bluuebunny/crossref_metadata_2025 huggingface dataset:
2441-PUB: Early-Onset Type 2 DM in Young and Middle-Aged Adults in a Diabetes Clinic
Authors: SUNTHARAMOORTHY KAJANA , DAVE SHRUTI , MUHAMMAD UMER , JAVAID EARAJ , GUPTA NIKHIL
Published: June 2019

Introduction: Incidence of type 2 diabetes (T2DM) among young adults has been increasing rapidly. We have noticed a significant increase in consultations received for patients with T2DM diagnosed at age <40 and much younger ages. Patients diagnosed at younger age are at higher risk of microvascular and macrovascular complications over their lifetime. We aim to characterize the clinical characteristics of this patient population.

Methods: All patients (new and follow-up) with T2DM and age≤ 50 years, at our Diabetes and Endocrinology Centre were included. 95 patients (21% of all patients in our diabetes registry) met the eligibility criteria. Demographic variables. comorbidities, diabetes complications, vitals, lab parameters and medications were reviewed.

Results: n=38 (40%) were females. Sixty-eight (71%) were South Asians. Mean age at diagnosis was 34 years(± 7.2). Normal, overweight and obese BMI was seen in 25%, 42% and 33% of South Asians and 12%, 25% and 62% of Caucasians, respectively. South Asians were diagnosed at a younger age with 9%, 16% and 57% diagnosed at age <20, 21-30 and 31-40, respectively, compared to Caucasians 0%, 12.5% and 50% for the same age distribution above. Prevalence of dyslipidemia (86%), Hypertension (62%), retinopathy (4%), neuropathy (21%), nephropathy (29%), CAD (4%), stroke 2% and PVD was 0%, reflecting the younger population in this study.

Conclusion: A large proportion of patients in our diabetes registry are young or middle aged. South Asian ethnicity increases risk of diabetes at a younger age and lower BMI. The epidemic of diabetes at a young age is likely related to increased sedentary lifestyle, inadequate sleep, stress and increasing use of technology and screens.

Disclosure

K. Suntharamoorthy: None. S. Dave: None. U. Muhammad: None. E. Javaid: None. N. Gupta: Consultant; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc., Sanofi.
245-LB: Association between the Risk of T2D Incidence and the Genetic Variants of GCK and HDAC4 Genes Interacting with Alcohol Consumption in Korea
Authors: YUN JI HO , JANG HAN BYUL , YOO MIN-GYU , LEE HYE-JA , PARK SANG IK
Published: June 2019

Chronic alcohol consumption is well-known as an independent risk factor for type 2 diabetes (T2D), which is related with impaired glucose homeostasis and insulin resistance. The identification of genetic variants and the association with diseases may help to explain the genetic etiology of type 2 diabetes. In this study, we aimed to search for the single nucleotide polymorphisms (SNPs) associated with T2D risk, which also interact with alcohol consumption. We conducted genome-wide interaction study using the Korea Association Resource (KARE) data. We found that two SNPs, HDAC4 (rs3791370) and GCK (rs758989) are associated with T2D and also interact with alcohol consumption (odds ratio [OR] 1.74, and OR 1.37, respectively). We further investigated the association between these SNPs and response to alcohol consumption in risk of T2D incidence. In alcohol consumption group, these SNPs significantly increased the risk of T2D incidence compared with nonalcohol consumption group (HDAC4; hazard ratio [HR] 1.29, GCK; HR 1.34). Moreover, genotype association analysis showed that the presence of the risky allele (hetero risky allele [CR] + minor homo risky allele [RR]) in GCK SNP significantly increased the risk of T2D incidence (1.47, p = 0.032) compared with major homo C allele [CC] in alcohol consumption group after adjustment with age, BMI, smoking, physical activity, and history of diabetes. However, presence of the risky allele in HDAC4 SNP marginally increased the risk of T2D incidence (1.47, p = 0.0652). Based on our data, we suggest that HDAC4 and GCK SNPs could be a potential factor for increase of T2D incidence risk, which may be helpful to better understand the genetic basis of T2D in association with alcohol consumption.

Disclosure

J. Yun: None. H. Jang: None. M. Yoo: None. H. Lee: None. S. Park: None.

Funding

Korea National Institute of Health (2019-NI088-00)
2451-PUB: Diabetes Kills Productive Years of Life
Authors: PANCHAL DHARMENDRA , SABOO BANSHI D. , GOKLANI RUTUL
Published: June 2019

Aim: To study the trend of prevalence of diabetes in different age groups.

Method: We have retrospectively analyzed diabetes patient coming to OPD in term of their age of onset and year of onset of diabetes in type 2 diabetes patients from 1st January 2018 to 31st December 2018. There were total 976 patients with type 2 diabetes who visited OPD.

Result: Age distribution of patients with type 2 diabetes attending OPD from 1st January 2018 to 31st December 2018 was as below:

Table: age distribution of patients with type 2 diabetes attending OPD from January 2018 to December 2018.

Conclusion: Average age of onset of type 2 diabetes is still mostly between 35 to 45 years. As the time advances the graph continue to affect more and more younger people in their productive age group which is 35 to 45 years. It not only affects individual’s productivity but also has power to affect any strong economy. There is a strong need to improve our lifestyle and behavior to food and physical activity to fight with this tsunami.

Figure 1. Age Distribution Over the Years for Onset of Type 2 Diabetes.

Figure 2. Average Age of Onset of Type 2 Diabetes.

Disclosure

D. Panchal: None. B.D. Saboo: None. R. Goklani: None.
2453-PUB: Changes in Metabolic Syndrome and Diabetes Risk: A Nationwide Longitudinal Cohort Study
Authors: LEE MIN-KYUNG , KWON HYUK-SANG , SONG KI-HO , LEE JAE HYUK
Published: June 2019

Background: Metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes. We aimed to examine whether changes in metabolic syndrome over a two-year span were associated with the development of type 2 diabetes.

Methods: This prospective cohort study included 10,806,716 adults aged >20 years without a history of type 2 diabetes, using the South Korean National Health Insurance Service database. Metabolic syndrome components were measured at baseline and two years later. Diabetes risk over a four-year period was estimated using Cox proportional hazards models.

Results: During a mean follow-up of 4.08 years, 848,859 individuals were diagnosed with type 2 diabetes. Multivariable-adjusted hazard ratios (HRs) for developing diabetes were 1.501 in individuals with metabolic syndrome at baseline and without it two years later, 1.768 in those without metabolic syndrome at baseline and with it two years later, and 2.327 with metabolic syndrome both at baseline and two years later compared with those without metabolic syndrome at either time point. The HRs for diabetes were increased with the number of metabolic syndrome components at baseline and two years later, and decreased significantly with a decrease in the number of components (p for trend < 0.0001). The risk of diabetes was more strongly associated with changes in metabolic syndrome in individuals aged between 20 and 39 years.

Conclusions: Changes in metabolic syndrome could predict the development of type 2 diabetes. In addition, the risk of type 2 diabetes showed a stronger association with metabolic syndrome in young adults. These observations suggest that improving metabolic syndrome is important to prevent type 2 diabetes, particularly for young adults.

Disclosure

M. Lee: None. H. Kwon: None. K. Song: None. J. Lee: None.

Funding

Korean National Research Foundation (2018R1D1A1B07049079)
2458-PUB: Prevalence and Correlates of Sleep Disorders in Greek Patients with Type 2 Diabetes: Comparison of an Urban and a Semiurban Population
Authors: PAPAZAFIROPOULOU ATHANASIA , STAMATELATOU MARIA , XOURGIA ELENI , MPOUMI LOUISA , GEORGOPOULOS ELIAS , TZIOMALOS GEORGE , SOLIDAKI SOFIA , DASENAKI MARIA , MELIDONIS ANDREAS
Published: June 2019

Background and Aims: Sleep disturbances are common among individuals with type 2 diabetes (T2D). The aim of this study was to estimate the prevalence and correlates of sleep disorders in Greek diabetics and differences between an urban and semi-urban population.

Materials and Methods: The study population was comprised of 308 T2D patients [139 patients from Piraeus (urban population, group A) and 169 patients from Sitia (semi-urban population, group B)]. In all patients, quality of sleep was evaluated by administering the Pittsburgh Sleep Quality Index (PSQI) through an interview. The PSQI is a self-report questionnaire that assesses sleep quality and quantity over a month-long period.

Results: Mean PSQI score of group A was 11.22 ± 6.44 and 88.5% (n=123) of the participants had a PSQI score ≥5, indicating poor quality of sleep. Mean PSQI score of group B was 12.48 ± 5.85, and 88.8% (n=140) had a PSQI score ≥5. Incidence of a PSQI score ≥5 did not differ between the two groups (P=0.13). Logistic regression analysis, after adjustment for sex, BMI, presence of hypertension and dyslipidemia, smoking, diabetes complications, and oral antidiabetic treatment, showed that PSQI ≥5 in total sample population was associated with insulin treatment [odds ratio (OR): 0.03, 95% confidence interval (95% CI): 0.31-0.99], and HbA1c (OR: 6.56, 95% CI: 1.93-16.14). In group A, poor sleep quality was associated with insulin treatment (OR: 0.02, 95% CI: 0.10-0.84), and HbA1c (OR: 7.55, 95% CI: 1.97-18.81). In group B, poor sleep quality was associated only with age (OR: 1.36, 95% CI: 1.06-1.74).

Conclusion: Our study suggested that Greek patients with T2D have a high prevalence of sleep disorders with similar incidence for urban and semi-urban population. Insulin treatment and HbA1c were the greatest predictors of sleep disorders. Identifying sleep disorders in T2D and treating them early might improve patient's quality of life.

Disclosure

A. Papazafiropoulou: None. M. Stamatelatou: None. E. Xourgia: None. L. Mpoumi: None. E. Georgopoulos: None. G. Tziomalos: None. S. Solidaki: None. M. Dasenaki: None. A. Melidonis: None.
247-OR: Real-World Effectiveness of SGLT2 Inhibitors vs. GLP-1 Receptor Agonists in Patients With and Without Cardiovascular Disease
Authors: PATORNO ELISABETTA , PAWAR AJINKYA , SCHNEEWEISS SEBASTIAN , GLYNN ROBERT J. , KIM DAE H. , EVERETT BRENDAN M. , BESSETTE LILY G. , KIM SEOYOUNG C.
Published: June 2019

Both SGLT2i inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) have shown cardiovascular (CV) benefits in CV outcome trials among patients with type 2 diabetes (T2D) and established CV disease (CVD). Whether these agents are associated with differential CV effects and mortality in real-world T2D patients with and without CVD is unclear. Using Medicare and 2 U.S. commercial claims datasets (4/2013-12/2016), we identified 1:1 propensity score-matched patients aged ≥18 years with T2D initiating a SGLT2i or a GLP-1 RA with and without CVD (32,064 and 101,210 matched pairs, respectively). We assessed a composite CV outcome [myocardial infarction (MI) or stroke], mortality, and hospitalization for heart failure (HHF), and estimated hazard ratios (HRs) and 95% CIs adjusting for >140 baseline covariates. Compared to GLP-1 RA, the HR for the composite CV outcome was 1.10 (95% CI 0.95-1.26) for SGLT2i initiators with CVD, and 1.23 (1.08-1.41) for initiators without CVD, over a mean 8.4-month follow-up (Table). Initiators of the two drugs with and without CVD had similar mortality risk, but SGLT2i users had 31-33% reductions in HHF risk [0.67 (0.55-0.81) and 0.69 (0.51-0.92)]. This study suggests robust reductions in rates of HHF associated with SGLT2i vs. GLP-1, but in primary prevention, where HHF was less common, benefits were offset by somewhat increased risk of MI and stroke.

Disclosure

E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Pawar: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. R.J. Glynn: Research Support; Self; AstraZeneca, Kowa Pharmaceutical Europe Co. Ltd., Novartis Pharmaceuticals Corporation, Pfizer Inc. D.H. Kim: None. B.M. Everett: Advisory Panel; Self; American College of Cardiology. Consultant; Self; Abbott Laboratories, Amgen Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Roche Diagnostic USA. Research Support; Self; Novartis Pharmaceuticals Corporation. Other Relationship; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; UpToDate. Other Relationship; Spouse/Partner; UpToDate. L.G. Bessette: None. S.C. Kim: Research Support; Self; Bristol-Myers Squibb Company, Genentech, Inc., Pfizer Inc.
2472-PUB: JNK1 Plays a Causal Role in Palmitate-induced ß-Cell Dysfunction In Vivo
Authors: MING YUNG JUSTIN HOU , NGA YEUNG LUCY SHU , NAHLE ASHRAF , KOULAJIAN KHAJAG , GIACCA ADRIA
Published: June 2019

In obesity, chronically elevated circulating free fatty acids (FFA) potentially cause ß-cell dysfunction which leads to type 2 diabetes (T2D). In vitro data have identified various cellular mechanisms leading to FFA-induced ß-cell dysfunction including activation of inflammatory kinase c-Jun N-terminal kinase (JNK). In the ß-cell, JNK1 responds to oxidative stress or ER stress, which can both be caused by FFA. Previous in vitro studies from our group have demonstrated that islets of JNK1-null mice are protected from the effect of palmitate but not oleate on inducing ß-cell dysfunction, suggesting that activation of JNK1 is specific to saturated FFA. Thus, we hypothesized that saturated FFA-induced ß-cell dysfunction is mediated in part by JNK.

Due to its detergent effects, palmitate cannot be infused directly into circulation. Thus, ethylpalmitate was used, as the ethyl group reduces the toxic effect. Mice can hydrolyze the ethyl group in circulation, producing palmitate and ethanol. JNK1-null (KO) mice and their littermate controls (WT) were infused with ethylpalmitate or ethanol vehicle for 48 hours, after which their pancreatic islets were isolated for ex vivo determination of insulin secretion.

We confirmed that ethylpalmitate infusion does significantly increase plasma FFA as compared to vehicle infusion. We found that WT mice infused with ethylpalmitate demonstrated significantly decreased insulin secretion as compared with WT mice infused with vehicle, whereas JNK1-null mice infused with ethylpalmitate had similar insulin secretion as controls. These data suggest that JNK1 plays a causal role in saturated FFA-induced ß-cell dysfunction in vivo.

Disclosure

J. Yung: None. L. Yeung: None. A. Nahle: None. K. Koulajian: None. A. Giacca: Research Support; Self; Jazz Pharmaceuticals.

Funding

Canadian Institutes of Health Research
2477-PUB: Blood Beta Hydroxybutyrate Levels in Adult Patients Presenting to Emergency Department
Authors: DEPCZYNSKI BARBARA , LEE ALEXANDRA T. , VARNDELL WAYNE F. , CHIEW ANGELA L.
Published: June 2019

Ketone bodies are an important alternate fuel source with fasting. Our aim was to describe point of care blood beta hydroxybutyrate (BHB) in patients presenting to emergency (ED). We performed a retrospective study. The population consisted of adult patients attending emergency department of a tertiary referral hospital who had a BHB measurement and venous blood gas measurement (VBG) performed at presentation to ED. Between March-September 2018 inclusive, 4356 patients had at least one VBG performed, and of these 842 patients had at least one BHB level performed whilst in ED. Of the whole cohort, 604 patients were admitted and 238 discharged from ED or short stay ward. Results are shown as mean±SD (range). Age was 62.5±21.6 years (16.1-102.5). 55% of cohort were male. Length of stay was 6.23±9.99 days (0.35-77.77), and Charlson score 1.91±2.03 (0-15). Blood glucose (BG) was 10.5 ±7.3mmol/L (2-54mmol/L), lactate 2.2±1.7mmol/L (0.3-21), and BHB 0.6±1.2mmol/L (0-8.4). Of the whole cohort, 404 patients had diabetes. Excluded from subsequent analysis were 18 cases of diabetic ketoacidosis and 6 cases of hyperosmotic hyperglycaemic syndrome. Of this cohort, BHB level did not differ according to diabetes status (0.52±0.9mmol/L those with diabetes versus 0.41±0.75mmol/L in those without) yet BG (13.7±7.4mmol/L versus 6.8±2.8mmol/L, p<0.01) was higher as was lactate (2.3±1.6mmol/L versus 2.1±1.8mmol/L, p<0.05). Where acute vomiting was documented to be present versus not recorded, BHB was higher (0.64±1.0 mmol/L versus 0.43±0.81mmol/L). Where acute ethanol intake was documented, BHB was not significantly higher (0.66±1.34mmol/L versus 0.44±0.79mmol/L). BHB ≥3mmol/L was seen in 2.9% of those with diabetes and 2.1% of those without diabetes. Although serum albumin was no different, BMI was lower in those with BHB ≥ 3mmol/L (23.5±7.7kg/m2 versus 27.6±6.9kg/m2). Ketosis is commonly seen in ED, is associated with reduced oral intake and is not confined to those with diabetes.

Disclosure

B. Depczynski: None. A.T. Lee: None. W.F. Varndell: None. A.L. Chiew: None.
2495-PUB: Negative Relationship between Obesity and Cardio Ankle Vascular Index in Diabetic Patients
Authors: SUYUAN WANG , CHENGHUI ZHANG , YUNHONG WU , MINGXIA LI
Published: June 2019

Introduction: The aim of this study is to explore the relationship between obesity and cardio-ankle vascular index (CAVI) in Tibet diabetic patients.

Method: Related data of hospitalized diabetic patients during May 2017 to November 2018 were collected and analyzed. Eligible patients were diagnosed diabetic patients aged from 18 to 80. The exclusion criteria were malignant tumor, patients who has been undertaken surgery in the past 6 months. Logistic regression was used to analyze the relationship between CAVI and Obesity.

Result: A total of 1025 patients were enrolled, 758(73.95%) were female. Patients were divided into 3 groups according their BMI, 335 patients were normal in weight(BMI≤24kg/m2), 463 were overweight(24kg/m2≤BMI≤28kg/m2) and 227 were obesity(BMI≥28kg/m2). The age of these patients were 54.81±9.6. CAVI among three groups were 8.58±1.12, 8.34±1.16, 8.12±1.2, respectively (P<0.001). After adjustment for age, gender, SBP, DBP, and duration of diabetes, BMI was negatively associated with CAVI (β=-0.067, 95% CI -0.090∼-0.059, P<0.001), CAVI was lower in overweight (β=-0.265, 95% CI -0.382∼-0.147, P<0.001)and obesity (β=-0.558, 95% CI -0.702∼-0.413, P<0.001) groups. We also found a negative relationship between waist circumference(β=-0.020, 95% CI -0.025∼-0.014, P<0.001), abdominal obesity (β=-0.369, 95% CI -0.494∼-0.245, P<0.001), and CAVI.

Conclusion: We found a negative relationship between BMI and CAVI in diabetic patients, further study is required to find out possible mechanism and its influence on the onset of CVD.

Disclosure

W. Suyuan: None. Z. Chenghui: None. W. Yunhong: None. L. Mingxia: None.
2497-PUB: Relationship between Visceral Obesity and Periodontal Disease in Women
Authors: JACOMOSSI ANGELO CÉSAR FERNANDES
Published: June 2019

Obesity consists in a risk condition to several chronic diseases. The relationship of excessive adiposity and oral health has been the target of extensive investigations. To assess the association of visceral obesity (VO) and periodontal disease (PD) we evaluated 24 visceral obese women, assessing the periodontal heathy and the body fat distribution. Visceral obesity was defined by the waist to hip measurement (W/H) greater than 0.85. Periodontal disease was assessed by the Community Periodontal Index (CPI). Bioimpedanciometry was performed in all women, in addition to blood sample collection to glucose and plasma insulin dosage to calculate the Homeostatic Model Assessment - Insulin Resistance (HOMA-IR). The data were correlated by the following statistical analysis: the Shapiro-Wilk test to analyze the normality of the data. Pearson's parametric correlation test to investigate the correlation between HOMA-IR, Body Mass Index (BMI), the ratio percentage of visceral fat and total fat (%VF/%TF) and W/H. Spearman's non-parametric correlation test to investigate the correlation among the HOMA-IR, CPI, percentual total fat (%TF) and visceral fat (%VF) variables. Spearman's nonparametric correlation test to investigate the correlation among the CPI, %TF, %VF, %VF/% TF, BMI and W/H variables. We found a positive correlation between CPI e CA/CQ [r:0,4442; 95% CI -0.01199 to 0.7473; P (two-tailed) 0,0498]; and between CPI e %VF [0,4522; 95% CI -0.001949 to 0.7517; P (two-tailed) 0,0453]. It was not possible to find a positive correlation between CPI and %TF [r:0.2681; 95% CI - 0.2114 to 0.6436; P (two-tailed) 0.2531], as well as for the relationship between CPI and HOMA-IR [r:-0,344; P (two-tailed) 0.35; ns]. The other analyzes performed did not also show positive correlation. The firsts results suggest a positive correlation between PD and VO. But, the lack of correlation between CPI and HOMA-IR, contradicts this. Further studies should be performed to better clarify this issue.

Disclosure

A.C.F. Jacomossi: None.
2499-PUB: Sagittal Abdominal Diameter (SAD): A Marker of Metabolic Syndrome, Insulin Resistance (HOMA-IR) among Saudi Type 2 Diabetes Mellitus (T2DM) Patients
Authors: TOURKMANI AYLA , RSHEED ABDULAZIZ BIN , ANSARA HEBA , ALHARBI TURKI , FOUAD MOSTAFA
Published: June 2019

Abdominal obesity has been identified as an important risk factor for T2DM. Anthropometric measures (BMI, waist circumference (WC) and hip circumference (HC) are commonly used in evaluating obesity. One major shortcoming of these measure are their inability to distinguish between abdominal and visceral adipose tissue. SAD (i.e., the height of the abdomen when lying supine) predict the amount of visceral fat and several studies showed its strong correlation with insulin resistance, hyperinsulinemia as well as its prediction of metabolic syndrome.

The study is ongoing and aimed to evaluate SAD as predictor of metabolic syndrome components and (HOMA-IR) among Saudi T2DM patients.

A cross-sectional sample of 433 T2DM subjects (256 female and 177 male) with mean age of 57.2±11.7 (18-86) years was suitable for analysis. Mean SAD, BMI, WC and HC were 15.6±3.7 cm, 32.9±6, 105.5±12 cm and 113.3±12.7 cm respectively; mean HbA1c and C-peptide were 8.5%±1.5 and 754.6±471pmol/L respectively. SAD (Sensitivity, specificity) with correspondence to metabolic syndrome were (77%, 77%) in males and (72%, 53%) in females. The area below the ROC curve was 14.1 cm for males and 14.75 cm for females.

In Females, Each 1 cm increase in SAD increased 29% of HOMA-IR (aOR 1.293), 95% CI: 1.084-1.542; P = 0.004) and HbA1c increased 70%of moderate to severe HOMA-IR(aOR 1.703, 95% CI: 1.285-2.256; P = 0.001). In males, HbA1c and total cholesterol increased moderate to severe HOMA-IR by 50% and 90% respectively (aOR 1.999, 95% CI: 1.123-3.56; P = 0.019). Insulin level among female (aOR1.051, 95% CI: 1.005-1.098; P = 0.028) and HbA1c among male (aOR1.427, 95% CI: 1.06-1.921; P =0.019) increased 5% and 42% of metabolic syndrome risk respectively.

SAD was a strong predicator of insulin resistance in Female Saudi T2DM patients. The lower cut-off points of SAD in both genders compared with International threshold as well as SAD prediction of metabolic syndrome should be further examined.

Disclosure

A. Tourkmani: None. A. Bin Rsheed: None. H. Ansara: None. T. AlHarbi: None. M. fouad: None.
2500-PUB: Mir-302 Protects against Glucolipotoxicity-Induced ß-Cell Dysfunction and Apoptosis through the Regulation of MST1 and PDX1
Authors: HUANG CHIEN-NING , LI HSIN-HUA , KORNELIUS EDY , YANG YI SUN , HO HSIAO-LI , BAI YI-CHIAO , KUO CHIEN-YIN , PENG CHIUNG-HUEI , LIN CHIH-LI
Published: June 2019

Evidence is now revealed that the cytotoxic effect caused by elevated levels of plasma glucose and free fatty acids, also called as glucolipotoxicity, is particularly harmful for pancreatic β-cell. In fact, the mammalian Ste20-like kinase 1 (MST1) can mediate glucolipotoxicity-induced β-cell damages by degradation of pancreatic and duodenal homeobox 1 (PDX-1), which is known to play an essential role in maintaining β-cell function and survival. Interestingly, the activation of the pluripotency-related microRNA cluster miR-302 can protect β-cells from glucolipotoxicity-induced apoptosis. However, few studies have examined the related mechanism in detail. In the present study, we investigated the protective roles of miR-302 on rat pancreatic RINm5F β-cells, and demonstrated that MST1 was confirmed as a target of miR-302. As a result, the activation of miR-302restored the expression of PDX1 by inactivating MST1 thus ameliorating glucolipotoxicity-induced β-cell impairments. In addition, miR-302 also upregulated endogenous antioxidant signaling and autophagic activities during glucolipotoxicity, suggesting the anti-aging process may be also involved in miR-302-mediated protection.

In conclusion, our study suggests that miR-302 may serve as a potential target for developing new diagnoses and therapies to reduce glucolipotoxicity in β-cells.

Disclosure

C. Huang: None. H. Li: None. E. Kornelius: None. Y. Yang: None. H. Ho: None. Y. Bai: None. C. Kuo: None. C. Peng: None. C. Lin: None.

Funding

Ministry of Science and Technology of Taiwan (105-2314-B-040-013-MY3)
255-LB: The Role of Th1, Th2, Th17, and Treg Cells in Various Clinical Phases of Type 1 Diabetes
Authors: OZGUR BURCIN AYDIN , CINAR SUZAN , OZTURK DERYA , COSKUNPINAR ENDER , GUROL ALI OSMAN , YILMAZ M. TEMEL
Published: June 2019

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycaemia due to insulin production/secretion disorder or insulin resistance caused by various pathogenetic mechanisms. T helper cells (Th) play an important role in the pathogenesis of the disease. In our study, peripheral blood mononuclear cells (PBMC) were isolated from peripheral blood samples from newly diagnosed, 1 year and 5 year type 1 diabetes (T1D) patients (8 patients) and 8 healthy controls, and cultured for 24 hours under unstimulated and stimulated conditions. After culture, the cell ratios of Th1, Th2, Th17, and regulator T (Treg) and the intracellular levels of IFN-γ, TNF-α, IL-10, TGF-β, IL-5, IL-13, IL-17 and IL-21 cytokines were evaluated using Flow Cytometry; whereas mRNA expressions of the transcription factors T-bet, GATA3, ROR-γt and FOXP3 of these cells were determined by Real-Time PCR. Reduced CD4+CD25high cell ratios were detected in newly diagnosed T1D patients under unstimulated conditions. CD4+CD25high cells were found to be reduced in the newly diagnosed and 1 year group of patients compared to healthy controls under IL-2 stimulated conditions. Intracellular IFN-γ and TNF-α levels were low in all patients under unstimulated and IL-12 stimulated conditions. IL-17A and IL-21 were found to be high in patients with unstimulated and IL-6 stimulated conditions. Expressions of IL-10 and TGF-β have been observed to be reduced in patients. Th1/Th2, Th17/Treg and Th1/Treg ratios were higher in the patient groups. FOXP3 and GATA3 mRNA expressions were found to be low in patients, while RORγt and T-bet mRNA levels were higher than healthy controls under stimulated and unstimulated conditions. Our results suggest that Th cell subgroups play an important role in the pathogenesis of T1D.

Disclosure

B. Aydin Ozgur: None. S. Cinar: None. D. Ozturk: None. E. Coskunpinar: None. A.O. Gurol: None. M. Yilmaz: None.
261-OR: Core-Shell Spherification: A New Microencapsulation Platform for Hyaluronic Acid and PEGDA
Authors: KARANU FRANCIS , HARRINGTON STEPHEN , OTT LINDSEY
Published: June 2019

Cell microencapsulation associated with islet transplantation is a rapidly expanding field. Traditional alginate microspheres still suffer from poor biocompatibility, and microencapsulation of more advanced hydrogels is challenging due to their slower gelation rates. We have developed a novel, non-cytotoxic, non-emulsion based method to produce hydrogel microspheres compatible with a wide variety of materials, called Core-Shell Spherification (CSS). Here, we demonstrate fabrication of microspheres via CSS derived from two slow-hardening hydrogels: hyaluronic acid (HA) and polyethylene glycol diacrylate (PEGDA). HA microspheres were manufactured with two different crosslinking methods: thiolation and methacrylation. Microspheres of methacrylated HA (MeHA) had the greatest swelling ratio, the largest average diameter and the lowest diffusion barrier. In contrast PEGDA microspheres had the smallest diameters, the lowest swelling ratio and the highest diffusion barrier, while microspheres of thiolated HA (ThHA) had characteristics that were in between the other two groups. To test the ability of the hydrogels to protect cells while promoting function, diabetic NOD mice received xenotransplants via intraperitoneal injections of PEGDA or MeHA microencapsulated canine islets. PEGDA microspheres reversed diabetes for the length of the study (up to 16 weeks). In contrast, islets encapsulated in MeHA microspheres at the same dose restored normoglycemia, but only transiently (3-4 weeks). Non-encapsulated canine islet transplanted at the same dose did not restore normoglycemia for any length of time.

In conclusion, CSS appears to offer several advantages to current cell encapsulation technologies, including a non-toxic microencapsulation procedure compatible with various hydrogel types.

Disclosure

F. Karanu: Employee; Self; LIkarda LLC. S. Harrington: Employee; Self; Likarda, LLC. L. Ott: Employee; Self; Likarda, LLC.
262-OR: INAD 012-776 Pilot Study: Allogeneic “Neo-Islets,” Composed of Mesenchymal Stem and Islet Cells, Are Immune Protected and Dose-Dependently and Durably Control Autoimmune T1DM in Pet Dogs
Authors: WESTENFELDER CHRISTOF , CHOWDHURY SABIHA S. , GOOCH ANNA
Published: June 2019

We demonstrated that allogeneic, ip administered “Neo-Islets” (NIs), aggregates of cultured islet cells (ICs) and immune- and cyto-protective Adipose Derived Stem Cells (ASCs), reestablished durable normoglycemia through omental engraftment and splenic and omental upregulation of Tregs, in autoimmune T1DM NOD mice without immunosuppressive agents (SCTM 2017;6:1631). Comparable euglycemia was achieved with dog- or human-derived NIs in STZ-diabetic NOD/SCID mice. Here we update our report on an FDA supervised study using NI therapy in diabetic pet dogs.

Insulin dependent, diabetic pet dogs, ≤12 kg, were included; 7 enrolled; 5 treated; and 4 followed for ≥6 mos. Pre-treatment serum samples were tested for islet autoantibodies. Comorbidities and blood glucose levels were treated. NIs were given once ip in a dose escalation protocol (2.5x10e5 to 5x10e5/kg bw). Blood glucose levels, insulin need and antibody responses were monitored.

Prior to treatment 3 dogs had islet autoantibodies indicating autoimmunity, and 1 dog had no islet autoantibodies, potentially indicating insulin resistance. NIs appear to engraft, redifferentiate and physiologically produce insulin, and are neither rejected by auto- or allo-immune attacks, as evidenced by (a) an absent IgG response to the administered NIs, and (b) progressively, durably (≥ 12 mos) and dose-dependently improved glycemic control, achieved with a 50% reduction in daily insulin need paralleled by a fall in HbA1c in one dog from 12.1 to 6.8%. One dog was not compliant with keeping blood glucose levels controlled in the first few weeks post treatment and failed to respond.

We conclude that this novel therapy may have significant translational relevance to human T1DM.

We thank site PIs Drs. R. Sellon, WSU, Pullman, WA, N. Loy Son and J. Fisher, Veterinary Specialty Hospital, San Diego, CA, for their excellent collaboration.

Disclosure

C. Westenfelder: Consultant; Self; SymbioCellTech. S.S. Chowdhury: Employee; Self; SymbioCellTech. A. Gooch: Board Member; Self; SymbioCellTech.
265-LB: Mitochondria-Targeted DNA Repair Glycosylase OGG1 Protects Against HFD-Induced Obesity and Insulin Resistance in OGG1 Deficient Mice
Authors: YUZEFOVYCH LARYSA , RACHEK LYUDMILA
Published: June 2019

Mitochondrial DNA (mtDNA) damage heightens mitochondrial oxidative stress, which is very critical for the development of insulin resistance. OGG1 (8-oxoguanine DNA glycosylase-1) is a DNA glycosylase mediating the first step in the base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mtDNA. Previous studies showed that Ogg1 deficiency results in an increased susceptibility to high fat diet (HFD)-induced obesity, metabolic dysfunction and IR in mice, suggesting a crucial role of Ogg1 in glucose metabolism. Here we performed studies in vivo using Ogg1 knockout and overexpressing genetic models: 1)Ogg1 -/- (KO); 2)KO mice with mitochondrial targeted hOGG1 (hOGG1, subunit 1-α; KO/Tg); 3) wild type (WT) mice. Male mice of all three genotypes were fed either high fat diet (HFD) or control low fat diet (LFD) for 16 weeks, and obesity and insulin resistance phenotypes were evaluated. Our results demonstrated that HFD-fed KO mice displayed increased obesity and whole-body insulin resistance phenotype compared to both WT and KO/Tg mice fed with HFD. Additionally, we have utilized a translational strategy of targeting the recombinant hOGG1 into mitochondria using a TAT-protein transduction system. KO mice were fed HFD and vehicle or MTS-hOGG1-TAT protein was administered intraperitoneally twice weekly for 9 weeks. Consistent with results obtained for genetic models, KO mice injected with MTS-hOGG1-TAT showed significantly lower blood glucose levels and insulin resistance phenotype compared to mice injected with vehicle. Our findings suggest that protecting mtDNA from damage might be crucial to prevent insulin resistance. Furthermore, our data provides strong rationale to use TAT-delivery of DNA repair enzymes into mitochondria as a new translational approach for treatment of insulin resistance.

Disclosure

L. Yuzefovych: None. L. Rachek: None.

Funding

American Heart Association (16GRNT29150012 to L.R.)
267-OR: Cardiomyocyte Insulin Resistance Manifests on High-Glucose Fibroblast-Derived Extracellular Matrix
Authors: NIEUWOUDT STEPHAN , WANG XINMING , SENAPATI SUBHADIP , PARK PAUL , SENYO SAM
Published: June 2019

The primary cause of death in diabetes is heart failure. Growing evidence suggests that remodeling of the physical microenvironment of the heart drives cardiomyocyte pathology, independent of hypertension and coronary artery disease. Several studies have thus far provided evidence that the extracellular matrix (ECM) changes with diabetic peripheral complications by vascular obstruction and fibrotic hypertension. Rather than a secondary phenomenon, our in vitro data implicates fibroblast derived ECM as a direct regulator of cardiomyocyte insulin sensitivity. Using published methods, we observe that ECM derived from plated primary neonatal cardiac fibroblasts is structurally altered when produced in low- (5mM) versus high-glucose (25mM), with respect to density indicative of collagen crosslinking (Aniline blue staining) and increased stiffening (Atomic Force Microscopy). Most importantly, plating primary cardiomyocytes on high-glucose (vs. low-glucose) fibroblast derived matrix reduces insulin sensitivity (Akt/PKB phosphorylation). We also observe reduced Focal Adhesion Kinase (FAK) activation and c-Jun N-terminal kinase (JNK) inactivation within this in vitro platform; pathways which have been shown to regulate insulin sensitivity via integrin binding to ECM proteins. The cardiac fibroblast derived matrix model serves as a high throughput in vitro platform, which we have thus far used to establish the direct relationship between ECM deposition and insulin sensitivity. Future work will use the platform to dig into the underlying mechanisms implicating ECM remodeling and sensing in the pathogenesis of diabetic cardiomyopathy and heart failure.

Disclosure

S. Nieuwoudt: None. X. Wang: None. S. Senapati: None. P. Park: None. S. Senyo: None.

Funding

Case Western Reserve University (RES221997); Wallace H. Coulter Foundation; National Heart, Lung, and Blood Institute (T32HL134622-02)
269-OR: miR-409-3p Regulates Angiogenesis Brown Fat Adiposity and Insulin Resistance
Authors: BECKER-GREENE DAKOTA R. , LI HAO , WU WINONA , OZDEMIR DENIZHAN , HOLLAN IVANA , FEINBERG MARK W. , ICLI BASAK
Published: June 2019

White and brown adipose tissues are highly vascularized organs, capable of plasticity based on metabolic demands and energy expenditure, which if maladaptive can lead to insulin resistance. Critical gaps remain in our understanding of how angiogenesis impacts adipose tissue dysfunction and overall metabolism. MicroRNAs (miRs) are implicated in the regulation of the angiogenic response to pathophysiological stimuli. Function of miRNAs regulating the angiogenic response in diet-induced insulin resistance remains poorly understood. Using a miRNA-Seq approach, we identified that miR-409-3p expression was significantly increased in endothelial cells (ECs) of brown adipose tissue (BAT) of diet-induced obese (DIO) mice and in human diabetic plasma samples compared to nondiabetic patients. Overexpression of miR-409-3p markedly inhibited EC growth and migration, whereas miR-409-3p inhibition had the opposite effects. miR-409-3p targets the 3’UTR of Zinc Finger E-box binding Homeobox 1 (ZEB1). Overexpression of miR-409-3p decreased ZEB1 expression in ECs and in human subcutaneous white adipose tissue (sWAT). SiRNA knock down of ZEB1 expression in ECs phenocopied the effects of miR-409-3p overexpression and significantly decreased cell proliferation and migration. In addition, 3T3-L1 cells co-cultured with supe harvested from ECs deficient in miR-409-3p had increased expression of brown fat markers (UCP1, Cidea, PGC1-α) by RT-qPCR and Western blot analyses. Systemic intravenous delivery of LNA-anti-miR-409-3p inhibitor to DIO mice significantly increased angiogenesis by CD31 staining, accompanied by higher UCP-1 in BAT and sWAT by RT-qPCR, Western blot and immunohistochemistry analyses, while improving glucose tolerance and overall metabolism. miR-409-3p plays a key regulatory role between impaired angiogenesis in diet-induced obesity and adipose tissue dysfunction, an effect that could be exploited for therapeutic intervention in obesity-induced insulin resistance.

Disclosure

D.R. Becker-Greene: None. H. Li: None. W. Wu: None. D. Ozdemir: None. I. Hollan: None. M.W. Feinberg: None. B. Icli: None.

Funding

American Diabetes Association (1-16-JDF-046 to B.I.)
273-LB: Leukocyte-Endothelial Interaction Is Reduced by Insulin-Induced Downregulation of Endothelial CXCR4
Authors: KUNKEMOELLER BRITTA , RATHJEN THOMAS , PATTI JAMES C. , LI QIAN , PARK KYOUNGMIN , KING GEORGE L. , RASK-MADSEN CHRISTIAN
Published: June 2019

An activated, pro-inflammatory endothelium is a key feature of obesity and type 2 diabetes and may contribute to adipose tissue inflammation, atherosclerosis and tumor formation. We have previously published a striking 4-fold increase in leukocyte adhesion to endothelium in mice with endothelial cell knockout of the insulin receptor. Here, we searched for insulin-regulated genes involved in leukocyte-endothelial cell interaction by performing RNA sequencing in primary human endothelial cells. Among genes with the largest change in expression after insulin treatment was C-X-C motif chemokine receptor 4 (CXCR4), which was downregulated by 54%. This reduction was completely prevented by pretreatment with wortmannin but not by U0126, an inhibitor of MAPK signaling. In CD31+ cells isolated by fluorescence-activated cell sorting of enzymatically dissociated tissue, CXCR4 mRNA in was 77% higher in mice with diet-induced obesity compared to lean controls and 37% higher in db/db mice compared to db/+ controls, consistent with upregulation of CXCR4 in endothelial cell insulin resistance. Stromal-derived factor-1 (SDF-1), the ligand for CXCR4, increased leukocyte adhesion to cultured endothelial cells. Insulin treatment of endothelial cells prevented 80% of this increase which in turn was abrogated by plerixafor, a clinically approved CXCR4 antagonist, or deletion of CXCR4 by gene editing. To study gain of endothelial cell insulin signaling in vivo, we examined transgenic mice with endothelial overexpression of insulin receptor substrate-1 (IRS-1). In vivo microscopy of mesenteric venules showed an increase in leukocyte rolling and adhesion after intravenous injection of SDF-1 in wildtype mice which was reduced by 83% in transgenic mice. We conclude that endothelial cell insulin signaling limits leukocyte-endothelial cell interaction through downregulation of CXCR4 and that targeting endothelial CXCR4 may protect against inflammation in insulin resistant states.

Disclosure

B. Kunkemoeller: None. T. Rathjen: Employee; Self; Bayer AG. J.C. Patti: None. Q. Li: None. K. Park: None. G.L. King: Research Support; Self; Sanofi. C. Rask-Madsen: None.
274-OR: Beta-Cell Dysfunction Is Associated with Impaired Insulin-Mediated Suppression of Glucagon in Obese Hispanic Americans
Authors: CHEN XI , MALDONADO CORCHADO ENRIQUE R. , MEROVCI AURORA , CASE EMINA , TRIPATHY DEVJIT , DEFRONZO RALPH A.
Published: June 2019

Recent studies have demonstrated an increase in the glucagon:insulin ratio in lean versus obese subjects. We assessed insulin-mediated suppression of plasma glucagon levels in 260 obese Hispanic Americans (59 NGT, HbA1c= 5.1±0.1%, BMI= 32.6±0.7; 109 Prediabetes, HbA1c= 5.8±0.1%, BMI= 33.8±0.5; 92 T2D, HbA1c= 7.3±0.2%, BMI= 34±0.5) with varying glucose tolerance. Subjects participated in a 2-h OGTT with measurement of plasma glucose, insulin, glucagon concentrations. During the OGTT, we quantitated insulin-mediated suppression of plasma glucagon concentration, Matsuda Index of insulin sensitivity, and the insulin secretion/insulin sensitivity (disposition) index using plasma C-peptide concentration. There was no difference in fasting plasma glucagon level between obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D). However, there was a progressive decrease in fasting glucagon:insulin ratio from NGT to prediabetes to T2D (8.71±0.72 vs. 6.92±0.53 vs. 5.66±0.41, P<0.01). During OGTT at 60 min, glucagon:insulin ratio increased from NGT to T2D (0.93±0.09 vs. 0.89±0.07 vs. 2.33±0.20, P<0.001), and the suppression of plasma glucagon (compared to basal value) was markedly decreased (10.3±3.4% vs. 9.3±1.9% vs. 2.5±2.8%, P<0.05). At 120 min (OGTT), glucagon:insulin ratio was increased in T2D versus NGT (1.28±0.17 vs. 2.0±0.20, P<0.01). The glucagon:insulin ratio was closely correlated with whole body insulin sensitivity and β-cell function during the fasting state (Matsuda Index, r= 0.51, P<0.001; Disposition Index, r= 0.30, P<0.001) and with Disposition Index during the OGTT at 60 and 120 min (r= -0.41, P<0.001; r= -0.21, P<0.01), respectively. Collectively, these findings indicate that insulin-mediated suppression of glucagon secretion is impaired with increasing severity of glucose intolerance in obese Hispanic Americans and is closely associated with insulin resistance and β-cell dysfunction.

Disclosure

X. Chen: None. E.R. Maldonado Corchado: None. A. Merovci: None. E. Case: None. D. Tripathy: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.
275-LB: Connectome Predictive Modeling May Identify Brain Connectivity Signatures to Help Predict Who Will Benefit from Low-Calorie Diet
Authors: GROSKREUTZ DEREK , LAM WAI , LACADIE CHERYL , ELSHAFIE AHMED , HWANG JANICE J. , SEO DONGJU , SAVOYE MARY , SINHA RAJITA , CONSTABLE TODD , SHERWIN ROBERT , BELFORT-DEAGUIAR RENATA
Published: June 2019

While studies have investigated changes in brain connectivity following diet and weight loss, it has not yet been explored whether baseline brain connectivity can be used to predict weight loss during diet or to identify individual subjects for which a particular diet may be effective. The following study uses Connectome-based predictive modeling (CPM), a data-driven analysis approach for producing predictive models of individual brain-behavior relationships from brain connectivity data using cross-validation, to help identify individual participants who will lose weight after an 8-week low calorie diet. 16 Healthy OB subjects (10F/6M, age 44.4±8 years, BMI 32.7±2) and 9 T2DM subjects (5F/4M, age 48±9, BMI 33.9±2) underwent functional MRI (fMRI) during a hyperglycemic-euglycemic clamp. Blood-oxygen-level-dependent (BOLD) brain activity was assessed while subjects viewed food (high-calorie, low-calorie) pictures and non-food images. The study was repeated after 8 weeks of a reduced calorie diet. CPM was applied to BOLD activity during hyperglycemia and euglycemia. Analyses show that models built on individual subject brain connectivity matrices averaged between hyperglycemia and euglycemia before an 8-week low calorie diet are able to predict 50.2% and 53.4% of the variance in BMI and weight loss (kg), respectively (p<0.05). While models built on brain connectivity matrices during euglycemia (similar to the post-prandial state), but not hyperglycemia predicted 42.2% of the variance in BMI change (p=0.017). These results suggest the possibility that individual brain connectivity signatures may be used to identify subjects for whom a low calorie diet might be an effective weight loss strategy, while also revealing the relevant functional connections associated with weight loss success.

Disclosure

D. Groskreutz: None. W. Lam: None. C. Lacadie: None. A. Elshafie: None. J.J. Hwang: None. D. Seo: None. M. Savoye: None. R. Sinha: None. T. Constable: None. R. Sherwin: Other Relationship; Self; ICON plc., IQVIA, MannKind Corporation. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitchens, Inc.

Funding

National Institutes of Health
277-OR: Lean Tissues as Novel Determinants of Pear vs. Apple Body Shape and Metabolic Health in Humans
Authors: KARASTERGIOU KALYPSO
Published: June 2019

Epidemiological studies have established that pear-, compared to apple-, body shape is associated with lower cardiometabolic risk. Up to date, body shape has been considered equivalent to fat distribution and significant research efforts investigated the biology of different fat depots and their metabolic effects. We undertook a systematic analysis of body and tissue compartments in participants in the NHANES 1999-2006 cycles to search for components of body shape, other than fat. As expected, among adults 20-69 years old, those with pear-body shape (defined as waist-to-thigh ratio < 1.65 - bottom quartile) had higher leg fat mass compared to those with apple-body shape (waist-to-thigh ratio > 1.95 - top quartile) by 1,967 g (95% CI 1,801-2,135 g), after adjustment for sex, ethnicity, age and BMI. Surprisingly it was also noted that subjects with pear-body shape had slightly higher leg bone mineral content (by 42 g, 95% CI 30-52 g) and significantly higher leg lean mass (by 1,218 g, 95% CI 1,072-1,365 g). Similar results were observed when analysis was restricted to subjects < 40 years old, women only, or in specific ethnicities. In multiple regression models, leg lean mass (or leg/total lean mass ratio, i.e., lean mass distribution) was an independent predictor of lower systolic blood pressure, HbA1c and CRP after adjustment for sex, age, ethnicity, BMI, and leg fat mass (or leg/total fat mass, i.e., fat distribution), but not a predictor of indices of insulin sensitivity (fasting insulin, triglycerides, HDL-cholesterol).

In conclusion, fat distribution is not the sole determinant of pear-body shape in humans. Rather, coordinated differences in fat and lean mass drive metabolic health and suggest a systemic developmentally-driven pattern of lower body expansion.

Disclosure

K. Karastergiou: None.

Funding

National Center for Advancing Translational Sciences (KL2TR001435)