bluuebunny/crossref_metadata_2025 huggingface dataset:
STIM1/Orai1 Inhibition Reduces Store-Operated Ca2+ Entry and Modulates a-Cell Glucagon Secretion
Authors: ALTMAN MOLLY K. , DADI PRASANNA , JACOBSON DAVID
Published: June 2018

In type 2 diabetic patients glucagon secretion becomes dysregulated under elevated glucose conditions worsening hyperglycemia. However, the mechanisms of glucose inhibition of glucagon secretion remain incompletely understood. Therefore, we sought to uncover the glucose dependent mechanisms that modulate pancreatic α-cell glucagon secretion. One mechanism that regulates α-cell Ca2+ influx in a glucose dependent manner is store-operated Ca2+ entry (SOCE). Therefore, in our studies we used a small molecule (AnCoA4) that inhibits the STIM1/Orai1 protein interaction and prevents store-operated Ca2+ channel activation. In whole mouse islet α-cells inhibition of SOCE with AnCoA4 reduced Ca2+ influx in 1 mM glucose (8.4% ± 1.1%). We went on to test the influence of SOCE on glucose modulation of glucagon secretion, in 1 mM glucose AnCoA4 reduced glucagon secretion in mouse pancreatic islets (53.5% ± 11%). However, there was no significant change in glucose inhibition of glucagon secretion by inhibition of SOCE at 11 mM glucose. To follow-up on this, we used transgenic mice without STIM1 in α-cells and showed that AnCoA4 does not influence Ca2+ fluctuations in knockout islet α-cells. This proves in our hands that AnCoA4 works selectively. Additionally, we used transgenic GCAMP3 mice without STIM1 in α-cells for whole islet confocal studies to measure SOCE in 1 mM and 11 mM glucose conditions. We found that in whole islet α-cells without functional STIM1, Ca2+ influx due to SOCE was reduced in 1 mM glucose. Next, we wanted to test this molecule in human islet calcium homeostasis studies. Human dispersed α-cells show inhibition of SOCE with AnCoA4 treatment in 1 mM glucose conditions. Thus, our findings identify that inhibition of STIM1/Orai1 reduces SOCE in low glucose conditions leading to decreased α-cell glucagon secretion.

Disclosure

M.K. Altman: None. P. Dadi: None. D. Jacobson: None.
Impact of Past and Current Smoking on Mortality Risk in Angiographied Coronary Patients with Type 2 Diabetes
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN DANIELA , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2018

The impact of smoking on mortality risk in angiographied coronary patients is unclear and is addressed in the present study. We enrolled 1804 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable coronary disease (CAD). Patients who had smoked within 30 days prior to angiography were considered current smokers. Prospectively, mortality was recorded over a mean follow-up time of 7.6±2.8 years. At baseline, both in patients with T2DM (n=522; 28.9% of the study cohort) and in nondiabetic subjects the prevalence of a past (44.1 and 39.5%; p=0.035) and, albeit less so, of current smoking (18.0 and 17.7%; p = 0.247) was high. Prospectively, current smoking independently predicted cardiovascular events after multivariate adjustment including baseline CAD in patients with diabetes (HR 1.78 [1.16-2.74]; p=0.009) as well as in nondiabetic patients (HR 1.68 [1.12-2.52]; p=0.013), whereas past smoking neither in patients with T2DM nor in nondiabetic subjects was associated with cardiovascular events (HRs 0.77 [0.54-1.10]; p=0.152 and HR 1.16 [0.87-1.53]; p=0.313, respectively). An interaction term diabetes x current smoking was not significant (p=0.564), indicating that current smoking was equally predictive of mortality in patients with T2DM and in nondiabetic subjects. We conclude that current but not past smoking strongly increases mortality risk angiographied coronary patients with T2DM independently from the baseline CAD state.

Disclosure

C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin: None. B. Larcher: None. A. Mader: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
Hyperbaric Oxygen Therapy Is Associated with Improved Six-Year Survival in People with Chronic Diabetic Foot Ulcers
Authors: LONDAHL MAGNUS , FAGHER KATARINA , NILSON ANDERS , KATZMAN PER
Published: June 2018

Both micro- and macrovascular components probably mutually contribute to the increased mortality in people with diabetic foot ulcers (DFU). We have previously shown that QTc-time is an important risk factor for mortality and that hyperbaric oxygen therapy (HBO) seems to reduce QTc-time prolongation. The aim of this study based on our randomized clinical trial was to evaluate the effect of HBO on 6-year survival in people with hard-to-heal DFU as well as a possible relation to QTs-time on survival.

Methods: People with DFU of ≥3 months duration without any indication or possibility of vascular surgical intervention were randomized to either HBO (2.5 ATA, 90 minutes) or hyperbaric air (Ctrl) treatment. Only those who fulfilled the pre-specified criterion of completing at least 36 out of 40 treatments sessions were included in the evaluation.

Results: No statistical differences in baseline characteristics were seen between groups. The 6-year survival was 58% (22/38) in the HBO, and 35% (13/37) in the Ctrl group (LogRank p<0.048). Survival in those with a baseline QTc-time > 420 ms are given in Figure 1. In a Cox Regression analysis including treatment allocation, presence of coronary heart disease and age, only treatment allocation was a statistically significant factor associated with survival (p=0.038).

Conclusion: HBO might be associated with improved 6-year survival in people with chronic DFU.

Disclosure

M. Londahl: Speaker's Bureau; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; ReApplix AS. K. Fagher: Speaker's Bureau; Self; AstraZeneca, Sanofi, Novo Nordisk A/S, Merck Sharp & Dohme Corp. A. Nilson: Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. P. Katzman: None.
Early Hospitalization for Diabetes Care Improves Glycemic Control in Patients with Type 2 Diabetes Reserved Insulin Secretion
Authors: IKEDA DAISUKE
Published: June 2018

Background and Aims: In Japan, early hospitalization for diabetes care is widely diffused, and keeps glycemic control good for the long term through intensive diabetes education in the short term. In recent years, new classes of antidiabetes medicine have been launched. Glycemic control in patients with type 2 diabetes, especially reserved insulin secretion, becomes easier. We aimed to know whether recent early diabetes hospitalization is still work for glycemic control of type 2 diabetes patients reserved insulin secretion.

Methods: Japanese type 2 diabetes patients ware without medication, with HbA1c >8.0 in their first visit and with good insulin secretion (δCPR >2.0 in glucagon stimulation test) within 3 months. Their first visits ware from April 2012 to Oct 2017 We retrospectively compared between 36 patients with early hospitalization and 35 patients without hospitalization. In our diabetes hospitalization, patients get a diabetes education. Most patients are canceled glucose toxicity by insulin and then changed any other applicable antidiabetic medicines without insulin possible.

Results: At baseline, HbA1c of patients in early hospitalization group was higher than no hospitalization group (11.6±1.9%, 10.3±1.4%, p=0.002). δCPR was no significant difference. HbA1c of early hospitalization group was lower than no hospitalization group over 3years(1y: 6.4±0.8%, 7.4±1.1%, p<0.001, 2y: 6.5±0.8%, 7.3±0.9%, p=0.008, 3y: 6.2±0.6%, 7.5±0.8%, p<0.001). Numbers of diabetic medicine classes in early hospitalization group ware smaller than no hospitalization group after 2 years (1.8±0.8, 2.5±0.9, p=0.010). Two patient in early hospitalization group interrupted to visit our hospital, although 9 patients in no hospitalization group.

Conclusion: Diabetes hospitalization is still one of very effective therapeutic method today. Education and earlier glycemic control may contribute to keep glycemic control good over a long lifetime.

Disclosure

D. Ikeda: None.
Comparison of Disparities between FGM/CGM Sensor Glucose Values and Blood Glucose Values in Type 2 Diabetic Patients Admitted for Glycemic Control
Authors: TANIZAWA MIKA , TAKAHASHI HIROSHI , MORI YUTAKA , UTSUNOMIYA KAZUNORI
Published: June 2018

Objective: The disparities were compared between flash glucose monitoring (FGM) sensor glucose (SG) values and SMBG blood glucose (BG) values vs. between continuous glucose monitoring (CGM) SG values and BG values to establish the accuracy of FGM SG values.

Methods: CGM (CGMS-Gold, Medtronic Minimed) and FGM (FreeStyle Libre Pro; Abbott Japan) were simultaneously put in place in 16 type 2 diabetic patients admitted for glycemic control (BMI, 28.7 ± 5.2 kg/m2; HbA1c, 9.8 ± 2.1%). SMBG BG values at 500 time points registered on CGMS-Gold for calibration purpose and CGM/FGM SG values at the same time points, were selected to examine the accuracy of FGM SG values. Both these devices were evaluated for accuracy in terms of 1) simple correlation coefficients between CGM/FGM SG values and BG values; and 2) mean absolute relative differences (MARD) in SG values of CGM/FGM relative to BG values as reference.

Results: 1) A strong positive correlations were found between the SMBG BG values and CGM/FGM SG values (r = 0.9462, p < 0.001 / r = 0.8797, p < 0.001). 2) The MARD in CGM/FGM SG values were 6.53 ± 6.35% (0-47.3%) / 10.35 ± 9.64% (0-65.5%), and the frequency of MARD showing 10% or less accounted for 79.0% of all CGM SG values, and 58.2% of all FGM SG values. The relationship between the MARD in CGM/FGM SG values and the durations of CGM/FGM put in place showed that while the MARD in CGM SG values was nearly constant, the MARD in FGM SG values varied from day to day. Again, the relationship between MARD in CGM/FGM SG values and BG value showed that while the MARD in CGM SG values remained constant, irrespective of BG values, the MARD in FGM SG values tended to increase with decreasing BG values. Additionally, the disparity between the FGM SG values and the BG values varied greatly depending on the individual patient.

Conclusions: Despite being an innovative device for glucose monitoring, FGM may be appropriately positioned as an adjunct, but not an alternative, to SMBG.

Disclosure

M. Tanizawa: None. H. Takahashi: None. Y. Mori: None. K. Utsunomiya: None.
Controlled Release of Insulin Granules from PLGA Microparticles for Glucose Modulation in Diabetes
Authors: PRIMAVERA ROSITA , MAGNONE MIRKO , MASCOLO DANIELE DI , ZOCCHI ELENA , PASCALE ANGELO DE , DECUZZI PAOLO
Published: June 2018

Diabetes is a chronic disease deriving from the insufficient production or utilization of insulin. So far, the treatment of diabetes relies on the daily subcutaneous injection of insulin. However, this approach suffers of poor patient compliance and fluctuations in blood glucose levels that increases the risk of hypoglycemia, cardiovascular disease, non-healing wounds and other comorbidities. In this work, a delivery system is proposed for the controlled release of insulin and regulation of glycaemia. Nanoscale granules of insulin were synthesized and encapsulated within the porous matrix of PLGA microparticles (i-μPLs). The granules were obtained with an accurate crystallization process returning spherical nanoparticles with a diameter of 209.9±15.8 nm. μPLs were prepared via a top-down approach resulting in 20 x 5 μm square microparticles, made out of a biodegradable polymer - poly(lactic-co-glycolic acid) (PLGA) - which is already used in clinical applications. In vitro studies were conducted on different cells, including macrophages, fibroblasts and endothelial cells, and confirmed the safety and biological activity of i-μPLs. After insulin stimulation, phosphorylated AKT at Ser473 was assessed in cell lysate using a commercial kit (In-Cell ELISA): i-μPL activity was comparable to that of free, commercial insulin. As preliminary in vivo studies, i-μPLs (0.25 U) or empty μPLs (control) were implanted in the spleen of mice. Twenty-four hours post implantation, fasted mice underwent an oral glucose tolerance test (1 g glucose/Kg body weight). In i-μPL treated mice, the mean blood glucose level was lower as compared to controls at time zero (before gavage) and at 15, 30, 60 and 120 min. Consequently, the glycaemia AUC was reduced in i-μPLs-treated vs. control mice (17828±1527 vs. 20543±413, p=0.06). This preliminary data would suggest that i-μPLs could be effectively used to modulate glucose content in diabetes.

Disclosure

R. Primavera: None. M. Magnone: None. D. Di Mascolo: None. E. Zocchi: None. A. De Pascale: None. P. Decuzzi: None.
Effects of Linagliptin on Endothelial Function and Global Arginine Bioavailability Ratio in Coronary Artery Disease Patients with Early Diabetes
Authors: ABERER FELIX , TRIPOLT NORBERT J. , URL JASMIN , HÖDL RONALD , DIMSITY GUDRUN , AZIZ FAISAL , RIEDL REGINA , HAFNER FRANZ , STRUNK DIRK , STOJAKOVIC TATJANA , BRODMANN MARIANNE , SOURIJ HARALD
Published: June 2018

Aims: To investigate the effects of the DPP-4 inhibitor Linagliptin in subjects with coronary artery disease (CAD) and early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements.

Materials and Methods: In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2h glucose >200mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy, HbA1c<75mmol/mol) and established CAD. Participants were randomized to receive either Linagliptin (5mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD).

Results: We investigated 43 patients with a mean age of 6±8 years. FMD at baseline was 3.5±3.1% in the Linagliptin group vs. 4.0±2.9% in the placebo group. The change in mean FMD in the Linagliptin group (0.4±4.8%) was not significantly different compared to the change in the placebo group (-0.45±3.01%; p=0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR); p=0.6and AOR; p=0.549), body weight, blood pressure and lipid parameters. Of note, HbA1c was significantly reduced in the linagliptin group (-1.5 vs. -0.4; p=0.026).

Conclusion: Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or GABR.

Disclosure

F. Aberer: None. N.J. Tripolt: None. J. Url: None. R. Hödl: None. G. Dimsity: None. F. Aziz: None. R. Riedl: None. F. Hafner: None. D. Strunk: None. T. Stojakovic: None. M. Brodmann: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..
Trends in Insulin Therapy—A1C and Age at the Time of Insulin Initiation in the Real-World Setting
Authors: KOVIL RAJIV , CHAWLA MANOJ S. , CHAWLA PURVI M. , KOTHARI MIKHIL C. , SHAIKH AMBARI F.
Published: June 2018

Majority of T2DM patients will eventually require insulin; yet not much is known about the trends and type of insulin choice for initiation in different geographies. We analyzed databases at two specialized diabetes care centers in urban India and identified patients initiated on insulin. A total of 673 eligible patients [males (N= 342), females (N=331)]initiated on insulin during the period of Jan to Dec 2017, were analyzed. Among trends observed, there was a predominant usage of premix insulin for initiation as compared to basal insulin (4.96:1),indicating the physician preference.

Results are presented in the Table. Patients in two groups, receiving basal insulin and premix insulin were further divided on the basis of age into sub-groups of less than 60 years and more than 60 years. In the premix insulin group, a statistically significant difference in the A1C levels at initiation was observed in between the age groups defined earlier [Mean A1C in < 60-year group was 9.5% vs. 9.2% in > 60-year group, p = 0.03.] High A1C at initiation reflects the physician-patient inertia in insulin initiation, despite several guidelines recommending early insulinization. Although our study has the limitation of being a two-center evaluation, the utilization pattern reflects a delay in insulin initiation and predominant premix insulin usage in the Indian population, in view of the high carbohydrate content of the Indian diet.

Mean Age and A1C at Insulin Initiation in Different GroupsMean ± SD95% CIMin, MaxAge (years) at Premix Initiation (N=560)57 ± 1356-5817, 86Age (years) at Basal Initiation (N=113)57 ± 1454-5918, 82Mean Age at Initiation (N=673)57 ± 1356-5817, 86HbA1c (%) at Premix Initiation (N=560)9.4 ± 1.89.2-9.54.1, 16HbA1c (%) at Basal Initiation (N=113)9.8 ± 1.89.5-106.4, 15Mean A1C at Initiation (N=673)9.5 ± 1.89.3-9.64.1, 16

Disclosure

R. Kovil: Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., MSD Pharmaceuticals Pvt. Ltd. M.S. Chawla: Speaker's Bureau; Self; IPCA Laboratories, Eli Lilly and Company, Novo Nordisk A/S, MSD Pharmaceutical Pvt. Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Spouse/Partner; Sanofi. P.M. Chawla: Speaker's Bureau; Self; Sanofi. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, IPCA LABORATORIES, Novo Nordisk A/S, MSD PHARMACEUTICALS PVT. LTD., Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. M.C. Kothari: None. A.F. Shaikh: None.
Refractory Nighttime Hypoglycemia in a Toddler—What Happens When Long-Acting Insulin Is Accidentally Used in a Pump?
Authors: BENITEZ SARA G. , MERJANEH LINA
Published: June 2018

Background: Hypoglycemia is the most common complication of type 1 diabetes (T1D) in children. Hypoglycemia prevents optimal glycemic control and can have deleterious effects on the developing brain.

Clinical Case: A 2-year-old female was diagnosed with T1D and started on an insulin regimen of detemir and lispro. At age 3, she was transitioned to a Medtronic 530 G insulin pump and Enlite continuous glucose monitor. For 7 months, she had stable insulin requirement without significant issues. Thereafter, the family started reporting severe nighttime hypoglycemia and daytime hyperglycemia. Overnight basal rates were decreased gradually to zero with persistence of hypoglycemia despite being fed continuously at night. Daytime insulin doses were increased with dose exceeding 0.9 u/kg/day with persistence of hyperglycemia and worsening of Hba1c. After one year, it was determined that the abnormal patterns were due to using detemir instead of lispro in the pump. This explains why the high doses given during the day did not lower the blood sugars but their effects were seen hours later causing refractory hypoglycemia at night.

Conclusion: We report refractory nighttime hypoglycemia in a toddler with T1D that is due to using long acting insulin in the pump. Clinicians should be aware of this possibility. Using only short acting insulin in the pump should be emphasized to patients and their families.

Disclosure

S.G. Benitez: None. L. Merjaneh: None.
Change in Glucose Levels during Pregnancy and Parturition in Normoglycemic Women Indicated by Flash Glucose Monitoring System
Authors: NISHIMURA AKIKO , FURUTA MARIE , CHIGUSA YOSHITSUGU , MAENO MIKA , FUKAMI MADOKA , HARASHIMA SHINICHI
Published: June 2018

Accurate knowledge of changes in plasma glucose levels during pregnancy and parturition in normoglycemic women is important for safe management of hyperglycemic disorders in pregnancy. However, there are few reports showing long-term changes in glucose levels over the entire pregnancy period. Flash glucose monitoring (FGM) is a new sensor technology that enables us to ascertain these glucose levels. This is the first study in Japan to monitor glucose levels during this period in normoglycemic, pregnant women by using FGM, which was performed once in non-pregnant women and up to 5 times (first trimester, second trimester, third trimester, parturition, and 3-month postpartum) in pregnant women. Twenty-one non-pregnant women and 9 pregnant women participated in the study. In non-pregnant women, the average age and BMI were 34.4±9.1 years and 20.4±1.5 kg/m2, respectively; the average glucose level was 101.9±20.8 mg/dL, with no difference in age groups. In pregnant women, the average age and BMI were 33.0±2.7 years and 19.0±1.4 kg/m2, respectively. The average glucose levels were 99.8±5.0 mg/dL at first trimester, 85.1±13.0 mg/dL at second trimester, 92.0±7.6 mg/dL at third trimester, 107.3±8.1 mg/dL during parturition, and 95.7±10.0 mg/dL at 3-month postpartum. Compared to glucose levels of non-pregnant women, those of pregnant women were significantly lower at second and third trimester, and returned to the same level at 3-month postpartum. The glucose level during parturition was significantly highest; the proportion of time to achieve optimal target glucose level of 80-110 mg/dL was 62.3±19.9% and the highest value was 244 mg/dL. Maternal and neonatal clinical courses were uneventful in all pregnant cases. It is thus necessary to evaluate to what extent peak value and duration of hyperglycemia affects birth outcome.

Disclosure

A. Nishimura: None. M. Furuta: None. Y. Chigusa: None. M. Maeno: None. M. Fukami: None. S. Harashima: Advisory Panel; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Sanofi K.K.. Research Support; Self; Sanofi K.K.. Speaker's Bureau; Self; Tanabe Mitsubishi KK. Advisory Panel; Self; Tanabe Mitsubishi KK. Speaker's Bureau; Self; Novartis Pharma K.K., Eli Lilly and Company, Ono Pharmaceutical Co., Ltd..
Evaluation of 24-Hour Blood Pressure and Arrhythmias through Simultaneous Ambulatory Blood Pressure Monitoring and Holter Monitoring in Type 2 Diabetes Mellitus Patients with Hypertension
Authors: REDKAR VIVEK , REDKAR SAGAR , REDKAR SUPRIYA , INAMDAR ANIKET , INAMDAR MANOHAR , RANE SHRADDHA , KHANOLKAR DARSHAN , JAGTAP MOHAN , YERALKAR DISHA , WADHWA NAVNEET
Published: June 2018

We studied 1200 (Males=868, Females =332) hypertensive, T2DM hospitalised for 24 hours to analyse the association of hypertension and arrhythmias simultaneously for three years (January 2015-December 2017), as part of the PREDICT protocol, a mixed methods approach, developed as a standard care of management at three tertiary care hospitals. We used Trillium 3000 Holter recorder (Forest Medical) and DynaPulse 5000A Ambulatory Blood Pressure monitoring (ABPM) and the Trillium Gold software, respectively for the recording and the data analysis. ANOVA, Graphpad was used for statistical analysis. The mean age was 51.2 ± 7.9 years (range 41-82 years). The tertile in the triad of age > 60 years, duration of diabetes > 20 years and HbA1c > 11% had the highest incidence of arrhythmias (p<0.0001). The socioeconomic status was high in 401 patients (43%), middle income in 436 (36.3%) and low income in 363 cases (30%). The commonest risk factors were sedentary lifestyle (64%), obesity (56%), dyslipidemia (37%), smoking (23%), sleep apnea (21%). The mean 24-hour BP was 143 ± 12 mmHg for the SBP and 92.6 ± 12.2 mmHg for DBP. The awake and asleep BP mean were respectively 147 ± 11 mmHg and 137 ± 13.7 mmHg for SBP, 89.5 ± 10.2 and 83.1 ± 8.9 mmHg for DBP. Arterial pressure variability and bradyarrhythmia were significantly associated with sleep apnea (p<0.0001). Patients with ST-T wave depression > 1 mm (26%) and tachycardia (31%) as a sub-group were significantly associated with both the reverse dippers and non-dippers. (p<0.0001). Chronotherapy in concurrence with the circadian rhythm to reduce the side effects, optimise the dosage, reduce the pill burden would be a suitable option to achieve a better BP control in T2DM. Nocturnal anti-hypertensive dosing to target the nocturnal hypertension would be an appropriate management approach.

Disclosure

V. Redkar: None. S. Redkar: None. S. Redkar: None. A. Inamdar: None. M. Inamdar: None. S. Rane: None. D. Khanolkar: None. M. Jagtap: None. D. Yeralkar: None. N. Wadhwa: None.
Timing of CGM Initiation in Pediatric Diabetes—The CGM TIME Trial
Authors: LAWSON MARGARET L. , COURTNEY JENNILEA , BRADLEY BRENDA J. , MCASSEY KAREN , CLARSON CHERIL , KIRSCH SUSAN E. , CURTIS JACQUELINE , MAHMUD FARID H. , RICHARDSON CHRISTINE , COOPER TAMMY , TANG KEN ,   THE CGM TIME TRIAL STUDY GROUP, JDRF CANADIAN CLINICAL TRIAL NETWORK CCTN1101
Published: June 2018

Background: The impact of timing of CGM initiation in pump naïve pediatric patients on CGM adherence and hemoglobin A1C remains unclear.

Methods: A 5-site RCT of pump naïve subjects (aged 5-18 years) with type 1 diabetes (T1D) > 1 year was conducted to compare simultaneous pump and CGM (“SIM” group) vs. standard pump therapy with CGM initiation delayed for 6 months (“DEL” group). A step-wise approach to CGM settings was used. Primary outcome was CGM adherence (hours per 28 days (MiniMed™ Veo™ system and CareLink Professional use)) assessed over six months after CGM initiation. The main secondary outcome, A1Cs, was measured centrally at baseline and every 6 months. Linear mixed-models and ordinary least squares models were fitted to further estimate the effect of intervention, and covariates of baseline age, T1D duration, and A1C, as well as gender and clinical site.

Results: We randomized 144 of 152 (95%) eligible subjects into the SIM or DEL intervention. Five (3 SIM, 2 DEL) withdrew before visit 1 and 1 (DEL) a week after pump start, with 70 SIM, 68 DEL eligible for analysis. Baseline mean age was 11.5±3.3(SD) years, T1D duration 3.4±3.1 years, and A1C 7.9±0.9% (range 5.5-11.2%). During the 6th month, median CGM adherence was 485.6 hours (95% CI: 229.5, 585.7) in SIM vs. 408.2 (95% CI: 134.9, 572.8) in DEL, with this difference in adherence translating into an additional 2.8 hours of CGM per day. Median 6-month A1C was 7.9 [IQR: 7.5, 8.4] for SIM vs. 7.8 [IQR: 7.4, 8.4] for DEL. Fitted models suggest those randomized to SIM had better CGM adherence (main effect = 74.4 [95% CI: 26.8, 121.9], p=0.002), with higher adherence among females (p=0.03). Overall, there was no difference in A1C 6 months after CGM initiation (-0.20 [95% CI: -0.45, 0.06], p=0.13).

Conclusion: CGM adherence was higher when initiated at the same time as pump therapy however there was no significant effect on A1C. More research is required to understand why CGM did not have an effect on A1C and examine how CGM may affect other measures of glycemic control.

Disclosure

M.L. Lawson: None. J. Courtney: None. B.J. Bradley: None. K. McAssey: None. C. Clarson: None. S.E. Kirsch: None. J. Curtis: None. F.H. Mahmud: None. C. Richardson: Advisory Panel; Self; Dexcom, Inc.. T. Cooper: None. K. Tang: None.
Diabetes Risk in Women Employees (DRIWE)—An Institution-Based Screening Model Detects High Prevalence of Women Employees at Risk of Type 2 Diabetes
Authors: SANKAR PRASANTH , SASIKUMAR PRIYANKA , MEDAYIL RITUNA , JACOB RITTIN , SASIDHARAN SARANYA
Published: June 2018

Background: Office employed women are exposed to unhealthy lifestyle. Indian Diabetes Risk Score (MDRF-IDRS) is a well validated method for detection of undiagnosed diabetes in the community.

Aim: To assess prevalence of diabetes risk among women employees, using MDRF-IDRS.

Methodology: A cross sectional study was done among 326 women employees in a semi urban hospital in South India to screen for risk factors for diabetes including age, waist circumference (WC), family history of diabetes (FH) physical activity (PA), gestational diabetes (GDM) and menopausal status. Those with high risk score (IDRS≥60) underwent testing for venous fasting plasma glucose (FPG). Statistical analysis was done using Chi-square test and Logistic regression.

Results: IDRS score ≥ 60 was present in 48.7%. Mean age of participants was 33.1±8.15. Preexisting diabetes and GDM was present in 3.4% and 4% respectively, while 7.1% were post-menopausal. Majority (64.1%) were younger than 35 years. WC <80cm, 80-89cm and >90cm was noted in 13.5%, 36.5% and 50%. Vast majority (87.4%) had sedentary lifestyle. Positive FH was present in 45.4%. There was significant association of score ≥ 60 with GDM and post-menopausal status (p<0.001). Association of increasing age with PA (p<0.001), suggesting that physical inactivity in younger women. Among those with score ≥ 60, FPG was ≥ 100mg/dl in 26.42%. Significant association of FPG ≥ 100mg/dl was noted with total IDRS score (p<0.001), positive FH (p=0.004), increasing age (p=0.018), history of GDM (p=0.034), and post-menopausal status (p=0.031), but not with PA or WC.

Discussion: Institution based screening is a novel strategy employed in DRIWE study. Results show high prevalence of diabetes risk among employed women. Physical inactivity in a vast majority is also noted. Screening women employees with help of a simple cost effective IDRS tool can help encourage those identified at-risk to adopt lifestyle changes to prevent diabetes.

Disclosure

P. Sankar: None. P. Sasikumar: None. R. Medayil: None. R. Jacob: None. S. Sasidharan: None.
Comparison of Different Methods for Carbohydrate Disorder Detection
Authors: DASKALOVA IVONA , TOTOMIROVA TZVETELINA , PETROV NIKOLAY
Published: June 2018

Measurement of fasting glucose and prandial glucose, as well as glycated haemoglobin (HbA1c) and oral glucose tolerance test (OGTT) could confirm diabetes or impaired glucose tolerance but they are invasive and time consuming methods. Some new technologies assessing dermal changes in perspiration like EZscan are used for defining carbohydrate state. We compare common methods used for detecting carbohydrate disorders with EZscan methodology assessing their potency to reveal diabetic and prediabetic patients. We studied 124 patients (64 males, 60 females, mean age 43.4±8.9years) with very high risk for diabetes. In these patients we measured HbA1c and performed OGTT and diagnosis diabetes or prediabetes was based on general recommendations. In addition patients underwent EZscan test in which diagnosis is based on measurement of electrochemical skin conductance. Only in 37 patients (29.8%) HbA1c was above 6.5% and in another 38 patients (30.6%) HbA1c was between 6.0-6.49%. After performing OGTT 22 patients (17.7%) were defined with increased fasting glucose (IFG) and 37 patients (29.8%) were with impaired glucose tolerance (IGT), 58 patients (46.7%) were with diabetes. Results from EZscan test show that 65 patients (52.4%) are with IFG/IGT and 55 patients (44.3%) are with diabetes. Age and gender did not have influence on the results. We conclude that EZscan could be used as test with similar to OGTT power for diagnosis of diabetes. HbA1c shows least potency for diagnosis. EZscan presents with some additional advantages being noninvasive method, taking no more than five minutes, with no need of special condition.

Disclosure

I. Daskalova: None. T. Totomirova: None. N. Petrov: None.
Air Pollution–Induced Diabetes Is Mediated via the Gastrointestinal Tract
Authors: BOSCH ANGELA J.T. , ROHM THERESA V. , ALASFOOR SHEFAA , DERVOS THOMAS , CAVELTI-WEDER CLAUDIA
Published: June 2018

Background: Epidemiological studies show an association between air pollution and increased diabetes risk. However, the causal mechanism remains poorly understood. While it is believed that air pollution particles inhaled into the lungs cause diabetes via local and systemic inflammation, these particles also reach the gastrointestinal (GI) tract by swallowing and mucociliary clearance and could thereby initiate diabetes.

Research Design and Method: To differentiate between the effects of air pollution particles reaching the lungs vs. the GI tract, male C57B6/N mice were exposed to diesel exhaust particles (DEP; weekly dose 60µg) either by oral gavage (5 days/week) or intratracheal instillation (twice/week) for up to 6 months and glycemia monitored by glucose tolerance tests.

Results: Mice orally treated with DEP showed impaired glucose tolerance with reduced insulin secretion already after two months of treatment, while insulin sensitivity was not affected. Furthermore, orally treated mice showed a distorted balance of pro- and anti-inflammatory intestinal macrophages with a specific loss of the anti-inflammatory subpopulation, which normally constitutes the majority of intestinal macrophages in the healthy gut. Although mice receiving DEP by intratracheal instillation had increased monocyte recruitment to the lungs, they did not show any impairment in glucose tolerance up to 5 months.

Conclusion: Exposure of DEP to the GI tract but not the lungs causes impaired glucose tolerance and a concomitant decrease in anti-inflammatory intestinal macrophages. Our results provide new insights into the mechanism of air pollution-induced diabetes with the gut as the primary organ mediating the disease and thus could be targeted by potential prevention and therapeutic strategies.

Disclosure

A.J.T. Bosch: None. T.V. Rohm: None. S. AlAsfoor: None. T. Dervos: None. C. Cavelti-Weder: None.
Urocortin-2 Gene Transfer Effectively Treats Type 1 Diabetes in Mice
Authors: GAO MEI HUA , LAI NGAI CHIN , GIAMOURIDIS DIMOSTHENIS , GUO TRACY Y. , XIA BING , KIM YOUNG CHUL , ESTRADA MONICA V. , NGUYEN HUU VIET ANH , SKOWRONSKA-KRAWCZYK DOROTA , KIRK HAMMOND H.
Published: June 2018

Type 1 diabetes (T1D) affects 1.3 million U.S. patients. Tight glucose control reduces microvascular complications and adverse cardiovascular events. Insulin therapy is essential but has shortcomings: a) only 1 in 3 patients achieve targeted glucose control; b) aggressive insulin use increases hypoglycemia; c) 25% of T1D patients develop insulin resistance. We previously reported that urocortin-2 (UCn2) gene transfer increases insulin sensitivity and release in mouse models of type 2 diabetes. In the present study, 3m-old male Akita mice with T1D (due to Ins2 mutation) received IV saline, AAV8. Null or AAV8.UCn2 (2x1012 gc/kg). Ten weeks after UCn2 gene transfer we saw normalization of fasting glucose, HbA1c and glucose tolerance (Table). Increased body weight and reduced water intake was seen after UCn2 gene transfer. Hyperinsulinemic euglycemic clamps showed increased insulin sensitivity and skeletal muscle glucose uptake. There was reduced nephropathy and retinopathy and increased survival (Table). Echocardiography showed improved ejection fraction (p<.001), end-systolic dimension (p<.001) and diastolic function (p<.0001). Data acquisition and analyses were blinded. The mechanisms for beneficial effects include increased insulin release and sensitivity. Thus, UCn2 gene transfer may be a viable therapy both for new onset T1D with detectable endogenous insulin, and for later stage T1D to reduce exogenous insulin needs.

UCn2 Gene Transfer in Akita Mice (Type 1 Diabetes)Saline or AAV8.Null (n)AAV8.UCn2 (n)pPlasma UCn2 (ng/mL)1±.2 (14)12±.9 (14)<.0001Urine Output (ml/hr).43±.06 (8).24±.06 (8).0412hr Fasting Glucose (mg/dL)272±25 (8)106±12 (8)<.0001HbA1c (%)8.2±.4 (5)5.5±.4 (5)<.002Glucose Tolerance Test (AUC)3128±215 (8)2062±286 (8)<.0001Insulin Release 2h post gluc (ng/ml).15±.01 (8).29±.4 (8).004Glucose Infusion Rate (mg/kg/min)12±2.89 (6)33.6±5.3 (5).001Vast Lat Glu Uptake (µM/m/100g)8.2±.4 (7)23.2±2.6 (6)<.0001Glomerulus Expansion Score1.7±.04 (8)1.5±.04 (8).01Urine Albumin/Creatinine (3hr)28±3 (8)17±3 (8).01Retinal Vascular Leak (%)43±1 (5)19±5 (4).001200-day Survival (%)0 (17 of 17 died)82 (3 of 17 died)<.0001Mean ± SE; p from Student’s t-test (unpaired, 2 tails); AAV8, Adeno-Associated Virus Type 8

Disclosure

M. Gao: None. N. Lai: None. D. Giamouridis: None. T.Y. Guo: None. B. Xia: None. Y. Kim: None. M.V. Estrada: None. V. Nguyen Huu: None. D. Skowronska-Krawczyk: None. H. Hammond: Stock/Shareholder; Self; Renova Therapeutics.
The Tyrosine Phosphatase LMPTP Is a Key Promoter of Adipogenesis
Authors: STANFORD STEPHANIE , ZHANG VIDA , BOTTINI NUNZIO
Published: June 2018

The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, acts as a regulator of insulin signaling by dephosphorylating the activation motif of the insulin receptor. Multiple human genetics studies suggest that high LMPTP catalytic activity promotes metabolic syndrome and severity of obesity. We recently reported that LMPTP is a critical promoter of insulin resistance in obesity through an action on the liver and that pharmacological inhibition of LMPTP reverses obesity-associated diabetes in mice. Since LMPTP is highly expressed in adipose tissue but little is known about its function in these tissues, we examined the role of LMPTP in adipocyte biology. Intriguingly, we found that LMPTP acts as a critical promoter of adipogenesis. Our data indicate a novel role for LMPTP in promoting adipocyte differentiation and suggest that there may be additional signaling pathways under control of LMPTP in these cells.

Disclosure

S. Stanford: None. V. Zhang: None. N. Bottini: None.
Some Indicators of Carbohydrate Metabolism in Individuals after the Abolition of the Use of Anabolic Androgenic Steroids
Authors: LYKHONOSOV MYKOLA P. , BABENKO ALINA Y.
Published: June 2018

Background: The use of anabolic androgenic steroids to form a sports figure is widespread. Anabolic androgenic steroids (AAS) are used in higer doses than in therapeutic practice. Studies of the side effects of AAS on carbohydrate metabolism are hampered due to the self-over-the-counter use of AAS.

Hypothesis: We assumed that with the abolition of AAS, the effect of high doses of testosterone (Ts) and nandrolone decanoate on the utilization of glucose is reduced.

Methods: After informational lectures among visitors in sports clubs in St. Petersburg on the impact of the AAS application on health, patients who expressed desire were included in the study. The inclusion criterion was the use of preparations of 19-nortestosterone with a course of 6 to 8 weeks in a weekly dosage of 300 to 700 mg in combination with Ts propionate and Ts enanthate, as well as the rejection of the subsequent use of anabolic steroids. BMI, HbA1c, immunoreactive insulin (IRI) and Fasting plasma glucose (FG), homeostatic model assessment-insulin resistance HOMA-IR were compared before and 3 months after the abolition of all AAS, while maintaining the previous physical activity and eating habits.

Results: We examined 24 pts (18M), age 27 ± 3.6. The average period of use of AAS is 7.3 weeks. After the abolition of the AAS, the IMB increased (mean difference = 4.7 kg, p = 0.012). The metabolism of glucose has changed in the direction of an increase in all the indicators considered: FG (mean difference = 1.02 mmol / l, p = 0.047), IRI (mean difference = 9.83, p = 0.023), HOMA-IR (mean difference = 7.31, p = 0.015) and HbA1c (mean difference = 0.25%, p = 0.031). However, no violations of glucose metabolism were detected in any case.

Conclusions: The abolition of AAS in athletes caused an increase in body weight and a shift in all glucose metabolism rates closer to the upper normal values, this trend deserves further study.

Disclosure

M.P. Lykhonosov: None. A.Y. Babenko: None.
Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo
Authors: LYU KUN , ZHANG DONGYAN , NOZAKI YUICHI , ZHANG YE , BHANOT SANJAY , CLINE GARY , SAMUEL VARMAN , SHULMAN GERALD I.
Published: June 2018

Diacylglycerol (DAG) has been proposed to mediate lipid-induced hepatic insulin resistance. Accumulated hepatic DAG activates PKCε which phosphorylates insulin receptor kinase (IRK) at T1160 to inhibit IRK activation and cause insulin resistance. However, the importance of DAG in lipid-induced hepatic insulin resistance remains controversial. To test the physiological effect of acute DAG accumulation on hepatic insulin sensitivity, we used antisense oligonucleotide (ASO) to specifically inhibit hepatic diglyceride acyltransferase 2 (DGAT2) which catalyzes the conversion of DAG to triglyceride. Previously, chronic DGAT2 inhibition was shown to paradoxically decrease hepatic DAG content due to decreased SREBP-1c-mediated lipogenesis and improve hepatic insulin sensitivity. However, we hypothesized that acute DGAT2 inhibition might provide a narrow window to transiently increase hepatic DAG content and allow us to identify the association between DAG, PKCε activation/translocation and hepatic insulin resistance. As hypothesized, an acute (2-day) DGAT2 inhibition increased hepatic DAG content and PKCε activation (cytosol to membrane translocation). DGAT2 ASO-treated rats on regular chow diet displayed impaired insulin-mediated suppression of hepatic glucose production. This defect of hepatic insulin action was at the level of IRK as indicated by impaired insulin-stimulated IRK Y1158/1162 phosphorylation. Furthermore, measured by a novel LC-MS/MS method, hepatic sn-1,2 DAG, which is the DAG stereoisomer capable of activating PKCε, was increased in the subcellular membrane compartment with DGAT2 ASO treatment.

Conclusion: These data support the importance of membrane sn-1,2 DAG in mediating lipid-induced hepatic insulin resistance through “increased membrane sn-1,2 DAG content -> PKCε activation/translocation -> increased IRK T1160 phosphorylation -> decreased IRK Y1158/1162 phosphorylation -> decreased IRK activity” in vivo.

Disclosure

K. Lyu: None. D. Zhang: None. Y. Nozaki: None. Y. Zhang: None. S. Bhanot: Employee; Self; Ionis Pharmaceuticals, Inc.. G. Cline: None. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..
Pancreatic Adipose Tissue in Diet-Induced Type 2 Diabetes
Authors: GARCIA BELEN CHANCLON , WU YANLING , NORDBECK ELIN BANKE , MUSOVIC SALIHA , OLOFSSON CHARLOTTA S. , RORSMAN PATRIK , ASTERHOLM INGRID WERNSTEDT
Published: June 2018

Obesity represents one of the most important health problems. Proper adipose tissue expandability is crucial for avoiding metabolic disorders. Furthermore, not all fat depots are functionally equal. Our previous work indicates that the expansion of the mesenteric adipose tissue (MWAT) plays a role in the intestinal barrier. Whether pancreas-associated adipose tissue (PAT) has a specific function is currently unknown. We hypothesize that storage of excess nutrients in PAT and PAT-derived adipokines (such as adiponectin) protect the pancreas against metabolic dysfunction during weight gain/obesity. An initial morphological study showed that PAT has an increased number of small, but fewer large adipocytes relative the adjacent MWAT. We compared the response to a 16-week high-fat diet (HFD)/obesity between PAT, other fat depots and pancreas. We found higher mRNA expression of inflammation markers in MWAT, inguinal (IWAT) and gonadal fat (GWAT), but not in PAT in response to HFD/obesity. HFD also downregulated the expression of insulin receptor and adiponectin in all fat depots, but not in PAT. The pancreas showed an increase in inflammatory and insulin resistance markers only after long-term (16 weeks) HFD exposure, a time point when also PAT displayed a reduction in insulin receptor and adiponectin expression. Smaller adipocytes are typically more functional than large adipocytes. Thus, these data suggest that PAT have an increased capacity for energy storage. This in turn may protect the pancreas against ectopic lipid accumulation and lipotoxicity. Moreover, our data show that PAT is protected against the deleterious effects of HFD, maintaining normal mRNA levels of adiponectin, insulin receptor and markers of inflammation.

In summary, we believe that PAT protects the pancreatic beta-cells from lipotoxicity through its increased capacity for energy storage, sustained insulin sensitivity and possibly also increased insulin exposure because of its anatomical location.

Disclosure

B. Chanclon Garcia: None. Y. Wu: None. E. Banke Nordbeck: None. S. Musovic: None. C.S. Olofsson: None. P. Rorsman: None. I. Wernstedt Asterholm: None.
Berberine Improves Mitochondrial Function in Colon Epithelial Cells to Protect L-Cells from Necrosis in Preservation of GLP-1 Secretion
Authors: YE JIANPING , LE JIAMEI , SUN YONGNING
Published: June 2018

Berberine (BBR) was reported to preserve the colon function in GLP-1 secretion in obese rodents through the butyrate-GPR43 pathway. However, the mechanism remains largely unknown except the pathway. Here, we tested BBR activity in the inhibition of clone epithelial necrosis in diet-induced obese mice. BBR was administrated in DIO mice through dietary supplementation for 8 weeks. Energy balance, insulin sensitivity and intestine mucosal function were monitored. Mitochondria were examined in the large intestine epithelial cells for structure and function to understand cell death. Mitochondrial structure was examined under the transmission electron microscopy and the function was determined using Seahorse XF24. Gut microflora was examined by Miseq sequencing and the fecal short chain fatty acids (SCFAs) were examined using gas chromatograph (GC). An increase in epithelial necrosis was observed in the colon mucosa together with a reduction in GLP-1 secretion and expression in DIO mice. Cristae loss and membrane rupture were observed in the mitochondrial structure of the colon epithelial cells. A disbalance of mitochondrial complexes was observed with an elevation in the complex I activity, and a fall in the complex II and IV activities. The abundance of short chain fatty acids were decreased along with the dysbiosis in the DIO mice. All of those alterations were corrected in DIO mice together with glucose disorder by the BBR treatment. The data suggest that BBR may protect the colon epithelial cells from necrosis in DIO mice to preserve GLP-1 secretion function. The effect was mediated by restoration of mitochondrial function from the disbalance among the complex I, II and IV. The direct and indirect effects of BBR are discussed.

Disclosure

J. Ye: None. J. Le: None. Y. Sun: None.
Association between Vitamin D and Metabolic Indexes in Patients with Polycystic Ovary Syndrome
Authors: SHANMEI SHEN , JIAYI LIU , YIKUN LI , CHENGCHENG QIAO , JIAMIAO YANG , BI YAN , ZHU DALONG
Published: June 2018

Objective: The aim of this study was to investigate the effect of vitamin D on the metabolic characteristics of polycystic ovary syndrome(PCOS) and its mechanism.

Methods and Results: 155 cases of PCOS patients and 74 non-PCOS women withmatched age and BMI were enrolled in this study.Data were collected from May 2016 to November 2017. Plasma 25-hydroxyvitamin D[25(OH)D], metabolic markers, and sex hormones were measured. Homeostasis model assessment(HOMA-IR), triglyceride(TG), testosterone(T), free androgen index(FAI) and uric acid(UA) were significantly increased(P<0.05) while 25-(OH)D, high-density lipoprotein cholesterol (HDL-C) and sex hormone binding globulin(SHBG) were lower(P<0.05) in PCOS than non-PCOS. Body mass index(BMI), fasting plasma insulin(FINS), HOMA-IR, TG, total cholesterol(TC) and T,FAI were higher(P<0.05) in Low-Vitamin D group than High-Vitamin D group. Postprandial plasma glucose(PPG) and postprandialplasma insulin(PINS) were higher(P<0.05) in Low-Vitamin D group than both High-Vitamin D group and Middle-Vitamin D group. Vitamin D was associated with BMI(r=-0.265, P=0.002), SBP(systolic blood pressure)(r=-0.267, P=0.002), HOMA-IR(r=-0.265, P=0.001),PINS(r=-0.252, P=0,002), TG(r=-0.265, P=0.001) and FAI(r=-0.211, P=0.027) in women with PCOS. However, after BMI was adjusted, vitamin D was no longer associated with these indexes. Vitamin D inoverweight/obese women with PCOS was lower than normal-weight women(P<0.05). Vitamin D was associated with DBP(r=-0.746,P=0.021) in overweight women with PCOS and was associated with PINS(r=-0.405,P=0.001)in obese women with PCOS.

Conclusion: Serum level of vitamin D was lower in women with PCOS than controls. Vitamin D in overweight/obese women with PCOS was lower than normal-weight women with PCOS. Vitamin D is associated with insulin resistance and cardiovascular disease risk in overweight/obese women with PCOS.

Disclosure

S. Shanmei: None. L. Jiayi: None. L. Yikun: None. Q. Chengcheng: None. Y. Jiamiao: None. Y. Bi: None. D. Zhu: None.