bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Reduction in Hyperglycemia in Advanced Type 1 Diabetes—The Value of Induced Aerobic Glycolysis by BCG Vaccinations
Authors: KUHTREIBER WILLEM , TRAN LISA , NGUYEN BRIAN , JANES SOPHIE E. , DEFUSCO AUDREY A. , FAUSTMAN DENISE L.
Published: June 2018

Mycobacteria are among the oldest co-evolutionary partners of humans. Attenuated Mycobacterium bovis, known as the Bacillus Calmette Guérin (BCG) vaccine, has been administered globally for 100 years for TB prevention. BCG vaccination shows clinical promise in numerous autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes (T1D). In published Phase II clinical trials in MS, BCG shows benefit starting 2 years after administration with continuing effectiveness at year 5. Here we report on the long-term stabilizing effect of BCG vaccination on blood sugar control in advanced T1D with 8 years of follow-up data. The data examines T1D subjects with long-term disease (>10 years duration) who received 2 doses of BCG 4 weeks apart. Starting after year 3, only BCG vaccinated T1D subjects had lowered HbA1c near normal (BCG treated 6.18+/-.34, placebo 7.07+/-.41, reference diabetic 7.22+/-.17, p=0.02; year 5 data with n=46 total subjects). Continued follow-up of 6 subjects for 8 years total confirmed the ability of BCG vaccinations to maintain lowered HbA1c levels without hypoglycemia (BCG treated 6.65+/-.26 vs. 7.22+/-.38, p=0.0002). Glucagon challenge tests were performed once HbA1cs were lowered but did not confirm a therapeutic return of C-peptide levels for improved blood sugar control. Pre-clinical NOD mouse data had shown in mice that BCG induces massive islet regeneration for restore murine blood sugars. In humans, BCG’s impact on blood sugars appears to be driven by a novel mechanism—a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization as measured by metabolomics, RNAseq and cellular glucose uptake, in subjects receiving a long-term benefit with BCG vaccinations. These clinical and novel mechanistic findings, buttressed with further murine testing, set the stage for a safe and cost effective way to possibly improve blood sugars in humans with diabetes.

Disclosure

W. Kuhtreiber: None. L. Tran: None. B. Nguyen: None. S.E. Janes: None. A.A. DeFusco: None. D.L. Faustman: None.
Metformin Improves Insulin Resistance (IR) and Vascular Health in Youth with Type 1 Diabetes (T1D)
Authors: NADEAU KRISTEN J. , BJORNSTAD PETTER , SCHÄFER MICHAL , BROWNE LORNA , BAUMGARTNER AMY , REYES YESENIA GARCIA , MANIATIS ARISTIDES , WADWA R. PAUL , NAYAK SUNIL , PYLE LAURA , CREE-GREEN MELANIE , REUSCH JANE E.
Published: June 2018

Cardiovascular disease is the leading cause of mortality in T1D and relates to IR. We demonstrated that lean and obese T1D youth have IR and that metformin improves surrogate markers of IR in obese T1D youth. Yet, little is known about vascular health in T1D youth or about the effect of metformin on directly-measured IR or vascular health. In The Effects of MEtformin on cardiovasculaR function in AdoLescents with type 1 Diabetes (EMERALD) study, we hypothesized that T1D youth have impaired vascular function and that metformin decreases IR and improves vascular health. 49 T1D youth ages 12-21 years (40% with BMI ≥ 90%ile; 44% male) and 24 controls of similar age, BMI and sex underwent phase contrast MRI of the ascending (AA) and descending aorta (DA) to determine aortic pulse wave velocity (PWV) and wall shear stress (WSS). T1D youth also had carotid intima-media thickness (cIMT) by ultrasound, DXA scan, fasting labs following overnight IV glycemic control, and a hyperinsulinemic-euglycemic clamp (80 mU/m2/min insulin) to assess IR (glucose infusion rate [mg/kg/min)]/insulin or M/I). T1D youth were then randomized 1:1 to 2g of metformin or placebo daily, and all measures repeated at 3 months. At baseline, T1D youth vs. controls had elevated aortic PWV (AA: 3.7±0.2 vs. 2.5±0.4 m/s, p<0.05; DA: 4.2±0.2 vs. 3.1±0.3 m/s, p=0.02) and WSS (AA: 1.1±0.04 vs. 0.9±0.N/m2, p=0.003; DA: 1.6±0.vs. 1.1±0.07 N/m2, p<0.0001). Compared to the placebo group, T1D youth in the metformin group had no baseline differences but had improvement at 3 months in M/I (12.2±3.2 vs. -2.4±3.6 uIU/uL, p<0.01), AA PWV (-1.1±1.1 vs. 4.1±1.6 m/s, p<0.04), AA WSS (-0.03±0.04 vs. 0.2±0.N/m2, p<0.03) and far wall diastolic cIMT (-0.04±0.01 vs. 0.00±0.01 mm, p=0.04) in baseline-adjusted models. T1D youth have IR and vascular dysfunction compared to controls of similar age, sex and BMI. Metformin mitigated IR and improved aortic and carotid health in T1D youth, and thus may hold promise as a cardiovascular protective intervention.

Disclosure

K.J. Nadeau: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. M. Sch fer: None. L. Browne: None. A. Baumgartner: None. Y. Garcia Reyes: None. A. Maniatis: None. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; MannKind Corporation, Dexcom, Inc., Xeris Pharmaceuticals, Inc., Bigfoot Biomedical. S. Nayak: None. L. Pyle: None. M. Cree-Green: None. J.E. Reusch: Research Support; Self; Merck & Co., Inc.. Board Member; Self; American Diabetes Association. Research Support; Self; AstraZeneca. Other Relationship; Self; Sanofi-Aventis.
Pediatric Case Series of Cystic Fibrosis and Type 1 Diabetes Autoimmunity
Authors: KIM GRACE , MERJANEH LINA
Published: June 2018

Background: Diabetes is the most common comorbidity in individuals with cystic fibrosis (CF) Autoimmunity was reported to be no greater in CF related diabetes (CFRD) than in the general population and routine screening for type 1 diabetes (T1D) antibodies is not recommended. We report 3 patients with CF, diabetes and T1D autoimmunity.

Clinical cases: Patient 1 and 2 are Caucasian siblings with CF, genotype ∆F5homozygous and pancreatic insufficiency. Patient 1 is a male who presented at age 16 with polyuria, polydipsia and weight loss. Fasting glucose was 350 mg/dL. C peptide was 1.1 ng/ml and Hba1c was >14%. T1D antibodies showed (Anti GAD 147, negative Islet cell antigen antibody 512 (IA2), ZNT8 and insulin antibodies). Current insulin requirement at age 22 is 0.8 units/kg/day with Hba1C ranging from 6.7-12.0%. Patient 2 is a female diagnosed with CFRD at age 9 with an oral glucose tolerance test. Fasting glucose was 92 mg/dL and 2-hour glucose 209 mg/dL. C peptide 7.1 ng/ml. Hba1c 6.7%. T1D antibodies were negative at presentation. At age 14, because of increase in insulin requirement, T1D antibodies were retested and positive (Anti GAD 31, IA2 52, znt8 0.955). Her current insulin dose at age16 is 0.7units/kg/day with Hba1c ranging 6.7-12.7%. Patient 3 is a prepubertal biracial (African American, Caucasian) female with CF, genotype 1 copy of ∆F5and 1 copy of ∆I507, pancreatic insufficiency and Hashimoto’s hypothyroidism. She presented at age 9 with polyuria, polydipsia and weight loss. She was in DKA with glucose 686 mg/dL, bicarbonate 5 mEq/L, BOHB 5.4 mmol/L, C-Peptide 0.1 ng/ml, HbA1C >14%. T1D antibodies were positive (Anti GAD 192, IA2 183, ZnT8 0.177, Insulin 0.017). Current insulin dose at age 11 is 0.55 unit/kg/day with Hba1c ranging 7.7-10.2%.

Conclusion: T1D needs to be considered in a CF patient with hyperglycemia when patient is prepubertal, symptomatic, in DKA, or requiring high insulin doses. Correct diagnosis allows for proper treatment and help prevent short and long-term diabetes complications.

Disclosure

G. Kim: None. L. Merjaneh: None.
Diet Choices at 3 and 12 Months for Women and Their Partners after Recent Gestational Diabetes (GDM)—Results of the Families Defeating Diabetes (FDD) Study
Authors: VEZINA ANICK , MCMANUS RUTH M. , DONOVAN LOIS E. , MILLER DAVID B. , GIROUX ISABELLE T.
Published: June 2018

Objectives: FDD was a 12 month, multi-centre, Canadian, randomized study translating diabetes-protective messages after GDM. Male partner participation was encouraged. We compared paternal vs. maternal food choices for interventional (INT) and control (CON) participants before and after FDD.

Methods: INT maternal and paternal participants received information promoting high fibre/low fat foods; portion control; healthy restaurant choices via postpartum seminar, access to branded FDD website and twice-monthly email contact. CON maternal subjects received a postpartum healthy living handout. One-day food records at 3 and 12 months were analyzed for fast food intake (FF) and Canada’s Food Guide (CFG) servings.

Results: 15 INT and 16 CON maternal/paternal pairs provided food records at 3 and 12 months. Considering INT and CON cohorts together: paternal and maternal grain products, milk/alternatives and meat/alternatives consumption met CFG guidelines at 3 and 12 months. Paternal and maternal vegetables and fruit (V and F) intakes were similar but lower than recommended (paternal: goal 8-10 servings/day; baseline 3.8±2.2; 12 months 4.6±2.9; maternal: goal 7-8 servings/day; baseline 4.1±2.8; 12 months 5.4±3.2). Paternal FF intake was higher than maternal at baseline: (0.41±0.61 vs. 0.12±0.34; p=0.03) but not at 12 months (0.44±0.62 vs. 0.34±0.40, p=0.6). Paternal and maternal V and F intakes were modestly correlated by 12 months (r=0.35, p=0.05).

Conclusions: Notable paternal and maternal postpartum diet choices were: servings of V and F did not meet CFG recommendations at 3 and 12 months for men or women; paternal FF intake was higher than maternal soon after delivery, but not at 12 months as maternal servings increased; paternal and maternal V and F intakes were correlated at 12 months postpartum. Therefore, it may be helpful to target both paternal and maternal food choices when promoting healthy living after GDM.

Disclosure

A. Vezina: None. R.M. McManus: None. L.E. Donovan: None. D.B. Miller: None. I.T. Giroux: None.
GDM—Impact of BMI in Maternal Bioquimical-Metabolic Variables and Its Association with Macrosomia
Authors: ARGERICH MARIA INES , DAVID RAUL ALEJANDRO , BOCCHINI ANDREA
Published: June 2018

Maternal Overweight/obesity increases risk of GDM and macrosomia

Objectives: Compare pregestational BMI. Frequency of macrosomia. Correlationship between BMI first trimester fasting glycemia (1stTFG>92) fasting glycemia OGTT (FGOGTT), glycemia 120 minutes OGTT (2HPG), maternal weight gain during pregnancy (MWG) and macrosomía

Research Design Methods: Analysis of 120 GDM medical records using ALAD diagnostic criteria. BMI categories were compared in Groups A ≥30 vs. ≤24.9 B 25-29.9 vs. ≤24.9 C ≥30 vs. 25-29.9 Variables: maternal age (MA), 1stTFG>92; FGOGTT, 2HPG, birth weight (BW), HbA1c, maternal triglyceridemia on last trimester (MTAG) maternal weight gain (MWG) SPSS V22.

Results: BMI ≥30 N:39 BMI 25-29.9 N:42 BMI≤24.9 N:33 Mean HBA1C for all groups 5%. Table 1 comparison groups. Macrosomía N:13 (N:5 BMI 25-29.9 N:8 BMI ≥30 N:0 BMI group ≤24.9) p0.026. Correlation of macrosomia and FG1stT> 92 FGOGTT 2HPG MWG ≥ 7KG in BMI ≥30 is p0.046 p0.017 p0.096 P0.0001 respectively. Correlation between macrosomia and FG1stT> 92 FGOGTT 2HPG MWG ≥ 11KG in BMI 25-29.9 is p0.0001 P0.011 p0.012 p0.001 respectively

Discussion: Pregestational BMI excessive MWG 1stTFG and higher levels of MTAG in BMI ≥30 increases risk of macrosomia. 1stTFG> 92 should considered as an independent risk factor for GD/macrosomia in overweight/obese pregancys. In BMI ≥25 consider lower thresholds of FG for GDM diagnostic criteria to prevent macrosomia.

Disclosure

M. Argerich: None. R. David: None. A. Bocchini: None.
Glycemic Variability during Pregnancy in T1D on CSII
Authors: DADLANI VIKASH , O'MALLEY GRENYE , KULINA GEORGIA , KUMARI KANCHAN , DESJARDINS DONNA , XIE YAN YAN S. , MCCRADY-SPITZER SHELLY K. , THAPA PRABIN , CASTORINO KRISTIN , PINSKER JORDAN E. , DASSAU EYAL , LEVY CAROL J. , KUDVA YOGISH C.
Published: June 2018

Artificial pancreas (AP) technology is achieving tight and safer glycemic control (GC) in non-pregnant T1D populations but has been insufficiently tested in pregnant T1D patients. We evaluated glucose variability (GV) in pregnant women with T1D on Continuous subcutaneous insulin infusion (CSII) during each trimester to facilitate design of future studies. Data from 17 pregnant women with T1D, age 29 ± 4 years, DOD 17.8 ± 6 years, gestational age at delivery 38.6 ±1 weeks and fetal weight 3525± 524 gms are presented. GV at initial visit and at least 2 weeks per trimester (6-8, 10-12, 21-23, 26-28, 32-34, and 36-38) and maternal/fetal outcomes were analyzed. GV indices are shown in the Table. Mean HbA1c 7.2 ± 1.3% at baseline decreased to 6.6 ± 1.2%, 5.8 ± 0.8% and 6.0 ±0.7% during 1st, 2nd and 3rd trimester respectively. Mean BMI during 1st trimester was 27.7 ± 7.3 kg/m2 and increased to 29 ± 7.7 kg/m2and 31.7 ± 7 kg/m2 during 2nd and 3rd trimesters respectively. 8 subjects had C-section, 7 preeclampsia; 3 excessive blood loss during delivery, and 1 preterm labor, polyhydramnios and maternal infection. Additionally, 4 infants were admitted to intensive care, 4 developed hypoglycemia, one was born with malformation and one with macrosomia. GV and maternal/fetal morbidity continue to be unacceptably high during pregnancy in T1D with current technologies stressing the urgent need for AP development and testing in this context.

Disclosure

V. Dadlani: None. G. O'Malley: None. G. Kulina: None. K. Kumari: None. D. Desjardins: None. Y.S. Xie: None. S.K. McCrady-Spitzer: None. P. Thapa: None. K. Castorino: None. J.E. Pinsker: Research Support; Self; Insulet Corporation, Dexcom, Inc., Tandem Diabetes Care, Inc. E. Dassau: Consultant; Self; Insulet Corporation. Research Support; Self; Insulet Corporation. Consultant; Self; Animas Corporation. Research Support; Self; Dexcom, Inc.. Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Roche Diabetes Care Health and Digital Solutions, Xeris Pharmaceuticals, Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Tandem Diabetes Care, Inc.. Other Relationship; Self; ModAGC. Research Support; Self; LifeScan, Inc., DreaMed Diabetes, Ltd. C.J. Levy: Advisory Panel; Self; Medtronic MiniMed, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Dexcom, Inc.. Y.C. Kudva: None.
d-ROMs and BAP as Potential Predictive Factors for New-Onset Diabetes
Authors: OKAHATA SUMIE , SAKAMOTO KENTARO , MITSUMATSU TAKAKO , YANO MASAO , ISHIZAKA YUKO , YAMAKADO MINORU , SHIBA TERUO
Published: June 2018

Background: Increased oxidative stress plays a role in the progression of atherosclerosis. Yet only few reports in NOD.

Method: Derivatives of reactive oxygen metabolites(d-ROMs) and biological antioxidant potential (BAP) were measured in 859 subjects undergoing general health screenings in both 2011 and 2015. 779 individuals (mean age 60.6, 562 men) were screened for NOD by the following criteria in 2015: (1) confirmed diagnosis of DM, or treatment with antidiabetic agent(s) between 2011 and 2015, (2) FPG≧126mg/dl or 2hPG≧200 mg/dl in 75gOGTT and HbA1c≧6.5%.

Results: Among 779 subjects, 70 were newly screened as DM in 2015. As for data in 2011 FPG (105/97), HbA1c (6.1/5.7), dROM (367/325U.CARR), and CRP (0.34/0.13mg/dl) were significantly higher in NOD population in 2015 than the rest, whereas BAP (2437/2527μmol/L) and BAP/d-ROM(6.86/8.0) significantly lower. In univariate regression analysis by data in 2011, HbA1c was correlated with d-ROMs positively and B/R negatively. By multivariate logistic regression analysis with B/R, BMI, SBP (mmHg), LDL (mg/dl), CRP(mg/dl), and eGFR (ml/min/1.73m2) as explanatory variables, NOD was associated with FBS, HbA1c positively, and B/R negatively.

Discussion and Conclusion: In addition to the conventional risk factors, indices for oxidative stress, B/R derived from d-ROMs and BAP exhibited significant predictive values for NOD by the composite criteria in 2015. Several reports have pointed out the involvement of oxidative stress in micro- and macrovascular complications. Only bilirubin, a powerful antioxidant, has been proven to show preventive value against NOD. Oxidative stress would be positioned as novel indicators for diabetes risk and target for prevention of NOD.

Disclosure

S. Okahata: None. K. Sakamoto: None. T. Mitsumatsu: None. M. Yano: None. Y. Ishizaka: None. M. Yamakado: None. T. Shiba: Speaker's Bureau; Self; Shionogi & Co., Ltd., Pfizer Inc., Merck Sharp & Dohme Corp., Kowa Company, Ltd., Daiichi Sankyo Company, Limited.
Identification and Characterization of a Novel Insulin Sensitizer to Treat Diabetes and Nonalcoholic Steatohepatitis
Authors: CHEN YANA , CHAMBERS KARI , MCDONALD WILLIAM , FINCK BRIAN N. , MCCOMMIS KYLE S.
Published: June 2018

Thiazolidinediones (TZDs) enhance insulin sensitivity and have efficacy for treating nonalcoholic steatohepatitis (NASH). However, the use of TZDs, like rosiglitazone and pioglitazone, has been curtailed by significant side effects mediated via the peroxisome proliferator-activated receptor γ (PPARγ). We conducted a screen to identify compounds with insulin-sensitizing effects that did not contain a thiazolidinedione ring and act independently of PPARγ. A lead candidate, MSDC-5514, was selected for further study due to its ability to induce uncoupling protein 1 expression in brown adipocyte precursors and an inability to bind and activate PPARγ even at high concentrations. We gavaged diet-induced obese (DIO) mice with 30 mg/kg/day MSDC-5514 for six days. MSDC-5514 treatment did not affect body weight, but completely normalized glucose tolerance in insulin-resistant DIO mice. DIO mice exhibited elevated plasma insulin, free fatty acid, and triglyceride concentrations compared to lean mice, all of which were corrected by MSDC-5514 treatment. Liver diacylglycerol and triglyceride content, which were markedly increased in DIO mice compared to lean controls, were significantly decreased by MSDC-5514. The resolution of hepatic steatosis may be due to increased fatty acid oxidation since the expression of several genes encoding fatty acid oxidation enzymes was significantly elevated in livers from MSDC-5514 treated mice and directly by treatment of hepatocytes with MSDC-5514 in culture. Markers of liver injury and NASH, including plasma ALT and liver expression of markers of inflammation, stellate cell activation, and fibrosis were also attenuated by MSDC-5514 treatment. Although the molecular target of MSDC-5514 remains unclear, chemical-genetic screens are ongoing to identify the mechanism of action.

In conclusion, these data suggest that MSDC-5514 may be a new PPARγ-independent insulin sensitizer with efficacy for treating diabetes and NASH.

Disclosure

Y. Chen: None. K. Chambers: None. W. McDonald: Stock/Shareholder; Self; Metabolic Solutions Development Company, LLC. B.N. Finck: Board Member; Self; Cirius Therapeutics. K.S. McCommis: None.
Screening for Diabetes Mellitus and Gestational Diabetes in a Resource-Poor Setting—Implementing a Selective Protocol
Authors: CABRERA KEVIN A. , PENDI ARIF , LASHKARI NASSIM , EL-TOBGY ERIC , LABROT BEN B.
Published: June 2018

Background: Screening for diabetes mellitus and gestational diabetes in resource-poor settings requires efficiency. To make the best use of resources, we proposed a selective diabetes screening protocol for patients in rural Panama as a cost-effective solution for diabetes screening in resource-limited settings. We proposed to screen adults aged 35 years or above and pregnant women of all ages.

Methods: Patients that attended a three-day clinic in Bocas del Toro, Panama established by the non-for-profit organization Floating Doctors were screened for non-fasting blood glucose levels. The proposed selective diabetes screening protocol was applied to determine whether it identified patients that were diabetic or prediabetic. Criteria for diabetes and prediabetes were based on existing American Diabetes Association guidelines: patients with a non-fasting blood glucose concentration of ≥200 mg/dl were considered diabetic and patients with a non-fasting blood glucose concentration of ≥140 mg/dl but < 200 mg/dl were considered prediabetic.

Results: Of 84 patients that attended clinic, 2 were diabetic (2.3%) and 55 were prediabetic (65.5%). The sub-group of 41 patients (48.8%) met the selective screening protocol criteria of being at or above the age of 35 years and/or pregnant. This group included 2 patients that screened positive for diabetes (4.9%) and consisted of 16 patients with prediabetes (39.0%). The group excluded by the proposed protocol (51.2%) consisted of no patients with diabetes and 17 with prediabetes (39.5%).

Conclusion: The proposed selective diabetes screening protocol effectively identified all patients with diabetes but only about half the patients with prediabetes, suggesting this protocol may have utility in diagnosing diabetes for treatment purposes. However, because a significant number of prediabetic individuals were excluded, other strategies are necessary for preventative efforts.

Disclosure

K.A. Cabrera: None. A. Pendi: None. N. Lashkari: None. E. El-Tobgy: None. B.B. LaBrot: None.
Characterization of Patients with Type 2 Diabetes (T2D) Who Discontinue DPP-4is following Insulin Initiation
Authors: FERNANDES GAIL , IGLAY KRISTY , LIU ZHIWEN , RAVI SHANKAR R. , GANTZ IRA , RAJPATHAK SWAPNIL
Published: June 2018

While discontinuation of oral drugs, such as DPP-4i, at the time of insulin initiation is not uncommon, the characteristics associated with this discontinuation are not well understood. We conducted a retrospective database study using the Optum claims data to describe the prevalence of and factors associated with discontinuation of DPP-4i among patients on dual therapy of metformin and DPP-4i after initiating insulin. Our study included adult T2D patients on this dual therapy who initiated insulin (index) from Jan 2006-Sep 2015. 3,388 T2D patients met the study criteria; mean age: 62 years, 55% male, and 61% and 88% reported micro- and macrovascular complications, respectively. 32% (n=1086) of the study population discontinued DPP-4i therapy within 12 months after insulin initiation, with 1075 patients discontinuing in the first 3 months. Median time to discontinuation was 25 days (IQR 13-31 days). Available patient characteristics between continuers vs. discontinuers are described in TABLE. Data available from claims showed that patients who discontinue had higher out of pocket costs and higher proportion of renal and liver disease. Limitation of this study is lack of information on A1C and other clinical variables such as BMI. A Cox regression model will be employed to further investigate if these factors are predictive of discontinuation.

Disclosure

G. Fernandes: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; Janssen Research & Development. Stock/Shareholder; Self; Merck & Co., Inc.. Stock/Shareholder; Spouse/Partner; Janssen Research & Development. K. Iglay: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. Z. Liu: Employee; Self; Merck & Co., Inc. R. Shankar: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; NGM Biopharmaceuticals. I. Gantz: Employee; Self; Merck Sharp & Dohme Corp. S. Rajpathak: Employee; Self; Merck & Co., Inc..
Metabolomic Profiling of Nonproteinogenic Amino Acids in Patients with Type 2 Diabetes and Hypertension
Authors: CIOBANU DANA M. , BALA CORNELIA G. , ROMAN GABRIELA
Published: June 2018

Introduction: Identifying the amino acid signature of increased blood pressure might help us understand hypertension pathophysiology. We aimed to investigate the relationship of non-proteinogenic amino acids with ambulatory blood pressure mean and variability in type 2 diabetes patients.

Methods: Serum non-proteinogenic amino acids’ profiling was performed by high performance liquid chromatography coupled with mass spectroscopy analysis. Blood pressure variability was calculated as standard deviation of mean systolic and diastolic blood pressure evaluated over 24-hour ambulatory monitoring.

Results: The study population consisted of type 2 diabetes hypertensive patients (n=80), 58% women, aged 59.8±7.7 years old with diabetes duration 9.0±8.7 years. Serum non-proteinogenic amino acids levels (nmol/mL) were: gamma-aminobutyric acid 0.2±0.1, aminoisobutyric acid 22.6±7.9, beta-aminoisobutyric acid 1.2±0.7, 4-hydroxyproline 12.2±9.9, 3-methylhistidine 4.7±2.8, alpha-aminoadipic acid 1.0±0.5, sarcosine 11.3±5.6. In linear regression analysis, aminoisobutyric acid was significantly associated with 24-hour systolic blood pressure variability (r=0.23; p=0.044), sarcosine was significantly associated with nighttime systolic blood pressure variability (r=0.27; p=0.017), while beta-aminoisobutyric acid was significantly associated with mean daytime (r=-0.25; p=0.024) and 24-hour (r=-0.24; p=0.032) diastolic blood pressure.

Conclusion: Serum metabolomes aminoisobutyric acid and sarcosine directly associated with ambulatory systolic blood pressure variability, while beta-aminoisobutyric acid inversely associated with mean diastolic blood pressure. Our results indicate changes in serum non-proteinogenic amino acids as consequences of increased blood pressure that should be further evaluated in connection to cardiovascular disease, particularly in the presence of type 2 diabetes.

Disclosure

D.M. Ciobanu: Other Relationship; Self; Sanofi, AstraZeneca, Merck Sharp & Dohme Corp., Eli Lilly and Company, Merck KGaA. C.G. Bala: Consultant; Self; Sanofi, AstraZeneca. G. Roman: None.
Metabolic Inflexibility Revisited—Muscle Substrate Oxidation Is Mechanistically Dissociated from Muscle Insulin Resistance in Rats
Authors: SONG JOONGYU D. , PERRY RACHEL J. , MUNK ALEXANDER , ZHANG YE , ZHANG DONGYAN , SHULMAN GERALD I.
Published: June 2018

The Metabolic Inflexibility Hypothesis and Randle Hypothesis posit that alterations in muscle glucose and fat oxidation are key factors in the pathogenesis of obesity (lipid)-associated skeletal muscle insulin resistance. In order to test these hypotheses we used a stable isotope tracer ([U-13C]glucose) to measure the ratio of pyruvate dehydrogenase flux and citrate synthase flux (VPDH/VCS), a highly tissue-specific index for the proportional contribution of glucose oxidation to total mitochondrial oxidation in vivo. We found that insulin resistant rats fed a high fat diet (HFD) for 4 weeks did not have altered substrate (VPDH/VCS) oxidation in soleus muscle in the fasting state (5.8%±2.5% vs. 2.6%±1.0%). Hyperinsulinemic-euglycemic clamps increased relative glucose oxidation in both normal and insulin resistant rats, although this increase was blunted in insulin resistant rats (51.6±4.9% vs. 33.3±4.5%, p<0.05), which could be mostly attributed to an impairment in insulin-stimulated muscle glucose transport flux (124.4±18.7 vs. 69.3±11.3 nmol/(g•minute), p<0.05). Additionally, we found that an acute infusion of lipid during a clamp in normal rats significantly reduced relative glucose oxidation in soleus muscle (49.0±3.6% vs. 26.7±2.7%, p<0.001) without any effects on insulin-stimulated peripheral glucose metabolism (27.2±1.4 vs. 24.3±1.5 mg/(kg•minute), NS) or muscle glucose transport (143.8±22.4 vs. 138.1±18.3 nmol/(g•minute), NS).

Conclusion: These data show that basal substrate preference in muscle is not altered in insulin resistant rats and that acute modulation of substrate oxidation in normal rats does not affect muscle insulin sensitivity, therefore challenging the Metabolic Inflexibility Hypothesis and Randle Hypothesis in the pathogenesis of lipid-induced muscle insulin resistance.

Disclosure

J.D. Song: None. R.J. Perry: None. A. Munk: None. Y. Zhang: None. D. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..
MALAT1 and HOTAIR—Key Epigenetic Regulators in Diabetic Retinopathy
Authors: BISWAS SAUMIK , THOMAS ANU A. , FENG BIAO , CHEN SHALI , AREF-ESHGHI ERFAN , GONDER JOHN , SADIKOVIC BEKIM , CHAKRABARTI SUBRATA
Published: June 2018

Introduction: With the increasing incidence of diabetic retinopathy (DR), the need for novel and specific therapy is essential. Genomic studies have identified several long non-coding RNAs (lncRNAs). However, majority of lncRNAs have not been characterized in DR. We examined the roles of lncRNAs MALAT1 and HOTAIR in DR.

Methods: Human retinal endothelial cells (HRECs) were cultured in 5 mM/L (NG) or in 25 mM/L (HG) glucose. RNA expressions of MALAT1, HOTAIR, and inflammatory and angiogenic cytokines were tested. HRECs were similarly examined following siRNA-mediated MALAT1 or HOTAIR knockdown, or treatment with histone (DZNep) and DNA methylation (52019-aza-dC) blockers. DNA methylation patterns and RNA-protein interactions were analyzed. Retinal tissues from Malat1 knockout (KO) and wild type (WT) mice with or without diabetes were examined. We further assessed MALAT1 a’nd HOTAIR in human diabetic and nondiabetic vitreous.

Results: HG caused upregulations of MALAT1, HOTAIR, IL-6, TNF-α, and VEGF-A transcripts in HRECs. HG increased binding of EZH2 (a PRC2 component) with MALAT1 and HOTAIR and evoked unique DNA methylation patterns in the MALAT1 and HOTAIR CpG regions. DZNep, 5-aza-dC and knockdown of MALAT1 or HOTAIR reduced mRNA expressions of IL-6, TNF-α, and VEGF-A. Similarly, diabetes-induced elevations of these inflammatory and angiogenic cytokines in the retina were prevented in the Malat1 KO mice. Furthermore, MALAT1 and HOTAIR levels were elevated in the diabetic vitreous.

Conclusions: Our findings allude to the importance of lncRNAs in influencing DR through epigenetic mediators. Understanding the role of lncRNAs may allow the development of better-targeted therapies in DR.

Disclosure

S. Biswas: None. A.A. Thomas: None. B. Feng: None. S. Chen: None. E. Aref-Eshghi: None. J. Gonder: None. B. Sadikovic: None. S. Chakrabarti: None.
Assessment of Body Shape Index for Predicting Type 2 Diabetes in Korean Elderly Population—The Chungju Metabolic Disease Cohort (CMC) Study
Authors: LIM SUN-YOUNG , LEE JIN-HEE , YOON KUN-HO
Published: June 2018

Obesity has known as the main cause of type 2 diabetes (T2DM). Many simple surrogate indices of obesity, such as body mass index (BMI), waist circumference (WC), waist-to-height ratio (WtHR) has been used, however, there is controversy about which indicator is most useful. Recently a new index (a body shape index, ABSI) was developed as a more reliable surrogate index than BMI in determination of the association between cardiovascular events and body composition. We aim to assess whether or not ABIS is better than BMI and WC to predicting T2DM incidence in Korea elderly population. The CMC study is a prospective cohort study of metabolic disease. A total of 5,390 subjects (2,034 men, 3,356 women) age 40 and older, free of T2DM at baseline (2003-2006) were included in the present study, and we estimated the cumulative incidence of T2DM after 4 years follow-up. ABSI was calculated using waist circumference, weight, height (WC/(BMI2/3height1/2)). Adjusted relative risk(RR) for diabetes was estimated by Poisson regression model where index values were computed separately for each control, and receiver operating characteristic (ROC) curve analysis was applied. There were no associations between ABIS and T2DM incidence in both sexes. In men, BMI and WC did not show significant associations either, and in women, the RR of highest quartile relative to the lowest quintile was significant (1.95 (1.27-3.01)) only in WC. AUCs (area under the ROC curve) and 95% CIs of WC were 0.613(0.591-0.634) in men and 0.642 (0.626-0.659) in women, and showed significant differences compared with the AUCs of ABSI (0.567 (0.545-0.588) for men, 0.580(0.563-0.597) for women) and BMI (0.578 (0.556-0.599) for men, 0.601 (0.584-0.618) for women) in both sexes. In this study, ABSI was not better than a WC in predicting the ability for T2DM, and WC was a good surrogate index of obesity to T2DM incidence especially in Korea elderly women.

Disclosure

S. Lim: None. J. Lee: None. K. Yoon: None.
Anemia Is Inversely Associated with Serum C-Peptide Concentrations in Patients with Type 2 Diabetes
Authors: CHUNG JIN OOK , PARK SEON-YOUNG , CHO DONG HYEOK , CHUNG DONG JIN , CHUNG MIN YOUNG
Published: June 2018

Results: The aim of the study was to investigate the relationship between anemia and serum C-peptide concentrations in Korean patients with type 2 diabetes. A total of 1,300 subjects with type 2 diabetes were investigated in this cross-sectional study. Fasting C-peptide concentration, 2-hour postprandial C-peptide concentration, and δC-peptide (postprandial C-peptide minus fasting C-peptide) concentration were measured in all patients. Anemia was defined according to the World Health Organization. Fasting C-peptide level, postprandial C-peptide level, and δC-peptide level was lesser in subjects with anemia. According to the grade of anemia, the average C-peptide levels were significantly different after adjusting for other covariates (fasting C-peptide level: no anemia, 0.73 mmol/l; grade I anemia, 0.66 mmol/l; grade II anemia, 0.62 mmol/l; P for trend = 0.002; postprandial C-peptide level: no anemia, 1.54 mmol/l; grade I anemia, 1.36 mmol/l; grade II anemia, 1.32 mmol/l; P for trend < 0.001; δC-peptide level: no anemia, 0.75 mmol/l; grade I anemia, 0.64 mmol/l; grade II anemia, 0.60 mmol/l; P for trend = 0.001). In the multivariate model, the association between anemia and serum C-peptide concentrations remained significant, after adjustment for confounding factors including age, gender, familial diabetes, body mass index, duration of diabetes, glycated hemoglobin, free fatty acid, hypertension, and hyperlipidemia (fasting C-peptide level: β= -0.057, P =0.032; postprandial C-peptide level: β= -0.098, P <0.001; δC-peptide level: β= -0.095, P <0.001, respectively). Our results showed that anemia was inversely associated with serum C-peptide concentrations in subjects with type 2 diabetes.

Disclosure

J. Chung: None. S. Park: None. D. Cho: None. D. Chung: None. M. Chung: None.
The Role of HbA1c on Mortality in Patients with Medical History of Ischemic Stroke and Paroxysmal Atrial Fibrillation
Authors: KANELLOPOULOU KONSTANTINA , MATSOUKIS IOANNIS L. , GANOTOPOULOU ASIMINA , ATHANASOPOULOU THEODORA , TRIANTAFILLOPOULOU CHRYSOULA , SIANNI ALEXANDRA
Published: June 2018

Objective: The correlation of HbA1c level with mortality in patients with ischemic stroke and Paroxysmal Atrial Fibrillation (pAfib).

Method: 278 patients with medical history of ischemic stroke and pAfib confirmed with cerebral Computed Tomography and electrocardiogram or rhythm Holter respectively, were included in the study. All patients visited for routine health screening examination or with minor deseases the departments of internal medicine of three tertiary hospitals. The mean age was 78±12 years. The participants were divited into two groups: In group A, 167 patients (60%) that had diabetes mellitus type II (DMT2) were included. Among them, 92 were women (55%) and 75 were men (45%). The remaining 111 patients (58 women (52%) and 53 men (48%)) had no medical history of DMT2, and were included in group B. Among others, HbA1c was measured in all patients in months 6,12,18,24,36 and a survival/ events follow-up was recorded. The study duration was 36 months.

Results: In group A, 20 deaths of patients (12%) were reported, among them 8 were men (40%) and 12 were women (60%) with average HbA1c measurements during the follow-up period: 2 patients (10%) with 6,5<HbA1c<7, 6 patients (30%) with 7<HbA1c<8,5 and 12 patients (60%) with HbA1c>8,5. In group B, 10 deaths (9%) were reported. Among them, 4 men (40%) and 5 women (60%) with measurement 6<HbA1c<6,5 and 1 woman (10%) with HbA1c<6. The mortality for patients with ischemic stroke and pAfib is increased with the increase of HbA1c in patients with DMT2 in a statistically significant manner (p 0.0031). An non-statistically significant increase in mortality was also observed in group B. (p 0.22).

Conclusion: The increase in the level of HbA1c increases the mortality in patients with ischemic stroke and pAfib especially in those with DMT2.

Disclosure

K. Kanellopoulou: None. I.L. Matsoukis: None. A. Ganotopoulou: None. T. Athanasopoulou: None. C. Triantafillopoulou: None. A. Sianni: None.
Poor Glycaemic Control—Identifying Variables Associated with Therapeutic Inertia and Lack of Therapeutic Adherence
Authors: CEBRIAN ANA , GUISASOLA FERNANDO ALVAREZ , COS FRANCESC XAVIER , QUINTERO MANUEL RUIZ , MILLARUELO JOSE MANUEL , BELTRAN DOMINGO OROZCO ,   SEMFYC DIABETES THE SPANISH SOCIETY OF FAMILY MEDICINE DIABETES GROUP
Published: June 2018

Two main causes of poor glycaemic control has been describe in diabetic patients: lack of patient adherence to antidiabetic drugs and lack of treatment intensification by the physician.

Aim: To analyse variables associated to therapeutic inertia(TI) or lack of adherence in diabetic patients with poor glycaemic control in Spanish primary care.

Methods: Observational cross sectional nationwide study. 48 primary care physicians (PCP) from the Spanish working group on diabetes mellitus from the Sociedad Española de Medicina de Familia. 4patients randomly selected from each surgery. Individualized glycemic targets were calculated according to the algorithm from Cahn A et al (Diabetes Care 2016). TI was defined as a patient with good adherence, according to PCP opinion, but with poor individualized glycaemic control (GC).

Results: 60.5% of patients had good GC (group A), and 39.5% had poor control, 22.1% due to TI (group B) and 17.4% due to poor therapeutic adherence (PTA) (Group C). All three group of patients differ according to the following variables, respectively: age (69.5 vs. 70.5 vs. 63.8 years; p=0.000); HbA1c (6.27 vs. 7.75 vs. 8.46%; p=0.000); number of antidiabetic drugs (1.3 vs. 2.0 vs. 2,1; p=0.000); prevalence of osteoarthritis (50.5 vs. 44.4 vs. 29,7%; p=0.013); risk of hypoglycaemia (66.7 vs. 64.3 vs. 37.5%; p=0.000); physicians time (years) in the practice (12.5 vs. 15.3 vs. 11.5 years; p=0.000). No differences were found in number of comorbidities, gender, cognitive impairment, micro or macro vascular complications, cancer, thyroid dysfunction, dyslipidemia, arterial hypertension, COPD, anxiety, or depression.

Conclusions: 39.5% of diabetic patients have poor glycaemic control according to individualized targets; 22.1% due to TI and 17.4% due to poor therapeutic adherence. Patients with TI compared to patients with PTA were older, with lower A1c, higher risk of hypos, higher prevalence of ostheoartritis and with a PCP with more years in the practice.

Disclosure

A. Cebrian: None. F. Alvarez Guisasola: None. F. Cos: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Sanofi Pasteur. Speaker's Bureau; Self; Sanofi Pasteur. Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi-Aventis. Research Support; Self; Eli Lilly and Company. M. Ruiz Quintero: None. J. Millaruelo: None. D. Orozco Beltran: None.
The MODY Masquerade
Authors: ENGLERT DANIEL , DENDY JARED
Published: June 2018

Introduction: Maturity Onset Diabetes of the Young (MODY) is a relatively uncommon, but increasingly recognized cause of diabetes. Many MODY patients are misdiagnosed as type 1 or type 2 diabetes mellitus (DM) and may be treated suboptimally for many years before they are recognized. We present one such patient who went 49 years before accurate diagnosis.

Case: A 59 year-old female with a history of type 2 DM presented with complaints of difficulty controlling her blood sugar. She was being treated with metformin, and had been recently started on low dose glimepiride due to persistently elevated hemoglobin A1c (HbA1c). She was diagnosed as type 2 DM at 10 years of age. Her weight was normal at the time of diagnosis, and she did not require insulin. Family history included many family members diagnosed as type 2 DM, including her maternal grandmother, mother, brother, sister, son, and two nieces. All were diagnosed in their teens, and only her son currently requires insulin. On exam, she was not obese (BMI 26 kg/m2) with no signs of insulin resistance. Antibodies to glutamic acid decarboxylase (GAD Ab) were undetectable, and C-peptide was elevated to 4.04 ng/mL in response to mild hyperglycemia. Genetic testing revealed a defect in the Hepatocyte Nuclear Factor 4 Alpha (HNF4A) gene, consistent with MODY subtype 1. The dose of glimepiride was increased, and her HbA1c improved from 8.1% to 6.1% after two months.

Discussion: MODY is a form of diabetes caused by single gene mutations related to beta cell development, regulation, and function. These defects lead to impaired glucose sensing and insulin release. MODY should be suspected in patients with a strong family history of diabetes, lack of signs of insulin resistance, onset at young age, and absence of features of type 1 DM (i.e., negative GAD Ab and detectable C-peptide). MODY subtype 1 patients are typically sensitive to sulfonylurea therapy, and this is considered first-line treatment. However, some patients may develop progressive beta cell dysfunction as they age and will ultimately require insulin therapy.

Disclosure

D. Englert: None. J. Dendy: None.
Effects of Diabetes on Retinal Protein Lysine Malonylation
Authors: ABCOUWER STEVEN F. , SHANMUGAM SUMATHI , HAGER HEATHER M. , LIN CHENG-MAO , FORT PATRICE E. , GARDNER THOMAS W. , SAS KELLI , PENNATHUR SUBRAMANIAM
Published: June 2018

Purpose: The addition of short chain acyl groups to lysines is emerging as key post-translational modifications (PTM) linking metabolite levels to metabolic enzyme activities. Malonyl-lysine (Kmal) targets and inhibits glycolysis and beta-oxidation enzymes. Recently, formation of Kmal was suggested to act as a sink for mitochondrial malate, preventing its inhibition of succinate dehydrogenase in the electron transport chain (ETC). Using the db/db T2DM mouse model, we recently found that diabetes increases retinal glycolysis and beta-oxidation metabolite levels, whereas malate was the only TCA cycle metabolite significantly increased. Metabolic flux measurement with 13C-labeled glucose also demonstrated increased enrichment of labeled malate. We therefore compared the relative levels of Kmal-modified proteins in retinas from diabetic mice as well as in postmortem retinas from diabetic patients to determine if this PTM is altered by diabetes.

Methods: Immunofluorescence (IF) with antibodies specific to acetyl-lysine, to succinyl-lysine and to Kmal was used to probe retinal sections from BKS-db/db mice and BKS-db/+ controls (n=9/group) at 24 weeks of age. Kmal modifications were also examined in mouse retinas from mice made diabetic with streptozotocin (STZ) and controls (n=6/group) and a limited number of retinal sections from postmortem eyes of diabetic (n=4) and control (n=2) patients. Antibodies to markers of retinal ganglion and glial cells were used to co-localize Kmal-modified proteins.

Results: Only Kmal IF intensity was significantly reduced by approximately 30% in both db/db and STZ diabetic mouse retinas. Kmal IF exhibited a 25% reduction in human diabetic retinas. Kmal-modified proteins were concentrated in the ganglion cell layer and largely coincided with Müller glia endfeet and/or astrocytes.

Conclusions: The results suggest that protein malonylation in glial cells is diminished in the diabetic retina, which may increase glycolysis and beta-oxidation while inhibiting the ETC.

Disclosure

S.F. Abcouwer: None. S. Shanmugam: None. H.M. Hager: None. C. Lin: None. P.E. Fort: None. T.W. Gardner: Research Support; Self; Novo Nordisk A/S. K. Sas: None. S. Pennathur: None.
Association of IL-6 and CRP Levels with Gestational Diabetes Mellitus
Authors: SIDDIQUI SAMREEN , WAGHDHARE SWATI , PANDA MANJU , DUBEY SHWETA , JHA SUJEET
Published: June 2018

Aim: Gestational diabetes mellitus (GDM) is a common clinical condition characterized by glucose intolerance of varying severity in the second or third trimester of pregnancy. Inflammatory mediators like interleukin-6 (IL-6) and acute phase protein like C-reactive protein (CRP) are supposed to contribute to development of GDM, however clinical data supporting this hypothesis is limited. This study was designed to analyze the association of inflammatory mediators like IL-6 and CRP with development of GDM in Indian females.

Methods: A case control study design included pregnant women diagnosed as GDM (n=53) and pregnant women having normal glucose tolerance (n=50), screened according to the criteria of American Diabetes Association. Serum levels of interleukin -6 (IL-6) and C-reactive protein (CRP) were analysed in study subjects by enzyme linked immunoassay and correlated with various clinical parameters.

Results: Serum IL-6 levels were significantly high (p<0.05) in GDM females as compared to non-GDM females. The IL-6 levels correlated with pre-pregnancy body mass index (BMI), fasting blood sugar (FBS) levels and postprandial sugar (PPBS) levels. Unlike IL-6, CRP levels did not show significant differences between the GDM and non-GDM females. However, we did observe a positive correlation of CRP levels with BMI, FBS and PPBS. GDM group also showed association with age, BMI and family history of diabetes. The occurrence of GDM was observed more in the females > 30 years of age in our population subset.

Conclusion: High IL-6 levels in gestational diabetes may indicate a possible role for inflammation in pathophysiology of GDM.

Disclosure

S. Siddiqui: None. S. Waghdhare: None. M. Panda: None. S. Dubey: None. S. Jha: None.
Self-Reactivity and T-Cell Receptor Repertoire of Effector and Regulatory T Cells in Autoimmune Diabetes
Authors: KONG YUELIN , SPROUSE MARAN L. , JING YI , BETTINI MATTHEW , BETTINI MARIA
Published: June 2018

T cell infiltration and accumulation in pancreatic islets during autoimmune diabetes is to a large degree driven by TCR reactivity to beta cell antigens. However, it is not fully clear whether the strength of TCR reactivity to beta cell antigens is an important determinant of effector or regulatory T cell function. We observed that CD5 expression is proportional to the level of self-reactivity based on Nur77-GFP reporter of TCR signaling and insulin tetramer staining of islet infiltrating T cells. Using RNAseq profiling, TCR sequencing, and cell transfer we show that CD5 segregates functionally and transcriptionally distinct effector and regulatory T cells, demonstrating that reactivity to beta cell antigens is an important determinant of effector and regulatory T cell function in autoimmune diabetes.

Disclosure

Y. Kong: None. M.L. Sprouse: None. Y. Jing: None. M. Bettini: None. M. Bettini: None.