEE
Published: June 2018

We wanted to investigate the changes in beta cell function and insulin sensitivity during long-term CSII therapy in patients with type 2 diabetes (T2D) up to for 3 years. We discontinued oral antidiabetic drugs and applied CSII therapy to T2D patients (number, 110 with 64% of male; age, 59.9 ± 9.1 years; duration, 12.0 ± 9.2 years; HbA1c 8.9 ± 2.0%; BMI 23.5 ± 2.5 kg/m2). Blood samplings were performed yearly for 3 years at overnight fasting and 120 minutes after ingestion of a standard mixed meal (500 kcal). Serum C-peptide, glucose, and HbA1c were measured, and Matsuda Index (MI) were calculated. The patients were grouped into high MI (insulin sensitive group) and low MI (insulin resistant group) groups by the mean value of baseline MI. Mean HbA1c decreased significantly from 8.9% to 6.5% and there was no difference in glycemic control between the two groups. In insulin sensitive group, mean serum C-peptide increased significantly during CSII therapy. In contrast, mean serum C-peptide did not change but mean MI increased significantly in insulin resistant group (Fig. 1).

In conclusion, by the physiological delivery of insulin using insulin pumps, the two main pathophysiologies of T2D, either insulin deficiency or insulin resistance, seemed to be corrected, respectively.

Disclosure

S. Choi: Stock/Shareholder; Self; SOOIL Developments Co., Ltd.. E. Hong: None. Y. Noh: None.