bluuebunny/crossref_metadata_2025 huggingface dataset:
CB4211 Is a Potential Treatment for Metabolic Diseases with a Novel Mechanism of Action—Sensitization of the Insulin Receptor
Authors: GRINDSTAFF KENT , MAGNAN REMI , SHANG ROBIN , STENGER EMILY , HOLLAND JENNA S. , PEREZ-TILVE DIEGO , CUNDY KENNETH C.
Published: June 2018

Metabolic dysfunction and insulin resistance are common underlying factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and many age-related diseases, including obesity and type 2 diabetes. CB4211 is a novel peptide analog of MOTS-c, a mitochondrially encoded peptide with a potential role in metabolic homeostasis. CB4211 reduces free fatty acid release from cultured adipocytes, improves NAFLD activity score (NAS) in STAM® mice, and selectively decreases fat mass in DIO mice. We investigated the mechanism of action (MOA) of CB4211 in regulating fatty acid metabolism, glucose homeostasis, and insulin sensitivity. CB4211 potentiated insulin mediated inhibition of lipolysis in isoproterenol stimulated adipocyte cultures without changing maximal response, while CB4211 alone had no effect. Inhibitors of IR auto-phosphorylation (GSK183705A) or downstream PI3K/Akt signaling pathway components (wortmannin, Akti-1/2) abolished the antilipolytic effects of insulin alone and in combination with CB4211. Further supporting sensitization of insulin signaling, CB4211 enhanced insulin mediated phosphorylation of IR, IRS-1, and Akt, without affecting IGF mediated phosphorylation of IGF-1R. Consistent with activity through IR, CB4211 potentiated insulin induced reduction in glucose production in H4-IIE cells. The acute in vivo effect of CB4211 on insulin tolerance was determined in fasted DIO mice. Administration of CB4211 with insulin enhanced insulin sensitivity, prolonging the reduction in blood glucose levels compared to insulin alone.

In conclusion, CB4211 potentiates insulin effects on fatty acid metabolism and glucose homeostasis by acting at the level of IR. The observed MOA of CB4211 therefore supports its potential utility for treatment of NASH, obesity, type 2 diabetes, and other metabolic disorders.

Disclosure

K. Grindstaff: Employee; Self; CohBar, Inc.. R. Magnan: None. R. Shang: Employee; Self; CohBar Inc. E. Stenger: Employee; Self; CohBar, Inc.. J.S. Holland: None. D. Perez-Tilve: Research Support; Self; Novo Nordisk A/S, Cohbar. K.C. Cundy: Employee; Self; CohBar, Inc.. Stock/Shareholder; Self; CohBar, Inc..
Pancreas Volume Declines over the First Year after Diagnosis with Type 1 Diabetes (T1D)
Authors: VIROSTKO JACK , HILMES MELISSA A. , WILLIAMS JONATHAN M. , WRIGHT JORDAN , DU LIPING , KANG HAKMOOK , RUSSELL WILLIAM E. , MOORE DANIEL J. , POWERS ALVIN C.
Published: June 2018

The pancreas is smaller in individuals with T1D, but it is unclear if these individuals are born with a smaller pancreas or whether their pancreatic volume declines as part of disease progression. To determine the dynamics of pancreas volume in new-onset T1D, we performed longitudinal magnetic resonance imaging (MRI) of the pancreas in individuals with recent-onset T1D (n = 51, mean age 13.7 y, range 8-24 y) within the first 100 days after diagnosis (mean 67 days), six months after diagnosis, and one year post diagnosis. In agreement with and extension of our results presented at 2017 ADA Scientific Sessions, we found that at disease onset, young individuals with T1D had a smaller pancreas (median volume = 29.6 ml) than similarly aged controls (median volume = 49.6 ml, n = 51, p < 0.001). Pancreas volume was lower in T1D individuals when normalized by subject weight (p < 0.001), as well as when adjusted for age, gender and body mass index (p < 0.001). Longitudinal measurements of pancreas volume increased in controls over the year, corresponding with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis (p < 0.001). Pancreas volume measurements normalized by body weight were stable in controls, but declined in subjects with T1D (p < 0.001). We also performed MRI in 14 individuals enrolled in TrialNet with multiple autoantibodies portending the development of T1D, and found that pancreas volume was similar to controls (median volume = 59.1 ml), but significantly greater than the T1D cohort (p < 0.001). To interrogate microstructural changes in the pancreas, we performed diffusion-weighted MRI and found that individuals with recent-onset T1D had a higher apparent diffusion coefficient (p = 0.023), indicating reduced restrictions on water diffusion in the pancreas in T1D. These results indicate the existence of ongoing pancreatic atrophy during the first year after diagnosis with T1D which may be reflected by microstructural changes in the pancreas.

Disclosure

J. Virostko: None. M.A. Hilmes: None. J.M. Williams: None. J. Wright: None. L. Du: None. H. Kang: None. W.E. Russell: None. D.J. Moore: None. A.C. Powers: None.
Comparison of Different Anthropometric Indices for Identifying Insulin Resistance in Two Indigenous Communities Living at Different Altitudes
Authors: HIRSCHLER VALERIA ,   SAN ANTONIO DE LOS COBRES STUDY GROUP
Published: June 2018

Background: Anthropometric measurements might be valuable tools for identifying children at risk of developing type 2 diabetes.

Objective: To compare the abilities of waist circumference (WC), BMI, and WC/height to identify children with insulin resistance in two indigenous communities from similar ethnic backgrounds, but living at different altitudes.

Methods: Cross-sectional study of 142 (66 f) indigenous school children (4-14 y) from San Antonio de los Cobres (SAC), 3,750 m above sea level, and 171 (86 f) from Chicoana (CH), 1,400 m, were assessed for weight, height, WC, glucose, and insulin levels. ROC curves were generated for BMI, WC, and WC/height, with HOMA-IR>III quartile as the dichotomous variable in both SAC and CH.

Results: There was not a significant difference in age between SAC and CH children (8. 9 vs. 9.3 years, respectively). However, SAC had a significantly lower z-BMI (-0.16 vs. 0.68), WC (59.8 vs. 67.3 cm), and WC/height (45.9 vs. 48.7) than CH. The prevalence of overweight and obesity was significantly lower in SAC than in CH (9.2% vs. 41.8%). Significant univariate association (P<0.05) was found between WC with insulin (r = 0.58), and HOMA-IR (r = 0.40); BMI with insulin (r = 0.51), and HOMA-IR (r = 0.37); and WC/height with insulin (r = 0.33), and HOMA-IR (r = 0.24). The areas under the ROC curve in SAC children were as following: WC= 0.81 ± 0.04 (95% CI 0.72-0.90), BMI= 0.80 ± 0.(95% CI 0.70-0.90), and WC/height= 0.71 ± 0.(95% CI 0.59-0.81). The areas under the ROC curve in CH children were as following: WC= 0.75 ± 0.(95% CI 0.66-0.85), BMI= 0.76 ± 0.(95% CI 0.67-0.85), and WC/height= 0.67 ± 0.(95% CI 0.56-0.79).

Conclusion: The prevalence of obesity was significantly lower in SAC than in CH probably due to high altitude-induced chronic hypoxia. However, WC and BMI were acceptable indicators for insulin resistance in both communities living at different altitudes; whereas WC/height was a fair indicator for insulin resistance.

Disclosure

V. Hirschler: None.
Are Black Pediatric Patients with Type 1 Diabetes (T1D) Prescribed Higher Doses of Insulin than White Patients?
Authors: CHALEW STUART , GOMEZ RICARDO , HEMPE JAMES M.
Published: June 2018

Black youth with T1D have been noted to have higher HbA1c’s, less frequent monitoring of capillary glucose and higher reported occurrence of hypoglycemia compared to white patients. We hypothesized that this combination of factors would be associated with higher prescribed doses of insulin in black patients compared to whites. A retrospective analysis was performed on data collected from patients at the Children’s Diabetes Center, New Orleans, LA who participated in a study of racial differences in hemoglobin glycation. Patients self-identified as either black or white and were under the clinical care of several different attending diabetologists. The influence of race on total daily prescribed dose of insulin per kg body weight (TDDI), was evaluated in a general linear model adjusted for HbA1c, insulin delivery method, gender, and chronologic age as well as the interactive effect of race and HbA1c. Hemoglobin Glycation Index (HGI) was also calculated and substituted in the model for HbA1c. The population studied consisted of 33 (19F, 14M) black patients and 52 (22F,30 M)whites. Average age was 14.0±3.6 years and duration of diabetes 5.7±3.9 years. As previously reported from this population blacks had higher HbA1c even after adjustment for age and mean blood glucose level (MBG). Mean TDDI was 0.89±0.33 units/kg/d. TDDI was highly correlated with both HbA1c (r=0.40,p<0.0001)and MBG (r=0.43,p<0.0001) before adjustment. In the linear model TDDI was significantly associated with HbA1c (p=0.0003) but not race, age, gender or insulin delivery mode. There was no interactive effect of race and HbA1c. There was no significant effect of HGI. We found that prescribed TDDI increased with increasing HbA1c in both black and white patients. This preliminary study suggests that prescribing physicians increase insulin dosage in an attempt to bring HbA1c to goal for their patients but do not vary dose based on ethnicity.

Disclosure

S. Chalew: None. R. Gomez: None. J.M. Hempe: None.
Maternal and Neonatal Outcomes in Pregnancy Complicated by Type 1 Diabetes Mellitus
Authors: BI YAN , XU QIANYUE , LU JING , HU JUN , LI JINGJING , GE ZHIJUAN , ZHU DALONG
Published: June 2018

Aims: To assess the risk of adverse pregnancy outcomes in pre-gestational type 1 diabetes mellitus (T1DM) as compared to gestational diabetes mellitus (GDM) or pregnancy without diabetes and examine the effect of glycemic control in late pregnancy on these outcomes in T1DM.

Methods: This retrospective study comprised of 61 cases of pre-gestational T1DM, 244 cases of GDM, and 244 control pregnancies. Data regarding demographics, obstetric and perinatal outcomes were extracted from the hospital discharge database.

Result: Compared to the pregnancies without diabetes, women with T1DM had higher risks of polyhydramnios [odds ratio(OR) 4.5] and cesarean section (OR 21.2), while the odd ratios for these outcomes in GDM were 2.4 and 1.9, respectively. Preeclampsia, preterm delivery, preterm premature rupture of membranes and postpartum hemorrhage occurred more in women with T1DM than GDM. Severe perinatal outcomes including stillbirth and congenital malformations were reported in T1DM only. Moreover, women with T1DM were more likely to present abnormal fetal growth, either low birthweight (OR 4.0) or large for gestational age (OR 5.0). Severe perinatal outcomes including stillbirth and congenital malformations were reported in T1DM only. Poorly controlled HbA1c in late pregnancy was significantly associated with an increased risk of preterm birth (OR 2.01) in T1DM.

Conclusions: Women with T1DM have considerably increased risks of adverse pregnancy outcomes, which appear more critical than the contemporary outcomes in women with GDM. Thus, a specific routine is required for pregnancy in T1DM to improve the glycemic control and obstetric care.

Disclosure

Y. Bi: None. Q. Xu: None. J. Lu: None. J. Hu: None. J. Li: None. Z. Ge: None. D. Zhu: None.
Alpha-1 Antitrypsin Therapy in Recent-Onset Type 1 Diabetes
Authors: LEBENTHAL YAEL , BRENER AVIVIT , HERSHKOVITZ ELI , SHEHADEH NAIM , SHALITIN SHLOMIT , GAI-CASTRO SHARON , STEIN MICHAL , TOV NAVEH , RACHMIEL MARIANNA
Published: June 2018

Previous phase I studies demonstrated that alpha-1 antitrypsin (AAT) was safe and well tolerated in type 1 diabetes (T1D) patients. This multicenter, randomized, placebo-controlled phase II trial was designed to test whether AAT could preserve C-peptide secretion in new-onset T1D patients aged 8-25 years. Seventy patients (37 males; mean age 13.1 ± 4.1 years) were randomized (1:1:1) to treatment with 22 IV infusions − 60 mg/kg AAT, 120 mg/kg AAT or placebo administered over 1 year. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test (MMTT) after 1 year. Secondary endpoints were HbA1c and safety parameters. Post-hoc sub-group analysis by age was performed. At 1 year, the decrease in C-peptide AUC was not different in AAT vs. placebo groups (P = 0.66 and 0.96, for 60 and 120 mg/kg AAT). Within 12-18 years subgroup (n=35), C-peptide AUC in placebo-treated and 60 mg/kg AAT-treated patients decreased significantly from baseline (-0.34 and -0.55 pmol/mL, respectively, P < 0.01) while no significant decrease was observed in the 120 mg/kg AAT-treated patients (-0.18 pmol/mL, P = 0.20). At 1 year, mean HbA1c levels were higher in placebo-treated patients and 60 mg/kg AAT-treated patients vs. 120 mg/kg AAT-treated patients (8.24 ± 1.42% and 7.85% ± 1.67% vs. 6.66% ± 1.01%, respectively, P = 0.for 120 mg/kg AAT vs. placebo); a lower percentage of patients attained HbA1c ≤ 7% in the placebo and 60 mg/kg AAT groups compared to 120 mg/kg AAT (25% and 28.6% vs. 70%, P = 0.07). The infusions were well tolerated with a similar safety profile in the AAT and placebo groups. Two patients in the 60 mg/kg treatment group had allergic reactions after 4 and 17 infusions. Although AAT intervention shows promise with a favorable safety profile, the efficacy of AAT in T1D patients is inconclusive. Further studies should be undertaken with appropriate patient stratification pre-randomization and implementation of biomarkers to determine whether AAT has a beneficial effect on beta cell preservation.

Disclosure

Y. Lebenthal: Speaker's Bureau; Self; Novo Nordisk Inc.. Consultant; Self; Kamada. A. Brener: None. E. Hershkovitz: None. N. Shehadeh: None. S. Shalitin: None. S. Gai-Castro: Employee; Self; Kamada. M. Stein: Employee; Self; Kamada. N. Tov: Employee; Self; Kamada. M. Rachmiel: Advisory Panel; Self; Novo Nordisk Inc.. Other Relationship; Self; Medtronic MiniMed, Inc.. Research Support; Self; Kamada.
The Awareness of Preconception Counseling in Childbearing Age Women with Type 1 Diabetes Mellitus in China
Authors: ZHOU YONGWEN , YAN JINHUA , LUO SIHUI , ZHENG XUEYING , LING PING , WU ZEKAI , LV JING , QIU LILING , YANG DAIZHI , WENG JIANPING
Published: June 2018

Objectives: To assess the awareness of preconception counseling in childbearing age women with T1DM (type 1 diabetes mellitus) in China.

Methods: Women with T1DM in childbearing age were enrolled from 11 hospitals in Beijing, Jinan, Nanjing, Shanghai, Chengdu, Changsha and Guangzhou from May 2015 to August 2017. Demographic data, clinical characteristics and information on preconception counseling were collected. Redcap was used to establish the database and SPSS 20.0 was adopted to analyze data.

Results: A total of 178 T1DM women with age 30.43±4.34 years and duration of T1DM 20.52±7.62 years were enrolled. Patients were pregnant (≤13 weeks, n=89; 13-28 weeks, n=30; ≥28 weeks, n=12) or planning pregnancy (n=47). There were 85.9% of patients realizing pregnancy was permitted when HbA1c< 7.0% while 2.2% worrying T1DM women cannot be pregnant due to genetic susceptibility or potential injury. Most patients had the awareness to perform thyroid function test (92.0%), blood/urine ketone test (94.2%), diabetic retinopathy (90.8%) and nephropathy screening (95.4%) before pregnancy. Patients considered it was necessary to tighten glycemic control(100.0%) and postprandial glucose monitoring should be included (90.1%). Most patients(93.6%) admitted intake of multivitamin and folic acid was essential and 96.0% of them knew weight control and exercise for at least 30 mins per day,while only 78.5% thought preparing for a delivery in advance of the third trimester was necessary. Among 131 pregnant women, 65.6% received preconception counseling; patients with preconception counseling had better glycemic control before pregnancy compared with those without counseling (HbA1c 6.73±0.93% vs. 7.55±1.38%, P=0.028; severe hypoglycemic 25.6% vs. 61.9%, P<0.001).

Conclusion: The awareness of preconception counseling had been improved but was still not sufficient. Effective preconception counseling was associated with better glycemic control before pregnancy in pregnant women with T1DM.

Disclosure

Y. Zhou: None. J. Yan: None. S. Luo: None. X. Zheng: None. P. Ling: None. Z. Wu: None. J. Lv: None. L. Qiu: None. D. Yang: None. J. Weng: None.
Country-Wide Capacity Building Model in Gestational Diabetes Management for Primary Care Physicians in India
Authors: CHANDWANI HARESH , KUMAR PUSHKAR
Published: June 2018

Background: Pregnancies complicated by GDM have fourfold increased risk of perinatal mortality and has a long-term health impact, with more than 50% of women with GDM going on to develop type 2 diabetes within 5-10 years of delivery. In India an estimated 4 million women have GDM.

Aims: The aim of this abstract is to highlight the components of a PAN India training model specifically designed to enhance the knowledge, skills, and core competencies of Primary Care Physicians (PCPs) in the management of GDM.

Methodology: Addressing the issue of dearth of trained professionals in specialised area like gestational diabetes by building the capacity of primary care physicians is an important strategy towards improving GDM management. A four modular course was developed jointly by Public Health Foundation of India and Dr.Mohan’s Diabetes Education Academy to train primary care physicians with strong course curriculum, vetted and approved by the eminent panel of national experts constituting of eminent endocrinologists and gynaecologists.

Result: Certificate Course in Gestational Diabetes Mellitus (CCGDM) has trained 3200 participants and covered 26 states, 3 Union Territories, 257 districts and 437 cities in the last 4 cycles. This model has been adopted by four state governments for training their medical officers. Out of the trained participants, 52% were post- graduates and 39% belonged to Government sector. The robust monitoring mechanism and precise certification method led to 90% pass percentage and 92% of trained physicians claimed that it helped them in better diagnosis, timely referral and management of GDM patients with significant knowledge improvement.

Conclusion: Focusing on GDM by training PCPs is a low-cost intervention both to improve maternal and child health as well as to prevent future diabetes. CCGDM is a well- defined progressive training model to build capacity among doctors in GDM Management and has the potential to be adopted by low income countries.

Disclosure

H. Chandwani: None. P. Kumar: None.
DXA-Determined Visceral Adipose Tissue Is Associated with Cardiometabolic Risk Factors Even in Healthy Young Adults from the Nutritionists’ Health Study—NutriHS
Authors: VALENTE ANGÉLICA M.M. , ALMEIDA-PITITTO BIANCA , FERRARO ALEXANDRE A. , FOLCHETTI LUCIANA , SILVA ISIS T. , FERREIRA SANDRA R.G.
Published: June 2018

Background: Association of excessive visceral adipose tissue(VAT) with cardiometabolic risk in middle-aged adults has been recognized. VAT determined by dual-x-ray absorptiometry(DXA) is an accurate measurement but its usefulness for early detection of cardiovascular risk at a younger age is less investigated. The NutriHS has examined several cardiometabolic markers in undergraduates and graduates from Nutrition courses in Brazil.

Aim: To evaluate whether DXA-VAT is associated with cardiometabolic markers in young adults with a normal cardiovascular risk profile.

Methods: In this cross-sectional analysis, 177 NutriHS participants(90% women, 70% Caucasians) underwent clinical examination, body composition(iDXALunarGE®) and blood sampling. Associations of DXA-VAT(exposure) with blood pressure(BP), waist and neck circumferences(WC and NC), BMI, triglycerides(TG), HDL-c, non-HDL-c, uric acid, fasting glucose, insulin, HOMA-IR and inflammatory biomarkers(outcomes) were tested by multiple linear regression, adjusted according to the directed acyclic graphs.

Results: Mean values of age, BMI and FG were 25.8±8.0years, 23.5±4.3kg/m2 and 83±9mg/dL, respectively. DXA-VATs were 693.6±640.3g for men and 235.7±322.6g for women. In regression models, DXA-VAT was directly associated with NC(r2 0.62, p<0.001), non-HDL-c(r2 0.21, p=0.022), TG(r2 0.39, p<0.001), uric acid(r2 0.34, p<0.001), E-selectin(r2 0.11; p=0.004), leptin(r2 0.10, p=0.006), insulin(r2 0.26; p=0.029) and HOMA-IR(r2 0.27; p=0.024), and inversely with HDL-c(r2 0.22, p=0.039) after adjustments, but not with BP, FG, interleukins and TNF-a.

Conclusion: Such associations of DXA-VAT with traditional and novel risk markers suggest that this method may be useful to identify those at an increased risk even in a selected sample of low-risk healthy individuals. Our follow-up is necessary to confirm the hypothesis raised in this study.

Disclosure

A.M.M. Valente: None. B. Almeida-Pititto: None. A.A. Ferraro: None. L. Folchetti: None. I.T. Silva: None. S.R.G. Ferreira: None.
Trends in High-Density Lipoprotein Cholesterol (HDL-C) among Hispanic vs. Non-Hispanic Adults with Normal Glycohemoglobin in the U.S., 2009–2014
Authors: CALDERON MORENO ROSSANA M. , FERNANDEZ MIGUEL MALDONADO , VASUNILASHORN SARINNAPHA
Published: June 2018

HDL-C, an independent cardiovascular risk factor, is often impacted by biological and environmental factors. Previous studies have observed lower HDL-C levels in Hispanics, with insulin resistance as a strong predictor; however, it is unclear how HDL-C changes over time. Using data from the U.S. National Health and Nutrition Survey (NHANES) 2009-2014, we evaluated trends in HDL-C levels among 2,190 Hispanic and 7,429 non-Hispanic adults with glycohemoglobin levels <5.7%, stratified by age and gender. Baseline characteristics using survey methods are reported in Table 1. In terms of trends in HDL-C levels among the 3 NHANES waves, older non-Hispanic women had significantly higher levels in 2013-2014 vs. 2009-2010 (β 5.23, p<0.01), adjusted for BMI and smoking status. Also, Hispanics had significantly lower HDL-C levels, specially men (age 20-59: β 2.16 p=0.009, ≥60: β 5.p=0.046), but only borderline in Hispanic women (β 2.03, p=0.07). Sex-specific low HDL-C prevalence was not significantly different by race, although suggested in Hispanic women ≥60 y/o (OR 2.04, p=0.07). These data indicate that Hispanics have overall lower absolute HDL-C levels, a trend that did not improve across NHANES waves. Although stronger in men, our findings highlight the importance of age and gender on HDL-C among Hispanics and the need for further research as reports vary across studies.

Table 1. Baseline Demographic Characteristics NHANES 2009-2014Hispanic Men (n=1,010; 49.54%)Hispanic Women (n=1,180; 50.46%)Hispanics, Total (n=2,190; N=20,016,409.4)Non-Hispanic Men (n=3,567; 47.94%)Non-Hispanic Women (n= 3,862; 52.06%)Non-Hispanics, Total (n= 7,429; N= 124,187,151)HDL-C mg/dl (mean ±SE)All Adults46.97±0.5355.5±0.4751.27±0.3949.32±0.3560.89±0.455.35±0.31HDL-C mg/dL(mean±SE)20-59 y/o46.85±0.5655.27±0.4851.07±0.4048.35±0.3460.19±0.4354.43±0.32HDL-C mg/dL(mean±SE) ≥60 y/o48.93±1.3658.56±1.3654.31±0.8854.18±0.9863.88±0.7959.55±0.75Low HDL-C n(%) All Adults(men <40 mg/dL, women <50 mg/dL)287 (27.72)424 (36.74)711 (32.27)880 (25.74)1,074 (25.26)1,954 (25.49)Low HDL-C n(%) 20-59 y/o248 (27.78)372 (37.24)620 (32.52)741 (27.34)898 (26.41)1,639 (26.86)Low HDL-C n(%) ≥60 y/o39 (26.6952 (29.82)91 (28.44)139 (17.73)176 (20.38)315 (19.19)Age yrs (mean ± SE)36.12±0.4036.89±0.4336.5±0.3343.26±0.4044.22±0.4043.8±0.42

Disclosure

R.M. Calderon Moreno: None. M. Maldonado Fernandez: None. S. Vasunilashorn: None.
Differences between Point-of-Care Blood Glucose Analyzers in Identifying Prediabetes
Authors: SZABLOWSKI CARRIE J. , MERCER KARMEN R. , MANALANG MILBEN , SUSCHA EMILY , MOSKOWITZ KEITH , ANDERSON JAMES H. , MECHLEY AMY
Published: June 2018

Background: According to the ADA, 84 million Americans have prediabetes and are at risk for developing diabetes. Ninety percent of those Americans don’t know they have it and are at a higher risk of serious health complications such as heart disease, stroke, kidney disease, and blindness. Early identification of prediabetes facilitated by corporate health and wellness screening companies is an important aspect of diabetes prevention.

Method: Approximately 25,000 blood glucose results were obtained between 2015 and 2016 from four corporate wellness sites using both the Alere Cholestech LDX® and the PTS Diagnostics CardioChek® Plus. The glucose results were compared to the CDC’s 2017 National Diabetes Statistics Report and the percent of nondiabetic, prediabetic, and diabetic populations were tabulated using clinical decision limits of < 100, 100-125, and ≥ 126 mg/dL, respectively. Fisher’s exact test was used to evaluate statistical differences between the U.S. population relative to the LDX or CardioChek Plus blood glucose results.

Results: Based on the CDC report, 12% of the U.S. population (> 18 years) is diabetic. The remaining population was calculated at 34% prediabetic and 54% nondiabetic. The LDX results under-reported the prediabetic population at 20% and over-reported the nondiabetic population at 73% (p=0.015). CardioChek Plus results were more aligned with U.S. population statistics at 32% prediabetic and 59% nondiabetic (p=0.645). Unlike prediabetes, there were no statistical differences in classifying diabetes with the LDX or CardioChek Plus.

Conclusion: Both point-of-care analyzers were helpful in screening for prediabetes. The CardioChek Plus more accurately categorized prediabetes relative to U.S. population statistics. The PTS Diagnostics CardioChek Plus offers reliable results to help recognize prediabetes and prevent its progression to diabetes.

Disclosure

C.J. Szablowski: Employee; Self; PTS Diagnostics. K.R. Mercer: None. M. Manalang: Other Relationship; Self; Provant Health Solutions. E. Suscha: Employee; Self; PTS Diagnostics. K. Moskowitz: Employee; Self; PTS Diagnostics. Stock/Shareholder; Self; PTS Diagnostics. J.H. Anderson: Employee; Self; PTS Diagnostics. Board Member; Self; GENEREX Biotechnology. A. Mechley: Consultant; Self; PTS Diagnostics.
The Establishment of a Registry of Elderly Patients with Diabetes and an Investigation of the Inhibitory Factor of Cognitive Dysfunction
Authors: OKAMOTO MISATO , ITOH JUN , SONODA NORIYUKI , MAEDA YASUTAKA , FUJII MASAKAZU , OGAWA YOSHIHIRO
Published: June 2018

Objectives: Diabetes and dementia has been considered to have pathological relevance. Early diagnosis and treatment for Mild Cognitive Impairment (MCI) are important to stop it from advancing to dementia. We investigated the rate of MCI or dementia, correlation between cognitive dysfunction (CD) and background factor in diabetes patients, a valuable marker for diagnosis and effective diabetes treatment for prevention of CD.

Approach and Results: We identified 161 patients aged ≥60 years, outpatient treatment at Kyushu University hospital from 2016/7 ∼ 2017/11. The Japanese versions of Montreal Cognitive Assessment (MoCA-J) and Mini-Mental State Examination (MMSE) were performed as screening. The patients who showed MMSE≤27 or MoCA-J≤25 had head MRI/SPECT, visited dementia specialist and were diagnosed with the disease type. The CD, screening results, diabetic clinical findings, contents of treatment and relative factors were analyzed by univariate or multivariate analysis. The subjects of investigation were aged 72.6±7.4 years, female 74/161 (46%), BMI 23.3±3.4, HbA1c 7.1±0.8%, duration14.4±10.6 years, insulin therapy 49/161(30.8%).

Screening Results: MMSE{MCI22(13.7%), dementia1(0.6%)}/{ MoCA-J: MCI 44 (27.3%), dementia 6 (3.7%)}. 22 patients visited a dementia specialist, and diagnosed with Alzheimer’s dementia 2, MCI 15 and normal 5. The sensitivity of MCI in MMSE, MoCA-J were 46.7% and 93.3%, respectively. Exercise therapy showed significant inhibition of CD in correlation between MoCA-J and diabetes treatment. BMI, insulin history, sulfonylurea history, solitary life, CK, ASO were chosen by stepwise regression, which objective variable was MoCA-J. Age and BMI were significant objective variable by age correction.

Conclusions: MMSE and MoCA-J showed significant correlation with treatment background of diabetes patients. MoCA-J is especially thought to be an eminent screening method for MCI in diabetes patients.

Disclosure

M. Okamoto: None. J. Itoh: None. N. Sonoda: None. Y. Maeda: None. M. Fujii: None. Y. Ogawa: Research Support; Self; AstraZeneca. Advisory Panel; Self; Gilead Sciences, Inc.. Research Support; Self; Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd..
Clinical Characteristics and Early Treatment Patterns of Newly Diagnosed Cystic Fibrosis–Related Diabetes in Two Tertiary Centers
Authors: MCCORRY ERIN , BASHEER HIBA , LASCANO JORGE E. , YOON JOHN , LEEY JULIO A.
Published: June 2018

The 2010 ADA/CFRD guidelines have recommended insulin for CFRD. However, these recommendations are often not followed in clinical practice. We performed a chart review of newly diagnosed CFRD patients at University of California Davis (UCD) and University of Florida (UF) for years 2011-2015.

Six new CFRD patients were diagnosed at UCD and 19 at UF. A BMI over 25 was more common in UCD than at UF (50% vs. 11%), whereas a BMI below 20 was more common at UF (0% vs. 21%). The prevalent method of diagnosis was A1c at UCD (100%) and OGTT at UF (63%). One year after diagnosis, insulin was prescribed in 31% of UF patients and none at UCD. A weight loss >3% was observed in 21% of patients in the preceding year at UF but none at UCD. The only patient started on insulin at UCD did so 14 months after the diagnosis whereas the median time was 4.5 months at UF. Of note, the OGTT screening rate was lower at UCD. Because OGTT detects CFRD earlier than A1c, patients diagnosed via OGTT would have experienced less weight loss, not more. While it remains unclear what accounts for the higher BMI at UCD, better nutritional status could have delayed the decision to initiate insulin.

In conclusion, newly diagnosed CFRD patients have divergent characteristics at different centers. Further studies assessing social and dietary differences can serve to evaluate center-to-center variations.

CharacteristicsUC Davis (n=6)U Florida (n=19)OGTT screening rate in 201619%43%Mean age of CFRD at onset in years (SD)31 (7.9)28.8 (7.6)Females66%47.3%BMI 20-25 Kg/m250%68%BMI below 20 Kg/m2None21%CFRD diagnosis vi OGTT50%63%

Disclosure

E. McCorry: None. H. Basheer: None. J.E. Lascano: None. J. Yoon: None. J.A. Leey: None.
The Risk Measure of Hypertension and Diabetes by National Health Insurance Data
Authors: CHUN KI HONG
Published: June 2018

Introduction: Korea’s health insurance is a social insurance that the government is the insurer and the whole nation. All of the national medical benefits are claimed,reviewed and paid for. PURPOSE The study purpose is to investigate the relative risk(RR) of stroke, myocardial infarction and chronic renal failure due to hypertension and diabetes, and the population attributable risk(PAR) by using health claim data for all Koreans in Korea.

Method: The research data are the claims for medical insurance fees from 1999 to 2006.We calculated the RR of stroke, myocardial infarction,and chronic renal failure in 2004 and 20respectively,among those who had been diagnosed with hypertension or diabetes even once in eight years from 1999 to 2006, compared with those in other populations.If a person who did not claim a medical fee for the disease for five years from 1999 to 2003 had a medical fee claim for that year,the person was defined as the treatment incidence.PAR of hypertension or diabetes for these complications was calculated using RR and treatment prevalence.

Result: In 2005, the treatment prevalence rate of hypertension over 30 years old was 23.1% and the diabetes was 10.5%.The National Health and Nutrition Survey, which is a nationwide survey,has 27.9% hypertension and 8.1% diabetes.The RR of stroke was 11.0,the RR of myocardial infarction was 13.6, and the RR of chronic renal failure was 30.3.The PAR of hypertension or diabetes to stroke was 73.0% over 30 years old. Myocardial infarction was 77.3% and chronic renal failure was 88.8%. In other words, 73% of patients with stroke, 77.3% of patients with myocardial infarction,and 88.8% of patients with chronic renal failure could not have developed if hypertension and diabetes is completely managed.

Discussion: Although it is different from the official cohort data because it is measurement using the health insurance fee claim data,it is meaningful to be able to generally see the disease prevalence and the occurrence status for the whole nation.

Disclosure

K. Chun: None.
Novel Associations of Adipokines and Atherosclerotic Markers with Rising Levels of Insulin Resistance in a Mexican-American Border Population
Authors: GUTIERREZ ABSALON D. , FLORES CARLOS A. , LEE MINJAE , LAING SUSAN , ASGARISABET PARISA , RESMAN MASHA , NAIK SAPNA , LEE MIRYOUNG , MCCORMICK JOSEPH B. , FISHER-HOCH SUSAN P.
Published: June 2018

Background: Epidemiological studies suggest that increased levels of leptin and resistin, and decreased levels of adiponectin are associated with worsening insulin resistance (IR) and atherosclerosis. However, it is unclear if these findings apply to Mexican-Americans, as few have been studied. We examined the relationship of these adipokines and carotid intima media thickness (cIMT) to IR and atherosclerosis in a Mexican-American population.

Methods: A retrospective cross-sectional analysis of the Cameron County Hispanic Cohort (CCHC) was performed. Adult participants were stratified into three groups of IR: no-diabetes, prediabetes, and diabetes mellitus (DM). We examined differences in levels of adipokines and cIMT across groups. We constructed multivariable linear and logistic regression models to account for confounding factors. There were 819 subjects (43%, 35%, and 22% for no-diabetes, prediabetes, and DM, respectively) for the study of adipokines and 249 subjects for the study of cIMT (34%, 50%, and 16% for no-diabetes, prediabetes, and DM, respectively).

Results: After controlling for gender, hypertension, age, and BMI, adiponectin levels lowered significantly across increasing levels of IR (p=0.002) and resistin levels did not change significantly across groups (p=0.10). Compared to no-diabetes, leptin levels surprisingly decreased significantly in DM (p=0.013). cIMT levels heightened across increasing levels of IR (p=0.01).

Conclusion: In a Mexican-American population, participants with DM unexpectedly displayed lower levels of leptin compared to no diabetes. Surprisingly, there was also no change in resistin across IR groups. In DM, adiponectin levels decreased and cIMT measurements increased. These findings support the need for more research to understand the relationship of leptin deficiency to DM in this population.

Disclosure

A.D. Gutierrez: Speaker's Bureau; Self; AstraZeneca, Med Learning Group. C.A. Flores: None. M. Lee: None. S. Laing: None. P. Asgarisabet: None. M. Resman: None. S. Naik: None. M. Lee: None. J.B. McCormick: None. S.P. Fisher-Hoch: None.
Gene Calorie Hypothesis—Proposed to Decode T2DM Pathogenesis
Authors: SHINDE SURESH N. , SHINDE RITUPARNA S.
Published: June 2018

Insulin and glucose parabolas of OGTT were studied in 1030 subjects, not previously diagnosed as having T2DM. The parabola shape was mainly influenced by adiposity, peripheral Insulin resistance (PIR), beta cell(BC) mass and glucose dose. Fasting hyperinsulinemia(HI) was strongly related to body mass index(BMI). Continued calorie excess(CCE) and BMI along with increase in insulin area under curve, which suggested recruitment of new insulin receptors, acted as BC stressor leading to HI. Fasting HI appears to be a physiological response to incremental BMI, independent of PIR. The rate of rise of insulin (RIR) sustained an angle theta with baseline and both were related to BMI and PIR. The RIR was directly related to rising BMI, fasting insulin and glucose but was inversely related to PIR, 120 min insulin and glucose. CCE affected the Degree of HI whereas PIR affected the Duration of HI (Fig 1). From NoDM category as CCE begins, RIR and theta increase until PIR becomes unmasked. RIR, which is related to PIR, can not rise further. As CCE continues, at variable maximum level of insulin, the individual’s BC capacity, betamax, is reached. The RIR and theta start falling hereafter, until the final values for DM category. Gene-Calorie hypothesis proposes that PIR is an inherited predisposing factor where as CCE with adiposity is an acquired precipitating factor which together cause continuous BC stress and subsequent BC failure leading to T2DM.

Disclosure

S.N. Shinde: Advisory Panel; Self; USV Private Limited, Alkem Laboratories, Lupin Laboratories, Troikka Ltd, IPCA laboratories. R.S. Shinde: None.
Nutritional Regulation of Hunger Circuits in Awake, Behaving Mice
Authors: KNIGHT ZACHARY
Published: June 2018

Food intake is controlled by specialized neural circuits that monitor nutritional signals from the body, but how nutritional state is represented in the dynamics of these circuits is unknown. I will describe recent work from my lab investigating the dynamics of AgRP neurons, a key neural population that controls hunger. To understand how these cells are regulated by physiologic signals, we have developed a preparation that enables recording of AgRP neuron activity during intragastric feeding of awake, behaving mice. Using this approach, we have shown that AgRP neurons are rapidly inhibited by gastrointestinal nutrients on a timescale of minutes. This rapid feedback is proportional to the number of calories infused, independent of macronutrient identity, and mediated by a combination of hormonal signals. I will discuss general principles of gut-brain communication that have been suggested by these findings as well as key questions that remain to be answered.

Disclosure

Z. Knight: None.
Cell Type–Specific Transcriptional and Epigenetic Profiles from a Rare Neuronal Population within the Arcuate Nucleus
Authors: HEYWARD FRANKIE D. , ROSEN EVAN
Published: June 2018

The arcuate nucleus (ARC) of the hypothalamus is home to a wide assortment of cell types, many of which uniquely contribute to the regulation of energy homeostasis. Given the high degree of cellular heterogeneity present within the ARC, solutions are needed to achieve a better appreciation for the distinct molecular characteristics of relevant cell types. Past approaches enabling cell type specificity are beset with limitations involving time- and labor-intensiveness, low cellular throughput, and processing-induced changes in cellular state. Moreover, to-date, there exist a paucity of techniques that allow for epigenetic profiling of rare cell types within the brain. The recently developed Nuclear tagging and Translating Ribosome Affinity Purification (NuTRAP) provides an unprecedented ability to obtain either cell type-specific transcriptional or epigenetic profiles. Here we examine the capacity of NuTRAP to obtain cell type specific transcriptional and epigenetic profiles in a relatively small population of energy state-sensitive neurons within the ARC.

Disclosure

F.D. Heyward: None. E. Rosen: None.
Role of ERK in IRF3-Mediated Immune Responses
Authors: CHANG PHOEBE F. , ACEVEDO DANIEL , REYNA SARA M.
Published: June 2018

Insulin resistance precedes and contributes to the development of type 2 diabetes mellitus, and it is now believed that chronic inflammation is a major contributor to insulin resistance. Both cellular and secreted factors participate in the pathological and physiological changes that occur to promote inflammation. However, the molecular signaling pathways that drive these processes remain elusive. The mitogen activated protein kinase, extracellular signal-regulated kinase 1 and 2 module (ERK1/2), and the transcription factor, interferon regulatory factor-3 (IRF3), are both activated downstream of Toll-like receptor 4 and associated with the development of insulin resistance. We examined whether inhibition of ERK activity blocked IRF3-mediated immune responses. ERK1 and ERK2 isoforms can have different cellular functions; thus, to determine which ERK isoform is involved in the regulation of IRF3 activity, we performed siRNA to knockdown either ERK1, ERK2, or both in RAW 264.7 macrophages and saw 70% knockdown of each ERK1 and ERK2. Knockdown of ERK1 or ERK2 or both blocked IRF3 translocation to the nucleus with LPS treatment (100 ng/ml, 1 hour), as determined by immunofluorescence using an antibody specific for nuclear IRF3. Because phosphorylated and dimerized IRF3 translocates to the nucleus to regulate the transcription of interferon (IFN)-beta expression, we investigated whether ERK1 or ERK2 inhibited IFN-beta release. Macrophages were treated with LPS (100 ng/ml, 6 hour). LPS induced an IFN-beta production of 791±18.0 pg/ml, but knockdown of either ERK1 or ERK2 decreased the release of IFN-beta to 199±12.3 and 282±32.7 pg/ml, respectively. However, double knockdown of ERK1 and ERK 2 had the greatest inhibition of IFN-beta release (121±15.2 pg/ml).

In summary, both ERK1 and ERK2 regulate IRF3 nuclear translocation and signaling in macrophages. We propose that ERK positively regulates IRF3-mediated immune responses and inhibition of ERK signaling will protect against insulin resistance.

Disclosure

P.F. Chang: None. D. Acevedo: None. S.M. Reyna: None.
Glucagon Regulates Hepatic Mitochondrial Biogenesis and Function through Foxo1
Authors: YANG WANBAO , YAN HUI , PAN QUAN , SHEN ZHENG , DAHANAYAKA SUDATH A. , WU CHAODONG , SUN YUXIANG , GUO SHAODONG
Published: June 2018

The liver is an important organ regulating the energy metabolism, which is tightly governed by multiple hormones. Glucagon secreted from the alpha-cell of the pancreatic islets is a counterregulatory hormone contrary to the action of insulin. In addition to promoting hepatic glucose production, glucagon also plays multiple roles in the liver via its G protein-coupled glucagon receptor. In this study, we found that glucagon attenuated the mitochondrial oxygen consumption and ATP production in primary mouse hepatocytes and decreased hepatic mitochondrial copy numbers. To investigate the molecular mechanisms, we found that glucagon increased the expression of Foxo1 in protein level, which controls the expression of genes responsible for heme biosynthesis, frataxin (FXN) and uroporphyrinogen decarboxylase (UROD). The lower production of heme by glucagon impaired the integrity of electron transport chain (ETC), reducing the heme-dependent complex III (Uqcrc1) and complex IV (mt-Co1). Furthermore, glucagon downregulated mitochondrial transcription factor A (TFAM) and nuclear transcription factors 1 (NRF-1), impairing the mitochondrial biogenesis, which was abolished in Foxo1 deficient primary hepatocytes. These results demonstrate that glucagon inhibits mitochondrial biogenesis and function in a Foxo1-dependent manner.

Disclosure

W. Yang: None. H. Yan: None. Q. Pan: None. Z. Shen: None. S.A. Dahanayaka: None. C. Wu: None. Y. Sun: None. S. Guo: None.
Betatrophin Is Associated with Type 2 Diabetes and Markers of Insulin Resistance
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , GEIGER KATHRIN , SAELY CHRISTOPH H. , BRANDTNER EVA-MARIA , EBNER JANINE , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2018

Betatrophin, also known as ANGPTL8, is secreted by the liver, and its expression is upregulated by nutrition. However, conflicting reports exist on the association of betatrophin with insulin resistance, type 2 diabetes (T2DM) and coronary artery disease (CAD). We therefore measured betatrophin in 553 patients undergoing coronary angiography for the evaluation of established or suspected CAD. T2DM patients (n=161) had higher betatrophin than those without T2DM (12.9±19.0 vs. 9.3±9.0 ng/ml; p=0.005). Betatrophin however did not differ significantly between patients with significant CAD (n=347) and those who did not have significant CAD (10.5±13.5 ng/ml vs. 10.2±11.8 ng/ml; p=0.654). Betatrophin was positively correlated with waist circumference (r=0.150, p=0.001), BMI (r=0.142, p=0.001), fasting glucose (r=0.133, p=0.002), HbA1c (r=0.125, p=0.003), serum insulin (r=0.221, p<0.001), the HOMA index of insulin resistance (r=0.226, p<0.001) and the fatty liver index (r=0.231, p<0.001). In multivariate analysis betatrophin proved to be an independent predictor of diabetes, with a standardized adjusted odds ratio of 1.23 [95% CI 1.01-1.51], p=0.043. We conclude that betatrophin is associated with T2DM and markers of insulin resistance.

Disclosure

A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
Mitogenic Insulin Receptor A Increases in the Rodent Pituitary at the Onset of Puberty
Authors: SALEH FARRAH , TAYLOR HUGH S. , FLANNERY CLARE
Published: June 2018

Physiological insulin resistance and hyperinsulinemia occurs at the onset of puberty, and is thought to contribute to peri-pubertal growth and development. However, in contrast to IGF-1, little is known about how insulin affects the hypothalamic-pituitary-ovarian (HPO) axis in peri-pubertal girls. Insulin has mitogenic and metabolic activity through splice-variant isoform receptors IR-A and IR-B, respectively. We hypothesize that insulin signaling in HPO tissues contributes to the initiation of puberty, and sought to determine whether IR isoform expression is differentially regulated during puberty.

We evaluated female, FVB/NJ mice: pre-pubertal, 3-4 week old mice (n=4) and peri-pubertal mice (n=7) identified within 24 hours of vaginal opening, an external marker of puberty. IR-A, IR-B, IGF-1R were quantified using a qRT-PCR assay previously validated for receptor comparison. Receptor expression was analyzed by Student’s t-test after log transformation.

IR-A was the predominant IR isoform in the prepubertal hypothalamus, pituitary, and ovary, in a 20:1, 10:1, and 2:1 ratio with IR-B, respectively (p<0.05, all). At puberty, IR-A did not change in the hypothalamus, whereas IR-A increased by 3.6-fold (p=0.059) in the pituitary. IR-B remained largely unchanged during puberty in both the hypothalamus and pituitary (p=NS, respectively). Interestingly, in the peripubertal ovary which has active folliculogenesis and steroid hormone synthesis, both IR-A and IR-B decreased by 33% and 68%, respectively (p<0.03). As expected, IGF-1R levels were higher than IR isoforms in HPO tissues, at both developmental stages. Similar to mitogenic IR-A, IGF-1R increased in the pituitary (p<0.059) during puberty.

An increase in pituitary IR-A expression at the onset of puberty suggests a role for insulin signaling in regulating pituitary hormone production related to puberty. Obesity, a known risk factor for early puberty development in girls, may alter normal insulin signaling in the HPO axis.

Disclosure

F. Saleh: None. H.S. Taylor: None. C. Flannery: None.