bluuebunny/crossref_metadata_2025 huggingface dataset:
1582-P: Glycemic Change from Baseline in the First Large-Scale Longitudinal Nationwide Study on Management and Real-World Outcomes of Diabetes in India (LANDMARC)
Authors: GHOSH ROMIK , DAS ASHOK K. , MITHAL AMBRISH , JOSHI SHASHANK , PRASANNA KUMAR K.M. , KALRA SANJAY , UNNIKRISHNAN AMBIKA GOPALAKRISHNAN , THACKER HEMANT , SETHI BIPIN , MOHANASUNDARAM SENTHILNATHAN , MENON SHALINI K. , NAIR ARJUN , RAIS NADEEM , WANGNOO SUBHASH KUMAR , CHOWDHURY SUBHANKAR , ZARGAR ABDUL H.
Published: June 2020

Glycemic change from baseline to 6-months was examined across various subgroups during first 6-months observational period in this 3 year prospective study (LANDMARC; CTRI/2017/05/008452). Descriptive statistics was used to assess glycemic trends in adults with T2D controlled/uncontrolled on ≥2 antihyperglycemic medications. Of 6236 enrolled participants, 5703 completed 6-month follow-up (visit 2 [V2]). A significant (p<0.0001) decrease in all glycemic parameters was noted at V2 from mean (SD) baseline A1C (8.05% [1.59]), FPG (142.80 [50.35]) mg/dL, and PPG (205.70 [72.26]) mg/dL; however, only 18.9% had reached optimum glycemic control (A1C<7%) (Table). On A1C subgroup stratification, significant reduction in number of participants was seen in 8-8.9% and ≥9% groups with more participants entering the 7-7.9% group (Table). In the CV risk factor and complications subgroups, glycemic parameters worsened in participants with family history of coronary disease and history of stroke. Interestingly, only participants with heart failure had optimal glycemic control and showed maximum reduction in FPG and PPG (Table). Within 6 months of study initiation, there was a marked improvement in the glycemic parameters in people with T2D; however notably only few had reached optimum control levels.

Disclosure

R. Ghosh: Employee; Self; Sanofi. A.K. Das: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. A. Mithal: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Johnson & Johnson, Lilly Diabetes, Novo Nordisk A/S. S. Joshi: Advisory Panel; Self; Novo Nordisk A/S, Roche Pharma, Sanofi. K. Kumar: None. S. Kalra: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; Novo Nordisk A/S, Sanofi-Aventis. A. Unnikrishnan: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Eli Lilly and Company, Ipca Laboratories, Merck Sharp & Dohme Corp., Novartis AG. H. Thacker: None. B. Sethi: None. S. Mohanasundaram: Employee; Self; Sanofi. S.K. Menon: None. A. Nair: Employee; Self; Sanofi. N. Rais: None. S. Wangnoo: None. S. Chowdhury: Advisory Panel; Self; Novo Nordisk A/S. A.H. Zargar: None.

Funding

Sanofi India Limited
1593-P: Real-World Inpatient Use of Oral Antidiabetes Drugs: A Multicenter, Retrospective, Hospital-Based Cohort Study
Authors: PASQUEL FRANCISCO J. , MAGEE MICHELLE F. , HOCHBERG IRIT , FORTIN CHARLIE , MIGDAL ALEXANDRA , CARDONA SAUMETH , FAYFMAN MAYA , GUO YI , PENG LIMIN , UMPIERREZ GUILLERMO E.
Published: June 2020

Professional guidelines recommend insulin therapy for treatment of type 2 diabetes (T2D) in the hospital. However, oral antidiabetes drugs (OAD) are commonly used despite the lack of safety and efficacy data. We analyzed individual level data from non-critically ill patients with T2D admitted to three large healthcare systems between 2008-2018 (N=187,396). We conducted propensity score matching analyses to determine the relative efficacy and safety of OAD. Patients were treated with basal insulin (20%), sliding scale insulin alone (28%), basal insulin with OADs (23%), metformin (21%), sulfonylureas (11%), or DPP-4 inhibitors (4%). Less than 1% were treated with thiazolidinediones or SGLT2 inhibitors. Patients started on basal insulin had more comorbidities and had higher glucose levels on admission. After matching for age, BMI, Charlson Comorbidity Index, and admission blood glucose, exposure to OADs, with or without basal insulin, was associated with non-clinically meaningful differences in glycemic control compared to basal insulin use alone (183.1± 53.8 vs. 175.7± 53.9 vs. 180.3± 54.9, p<0.001). The use of OADs with SSI was associated with a lower incidence of hypoglycemia. However, among OADs without basal insulin, sulfonylureas were associated with the highest rate of hypoglycemia (30%), compared to Metformin (16%), DPP-4i (15%) or TZDs (14%), p<0.001. There were no differences in lactic acidosis between groups. Patients treated with basal insulin had a higher mortality (2%) compared to basal insulin+ OAD (0.3%) or OAD alone (0.6%).

In summary, the use of OADs with or without basal insulin is associated with acceptable glycemic control compared to insulin therapy. Basal insulin use and the use of sulfonylureas is associated with a high incidence of hypoglycemia.

Disclosure

F.J. Pasquel: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. Research Support; Self; Dexcom, Inc., Merck Sharp & Dohme Corp., National Institutes of Health. M.F. Magee: Consultant; Self; Mytonomy. Employee; Spouse/Partner; U.S. Food and Drug Administration. Research Support; Self; AstraZeneca, Eli Lilly and Company, National Institute of Diabetes and Digestive and Kidney Diseases. Speaker’s Bureau; Self; American Diabetes Association, Pri-Med LLC. Other Relationship; Self; Endocrine Society. I. Hochberg: None. C. Fortin: None. A. Migdal: None. S. Cardona: None. M. Fayfman: None. Y. Guo: None. L. Peng: None. G.E. Umpierrez: None.

Funding

Jacobs Family Funds
1595-P: Evaluating Social Support and T2D Risk Factors among Members of Rural-Dwelling Grandparent-Headed Households
Authors: SMALLS BRITTANY L. , PALMER KELLY N. , CONTRERAS OMAR A. , HATCHER JENNIFER
Published: June 2020

Objective: The purpose of this paper is to elucidate factors impacting the health, development and management of chronic illnesses, particularly type 2 diabetes of rural grandparent-headed households (GHH).

Research Design and Methods: Prospective data were collected from rural-dwelling members of GHHs living in Appalachia Kentucky with no known diagnosis of T2D. Data collected on family characteristics, T2D clinical risk factors, and social support were assessed using the Medical Outcomes Survey (MOS) Social Support and the Child and Adolescent Social Support Scale (CASSS).

Results: Sixty-six grandparents and 72 grandchildren participated in the study. The average age and HbA1Cs were 59.4 years and 6.2% ± 1.4 for grandparents and 11.8 years and 4.9% ± 0.6 for grandchildren. The majority of grandparents were found to have prediabetes (31%) or undiagnosed diabetes (28%). The number of people living in GHHs were associated with grandparents’ triglycerides, HDL, and BMI whereas custody status was associated with BMI. Average social support scores among grandparents suggested moderately high perceived social support (79 ± 3.4). For grandchildren, social support provided by grandparents had no association with T2D risk factors, whereas support from teachers, classmates, and close friends was associated with HbA1C, BMI, and blood pressure in grandchildren.

Conclusion: This study shows that rural-dwelling grandparent caregivers are at an increased risk for T2D. In addition, increased responsibility may provide a determinant of health due to the potential stress of caregiving for grandchildren. Social support between grandparents and grandchildren has no effect on T2D risk factors. However, social support provided by peers, teachers, and close friends were associated with T2D risk factors in grandchildren. These findings support the use of peer support and school settings as mechanisms for interventions to reduce T2D in adolescents, particularly those of GHHs.

Disclosure

B.L. Smalls: None. K.N. Palmer: None. O.A. Contreras: None. J. Hatcher: None.

Funding

National Institute for Diabetes and Digestive and Kidney Diseases (R03DK101705 to J.H.)
1597-P: Increased Pancreatic Cancer Risk Associated with Dietary Iron in Whites, but Not Blacks with Diabetes
Authors: CONWAY BAQIYYAH , HUDSON ALANA G. , MCCLAIN DONALD A. , BLOT WILLIAM J.
Published: June 2020

Iron is a risk factor for both diabetes and pancreatic cancer, but whether iron works synergistically with diabetes to increase pancreatic cancer is unknown. Furthermore, risks of both diabetes and pancreatic cancer are increased among African Americans (AA), without clear differences in either iron stores or dietary iron consumption. We therefore tested whether dietary iron consumption increased risk of subsequent pancreatic cancer in a population of AA and Whites with and without diabetes. We conducted a follow up study of pancreatic cancer incidence (2002-2015), using the Southern Community Cohort, a population of mostly low income AA and White participants aged 40-79, with (n=23,489, 40%) and without (n=35,105, 60%) diabetes, recruited from federally qualified health centers. Logistic regression was used to compute ORs (95% CIs) for the risk of incident pancreatic cancer. All models accounted for age, sex, race, BMI, alcohol consumption, and dietary iron consumption. Alcohol and iron consumption were natural log transformed before analyses. There were 262 incident pancreatic cancer cases. Risk of pancreatic cancer and dietary iron consumption were not associated in subjects without diabetes (OR=1.08, 95% CI=0.81-1.45), but trended toward an association in those with diabetes (OR=1.26, 95% CI=0.84-1.90). However, there was a significant three-way interaction among diabetes, race, and total dietary iron consumption (p-interaction=0.04). When stratified by diabetes and race, total dietary iron consumption increased pancreatic cancer risk by over two-fold among Whites with diabetes (OR=2.47, 95% CI=1.14-5.37), but showed no association in any of the other three groups, namely AA with (1.00, 0.97-1.03) and w/o (1.09, 0.78-1.53) diabetes and Whites w/o diabetes (1.03, 0.56-1.89). Our data suggests that increased dietary iron consumption increases risk of pancreatic cancer among Whites with diabetes.

Disclosure

B. Conway: None. A.G. Hudson: None. D.A. McClain: None. W.J. Blot: None.

Funding

5U01CA202979-04
1605-P: Incidence of Hepatocellular Carcinoma in Type 2 Diabetes with Cirrhosis Who Were Treated with Metformin
Authors: TANGJARUSRITARATORN THANIDA , KUNAVISARUT TADA , TANGJITTIPOKIN WATIP
Published: June 2020

Several studies demonstrated an association between type 2 diabetes (T2D) and a higher risk of hepatocellular carcinoma (HCC). Metformin is widely prescribed for T2D. Metformin has been shown to prevent various cancer developments. The association of metformin use and development of HCC among T2D with cirrhosis is investigated. This study aims to determine if metformin significantly reduces the incidence of HCC in this population. T2D with cirrhosis patients from 2006 to 2014 with age 20 to 80 years were studied as a retrospective cohort. An incidence of HCC in T2D with/without metformin exposure after cirrhosis diagnosis within 5 years was determined by Chi-square test. The exposure was defined as a drug intake at the time of cirrhosis diagnosis, continuing for at least 90 days beyond the diagnosis. The 5-year disease-free survival of HCC in each group was compared using the log-rank test and Kaplan-Meier method. The total of 1,061 T2D with cirrhosis included metformin exposure (N=719) and metformin non-exposure (N=342). The overall HCC incidence was 253 (23.85%). Among patients with metformin exposure, the HCC incidence was 125 (17.39%), compared to 128 (37.42%) in non-exposure group. The development of HCC within 5 years was significantly lower in metformin exposure than in non-exposure group (RR=0.76; 95% CI:0.69-0.83; P<0.001). The 5-year disease-free survival of HCC with metformin exposure is greater than that of non-exposure (0.80 vs. 0.57; HR=0.42; 95% CI:0.33-0.54; p<0.001). Moreover, the result shows that male gender (HR=1.64; 95% CI:1.25-2.14), HbA1C≥7.5% (HR=1.30; 95% CI:1.00-1.68), HBV cirrhosis (HR=1.80; 95% CI:1.13-2.85), HCV cirrhosis (HR=2.31; 95% CI:1.43-3.74), smoking and drinking cessation ≥5 years (HR=1.78; 95% CI:1.31-2.42 and HR=1.74; 95% CI:1.27-2.38 respectively) were linked to a rising 5-year HCC incidence in T2D.

Conclusion: The metformin treatment might reduce the incidence of HCC in T2D with cirrhosis during 5-years and benefit HCC prognosis.

Disclosure

T. Tangjarusritaratorn: None. T. Kunavisarut: None. W. Tangjittipokin: None.
1610-P: Heterogeneity in Diabetes across Socioeconomic Subgroups of Asian-Americans in the U.S.
Authors: SHAH MEGHA K. , GANDRAKOTA NIKHILA , GUJRAL UNJALI , ALI MOHAMMED K. , NARAYAN K.M. VENKAT
Published: June 2020

Background: In the U.S., some Asian subgroups have disproportionately higher burdens of diabetes which vary by country of origin. Social determinants of health (SDOH)—the conditions in which one grows, lives and works- also influence health disparities. We examined whether diabetes prevalence in Asian subgroups varies by SDOH indices using data from a nationally representative sample.

Methods: We pooled weighted data from National Health Interview Survey 2009-2018 for 6,467 participants who reported their ethnicity as Asian (Chinese, Filipino, Asian Indian, and Other Asian [Korean, Vietnamese, Japanese, and other]). We built multivariate logistic regression models assessing the likelihood of diabetes among Asian subgroups by sociodemographic strata of poverty, marital status, education, health insurance and income, adjusting for age, sex, and overweight/obesity status.

Results: Higher income, compared to poverty status was associated with higher odds of diabetes among Chinese (aOR 2.55, 95%CI 2.51-2.60) and lower odds of diabetes among Filipino, Asian Indian and Other Asian groups (aOR 0.93, 95%CI 0.92-0.94; aOR 0.82, 95%CI 0.81-0.83; aOR 0.60, 95%CI 0.60-0.61, respectively). College education was associated with increased odds of diabetes among Asian Indians, compared to less than high school (aOR 1.55, 95%CI 1.51-1.58) though lower odds of diabetes among Chinese, Filipino, and other Asian groups (aOR .09, 95%CI .09-.09; aOR 0.98, 95%CI 0.96-0.99; aOR 0.51, 95%CI 0.50-0.52, respectively). Health insurance coverage was associated with higher odds of diabetes across all groups. Married status was associated with lower odds of diabetes among Chinese (aOR 0.77, 95%CI 0.76-0.78) but higher for Filipino, Asian Indian, and Other Asian groups.

Discussion: Our data show that SDOHs do not have a uniform influence on diabetes risk in Asian subgroups. Future research should account for this variation and consider subgroup-specific solutions to address diabetes-related health disparities.

Disclosure

M.K. Shah: None. N. Gandrakota: None. U. Gujral: None. M.K. Ali: Research Support; Self; Merck & Co., Inc. K. Narayan: None.

Funding

National Center for Advancing Translational Sciences (UL1TR002378, KL2TR002381)
1618-P: Insulin Secretion Variability According to the Specific Type 1 Diabetes (T1D) Risk Predictor
Authors: JACOBSEN LAURA M. , NATHAN BRANDON M. , ISMAIL HEBA M. , REDONDO MARIA J. , SCHATZ DESMOND , HALLER MICHAEL J. , SIMS EMILY K. , SKYLER JAY S. , PALMER JERRY P. , HEROLD KEVAN C. , SOSENKO JAY
Published: June 2020

The risk for T1D, a major criterion for entry into disease prevention trials, can be assessed in various ways, but usually includes autoantibody (Ab) and/or metabolic measures. Given inherent variations in these biomarkers, it is possible that informative characteristics differ between populations selected by different risk measures. Thus, we assessed whether indices of insulin secretion [C-pep; first phase insulin response (FPIR)] vary between groups defined by distinctive risk measures. We used data from Diabetes Prevention Trial-Type 1 (DPT-1) participants, all being ICA positive subjects with or without biochemical Ab (bAb) positivity (GADA, IA-2A, mIAA). C-pep and FPIR values from baseline oral and intravenous glucose tolerance tests were compared between those who had 2-3 bAbs (≥2bAb) and those who had 0-1 bAb plus Index60≥0.40 (≤1bAb+Ind60). Index60 is a composite C-pep and glucose measure. These groups were chosen so that T1D risk would be similar (50% 5-year risk for both, log rank p=0.95). Ages (mean±SD) for ≥2bAb (n=289) and ≤1bAb+Ind60 (n=175) were 12.8±8.2 and 13.3±9.6 yrs, respectively (p=0.53). BMI Z-score was greater for ≥2bAb (0.42±1.12 vs. 0.15±1.09, p=0.01). C-pep levels were consistently higher for ≥2bAb than ≤1bAb+Ind60 [30-0 minute C-pep: 2.73±1.58 vs. 2.04±1.12 ng/mL, p<0.0001; area under the curve (AUC) C-pep: 3.70±1.55 vs. 3.27±1.12 ng/ml, p=0.013; AUC C-pep/AUC glucose: 0.030±0.013 vs. 0.025±0.007 (ng/ml)/(mg/dl), p<0.001]. FPIR was also higher for ≥2bAb (122.0±87.3 vs. 96.2±47.1 µU/ml, p<0.01). All comparisons remained significant with adjustments for age and BMI Z-score. Of those with ≤1bAb+Ind60, 0 bAb did not differ from 1 bAb for C-pep indices or FPIR.

In conclusion, C-pep and FPIR values can differ appreciably according to the measure that defines risk. This should be considered in choosing risk measures for prevention trials.

Disclosure

L.M. Jacobsen: None. B.M. Nathan: None. H.M. Ismail: None. M.J. Redondo: None. D. Schatz: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. J.P. Palmer: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. J. Sosenko: None.
162-LB: Impact of High-Fat Meal on Circulating microRNA in Youth with T1DM
Authors: TRYGGESTAD JEANIE B. , TEAGUE APRIL M. , SHORT KEVIN R.
Published: June 2020

MicroRNA (miRNA) are small non-coding RNAs that impact translation via degrading or repressing mRNA. From animal models, circulation abundance of miRNA is impacted by feeding. The goal of this project was to compare levels of specific circulating miRNAs between youth with T1DM and controls and the impact of a high fat meal on miRNA abundance. Fourteen youth (6 females, 8 males) with T1DM and 29 normal weight control youth (14 females, 15 males) ingested a milkshake with 830 kcal; 36% carbohydrate, 54% fat (31 grams of saturated fat), and 10% protein. Circulating miRNAs (miR-122, 126, and 130b) at baseline and 150 minutes post-ingestion were measured by qPCR. The group with T1DM had a median A1c of 8.4% (7.4, 8.9) with an average duration of 7 years. At baseline, miR-126 tended to be higher in the youth with T1DM (47%, p=0.072). In pooled groups, all three miRNAs decreased at 150 min (miR-122: -21%, p=0.036; miR-126: -37%, p=0.001; and miR-130b: -33%, p=0.023). Within the control group, miR-122 and miR-126 decreased 26% and 28% from baseline (p=0.037 and p=0.035, respectively). Within the T1DM group, miR-126 and miR-130b decreased 49% and 50% from baseline (p=0.007 and p=0.011, respectively). The decrease in miR-122 from baseline was correlated with the total energy expenditure for the meal (r=0.-0.379, p=0.017) and insulin under the curve (r=0.350, p=0.029). The decrease in miR-126 and miR-130b were negatively correlated with glucose area under the curve (r=-0.369 and -0.358, p=0.021 and 0.025, respectively), and the decrease in miR-130b was negatively correlated with baseline NEFA (r= -0.328, p=0.042). miR-122 and 130b both target AMPK, which could alter lipid metabolism, thus explaining the associations with NEFA and energy expenditure. miR-126 is known to target both IRS1 and PI3K in the insulin signaling pathway, potentially explaining the association with glucose. It is clear that the circulating abundance of these miRNAs is reduced following a high fat meal, and that response may be modified by the presence of T1DM.

Disclosure

J.B. Tryggestad: None. A.M. Teague: None. K.R. Short: None.

Funding

Harold Hamm Diabetes Center; Ardmore Institute of Health
163-OR: Metabolically Unhealthy Obese Is Transient and Improves with Aerobic Exercise
Authors: HODDY KRISTIN K. , AXELROD CHRISTOPHER L. , MEY JACOB T. , HARI ADITHYA , BEYL ROBBIE A. , KIRWAN JOHN P.
Published: June 2020

Introduction: A subset of adults with obesity may be classified as having metabolically healthy obesity (MHO). There is a high conversion rate from the MHO condition to a metabolically unhealthy obesity (MUO) condition over time. The insulin sensitizing effects of exercise across these metabolic states has not been established and may inform more precise obesity treatment.

Methods: Sedentary adults (n=43) with obesity, but not diabetes, underwent inpatient testing (anthropometric measurements, blood chemistries, aerobic capacity (VO2MAX), and insulin sensitivity (euglycemic clamp) before and after 12 weeks of aerobic exercise training (5x/week, 60 min/session, ∼85% HRMAX). A metabolic health score (MetScore) was calculated using baseline values (BMI, VO2MAX, HOMA-IR, triglycerides, and cholesterol) to stratify participants with MHO (n= 21; MetScore ≤ 237) or MUO (n=22; MetScore > 237). Linear mixed models determined group differences over time.

Results: MHO and MUO groups differed by MetScore at baseline (202 and 325; P<0.01) and after 12 weeks of exercise (181 and 261; P<0.01), but MHO had lower fasting glucose, insulin, HOMA-IR, and higher HDL-C along with superior M/I, than MUO participants. MetScore improved in the group with MUO (-64; P<0.01) compared to MHO (-20; p=0.06)(P<0.01, between groups). Both groups (MHO v. MUO) experienced similar improvements in VO2MAX (+6.8 and +9.3 ml/kg/min), body weight (-8.8 and -7.5 kg), body fat (-4.2 and -2.9%), triglyceride concentrations (-31.7 and -25.8 mg/dl), and M/I (0.0183 and 0.0166 mg/kg/min/μU/ml) (P>0.20, all between groups). Insulin (-2.62 μU/ml; P=0.0185) and HOMA-IR (-0.71; P=0.022) decreased in the group with MUO with no between group differences (P=0.75 and P=0.52, respectively).

Conclusion: Aerobic exercise enhances individual components of health similarly in persons with MHO and MUO after 12 weeks. However, those with MUO experienced the greatest collective improvement, thus presenting an opportunity for intervention.

Disclosure

K.K. Hoddy: None. C.L. Axelrod: None. J.T. Mey: None. A. Hari: None. R.A. Beyl: None. J.P. Kirwan: None.

Funding

National Institute on Aging (AG012834); National Institute of General Medical Sciences (GM104940); Louisiana Clinical & Translational Science Center (U54-GM104940)
1631-P: Age at Menarche and Its Association with the Metabolic Syndrome in Type 1 Diabetes
Authors: JU JINGHUI , RUBINSTEIN DEBRA , EL KHOUDARY SAMAR R. , ORCHARD TREVOR J. , COSTACOU TINA
Published: June 2020

Early menarche has been associated with a higher risk of metabolic syndrome (MetS), CVD and its risk factors in the general population. However, limited data exists regarding the association between age at menarche and MetS in women with type 1 diabetes (T1D), a population in which menarche may be delayed. We thus assessed the ability of age at menarche to predict incident MetS in female participants (n=235) of the EDC study, a cohort of childhood onset T1D. MetS was defined using modified AHA NCEP ATP III criteria: waist circumference ≥ 89 cm; triglycerides ≥ 150 mg/dL or treatment for elevated triglycerides; HDL cholesterol < 50 mg/dL; systolic/diastolic blood pressure ≥130/85 mmHg or on antihypertensive medications. Since all participants met the criteria of hyperglycemia, any two of the remaining four criteria were required for diagnosis of MetS. Participants were divided into 3 menarche timing groups: early (≤11 years, n=22), normal (12∼14 years, n=163) and delayed menarche (≥15 years, n=50). At baseline, women with delayed menarche were with longer diabetes duration and more likely to have lower estimated glomerular filtration rate (eGFR) compared with the other groups (all p-values<0.05). However, univariately, the incidence of MetS during the 25-year follow-up did not differ by menarche timing group (63.6% vs. 49.1% vs. 46.0%, respectively, p=0.37). In multivariable Cox models, compared with the normal menarche group, women with early and delayed menarche had non-significantly higher (HR =1.42, p=0.26) and lower (HR =0.89, p=0.64) hazards of developing MetS, respectively. Duration of T1D, HbA1c, BMI and smoking history were significantly associated with a greater risk of MetS, whereas eGFR was significantly associated with a lower hazard of MetS.

In conclusion, unlike findings in the general population where early menarche increased the risk of MetS, in this cohort of women with T1D the incidence of MetS did not differ significantly by menarche timing group.

Disclosure

J. Ju: None. D. Rubinstein: None. S.R. El Khoudary: None. T.J. Orchard: None. T. Costacou: None.

Funding

National Institutes of Health (DK34818)
1638-P: Functional Characterization of HNF1B Variants Can Enhance Diabetes Precision Medicine
Authors: JOHANSSON BENTE B. , PAVITHRAM AISHWARYA , ZHANG HAICHEN , MALONEY KRISTIN A. , RINGDAL MONIKA , KACI ALBA , SAGEN JORN V. , KLEINBERGER JEFFREY , JENG LINDA , NJØLSTAD PÅL RASMUS , POLLIN TONI I. , MOLNES JANNE
Published: June 2020

Genetic variants in HNF1B encoding the transcription factor hepatocyte nuclear factor-1 beta (HNF-1B) cause Maturity-Onset Diabetes of the Young type 5 (MODY5; HNF1B-MODY) and are the most common known monogenic cause of developmental kidney disease. The aim of this study was to assess pathogenicity of HNF1B variants identified among 312 patients suspected of monogenic diabetes from the Personalized Diabetes Medicine Program (PDMP) at the University of Maryland. Patients suspected of monogenic diabetes underwent next generation sequencing for 40 genes, including HNF1B. Variants were classified according to ACMG/AMP variant interpretation guidelines. To investigate the effect of HNF1B variants on normal HNF-1B transcriptional activity, we used a Dual-Luciferase assay system in transfected HeLa cells. DNA-binding ability was studied by EMSA and protein localization was determined by fractionation and confocal microscopy. Seven HNF1B variants were identified in 7 unrelated individuals. One variant (p.H336Pfs*22) was classified as pathogenic, 5 (p.T88A, p.A167P, p.N394D, p.V458G, p.T544A) as unknown significance (VUS) and 1 variant as benign (p.D82N). Two variants, p.A167P and p.H336Pfs*22, inferred severely reduced transactivation potential (25% and 34% of WT, respectively). In addition, p.A167P demonstrated decreased protein expression (26% of WT) and a significant loss in DNA binding ability (19% of WT). The p.H336Pfs*22 variant carrier has renal agenesis, often associated with HNF1B mutations, while the p.A167P carrier lacks extra-pancreatic features. The functional evidence allowed p.A167P to be reclassified as likely pathogenic when added to existing evidence (computationally predicted deleteriousness and absence from population databases). Obtaining functional data can improve variant interpretation and enable a more precise diagnosis in patients carrying an HNF1B variant.

Disclosure

B.B. Johansson: None. A. Pavithram: None. H. Zhang: None. K.A. Maloney: None. M. Ringdal: None. A. Kaci: None. J.V. Sagen: Other Relationship; Self; Novo Nordisk A/S. J. Kleinberger: None. L. Jeng: None. P. Njølstad: None. T.I. Pollin: None. J. Molnes: None.

Funding

Western Norway Regional Health Authority; University of Bergen; Norwegian Diabetes Foundation
1639-P: Correlates and Prevalence of Hypogonadism in Male Patients with Latent Autoimmune Diabetes, Classic Type 1 Diabetes, and Classic Type 2 Diabetes
Authors: CAI MEILI , GAO JINGYANG , SHENG CHUNJUN , LI HONG , SHENG HUI , QU SHEN , ZHANG MANNA
Published: June 2020

Objectives: The study aims to compare the prevalence of hypogonadism in male patients with latent autoimmune diabetes (LADA) and classic type 1 diabetes (T1DM) and type 2 diabetes (T2DM), and explore risk factors for hypogonadism in those patients.

Methods: Form 1 January 2016 and 9 October 2019, a total of 399 male patients with LADA(n=71), T1DM (n=72) and T2DM (n=256) respectively were recruited from the endocrinology department in Shanghai Tenth People’s Hospital for this cross-sectional study. Serum FSH, LH, testosterone, lipid profile, uric acid, HbA1c, and beta-cell function were determined in blood samples. The diagnosis of hypogonadism was based on the levels of LH, FSH, and total testosterone.

Results: The mean age of male patients with LADA, T1DM and T2DM was 54.44 ± 1.54, 47.50±1.83 and 56.55±0.74 years old, respectively. The serum total testosterone concentration in the LADA group was similar to the T1DM group, but higher than those in the T2DM group. The rate of hypogonadism in the LADA group, T1DM group, T2DM group were 1.6%, 2.4% and 20.8%, respectively (p <0.05). Total testosterone was positively correlated with SHBG and HDL-c, and negatively correlated with uric acid, HbA1c, BMI, SBP, DBP and TG in all, LADA, T1DM and T2DM groups. Logistic regression indicate that after adjusting for age, duration of diabetes, smoking, drinking and family history of diabetes, the independent risk factors for developing hypogonadism in male with diabetes were BMI (OR=1.31, P<0.05), C-peptide (OR=1.88, P<0.05), HDL-c (OR=0.41,P<0.05) and SBP (OR=1.01,P<0.05).

Conclusion: Our results indicate that in a population of admission to a large urban hospital in China, the rate of hypogonadism was lower in LADA patients and T1DM patients than T2DM patients. High levels of BMI, C-peptide, SBP and low level of HDL-c are risk factors for developing hypogonadism in male with diabetes.

Disclosure

M. Cai: None. J. Gao: None. C. Sheng: None. H. Li: None. S. Qu: None. M. Zhang: None.

Funding

National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677)
164-LB: Lower Pediatric HbA1c in Sweden during Recent Years Is Associated with a Lower HbA1c Nadir during the First Year after Onset
Authors: HANAS RAGNAR , STEINECK ISABELLE I. , ANDERZÉN JOHAN , EEG-OLOFSSON KATARINA , EKELUND JAN , GUDBJ ÖRNSDOTTIR SOFFIA , HANBERGER LENA , NÅTMAN JONATAN , LYCKÅ AUSTE PUNDZIUTE , SVENSSON ANN-MARIE , SÄRNBLAD STEFAN , AKESSON KARIN
Published: June 2020

Background: There is a large variation in mean HbA1c levels even between high-income countries, with a decrease over time in HbA1c in some countries but an increase in others. Sweden has experienced a steady decrease in HbA1c over the past 10 years. The aim of this study was to illustrate how changes in HbA1c during the first two years after diagnosis in children and adolescents is related to calendar year for diagnosis of type 1 diabetes from 2010 to 2017.

Methods:The Swedish SWEDIABKIDS registry collects data every ~3 months and has > 95% coverage up to age 18 years. We plotted all available HbA1c data vs. diabetes duration, presented as separate Loess curves per 2 consecutive year groups.

Results: In total, 5,102 patients contributed with 51,550 HbA1c values over 8 years. HbA1c at onset has slightly increased from 93.9 to 95.0 mmol/mol (10.7 to 10.8 %) between 2010 and 2017. The HbA1c nadir (lowest level during first year) is around 4 months, and has become lower over the years. Early HbA1c tracking is apparent and is established with a difference between the groups from 1 year’s diabetes duration.

Conclusions: Intensification of early diabetes treatment, resulting in a lower HbA1c nadir at 4 months and lower HbA1c from 1 year onwards is related to HbA1c two years after diagnosis. Thus, a modifiable factor for a long-term improvement in metabolic control has been identified.

Disclosure

R. Hanas: Advisory Panel; Self; Abbott, Novo Nordisk A/S. Speaker’s Bureau; Self; Sanofi. Other Relationship; Self; AstraZeneca. I.I. Steineck: None. J. Anderzén: None. K. Eeg-Olofsson: None. J. Ekelund: Employee; Spouse/Partner; AstraZeneca. S. Gudbjörnsdottir: None. L. Hanberger: None. J. Nåtman: None. A. Pundziute Lyckå: None. A. Svensson: None. S. Särnblad: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. K. Akesson: None.
1643-P: A Recessive Genome-Wide Meta-analysis of Type 2 Diabetes in 300,000 Individuals of European Ancestry Identifies Multiple Novel Variants of Large Effect Size
Authors: O’CONNOR MARK J. , CORTES-SANCHEZ PAULA , BONÀS-GUARCH SÍLVIA , COLE JOANNE B. , TORRENTS DAVID , LEONG AARON , FLOREZ JOSE C. , MERCADER JOSEP M.
Published: June 2020

Introduction: Most genome-wide association studies (GWAS) of polygenic traits are based on the assumption that allelic effects are additive. Hundreds of loci associated with type 2 diabetes (T2D) have been identified using this approach, but a significant proportion of heritability remains unexplained. Many genetic variants behave in a recessive fashion, and rare variants of this type can be missed by additive analyses.

Methods: We used a recessive model to conduct a GWAS of T2D in unrelated individuals of European ancestry in the UK Biobank and then meta-analyzed the results with publicly available data from five European-ancestry cohorts known collectively as 70KforT2D. We used approximate conditional analysis to identify distinct secondary signals within genome-wide significant loci.

Results: In total, there were 30,661 cases and 267,948 controls. We identified 54 associated loci and 15 other conditionally independent signals. Six associations were distinct from the set of previously reported signals, including results from larger additive analyses, and three were over a million base pairs away from the closest known locus. Five of the novel variants - located near the genes PELO, ADAMTS6, JAZF1, IL7, and FCHSD2 - were rare, with allele frequencies under 5%, and had large effect sizes, with odds ratios for homozygous carriers ranging from 2.7 to 7.9.

Conclusions: Our results demonstrate that recessive analysis identifies loci missed by additive GWAS, confirming the value of recessive analyses. Some of the variants we detected have large effect sizes and could be useful for patient risk stratification. Collectively they add to our knowledge of the genetic architecture of T2D.

Disclosure

M.J. O’Connor: None. P. Cortes-Sanchez: None. S. Bonàs-Guarch: None. J.B. Cole: None. D. Torrents: None. A. Leong: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. J.M. Mercader: None.
1647-P: Rare Disruptive Loss of Function Mutations in the Cluster of Differentiation 36 (CD36) Gene Overwhelmingly Cause a Metabolic Syndrome in Multiple Members of an Inbred Pedigree from One Village in Northern Israel
Authors: LEVIN NEHAMA ZUCKERMAN , BERCOVICH DANI , PASTERNAK IDIT , GERSHONI-BARUCH RUTH , SHEHADEH NAIM
Published: June 2020

The metabolic syndrome consisting of type 2 diabetes (T2DM), obesity, dyslipidemia and arterial hypertension, is a complex disorder whose molecular basis is largely unknown. The cluster of differentiation 36 (CD36), a multifunctional class B scavenger receptor, has been acknowledged as a promising candidate for T2DM and its complications. More than a decade ago, a rare nonsense mutation, namely c.1079T>G (p.L360X) was identified in one Caucasian pedigree presenting with autosomal dominant diabetes (Hum mutation 2004). Recent studies however, have disputed the contribution of rare coding mutations in CD36 to T2DM and additional metabolic complications (Scientific Reports 2019). In an extended pedigree of Israeli Muslim Arab ancestry from a single village in northern Israel multiple members (n=33) with T2DM, obesity, dyslipidemia and arterial hypertension were investigated. Three affected individuals from three nuclear inbred families, originating from an extended Arab Muslim clan, underwent whole-exome sequencing that displayed several disruptive rare mutations in CD36 namely c.1011_1014delins26; p.(Arg337Serfs*23); c.1079T>G; p.(Leu360*); and c.1202_1205delTATT; p.(Val401Glufs*4). Sanger sequencing was thereafter employed to show that these mutations segregated in 30 additional affected individuals from the same clan. Our findings substantiate that CD36 plays a pivotal role in glucose homeostasis and lipid metabolism. Mutations in this gene prompt insulin resistance, obesity and dyslipidemia in humans. A rare nonsense mutation (p.L360X) in CD36 was previously found in a French pedigree presenting with autosomal dominant diabetes. Here we provide evidence that other than the p.L360X mutation, rare loss-of-function coding mutations in CD36 evoke impaired fatty acid metabolism, glucose intolerance, type 2 diabetes and arterial hypertension.

Disclosure

N. Zuckerman Levin: None. D. Bercovich: None. I. Pasternak: None. R. Gershoni-Baruch: None. N. Shehadeh: None.
166-OR: Lower Response of Connective Tissue Growth Factor (CTGF) to Exercise Characterizes Insulin Resistant Muscle
Authors: BUSTOS ROCIO ZAPATA , LANGLAIS PAUL R. , COLETTA DAWN K. , DE FILIPPIS ELENA A. , GRANDJEAN DANIELLE , MANDARINO LAWRENCE
Published: June 2020

This study was undertaken to identify transcription factors that differentially respond to exercise in insulin resistance. Candidate transcription factors were identified from analysis of 5’-untranslated regions (5’-UTRs) of exercise responsive genes and from analysis of the 5’-UTRs of genes coding for proteins that differ in abundance in insulin resistance. Muscle biopsies were obtained from lean and obese subjects before, 30 min and 240 h. after a single exercise bout. Insulin sensitivity was assessed through glucose clamps. Obese subjects (n=8) were insulin resistant compared to lean (n=12) (7.0 ± 0.95 vs. 11.3 ± 0.8 mg∙kg FFM-1∙min-1, P<0.05) but performed exercise at the same intensity (VO2peak 35.0 ± 1.9 vs. 35.2 ± 3.9 ml∙min-1∙kg FFM-1, NS). Statistical over-representation analyses showed that proteins differing in abundance between healthy and insulin resistant resting muscle included those involved in mitochondrial function, protein targeting and translation, and metabolism. Transcription factor enrichment analysis of genes coding for these proteins revealed new candidate transcription factors. Q-rt-PCR analysis from pre and post-exercise muscle biopsies revealed several transcription and growth factors had altered responses to exercise in insulin resistant subjects, including EGR3, RELA, ATF2 and SP1. We previously showed that higher CTGF abundance and expression were associated with insulin resistance induced by a lipid emulsion infusion, along with extracellular matrix reorganization and tissue remodeling. Here, CTGF mRNA responded briskly 30 min after exercise in insulin sensitive but not insulin resistant subjects (4.7 ± 1.0 vs. 1.0 ± 0.22), returning to near-basal levels in both groups after 24 h. The lower response of CTGF expression to exercise in insulin resistance suggests that it may mediate the capacity of muscle to remodel itself following exercise, and partially explain the exercise resistance associated with insulin resistance.

Disclosure

R. Zapata Bustos: None. P.R. Langlais: None. D.K. Coletta: None. E.A. De Filippis: None. D. Grandjean: None. L. Mandarino: None.

Funding

National Institutes of Health (R01DK047936, DK066483, R01DK094013)
1667-P: Diabetes Incidence following Adoptive Transfer of Splenocytes Correlates with Increased Generation of Proinflammatory Lipids
Authors: WHITE TAYLEUR , CHALFANT CHARLES , RAMANADHAM SASANKA
Published: June 2020

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic islet β-cells. An understudied area is the role of lipid signaling. We find that the Ca2+-independent phospholipase A2β (iPLA2β) is induced under a diabetic milieu and that mitigation of iPLA2β activity attenuates β-cell death. iPLA2β hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid. When the fatty acid is arachidonic acid, it can be metabolized to bioactive eicosanoids, many of which are pro-inflammatory. To address our overarching hypothesis that iPLA2β-derived lipids (iDLs) contribute to T1D development, we investigated the role of immune cell-iDLs in this process by utilizing a splenocyte adoptive transfer protocol. Splenocytes were prepared from 12-week-old female spontaneous diabetes prone non-obese diabetic (NOD, WT) and NOD.iPLA2β+/- (HET) donor mice and transferred into 5-week-old female immunodeficient (NOD.scid) recipient mice. Our overall findings revealed that: (1) splenocyte-iPLA2β mRNA in HET donor mice was ca. 40% of that in WT donor mice, (2) temporal IPGTTs revealed that the recipient mice of the HET genotype were more glucose tolerant, compared to recipients of the WT splenocytes; (3) weekly blood glucose monitoring revealed that all WT recipient mice developed diabetes between 11-16 weeks of age. In contrast, onset of diabetes in the HET recipient mice was delayed 3 weeks and by 16 weeks of age, 50% of these mice remained diabetes-free, (4) HET donor T-cell differentiation to Th1 phenotype is mitigated, (5) HET donor T-cell production of select pro-inflammatory lipids (i.e., 6-keto PGF1α, PGE2, and DHETs) is decreased, relative to WT donors, and (5) similar lipid signatures are evident in the terminal plasma of recipient mice. These findings suggest that immune T-cell-iPLA2β is a critical contributor to T1D development and could be targeted for therapeutics.

Disclosure

T. White: None. C. Chalfant: None. S. Ramanadham: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)
169-LB: Is It Time for Country-Specific Glucose Cut-Off Values for Diagnosing Gestational Diabetes Mellitus in the Indian Population?
Authors: BABU GIRIDHARA R. , LEWIS MELISSA G. , R DEEPA , LOBO EUNICE , KINRA SANJAY , MURTHY GVS V.
Published: June 2020

Background: Gestational diabetes mellitus (GDM) affects nearly 5 million pregnancies in India and is associated with multiple adverse pregnancy outcomes. Exposure to intrauterine hyperglycemia predisposes infants to increased risk obesity and diabetes. Indian phenotype tends to deposit excess central fat, which is linked to insulin resistance. Our study aimed to determine the effect of varying plasma glucose concentrations in predicting adverse maternal and infant outcomes in participants of a birth cohort in India.

Methods: We examined a prospective cohort of pregnant women in the public hospitals of Bengaluru. We conducted a 2-hour 75g Oral glucose Tolerance Test (OGTT) in 1847, pregnant women between 24 to 36 weeks. We followed up women and children at delivery, and recorded skinfold thickness of babies at biceps, triceps, and subscapular region. We fitted 240 robust Poisson models to estimate the risk of the sum of skinfold thickness (SSFT) infants and caesarian section delivery with the FBS and PPBS. With one-unit increase beginning from FBS≥87 up to 92 mg/dL and PPBS ≥134 up to 153 mg/dL were tested with the sum of skinfold Thickness (SSST) and C section delivery.

Results: We found that 10.65% (95% CI 9.19%, 12.30%) of 1847 infants had SSFT above 90th percentile, and 46.91% (95% CI 44.45%, 49.38%) of the women underwent caesarian section. The results indicate that FBS≥87 mg/dL and PPBS of ≥134mg/dl was associated with risk of increased SSST in infants [adjusted RR 1.70 (95% CI 1.06, 2.74)] and caesarian section delivery [Adjusted RR 1.19 (1.07,1.32)] after adjusting for age, parity, socioeconomic status, height and adiposity in mothers.

Discussion: The pregnant women in India are at a higher risk of adverse birth outcomes with lower glucose cut-off values, compared to the international classification systems. These findings offer insights to revise the cut off points based on contextual settings in LMIC countries.

Disclosure

G.R. Babu: None. M.G. Lewis: None. D. R: None. E. Lobo: None. S. Kinra: None. G.V. Murthy: None.

Funding

UK Wellcome Trust/DBT India Alliance Fellowship (IA/CPHI/14/1/501499 to G.R.B.)
169-OR: Differential Effects of Amount, Intensity, and Mode of Exercise Training on the Diabetes Risk Index
Authors: ROSS LEANNA M. , SLENTZ CRIS A. , SHALAUROVA IRINA Y. , OTVOS JAMES D. , CONNELLY MARGERY A. , BALES CONNIE W. , HOUMARD JOSEPH A. , KRAUS WILLIAM E.
Published: June 2020

Objective: Examine the effects of amount, intensity, and mode of exercise training on type 2 diabetes (T2D) risk.

Methods: A total of 531 men and women with dyslipidemia [STRRIDE I (n=222), STRRIDE AT/RT (n=142) or prediabetes [STRRIDE-PD (n=167)] were randomized to control group or one of 10 exercise interventions, ranging from doses of 8-22 kcal/kg/week; intensities of 50-75% V?O2peak; and duration of 6-9 months. Two groups included resistance training and one included dietary intervention (weight loss goal of 7%). Fasting plasma samples were obtained at baseline and 16-24 h after last exercise bout. The Diabetes Risk Index (DRI) and its components—Lipoprotein Insulin Resistance Index (LP-IR) and branched chain amino acids (BCAA) valine and leucine—were determined by NMR spectroscopy. DRI scores range from 1-100, the latter representing those at greatest T2D risk. Paired t-tests determined significance within groups (p<0.05). Study-specific ANCOVA determined differences among groups.

Results: The inactive control group did not significantly change DRI score. After training, four of ten exercise groups significantly improved DRI scores, ranging from -2.8 ± 8.2 to -8.3 ± 10.4. In STRRIDE AT/RT, only the aerobic-plus-resistance group significantly improved DRI. In STRRIDE-PD, the moderate-intensity-plus-diet group had a greater DRI change than the other exercise-only moderate intensity groups. Reductions in DRI appeared to be driven largely by decreases in insulin resistance (LP-IR) but not dysmetabolism (BCAA), except for the moderate-intensity-plus-diet group, which exhibited a reduction in both.

Conclusions: Multiple exercise interventions led to improvements in DRI scores. Results provide compelling evidence that adding resistance to aerobic training elicits a synergistic effect on insulin resistance and T2D risk. In individuals with prediabetes, incorporating dietary intervention with aerobic training results in the most robust improvement in T2D risk.

Disclosure

L.M. Ross: None. C.A. Slentz: None. I.Y. Shalaurova: None. J.D. Otvos: Employee; Self; LabCorp. M.A. Connelly: Employee; Self; LabCorp. C.W. Bales: None. J.A. Houmard: None. W.E. Kraus: None.

Funding

National Institutes of Health (R01HL057354, R01DK081559, T32HL007101)