bluuebunny/crossref_metadata_2025 huggingface dataset:
Liver Fibrosis as Assessed by the FIB-4 Index in Patients with Type 2 Diabetes (T2DM)
Authors: FILOZOF CLAUDIA M. , JONES STEPHEN , GOLDSTEIN BARRY J.
Published: June 2018

Data about liver fibrosis in T2DM are scarce. The FIB-4 index is a non-invasive panel to evaluate underlying hepatic fibrosis. FIB-4 values <1.45 and ≥3.25 were reported to have a negative predictive value (NPV) of ∼90% and PPV of∼65% for advanced fibrosis. FIB-4 values ≥ 2.67 were reported to be associated with 16X increase in clinical outcomes in NAFLD. FIB-4 range ≥1.45 < 2.67 is suggested to be an indeterminate area. We assessed FIB-4 values and their changes over 4 years in 334,076 patients (48% males) with T2DM. A total of 75.2%, 22.3%, 1.3% and 1.2% of subjects had FIB-4≥ 1.45 (G1), ≥1.45 <2.67 (G2), ≥ 2.67<3.25 (G3) and ≥3.25 (G4). Subjects with low FIB-4 were younger, had lower ALT/AST and higher platelet counts (Table). Almost 50% of the patients with FIB-4≥ 2.67 had ALT/AST within reference ranges (RR). Mean plasma TG and HbA1C were similar among groups. Among G1 patients, 83% stayed G1, 16.3% progressed to G2 and 0.7% had FIB-4 ≥ 2.67 after 4 years. A total of 10% and 27% of patients initially in G2 and G3 progressed to FIB-4 associated with higher risk of liver outcomes.

Conclusion: Only 75% of the patients had FIB-4 suggesting absence of advanced liver fibrosis, ∼ 50% of subjects at risk of liver outcomes had ALT/AST within RR. FIB-4 is a simple, inexpensive method that may help identify patients at risk of liver outcomes. Strategies to slow the growth of liver complications and therapeutic options are necessary to mitigate disease burden.

Disclosure

C.M. Filozof: Employee; Self; Covance Inc.. S. Jones: None. B.J. Goldstein: Employee; Self; Covance Inc..
Using Claims and Consumer Wearable Devices Data to Quantify Influenza-Related Outcomes among Type 2 Diabetes Patients—A Large Population Study
Authors: SAMSON SANDRINE I. , LEE WEI-NCHIH , QUISEL THOMAS , FOSCHINI LUCA , LISKA JAN , MILLS HENRY G. , HOLLINGSWORTH ROSALIND C. , GREENBERG MICHAEL E. , BEAL ANNE C.
Published: June 2018

Influenza causes substantial morbidity in people with diabetes; annual vaccination is recommended. We conducted a retrospective study of influenza-related outcomes (IRO) among fully insured type 2 diabetics from a large U.S. payer over a 1 year period covering the 2016-17 influenza season. We used bivariate analysis (54,656 diabetics, mean age 54.8 years, s.d. = 10.2) to compare IRO’s inferred from claims data against IRO’s for 113,016 age and gender matched nondiabetics. Diabetics had more influenza events (per ICD-9 and ICD-10 codes, 1.96% vs. 1.37%, p<0.001), and were prescribed more influenza antivirals per 100 ppl (27.1 vs. 22, p<0.001). Within 2-weeks before and 4-weeks after a medical claim for influenza, diabetics with influenza had more observed hyperglycemic events than in a comparable non-influenza period in the same year (3.81% vs. 2.18%, p<0.001), with substantial increases in pneumonia, sepsis and coronary disease (5.5% vs. 0.7%, 5.5% vs. 3.5%, 1.6% vs. 0.3%, p<0.001), and more outpatient antibiotic use per 100 people (54.5 vs. 16.9, p<0.001). 8.2% of type 2 diabetics (vs. 9.1% controls, p<0.001) used commercially available activity and sleep trackers, sharing data through an insurer provided wellness platform. Activity trackers showed that diabetics slept fewer hours compared to controls (6.48 vs. 6.69 hours, p<0.001), and had statistically significant changes in sleep and walking habits in the days around an influenza event as compared to baseline (about 2% more of the night spent restless and 10k fewer steps). This is the first population scale study to use medical claims linked with activity tracking data to quantify the behavioral and clinical effects of influenza in type 2 diabetes. These data highlight the impact of influenza on glycemic control and the daily lives of the Diabetic population, and reinforce the need for annual influenza vaccine, as recommended by the WHO and other global public health bodies.

Disclosure

S.I. Samson: Employee; Self; Sanofi Pasteur. W. Lee: None. T. Quisel: None. L. Foschini: None. J. Liska: Employee; Self; Sanofi. H.G. Mills: Employee; Self; Sanofi. R.C. Hollingsworth: Employee; Self; Sanofi Pasteur. M.E. Greenberg: Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi, GlaxoSmithKline plc., Pfizer Inc. A.C. Beal: Employee; Self; Sanofi. Board Member; Self; AcademyHealth.
Efficacy of A1C in the Presence of HbC Trait Needs Evaluation
Authors: BRIKER SARA M. , KABAKAMBIRA JEAN DAMASCENE , BAKER RAFEAL L. , DUBOSE CHRISTOPHER , MABUNDO LILIAN , CHUNG STEPHANIE T. , SACKS DAVID B. , SUMNER ANNE E.
Published: June 2018

Hemoglobin C (HbC) trait is a Hb variant found in 15% of West Africans. Similar to HbS, HbC occurs because of a single nucleotide substitution on the beta-globin chain of hemoglobin. Many studies have evaluated whether HbS trait influences the diagnostic efficacy of A1C. Data on the effect of HbC trait on A1C is scant. Our goal was to determine by Hb-type the sensitivity and specificity of A1C as a diagnostic test for the detection of abnormal glucose tolerance (abnl-GT) in 369 blacks born in Africa and currently living in the Washington, DC area (age 38±10y (mean±SD), BMI 27.5±4.5 kg/m2). OGTT and Hb electrophoreses were performed. Abnl-GT was defined as fasting glucose≥100 mg/dL or 2h glucose≥140 mg/dL. A1C ≥5.7% was considered diagnostic for abnl-GT. The frequencies of normal Hb-type, HbS trait and HbC trait were: 82%, 14% and 4%, respectively. The prevalence of abnl-GT in each group was: 38%, 42%, and 50% (P=0.59), respectively. Sensitivity and specificity of A1C by group are provided in the Table. No one in the HbC trait group with abnl-GT was detected by A1C. Hence, sensitivity was 0%. Furthermore, specificity of A1C in the HbC trait group was 100% as no one with normal glucose tolerance had A1C≥5.7%. The number of individuals with HbC trait was small but our findings suggest the need for greater investigation into the diagnostic efficacy of A1C in the presence of HbC trait.

Disclosure

S.M. Briker: None. J. Kabakambira: None. R.L. Baker: None. C. DuBose: None. L. Mabundo: None. S.T. Chung: None. D.B. Sacks: Other Relationship; Self; Sebia, Trinity Biotech. A.E. Sumner: None.
SGLT2 Inhibitors Suppress NLRP3 Inflammasome Activity via Changes in Ketones and Insulin in Type 2 Diabetes and Cardiovascular Diseases
Authors: LEE YONG-HO , KIM SO RA , BAE JAEHYUN , LEE BYUNG-WAN , KANG EUN SEOK , AHN CHUL WOO , CHA BONG-SOO
Published: June 2018

SGLT2 inhibitors significantly reduce cardiovascular events in humans with T2D; however, the underlying mechanism remains unclear. Activation of NLRP3 inflammasome and subsequent IL-1β release induces atherosclerosis and heart failure. Recently, it was revealed that ketone bodies, i.e., β-hydroxybutyrate (BHB) suppresses activation of NLRP3 inflammasome in macrophages. As SGLT2 inhibitors cause increases in serum BHB by pharmacologic profile, we assessed the effect of SGLT2 inhibitor on NLRP3 inflammasome activity. In a randomized, active-controlled study, a total of 61 patients with T2D and high cardiovascular risk (mean age and HbA1C were 64.4 years and 7.32%, respectively) received SGLT2 inhibitor or sulfonylurea for 30 days. NLRP3 inflammasome activation was analyzed in macrophages and the serum levels of glucose, BHB, and insulin from baseline to the end of treatment were tested. While SGLT2 inhibitor’s glucose-lowering capacity was similar to sulfonylurea, it significantly decreased IL-1β secretion compared to baseline (2,394 ± 236 to 1,748 ± 295 pg/mL, p <0.001), whereas sulfonylurea had no effect on IL-1β secretion (2,273 ± 279 to 2,755 ± 331 pg/mL, p = 0.05) (time × group interaction p <0.001). SGLT2 inhibitor caused a significant increase in fasting serum BHB and decrease in serum insulin, while sulfonylurea had no significant effects on these measurements. We performed ex vivo experiments using human macrophages to investigate whether BHB and insulin could affect NLRP3 inflammasome activity. BHB dose-dependently inhibited IL-1β secretion from macrophages. However, co-treatment with insulin attenuated the inhibitory effect of BHB on NLRP3 inflammasome activation.

In conclusion, SGLT2 inhibitors attenuate NLRP3 inflammasome activation, in part, via increased serum BHB and decreased serum insulin and glucose, which might help to explain the cardioprotective effects of SGLT2 inhibitor (clinicaltrials.gov NCT02964572).

Disclosure

Y. Lee: None. S. Kim: None. J. Bae: None. B. Lee: None. E. Kang: None. C. Ahn: None. B. Cha: None.
Proteomic Profile of Adipose Tissue-Derived Exosomes and Their Potential Role on Placental Glucose Metabolism in Gestational Diabetes Mellitus
Authors: JAYABALAN NANTHINI , ORMAZABAL VALESKA , LAI ANDREW , LAPPAS MARTHA , SALOMON CARLOS
Published: June 2018

Emerging studies suggest that adipose tissue derived exosomes involves in regulating insulin action and glucose homeostasis. In this study, we hypothesised the protein content of adipose tissue derived exosomes (exo-AT) differs in normal glucose tolerant (NGT) and gestational diabetes mellitus (GDM) pregnancies which lead to changes in placental glucose metabolism. Human omental adipose tissue was obtained from GDM (n=60) and BMI-matched NGT (n=48) pregnancies at the time of term Caesarean section. Exosomes were isolated from tissue-conditioned media by differential centrifugation and characterised using nanoparticle tracking analysis and SWATH mass spectrometry. The effect of exosomes on human placental cells was evaluated using a Human Glucose Metabolism RT² Profiler PCR Array. The total number of exosomes (number of vesicles/mg adipose tissue/24 hour) were significantly higher in GDM compared to NGT. The number of exosomes positively correlated with maternal BMI and fetal weight. We identified 122 proteins upregulated in the exo-AT from GDM compared to NGT. Ingenuity pathway analysis revealed the upregulated proteins are associated with mitochondrial dysfunction and oxidative phosphorylation (OXPHOS). When compared to NGT exo-AT, GDM exo-AT increased ALDOB, PGK2 and GCK in placental cells. The data obtained in this study suggest that exosomes secreted from adipose tissue regulates placental glucose metabolism in GDM. Improving the communication of exo-AT to placental tissues may serve as an effective intervention strategy to prevent the consequences of GDM such as fetal overgrowth.

Disclosure

N. Jayabalan: None. V. Ormazabal: None. A. Lai: None. M. Lappas: None.
SGLT2 Inhibitors and Stroke Risk in Patients with Type 2 Diabetes—A Systematic Review and Meta-analysis
Authors: GUO MAN , XU YONG
Published: June 2018

Aims: SGLT2 inhibitors are a novel drug used to treat diabetes. They also have positive cardiovascular benefits. However, there is some debate regarding possible effects of SGLT2 inhibitors on stroke risk. Here, we conduct a meta-analysis of relevant RCTs to evaluate the effects of SGLT2 inhibitors on stroke risk with T2DM.

Materials and Methods: We searched Pubmed, Embase, CENTRAL and ClinicalTrials.gov from database inception up to September 19, 2017. We included RCTs that enrolled patients with T2DM, compared SGLT2 inhibitors vs. placebo or other comparators for at least 24 weeks, and reported the observed effects of SGLT2 inhibitors on stroke events. Subgroup analyses were performed for gender, age, duration of diabetes, race, BMI, and HbA1C levels. A random-effects meta-analysis was performed to calculate the RR with 95% CI.

Results: We identified 32 eligible trials enrolling 75,540 participants that compared three SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to placebo and other active antidiabetic treatments. The incidence of stroke in groups with SGLT2 inhibitor monotherapy or combination therapy was not significantly different from that in control groups, with RR=1.01 (95% CI 0.93-1.10, p=0.972) and RR=1.0 (95% CI 0.92-1.09, p=0.846), respectively. There were no significant differences in RRs between three SGLT2 inhibitors; canagliflozin, RR=0.91; dapagliflozin, RR=0.99; and empagliflozin, RR=1.03. Subgroup analyses showed that the RR values were not affected by gender, age, duration of diabetes, BMI, and HbA1C levels; however, there was a small racial disparity, with black participants having a lower incidence of stroke than white or Asian participants.

Conclusions: SGLT2 inhibitor therapy does not increase stroke incidence, and no significant differences in the RR for stroke were observed among three SGLT2 inhibitors (class effect). However, black patients did have a lower stroke incidence than white or Asian patients.

Disclosure

M. Guo: None. Y. Xu: None.
Presentation and Clinical Characteristics of Patients with Maturity Onset Diabetes of the Young (MODY) at Women and Children’s Hospital of Buffalo
Authors: SAADEH LINA , MASTRANDREA LUCY D.
Published: June 2018

Background: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes. It is rare, representing the final diagnosis in 1-2% of individuals with diabetes. In the pediatric cohort, it can be confused with type 1 diabetes. Clinical diagnosis is suspected in the case of hyperglycemia, lack of autoantibodies, and autosomal dominant transmission. This retrospective chart review evaluated the clinical presentation and characteristics of patients diagnosed with MODY by our practice with a goal of identifying patients that can be candidates for genetic testing.

Methods: Using ICD10 codes for MODY, we performed a retrospective chart review of patients carrying MODY diagnosis confirmed by genetic testing, who received their care at the Diabetes Center at Women and Children’s Hospital of Buffalo.

Results: We identified 10 subjects with confirmed genetic testing for MODY. Median age of presentation with hyperglycemia was 13.1 years (range of 3.6-17.3 years). Median HbA1c at presentation was 6.3% (range 6%-14%). While the initial referring diagnosis was elevated fasting BS (FBS) in 50% of subjects, FBS (mean 120±21 mg/dL) was abnormal for all but 1 subject at their first contact visit. All subjects had negative pancreatic autoantibodies. In our cohort, confirmatory testing was as follows: MODY2 (n = 6), MODY3 (n = 2), MODY 4 (n=1), and MODY5 (n=1). Three subjects were assigned a MODY diagnosis prior to genetic testing. Two were siblings with family history of maternal MODY2. The third subject had a history of polycystic kidney disease, septate uterus, and HbA1C in the prediabetes range. This subject was assigned a presumptive diagnosis of MODY 5 prior to genetic test.

Conclusion: In our practice, all subjects with confirmed MODY diagnosis had negative pancreatic autoantibodies with most meeting criteria for prediabetes diagnosis. Clinicians should have a high index of suspicion for MODY in subjects who do not fit criteria for T1DM or T2DM.

Disclosure

L. Saadeh: None. L.D. Mastrandrea: Research Support; Self; Novo Nordisk Inc., AstraZeneca, Sanofi-Aventis. Advisory Panel; Self; Pediatric Diabetes Consortium. Other Relationship; Self; American Academy of Pediatrics. Advisory Panel; Self; JAEB Center For Health Research.
Trends in Type 2 Diabetes Mellitus Complications, Drug Utilization, and Laboratory Outcomes, 2012–2017
Authors: NAIR RADHIKA , ZHAO ZHENXIANG , GANDHI PRANAV , LI YONG , BRODOVICZ KIMBERLY , MEAH YUNUS A. , KALIRAI SAMANEH , MORETZ CHAD , MACKENZIE MICHELE , CURTIS BRADLEY , PREWITT TODD G.
Published: June 2018

Understanding the natural progression of type 2 diabetes mellitus (T2DM) is crucial in determining the appropriate approaches to care and effective management among these patients. Patients with a diagnosis for T2DM between January 2012 to December 2013 and treated with a non-insulin glucose-lowering medication were identified from a large national health plan using medical and pharmacy claims. The first occurring diagnosis for T2DM was considered the index date. Patients were required to be enrolled ≥ 6 months prior to index and be 18-89 years at index. Based on presence or absence of diagnosis for T2DM during the pre-index period, patients were categorized as prevalent or incident. Patients were followed for a maximum of five years allowing longitudinal assessment of T2DM progression and trends in comorbidities, treatment regimens, and laboratory outcomes. The quarterly cohorts declined from 147,900 and 20,066 in 2Q2012 to 52,091 and 11,454 in 2Q2017 in the prevalent and incident cohorts, respectively. Despite the increasing utilization of glucose-lowering medications, glycemic control remained suboptimal, with increasing prevalence of complications such as kidney disease in both prevalent and incident cohorts as patients progressed through their diabetes.

Disclosure

R. Nair: Other Relationship; Self; Eli Lilly and Company. Z. Zhao: None. P. Gandhi: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Y. Li: None. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Y.A. Meah: Employee; Self; Humana Inc. S. Kalirai: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Moretz: None. M. MacKenzie: Other Relationship; Self; Boehringer Ingelheim GmbH. B. Curtis: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T.G. Prewitt: None.
SGLT2 Inhibitors Suppress Alpha-Adrenergic Tone and Morning Elevation of Plasma Glucose Levels
Authors: YAMAUCHI KEISHI
Published: June 2018

Previously, we reported that morning plasma glucose (PG) elevation before wake-up (W1) and after wake-up (W2), occur through different mechanisms in patients with type 2 diabetes. W1 was related to insulin deficiency as already-known reports. W2 could be explained by heightened ambient alpha-adrenergic tone, within the normal range since urinary normetanephrine was strongly related to W2. Urinary normetanephrine are reflected production levels of norepinephrine. Although epinephrine activates both of α and β adrenergic receptors, norepinephrine only stimulates α adrenergic receptor. In the study, we estimate the effect of SGLT2 inhibitors on urinary metanephrines, other antagonistic hormones and W2. Ipragliflozin (50mg) or dapagliflozin (5mg) administered 8 diabetic patients with W2 for 3 month. Those with insulin therapy or overtly elevated fasting PG (>11 mmol/L) were excluded. SGLT2 inhibitors suppressed δPG(8 am PG minus 6 am PG) (2.7±1.1 mmol/L to 1.9±0.9 mmol/L, p<0.05)(Figure) and urinary normetanephrine(0.27±0.19 mg/gCre to 0.20±0.11 mg/gCre, p<0.05). But those did not change urinary metanephrine(0.19±0.10 mg/gCre to 0.17±0.mg/gCre, p>0.05) and other antagonistic hormones. Adrenergic tone-induced alterations of glucose metabolism may be mediated via regulation of SGLT2 inhibitor.

Disclosure

K. Yamauchi: None.
Diabetes Prevalence in North America and Caribbean Region in 2017 and 2045
Authors: HUANG YADI , KARURANGA SUVI , BOYKO EDWARD J. , MALANDA BELMA
Published: June 2018

Aims and Objectives: Diabetes is a serious and increasing global epidemic, and accurate estimates are essential for more efficient allocation of resources. The International Diabetes Federation (IDF) North America and Caribbean Region (NAC) consist of the U.S.A, Mexico and Canada, as well as 25 Caribbean countries and territories. The new edition of the International Diabetes Federation (IDF) Atlas (IDF, 2017) provides estimates of the numbers of people (18-99 years) living with diabetes in the IDF North America and Caribbean (NAC) Region.

Methodology: Estimates for diabetes in adults were taken from 24 data sources in the IDF NAC region, representing 14 out of 28 countries. Selected characteristics of these data sources are as follows: Barbados, Mexico, Suriname, Trinidad and Tobago and the U.S. had studies conducted within the last five years; Belize, Haiti, Mexico and the U.S. Virgin Islands had studies that performed oral glucose tolerance tests. Prevalence rates for other countries may be underestimated due to limited data sources on oral glucose tolerance test. The details of the methodology were described in IDF Diabetes Atlas 8th Ed.

Results and Conclusion: Approximately 50.1 (41.8-56.1) million people or 13.1% (10.9-14.6%) of adults aged 18-99, are living with diabetes in the IDF NAC region in 2017. The age-adjusted prevalence is 10.8%, which is highest among all seven IDF regions. If the trend continues, the number of people with diabetes is projected to reach 73.4 (58.8-83.4) million in 2045. About 37.6% of those people living with diabetes in this region are estimated to be undiagnosed in 2017. The number of deaths attributed to diabetes from age 20 to 99 years is 378,720 in 2017. The total healthcare expenditure related to diabetes in NAC region is USD 439,858 million in 2017 and will reach USD 508,315 million by 2045. Diabetes exerts a heavy burden in this region. Therefore effective diabetes prevention and management programs should be implemented in order to control diabetes prevalence.

Disclosure

Y. Huang: None. S. Karuranga: None. E.J. Boyko: None. B. Malanda: None.
Trends in Glycemic Control Based on A1C Factorisation across Different Clinical Settings
Authors: CHAWLA PURVI M. , ASHTEKAR CHANDRASHEKHAR , DHOPE RAHUL M. , SHAIKH AMBARI FIRDOUS. , KOTHARI MIKHIL C. , CHAWLA MANOJ S.
Published: June 2018

Approximately, 20-40% patients with diabetes achieve the glycemic target (A1C< 7%), globally. A retrospective analysis of glycemic trends based on A1C across three diabetes speciality centers [metro city (A), second tier city (B), district headquarter (C)] including 11,162 patients [A (n=3601), B (n=815), C (n=6746)] either newly diagnosed or following up at over past two years, was undertaken. Being treated as per standard guidelines with at least one HbA1c level reported within this period and classified as well-controlled (A1C <7%) or uncontrolled (A1C <7%) based on glycemic factorization. Table 1 shows the ANOVA results[1264 patients (11.32%) achieving an A1C <6%, and 2709 patients (24.27%) between 6-6.9% across centers]; representing well-controlled patients and the uncontrolled patient population (A1C>7%). The latter group with 22.52% (n=2514) and 23.49% (n=2622) patients with A1C between 7-7.9% and 8-9.9% respectively, represented a group that should be aggressively treated to mitigate the “missed opportunities” in achieving glycemic control and increase the overall percentage of patients achieving target goals. Furthermore, sub-group analyses across individual centers (A, B, C) revealed that differences in factorized HbA1c levels were statistically highly significant (p=0.002) necessitating a high-quality, uniform standard of care, irrespective of the setting to help burden of this disease.

Table 1 - Glycemic Factorisation Across Three Different Diabetes Care Centers Over 24 Months.HbA1c FactorisationMetro City (A)Second Tier City (B)District Headquarter (C)TotalPercentage (%)< 626152951126411.326-6.99991871523270924.277-7.910371911286251422.528-9.99112241487262223.4910-10.9183724827376.611-11.9116303615074.54>1294596568097.25Total3601815674611162

Disclosure

P.M. Chawla: Speaker's Bureau; Self; Sanofi. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, IPCA LABORATORIES, Novo Nordisk A/S, MSD PHARMACEUTICALS PVT. LTD., Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. C. Ashtekar: Speaker's Bureau; Self; Novo Nordisk A/S, USV Private Limited, MSD Pharmaceuticals Pvt. Ltd., Abbott, LUPIN, Eris Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. R.M. Dhope: Speaker's Bureau; Self; USV Private Limited, SUNPHARMA, LUPIN, Novartis Pharmaceuticals Corporation, AstraZeneca, SERDIA PHARMACEUTICALS, GLENMARK. A.F. Shaikh: None. M.C. Kothari: None. M.S. Chawla: Speaker's Bureau; Self; IPCA Laboratories, Eli Lilly and Company, Novo Nordisk A/S, MSD Pharmaceutical Pvt. Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Spouse/Partner; Sanofi.
Hidden Epidemic—Half of T1DM Is Diagnosed in Adulthood
Authors: SALAM MAAMOUN , BAO YICHENG , HERRICK CYNTHIA J. , MCGILL JANET B. , HUGHES JING
Published: June 2018

Objective: To determine the distribution of age of onset of T1DM in an adult cohort of patients with T1DM.

Methods: T1DM patients from an adult academic diabetes center provided informed consent, completed a questionnaire and gave permission for medical record review. Demographics included age, gender and race. T1DM diagnosis was confirmed by history, occurrence of DKA, C-peptide and/or positive T1DM autoantibodies. Patients with diabetes due to pancreatic disease, chemotherapy, genetic syndromes or unclear etiology were not included.

Results: Of the 1167 confirmed cases of T1DM, 563 (48.2%) were male and 604 (51.8%) were female; 107 (9.2%) were African-American and 1060 (90.8%) were Caucasian or other (<1% Asian). Mean age of participants was 46.9 +/- 16.2 years. T1DM was diagnosed at ages <1 to 78 years with mean age at onset of 21.3 +/- 14.4 years. Age at onset of <18 years occurred in 576 participants (49.4%), 18-30 years in 313 (26.8%), and >30 years in 278 (23.8%). Males and females age at onset of T1DM ≥18 years were 53.1% and 48.3% respectively, NS (p=0.11). African-Americans and non-African-Americans diagnosed with T1DM at ≥18 years: 52.3% and 50.5% respectively, NS (p=0.71). In a subset of patients with current age ≥30 (n=971), the mean age of onset of T1DM was 23.2+/-14.8 years.

Conclusion: In this cohort of adults with T1DM, over half of all patients were diagnosed at age ≥18 years, and 23.8% at age >30 years. This trend was consistent across race and gender and more pronounced in the subset with age ≥30 years. These findings challenge historical data that the mean age of onset of T1DM is in childhood. The strength of this dataset is accuracy of age of onset and diagnosis. The major limitation is that it is not population based. Because the reported age at onset of T1DM is highly dependent on the age of the cohort studied, epidemiologic studies of T1DM should include the entire age spectrum. Better awareness of T1DM in adults is needed to provide appropriate medical management and to ensure patient safety.

Disclosure

M. Salam: None. Y. Bao: None. C.J. Herrick: Stock/Shareholder; Spouse/Partner; Cardinal Health. J.B. McGill: Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Aegerion Pharmaceuticals. Consultant; Self; Bayer AG, Dexcom, Inc., Intarcia Therapeutics, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., MannKind Corporation. Research Support; Self; Novartis Pharmaceuticals Corporation. Consultant; Self; Novo Nordisk A/S. J. Hughes: None.
Genetic Effects on Enhancer Activity in Human Pancreatic Islets
Authors: VARSHNEY ARUSHI , PARKER STEPHEN ,   FUSION TISSUE STUDY
Published: June 2018

Genome-wide association studies (GWAS) have identified >100 single nucleotide polymorphisms (SNPs) that modulate risk for type 2 diabetes (T2D) and related traits. Using functional genomic profiling, we and others have shown that T2D GWAS SNPs are significantly enriched to overlap pancreatic islet stretch enhancer chromatin states, implicating these regulatory elements as biological mediators of disease risk. Recent studies that integrate genetic variation and islet gene expression have identified expression quantitative trait loci (eQTL) that nominate target effector transcripts for T2D GWAS SNPs. However, the subset of causal regulatory SNPs that mediate genetic control of gene expression are unknown. To help close this gap in knowledge, we have performed capped analysis of gene expression (CAGE) on RNA enriched for active enhancers (eRNA-CAGE) across 40 human islet samples. Comparison of these profiles to previously published islet chromatin maps revealed significant enrichment for active chromatin states (P<0.001). Interestingly, we observe unbalanced bidirectional transcription at chromatin-defined intronic enhancer regions, where the predominant direction of enhancer transcription is concordant with the transcribed direction of the endogenous gene, suggesting interactions between gene and enhancer activity. One such example is an ABCC8 intronic enhancer that we previously functionally validated using a mouse transgenic reporter assay. We further performed genotyping and imputation, which allowed us to run an eRNA-QTL scan. We identified 4associations (P<0.for beta distribution adjusted P-value; QTLtools package), which are significantly enriched (P=7.3x10-7) to occur in islet active enhancer chromatin states. Notably, we found islet eRNA-QTL that overlap T2D GWAS SNPs and islet eQTL. Together, these results form a genetic map of human islet enhancer activity that is a foundation for interpreting regulatory mechanisms at T2D GWAS loci.

Disclosure

A. Varshney: None. S. Parker: None.
Inhibition of PPAR Gamma, Adipogenesis, and Insulin Sensitivity by MAGED1
Authors: WANG QINGHUA , TANG JING , GAO XIANG , RUAN HAI-BIN
Published: June 2018

Adipocytes serve as critical integrators of energy balance and glucose homeostasis by storing excess energy to prevent ectopic fat accumulation in non-adipose tissues and by secreting various adipokines to modulate whole-body metabolism. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE Family Member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation, and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and MAGED1 inhibited preadipocyte proliferation and adipogenesis in vitro. Mechanistically, MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to wild type littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors, and hyperplasia of white adipose tissues (WATs) at young ages. Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity. Lipid profiling showed that obesity in MAGED1 knockout (KO) mice did not cause increased levels of serum lipids. On the other hand, expression and secretion of adipokines such as leptin and adiponectin were upregulated in KO mice. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis, and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

Disclosure

Q. Wang: None. J. Tang: None. X. Gao: None. H. Ruan: None.
Evidence against Pathway-Selective Hepatic Insulin Resistance in Mice
Authors: VATNER DANIEL F. , PETERSEN MAX C. , LI XIRUO , ROGERS JILLIAN C. , CLINE GARY , SAMUEL VARMAN , SHULMAN GERALD I.
Published: June 2018

Insulin suppresses hepatic glucose production and increases hepatic de novo lipogenesis (DNL). Paradoxically, hepatic DNL remains elevated in insulin-resistant subjects, leading to the hypothesis that hepatic insulin resistance is pathway-selective. Prior studies of DNL in hepatic insulin resistance are complicated by confounders, such as use of markedly unphysiologic animal models or comparison of animals on different diets and thus different availability of DNL precursors. We measured DNL in InsrT1150A knockin (KI) mice, a strain protected from diacylglycerol-mediated hepatic insulin resistance, and in littermate controls. Diets were matched: 60% high fat diet (HFD) with 1% dextrose in drinking water. After two days of fat-feeding, before the development of significant insulin resistance, KI and WT mice displayed similar rates of DNL (KI 24.3% ± 3.6; WT 22.2% ± 3.5). After 9 days of HFD, when WT but not KI mice have developed hepatic insulin resistance, rates of DNL were reduced in WT mice but preserved in KI mice (KI 16.4% ± 2.4; WT 7.4% ± 1.3; P < 0.01). After 4 weeks of HFD, with the development of skeletal muscle resistance, rates of DNL increased in WT mice to reach those observed in KI mice (KI 19.3% ± 2.6; WT 15.9% ± 2.3). Consistent with the insulin-resistant phenotype, Srebp-1c cleavage was reduced in the setting of hepatic insulin resistance in WT mice; this effect was attenuated in KI mice. The Srebp-regulated lipogenic proteins Fasn and Scd1 were both reduced in 9d HFD fed livers regardless of genotype; at 4 weeks, protein abundance remained suppressed in WT mice but was restored in KI mice. Pklr, a protein associated with DNL but not regulated by Srebp, was unaffected by HFD-induced hepatic insulin resistance.

Conclusion: Regulation of DNL is subject to lipid-induced hepatic insulin resistance, challenging the selective hepatic insulin resistance hypothesis. Increased DNL seen in insulin resistant subjects may be due to hyperinsulinemia and diversion of substrate from the insulin resistant periphery.

Disclosure

D.F. Vatner: None. M.C. Petersen: None. X. Li: None. J.C. Rogers: None. G. Cline: None. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..
Incidence and Evolution of Prediabetes among Older Adults—A Population-Based Cohort Study
Authors: SHANG YING , FRATIGLIONI LAURA , MARSEGILIA ANNA , WANG RUI , WELMER ANNA-KARIN , WANG HUIXIN , XU WEILI
Published: June 2018

Objective: The incidence and evolution of prediabetes in older adults is still unclear. We aimed to estimate the incidence of prediabetes, the rates of prediabetes reverting to normoglycemia or progressing to type 2 diabetes, and to identify possible prognostic factors among older adults with prediabetes.

Methods: In the Swedish National Study on Aging and Care-Kungsholmen Project, 3049 diabetes-free participants aged ≥60 years were examined at baseline (2001-2004), and were followed-up to 12 years (2013-2016). At each wave, type 2 diabetes was ascertained based on self-report, antidiabetic drug use, medical records, or glycated haemoglobin (HbA1c) ≥6.5% (48 mmol/mol). In diabetes-free participants, prediabetes was assessed as HbA1c ≥5.7% (39 mmol/mol), and normoglycemia was defined as HbA1c <5.7%. Data were analysed with Poisson regression and multinomial logistic regression.

Results: During 12 years follow-up, among 1972 (64.7%) participants with normoglycemia, 505 (25.6%) developed prediabetes (incidence=4.3/100 person-years, 95% CI 3.9-4.8). Of the 1077 (35.3%) participants with prediabetes at baseline, 204 (18.9%) reverted to normoglycemia (reversion rate=3.1/100 person-years, 95% CI: 2.6-3.6) and 119 (11.0%) progressed to type 2 diabetes (progression rate=1.7/100 person-years, 95% CI: 1.3-2.1). The reversal to normoglycemia was significantly associated with lower systolic blood pressure and weight loss, while, obesity and weight gain were risk factors for progression to type 2 diabetes.

Conclusions: The incidence of prediabetes is high (about 26%) among older adults. Around 19% of people with prediabetes may revert to normoglycemia and 11% progress to type 2 diabetes. Weight change and systolic blood pressure may play a role in such evolution.

Disclosure

Y. Shang: None. L. Fratiglioni: None. A. Marsegilia: None. R. Wang: None. A. Welmer: None. H. Wang: None. W. Xu: None.
Differential Impacts of Insulin Analogs Lispro and Glulisine on Glucose and Lipid Homeostasis during Hyperinsulinemic Euglycemic Clamp in Streptozotocin-Induced Diabetic Rats
Authors: BRIAND FRANÇOIS , BROUSSEAU EMMANUEL , BURCELIN RÉMY , SULPICE THIERRY
Published: June 2018

In addition to their benefits on glycemia, the specific actions of insulin analogs on glucose and lipid metabolism should be depicted. Here we analyzed the effects of Lispro (LIS) and Glulisine (GLU) insulin-analogs in diabetic rats. Diabetes was induced in Wistar male rats following an i.v. injection of streptozotocin (STZ) at 60mg/kg. Conscious rats underwent a 2-hour hyperinsulinemic (LIS or GLU at 0.8U/kg/h) euglycemic clamp with a constant infusion of 3H-glucose (4µCi/kg/min), with n=8 rats per each group. Glycemia was monitored continuously to adjust glucose infusion rate (GIR) to maintain euglycemia during the LIS or GLU perfusion. Blood, muscle and liver samples were collected for biochemical and radioactivity analysis. Compared to GLU, mean GIR was 51% higher in LIS treated rats (LIS: 18 +/- 1mg/kg/min, GLU: 12 +/- 1 mg/kg/min, p<0.01). Importantly, the higher GIR observed with LIS was associated with a strong inhibition of hepatic glucose production, which remained elevated in rats treated with GLU (LIS: 0.4 +/- 0.9mg/kg/min, GLU: 6.4 +/-1.6 mg/kg/min, p<0.01). Whole body glycolysis, glycogen, as well as liver and muscle glycogen synthesis rates remain similar between groups. Compared with LIS, rats treated with GLU showed a better reduction in plasma free fatty acids and glycerol levels during the clamp experiment, with a 50% and 139% lower plasma free fatty acids and glycerol area under the curve (p<0.and p<0.01 vs. LIS, respectively). 3H-glucose incorporation in muscle and liver lipid stores was not different, indicating that lipolysis rather than lipogenesis was differentially impacted.

In conclusion, hyperinsulinemic euglycemic clamps in STZ rats enabled to detect a strong inhibition of hepatic glucose production by LIS, while GLU better suppresses lipolysis. Our experimental setting should help to differentiate other insulin analogs and dissect their mechanisms of action.

Disclosure

F. Briand: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S. E. Brousseau: Employee; Self; Physiogenex S.A.S. R. Burcelin: Stock/Shareholder; Self; Physiogenex S.A.S. T. Sulpice: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S..
Improving Sleep by Trazodone Improves Glucose Control
Authors: SAKKAL SAAD
Published: June 2018

Background: 77% of people with diabetes have some form of insomnia. Sleep disturbance results in impaired glucose control in healthy individuals or worsens glucose control in people with diabetes. Short-term sleep studies (1-6 weeks) improved glucose control and insulin resistance in obese “healthy” individuals. We have shown before the superior benefit Trazodone has in treating neuropathy over gabapentin. We show, in this abstract, the impact of improving sleep may have on glucose control.

Methods: we treated 200 type 2 patients with diabetic neuropathy with either trazodone (100), or Gabapentin(100), compared the change in neuropathy, sleep and glucose control. We quantified their neuropathy with our previously published neuropathy grading system (Sakkal’s Scale: level of vibration sensory loss by the 128 tuning fork) we quantified their sleep with shortening latency of sleep onset, and sleep duration extension. We measured their glucose control with AM insulin-to-glucose ratio, HgA1c, and in-target glucose when CGMS was available (20 patients). We excluded patients with OSA. All patients followed our standard diabetes treatment protocol for type 2.

Results: At 12 months, Trazodone improved the scale of diabetic neuropathy in 80% of patients, sleep hygiene in 70%; Sleep increased by 40 minutes, and sleep onset latency decreased by 10 minutes. Insulin/glucose ratio was 21/142=0.147, HgA1c 7.2%, HgA1c<7 in 68%, and in-target glucose in 72% on CGMS(12 patients). Gabapentin improved the scale of diabetic neuropathy in 66%, sleep hygiene in 44%; with sleep increasing by 14 minutes, and sleep onset latency decreased by 4 minutes. Insulin -to-Glucose ratio was 33/166=0.19, HgA1c 7.8%,HgA1c,7 in 56%, and in-target-glucose in 58% on CGMS (8 patients.) analysis. A maximum number of diabetes medications used were 3 in both groups. Percentage needing basal insulin at the end was 12% in the Trazodone group, 21% in the Gabapentin group.

Conclusion: Improved sleep and neuropathy with Trazodone improved glucose control.

Disclosure

S. Sakkal: None.
Population Screening for T1D and Celiac Disease—Autoimmunity Screening for Kids (ASK)
Authors: GENO RASMUSSEN CRISTY R. , REWERS MARIAN , BAXTER JUDITH , WAUGH KATHLEEN , STECK ANDREA , FROHNERT BRIGITTE I. , YU LIPING , LIU EDWIN
Published: June 2018

Early detection can prevent morbidity associated with type 1 diabetes (T1D) and celiac disease (CD). ASK is a 4-year program with the goal to screen Denver metro-area children for pre-symptomatic T1D and CD, increase public awareness of these diseases, and provide evidence for universal screening. We are reporting first-ever prevalence data for pre-symptomatic T1D and CD in the U.S. general population children aged 2-17 y.

In 2017, ASK approached ∼15,000 children for consent, screened 5090 with results available for 4915. Study participant age, sex, and race/ethnicity closely reflected Denver’s general population; 4% had a T1D first-degree relative (FDR). Standard radiobinding assays (RBA) and more specific electrochemiluminescence (ECL) assays for autoantibodies to insulin, GAD, IA-2, ZnT8 and transglutaminase (TGA) were used for screening and confirmation. Children with confirmed persistent islet autoantibodies received follow-up with education to prevent DKA, psychological support, and referrals to prevention trials or clinical services.

Multiple islet autoantibodies, predicting a 44% 5-y risk of T1D, were found in 32 (0.7%) children; of the 30 children retested to date, all remained persistently positive, six developed dysglycemia and one progressed to T1D. A single islet autoantibody, confirmed as high-affinity by ECL (29% 5-y risk of T1D), was found in 27 (0.5%); 18/19 children retested remained positive, 5 developed dysglycemia and one T1D. Over 86% (50/59) of the screening-detected children at risk for T1D did not have an FDR with T1D. The prevalence of TGA by both RBA and ECL was 2.2% and persistent in 74/76 (97%) children retested so far.

This novel population-based screening program for the two most common autoimmune diseases of childhood reports high prevalence of pre-symptomatic T1D and CD in Denver children. Prospective follow-up of screening-detected cases for clinical outcomes and cost-effectiveness analysis will inform potential future universal screening.

Disclosure

C.R. Geno Rasmussen: None. M. Rewers: None. J. Baxter: None. K. Waugh: None. A. Steck: None. B.I. Frohnert: None. L. Yu: None. E. Liu: None.
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Dramatically Reduces Hepatic Collagen in a Mouse Model of NASH
Authors: BEATON MICHELLE , GUIONAUD SILVIA , CONWAY JAMES P. , GRIMSBY JOE , RHODES CHRISTOPHER J. , JERMUTUS LUTZ , TREVASKIS JAMES
Published: June 2018

Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation and fibrosis is an unmet medical need. MEDI0382, a balanced GLP-1/glucagon dual receptor agonist, is under development for the treatment of T2DM. Here we examined the effects of MEDI0382 on NASH compared to liraglutide, a GLP-1 analog. Leptin-deficient ob/ob mice were maintained on high trans-fat, fructose and cholesterol diet for 8 weeks to induce NASH then randomized to four treatment groups: vehicle, MEDI0382 (30 nmol/kg), liraglutide (30 nmol/kg) or vehicle-treated and switched to low-fat diet (LFD). Treatment with MEDI0382 and liraglutide reduced body weight and improved glucose tolerance. Hepatic lipid was reduced by 40% with MEDI0382 treatment (p<0.0001), which was more effective than liraglutide or switch to LFD. Hepatic collagen, quantified by type 1 collagen immunohistochemistry, was increased more than 2-fold with NASH and was reduced by 40% in MEDI0382-treated mice (p=0.005). Consistently, type 1 collagen gene expression increased 2-fold with NASH and was reduced by 85% in MEDI0382-treated livers (p<0.0001). No reductions in collagen were observed with liraglutide or switch to LFD. The NASH score, integrating pathology scores for steatosis, lobular inflammation, fibrosis, hepatocyte ballooning, biliary hyperplasia, and CD68 expression was significantly reduced by MEDI0382 (p<0.0001), greater than liraglutide or switch to LFD. Consistent with histopathology improvements, MEDI0382 treatment also reduced inflammatory gene expression (Tnf, Tgfb1, Il1b, and Ccl2) to a greater extent than liraglutide or LFD switch.

In conclusion, MEDI0382 exerted similar metabolic control relative to liraglutide, but exhibited superior effects on primary NASH endpoints.

Disclosure

M. Beaton: Employee; Self; MedImmune. Employee; Spouse/Partner; MedImmune. S. Guionaud: None. J.P. Conway: None. J. Grimsby: Employee; Self; AstraZeneca. C.J. Rhodes: Stock/Shareholder; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
Sex Differences in the Response of C57BL/6 Mice to Ketogenic Diets
Authors: COCHRAN JESSE , TAUFALELE PAUL V. , LIN KEVIN D. , ZHANG YUAN , DALE ABEL E.
Published: June 2018

Since the initial use of ketogenic diets (KD) as adjunctive treatment for epilepsy, these diets are being increasingly used to promote weight loss and to reduce the risk of metabolic sequelae of obesity. Typical KD are very low in carbohydrate and high in fat, promoting hepatic production of ketone bodies. Few studies have evaluated gender differences in response to KD, and many animal studies tend to be performed in male mice. To explore sex differences in response to KD, female and male wild type mice on the C57BL/6J background were fed either a control diet (CD- 7% fat, 47% carb., 19% protein) or KD (75% fat, 3% carb., 8% protein), following weaning. Females on the CD manifested higher levels of circulating β-hydroxybutyrate (β-HB) than males (2.86-fold, p<0.05). Circulating β-HB concentrations increased with KD in males and females (1.30-fold and 5.05-fold, p<10-4 and p<0.01 respectively) with higher concentrations in females. After 8 weeks, females on KD displayed an increase in body weight (1.07-fold KD vs. CD, p<0.05) while body weight declined in males (0.88-fold, p<0.05). Nuclear magnetic resonance analysis revealed elevated lean mass in females (1.07-fold, p<0.05), but a significant reduction in fat mass in males (0.49-fold, p<0.05) relative to sex-matched mice on CD. The female mice on KD developed impaired glucose tolerance with a 1.35-fold increase in glucose tolerance test area under the curve (GTT AUC) relative to females on CD (p<0.001). In contrast, fasting glucose levels were lower in males on KD (131.8 ± 12.5 mg/ dl vs. 169.2 ± 6.3 mg/dl, p<0.05). Despite no significant change in GTT AUC, the male mice on KD displayed elevated blood glucose concentrations 30 minutes after injection relative to males on CD (344.9 ± 18.7 mg/dl vs. 272.0 ± 10.3 mg/dl, p<0.05). However, after 120 minutes, blood glucose levels returned to initial fasting levels.

In conclusion, significant sex differences exist in terms of body composition and metabolism in response to ketogenic diets via mechanisms that remain to be elucidated.

Disclosure

J. Cochran: None. P.V. Taufalele: None. K.D. Lin: None. Y. Zhang: None. E. Abel: None.