bluuebunny/crossref_metadata_2025 huggingface dataset:
The Safety of Linagliptin vs. Other Antidiabetic Agents with Regard to the Risk of Heart Failure Hospitalization in Routine Care in the U.S.
Authors: PATORNO ELISABETTA , MAHESRI MUFADDAL , GOPALAKRISHNAN CHANDRASEKAR , BRODOVICZ KIMBERLY , MEYERS ANDREA , BARTELS DOROTHEE , SCHNEEWEISS SEBASTIAN
Published: June 2018

The safety of linagliptin with regard to the risk of hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) as treated in routine care remains of interest. We compared the risk of HHF associated with the initiation of linagliptin vs. other antidiabetic agents. In two large commercial U.S. health insurance datasets (Optum Clinformatics and Truven MarketScan), we identified T2DM patients who initiated linagliptin, sitagliptin, saxagliptin, or sulfonylureas (SU) between 5/2011 and 9/2015 and had no previous Heart Failure (HF) history or HF treatment. We estimated hazard ratios (HR) of HHF in 3 separate propensity score matched cohorts that balanced over 130 baseline characteristics. We combined HRs via a fixed-effects meta-analysis. Mean follow-up was nearly 8 months. Linagliptin initiators had no significant difference in the risk of HHF compared with sitagliptin (HR= 0.83 [95% CI=0.58, 1.20]), saxagliptin (HR= 1.13 [0.74, 1.71]), or SU (HR= 0.71, [0.46, 1.10]). In contrast to high cardiovascular (CV) risk clinical trial populations, in a population of T2DM patients without HF history, aged 57 years on average, we did not find a difference in HHF risk between DPP-4 inhibitors with sufficient certainty. Consistent with prior studies, there may be a reduced HHF risk vs. SU; further evidence is expected from ongoing linagliptin CV outcomes trials.

Disclosure

E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim GmbH, GlaxoSmithKline plc.. M. Mahesri: None. C. Gopalakrishnan: None. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. A. Meyers: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D. Bartels: Employee; Self; Boehringer Ingelheim GmbH. S. Schneeweiss: Consultant; Self; WHISCON, LLC. Other Relationship; Self; Aetion, Inc.. Research Support; Self; Genentech, Inc., Bayer AG, Boehringer Ingelheim GmbH, U.S. Food and Drug Administration, Patient-Centered Outcomes Research Institute.
Leptin Concentration Predicts Future Metabolic Syndrome Risk in Japanese Americans Independent of Body Composition
Authors: LIAO CHUN-CHENG , FUJIMOTO WILFRED Y. , KAHN STEVEN E. , LEONETTI DONNA L. , BOYKO EDWARD J.
Published: June 2018

Aims: Leptin has been shown to predict risk of metabolic syndrome (MetS), but it is not known whether this association is independent of body composition. Thus, we examined whether plasma leptin concentration predicted risk of MetS after adjustment for body composition measured using imaging.

Methods: We used the modified ATP III MetS criteria for an Asian population to classify participants in the longitudinal Japanese-American Community Diabetes Study as to presence of MetS. Participants without MetS at baseline (n=283) were followed for its development over 5 years. CT-measured adipose depots included baseline and 5-year intra-abdominal and abdominal subcutaneous fat areas at the level of the umbilicus, subcutaneous mid-thigh fat area, and subcutaneous thorax fat area at the nipple level. Other measurements included fasting plasma leptin and serum HDL-cholesterol and triglyceride concentrations, fasting and 2 hour glucose from a 75 g OGTT, systolic blood pressure (SBP), and medication use. Logistic regression analysis was used to estimate the odds of incident MetS by leptin concentration, body composition, and baseline MetS features.

Results: 65 participants developed MetS at 5-year follow-up. Multivariable logistic regression models showed a lower odds of incident MetS with 1-SD greater leptin concentration (OR = 0.45; 95% CI = 0.25-0.79; p = 0.006) adjusting for age, sex, CT-fat areas at baseline, and 5-year change in CT-fat areas. Additional adjustment for other MetS features at baseline (fasting and 2 hour glucose, triglycerides, HDL-cholesterol, SBP) yielded similar results (OR = 0.38; 95% CI = 0.20-0.71; p = 0.002).

Conclusions: Leptin concentration predicts MetS risk in Japanese Americans independent of body composition. Further research is needed to confirm this association in other populations and to understand potential underlying biologic mechanisms.

Disclosure

C. Liao: None. W.Y. Fujimoto: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. D.L. Leonetti: None. E.J. Boyko: None.
Association between HbA1c and Haemoglobin of Healthy Adults Visiting a Tertiary Care Hospital in India
Authors: BHARGAVA AMIT , SINGH PARAS , WAGHDHARE SWATI , SIDDIQUI SAMREEN , JHA SUJEET
Published: June 2018

Objective: To correlate Hemoglobin (Hb) and Glycosylated hemoglobin (HbA1c) levels and to study interquartile differences in HbA1c values of subjects having low Hb (first quartile) vs. High hemoglobin (last quartile).

Methods: We conducted a retrospective study on 1,040 normal healthy adults (Indians and Afghanis) attending a tertiary care hospital to assess the correlation between Hb and HbA1c. Data of past 5 years (2010-2015) was extracted from hospital records. The cohort was divided into 4 groups according to the quartiles of the Hb level (QI = <13 g/dl, QII = 13-14.1 g/dl, QIII = 14.1-15.4 g/dl, QIV >15.4 g/dl). We studied interquartile differences in HbA1c values of subjects having low hemoglobin (first quartile) vs. High hemoglobin (last quartile) values.

Results: The mean of hemoglobin and HbA1c among the Indian subgroup was (13.49 g/dl ± 1.39) and (5.52% ± 0.45) respectively. On the other hand, the mean hemoglobin and HbA1c among Afghani subjects was (14.80 g/dl ± 1.47) and (5.34% ± 0.43), respectively. Mean Hb of Indian males was 14.04±1.28 g/dL and females was 12.56±1.g/dL vs. 15.38±1.16 g/dL in Afghani males and 13.24±1.07 g/dL in Afghani females. Further analysis revealed that HbA1c declines by an average of 0.03% when Hb increases by 1 g/dl in combined dataset. The difference in average FBS level of subjects in quartile 1 of Hb level (99.42 mg/dL) was significantly different from subjects of 4th quartile (95.14 mg/dL), (t = 2.414 and p-value = 0.016).

Conclusion: In our study we had found that Indians have higher BMI, FBS and HbA1c, inspite of having lower Hb as compared to Afghani population. The findings of our study show that with an increase in hemoglobin levels, there is a decrease in Hb1Ac levels. However the same is not clinically significant. Larger studies of subjects with IDA would be useful in examining the impact of IDA on measurement of HbA1c.

Disclosure

A. Bhargava: None. P. Singh: None. S. Waghdhare: None. S. Siddiqui: None. S. Jha: None.
Visiting the Dentist May Help Diagnose Prediabetes
Authors: CZUPRYNIAK LESZEK , SZYMANSKA-GARBACZ ELEKTRA , BIJOS PAWEL
Published: June 2018

Diabetes is a well known risk factor for periodontal and dental diseases. Despite increasing diabetes awareness, up to a third of diabetes cases remain undiagnosed. We assumed that a visit at the dentist’s is an opportunity to assess one’s glucose tolerance. We conducted a nationwide cross-sectional study evaluating whether a dentist can help diagnose diabetes in at-risk subjects. The study was performed between March and June 2017. Thirty dental surgeries across the country participated in the study. Each surgery was given 20 laboratory referral notes for free fasting plasma glucose (FPG) measurement to be handed over to 20 consecutive eligible individuals who gave their consent to take part in the study. The referred patients were asked to perform FPG test during the following 4 weeks. The study inclusion criteria were: age ≥18 years, any degree of any dental or periodontal disease, presence of at least one diabetes risk factor (i.e., BMI ≥25 kg/m2, family history of diabetes, sedentary lifestyle, past gestational diabetes, hypertension, dyslipidemia, cardiovascular disease, policystic ovary syndrome) and negative history of any glucose intolerance. Out of 600 referred patients, 469 (78.2%, 330 [70.4%] women, mean [±SD] age 53.7±15.4 years) had FPG assessed. Mean FPG in all subjects was 97.2±20.9 mg/dl (range 63-377 mg/dl). In 140 subjects (29.9% of those tested and 23.3% of those referred) impaired fasting glucose (IFG; i.e., FPG ≥100 and <126 mg/dl) was diagnosed. 19 subjects had FPG ≥126 mg/dl. IFG subjects were older than those with normal FPG: 60.1±12.6 vs. 50.9±15.7 years (p<0.001), and were more often men (40% vs. 27%; p<0.01). Odds ratio for IFG in subjects aged ≥60 vs. those <60 years was 3.413 (95% CI 2.215-5.264).

In conclusion, approx. every fourth patient with at least one diabetes risk factor visiting the dentist’s presents with IFG. Dentists should be concerned about prediabetes particularly in their male patients aged ≥60. Increasing diabetes awareness among the dentists may help diagnose prediabetes and thus further prevent diabetes.

Disclosure

L. Czupryniak: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Merck & Co., Inc., Polpharma, Servier. E. Szymanska-Garbacz: Speaker's Bureau; Self; Sanofi, Eli Lilly and Company, Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Merck & Co., Inc. P. Bijos: Employee; Self; Teva Pharmaceutical Industries Ltd..
Lunapark, a Novel Target to miR-126—Its Potential Role in Maintenance of ER and Glucose Homeostasis
Authors: FARIA JULIANA DE A. , GUIMARAES DANIELLA DUQUE , PANTALEAO LUCAS , ONG THOMAS P. , OZANNE AUSAN
Published: June 2018

Strong evidence suggests that an adverse in utero and/or early postnatal environment impacts on long-term risk of developing type 2 diabetes. We showed previously that miR-126 is increased in adipose tissue of mouse offspring born to obese mothers which leads to impaired insulin signaling pathway by silencing IRS-1 at the translational level. However, the full spectrum of targets of miR-126 and consequently the consequences of its overexpression for adipose tissue function are unknown. The aim of the current study was therefore to identify novel targets of miR-126 using the proteomic technique, known as Pulsed Stable Isotope Labeling by Amino Acids (pSILAC). 3T3-L1-cells were transfected with miR-126 and their proteome compared to those transfected with a scrambled sequence. We detected 4567 proteins that were translated in adipocytes and of these 401 demonstrated a >1.3 fold decrease following over-expression of miR-126. Bioinformatic analysis revealed that 43 of these contained a miR-126 seed sequence in their 3’un-translated region. This included known miR-126 targets such as IRS-1 and VCAM-1 as well as novel targets. One of the largest changes in expression was observed for Lunapark and through the use of luciferase assays and western blotting we independently confirmed this was a direct target of miR-126. Lunapark is a key component for stabilization of nascent three-way junctions in the endoplasmic reticulum (ER). Consistent with this role we observed altered levels of mTOR and XBP1 in cells treated with miR-126, reflecting the presence of ER stress. Together, the results suggest that overexpression of miR-126 can lead to both ER stress and Insulin Resistance and therefore represent a novel link between two pathways that contribute to development and progression to T2DM.

Disclosure

J.A. Faria: None. D. Duque Guimaraes: None. L. Pantaleao: None. T.P. Ong: None. A. Ozanne: None.
Loss of Hypothalamic Somatostatin (SST) Contributes to Bone Marrow (BM) Dysfunction and Diabetic Retinopathy (DR) in Type 2 Diabetic Rats
Authors: LONGHINI ANA LEDA , THINSCHMIDT JEFFREY , BOULTON MICHAEL , KING MICHAEL A. , GRANT MARIA B.
Published: June 2018

Purpose: Since loss of retinal SST and circulating SST occurs in DR, we asked if loss of hypothalamic SST production would impact the innervation and function of the BM and influence DR in T2D rat model.

Methods: Brain sections of BBZ/Wor rats with 4 months of diabetes and age-matched nondiabetic lean BBZ rats were immuno-stained for SST, Iba-1 and Neu-N. To examine the neuronal connection between the BM and pre-sympathetic brainstem and hypothalamic areas, both control and diabetic rats were injected in a blinded manner with GFP-transgenic pseudorabies virus (PRV-152) into their femurs. Four days later rats were euthanized and brain sections prepared for colocalization of GFP with SST. DR was assessed by enumeration of acellular capillaries in trypsin-digested retinas.

Results: Injection of PRV into femur showed the presence of active virus in neurons of the paraventricular nucleus of the hypothalamus (PVN), rostral ventrolateral medulla and nucleus tractus solitarius of the brain of control rats. Colocalization studies showed that periventricular hypothalamic SST neurons were also GFP+ and directly innervated the BM. Quantitation showed that diabetic rats had significantly fewer GFP+ neurons in the PVN (n=6, *P<0.05), supporting neuronal loss. SST staining of brain sections showed significant reduction in the number of SST+ cells in diabetic rats (58±5) compared with nondiabetic rats (88±6) (n=6, *P<0.05). The density of Iba-1+ microglia increased, while the NeuN+ neurons decreased in the hypothalamus supporting an increase of regional inflammation and neuronal loss. Diabetic rats showed an increase in acellular capillaries compared to controls (15± 4 vs. 4±1mm2) (p<0.001).

Conclusions: These studies support the notion that periventricular hypothalamic SST neurons directly innervate BM and that preservation of this small, but important population is relevant to prevention of diabetes induced-BM dysfunction and development of DR.

Disclosure

A. Longhini: None. J. Thinschmidt: None. M. Boulton: None. M.A. King: None. M.B. Grant: None.
Chronic Kidney Disease (CKD) in U.S. Adults with Type 2 Diabetes (T2D) and Cardiovascular Diseases (CVD)—A National Estimate of Prevalence by KDIGO 2012 Classification
Authors: WANG TONGTONG , XI YUZHI , LUBWAMA ROBERT N. , KORO CAROL
Published: June 2018

Data on the prevalence of CKD among U.S. adults with T2D and CVD are limited.

The aim of this study was to provide such estimates for T2D, both overall and in those with CVD. Using the NHANES 2007-2014 data, we conducted a cross-sectional analysis of an adult sample with diagnosed and undiagnosed T2D (n=3271), aged ≥18 years. Appropriate sample weights were used to obtain a national estimate.

Results of prevalence of CKD in U.S. adults with T2D are presented in Table 1. The prevalence of moderately to severely decreased renal impairment based on eGFR < 60 ml/min/1.73m2 (Stage 3-5) was 18.0%. The prevalence of mildly decreased renal impairment (Stage 2, eGFR=60-90 ml/min/1.73m2) was 36.9%, including 28.3% with UACR<30 mg/g, 7.0% with UACR ≥ 30-300 mg/g and 1.6% with UACR>300mg/g.

For T2D and CVD subgroup (n=837), the prevalence of moderately to severely decreased renal impairment was 33.6% (Stage 3a: 16.1%; Stage 3b: 12.3%; Stage 4 or 5: 5.2%). The prevalence of mildly decreased renal impairment (Stage 2) was 42.8%, including 29.0% with UACR<30 mg/g, 11.8% with UACR≥ 30-300 mg/g and 2.1% with UACR >300mg/g.

This study confirms the high prevalence of CKD in patients with multiple comorbidities: T2D and CVD. It also provides insights into prevalence of all CKD categories based on KDIGO 2012 classification for U.S. adults with T2D, both overall and those with CVD.

Disclosure

T. Wang: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Y. Xi: None. R.N. Lubwama: None. C. Koro: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; GlaxoSmithKline plc..
Dipstick Proteinuria as a Predictor of End-Stage Renal Disease in Japanese Adults With and Without Diabetes Mellitus (DM)
Authors: FURUYA ATSUSHI , FUJIHARA KAZUYA , OSAWA TAEKO , YAMAMOTO MASAHIKO , HARADA MAYUKO , ISHIZAWA MASAHIRO , SEIDA HIROYASU , YAMANAKA NAUTA , MATSUBAYASHI YASUHIRO , SONE HIROHITO
Published: June 2018

Although proteinuria is an established potent predictor of the initiation of dialysis, it is unclear whether the impact and clinical relevance of widely used dipstick proteinuria on dialysis differs between adults with and without DM. To clarify this, we longitudinally analyzed a nationwide claim-based database that included 138,554 people aged 18-72 y in Japan. Urinary protein was assessed by test strip, the results of which ± corresponds to ≥15 mg/dL. During the 7-y period, there were 46 and 20 incident cases of dialysis among people with and without DM, respectively. Multivariate Cox analysis showed that, among people without proteinuria, those with DM had a 3.4-fold increased dialysis risk than those without DM whereas, even among individuals without DM, dipstick proteinuria confers a far higher risk of around 20 fold (Table, upper). DM and dipstick proteinuria seemed to additively affect (Table, middle) the initiation of dialysis although those with both DM and proteinuria did not have a significantly higher risk of dialysis than those without DM but with proteinuria (Table, lower). Proteinuria detected by dipstick confers a far higher risk of subsequent dialysis than diabetes per se, but clinicians should be aware of the greatly increased risk for dialysis in those with both DM and dipstick proteinuria, which implies the necessity of intensified interventions.Table Adjusted HRs (95% CI) for initiation of dialysis in individuals with and without DM according to presence or absence of dipstick proteinuria(events / n)Non-DM (46/128,529)DM (20/10,015)Dipstick proteinuriaHR (95% CI)P-valueHR (95% CI)P-value-ref3.37 (1.02-11.1)0.046± or moreref1.98 (0.76-5.13)0.16-ref3.51 (1.35-9.46)<0.01± or more19.0 (10.5-34.3)<0.0135.7 (14.1-90.1)<0.01-0.(0.03-0.10)<0.010.19 (0.07-0.48)<0.01± or moreref1.88 (0.79-4.49)0.15Adjusted for age, sex, BMI, WC, SBP, HbA1c, smoking, HDL-C, LDL-C, TG

Disclosure

A. Furuya: None. K. Fujihara: None. T. Osawa: None. M. Yamamoto: None. M. Harada: None. M. Ishizawa: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..
Restoration of Insulin-Receptor Expression in Adulthood Reverses Diabetic Phenotype in Type 2 Diabetes Models
Authors: WANG YICHEN , ZHOU HEATHER , MU JAMES
Published: June 2018

Type 2 diabetes mellitus (T2DM) is characterized by ineffective insulin action due to adult onset insulin resistance. Insulin receptor (IR) tissue content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation attained beneficial effects. However, such an approach has not been considered as a treatment option since it did not always match physiological expression level or tissue selectivity and was accompanied with developmental defects as reported. In the current study, we showed that expression of human IR (hIR) via a single adeno-associated virus (AAV) administration in adult ob/ob mice normalized blood glucose and plasma triglyceride (TG) to the levels of healthy control mice and significantly lowered liver TG level with long-lasting improvement in insulin sensitivity. To further examine if this approach is applicable for treating adult onset diabetes, we generated inducible whole body IR knockout (iIRKO) mice and successfully induced hyperglycemia, hyperinsulinemia and abnormal liver TG level at 3 months of age. Injection of AAV-hIR reversed tamoxifen-induced diabetic phenotype in iIRKO mice. Western blot analysis showed that while ob/ob and iIRKO mice had IR reduction detected in all metabolic tissues, their diabetic phenotypes were largely rescued by liver tropic IR expression via AAV delivery. More interestingly, the current method had no significant effect on IR expression or metabolism in healthy animals, suggesting that the approach restores IR level only as “needed” to maintain normal energy metabolism so it does not increase the risk of excessive insulin action, such as hypoglycemia. The approach described here effectively restores IR expression and insulin signaling with long lasting efficacy and low risk, which supports its therapeutic utility in the treatment of T2DM and metabolic disorders.

Disclosure

Y. Wang: None. H. Zhou: Employee; Self; Merck & Co., Inc.. J. Mu: None.
Epigenetics and Mitochondrial Stability in Diabetic Retinopathy
Authors: KOWLURU RENU , MISHRA MANISH
Published: June 2018

Mitochondria constantly fuse and divide to form a cellular network, and this dynamic fusion-fission controls their function and genome stability. Although both, mitofusin 1 and 2 (Mfn1 and 2) regulate outer mitochondrial membrane fusion, Mfn2 itself is sufficient to modulate mitochondrial metabolism. In diabetes, retinal mitochondria are swollen, respiration is impaired, Mfn2 is decreased and mtDNA is damaged. Diabetes also facilitates epigenetic modifications, altering gene expressions without changing their DNA sequences. This study aims to investigate the role of DNA methylation of Mfn2 in the development of diabetic retinopathy.

Methods: Human retinal endothelial cells, incubated in normal (5mmols/L) or high glucose (20mmols/L) for four days, in the presence/absence of DNA methyltransferase (Dnmt) inhibitors (5-Azacytidine or Dnmt1-siRNA), were analyzed for methylated cytosine (5mC) at Mfn2 promoter by immunocapturing method. Mitochondrial integrity was evaluated by membrane permeability, coenzyme Q: cytochrome-c reductase (complex-III) activity, and transcripts of mtDNA-encoded cytochrome b (Cytb). Similar measurements were made in the retinal microvessels from streptozotocin-induced diabetic mice receiving 5-Aza (2.5mg/kg, i.p.) or Dnmt1-siRNA (2µg/2µl, intravitreal).

Results: High glucose increased 5mC levels at Mfn2 promoter by over 2 fold, and decreased Mfn2 expression. Dnmt inhibition ameliorated glucose-induced increase in 5mC at Mfn2 and mitochondrial membrane permeability, and decrease in Mfn2 expression, complex III activity and Cytb transcripts. Similarly, in mouse retinal microvessels, inhibition of Dnmt prevented diabetes-induced increase in 5mC at Mfn2 promoter and decrease in Mfn2 expression.

Conclusions: In diabetes, epigenetic modifications of Mfn2 promoter impair mitochondrial functional and genomic stability. Thus, targeting DNA methylation could help maintain mitochondrial homeostasis, and halt/retard the development of diabetic retinopathy.

Disclosure

R. Kowluru: None. M. Mishra: None.
Increased Hemoglobin A1c Correlates with Increased Liver Stiffness in a Mexican-American Population
Authors: WATT GORDON P. , LEE MIRYOUNG , PAN JEN-JUNG , FALLON MICHAEL , MCCORMICK JOSEPH B. , FISHER-HOCH SUSAN P.
Published: June 2018

Introduction: Liver stiffness measured by transient elastography (TE) predicts liver fibrosis progression and risk of hepatocellular carcinoma. Studies have shown associations between liver stiffness and diabetes, insulin resistance, and obesity, independent of steatosis. In this study, we aimed to determine whether glucose control (hemoglobin A1c) was associated with liver stiffness in a sample of Mexican Americans with high rates of liver disease in south Texas.

Methods: Liver stiffness was measured in 159 participants in the community-based Cameron County Hispanic Cohort study in Brownsville, Texas. Univariable and multivariable linear regression was used to determine associations between HbA1c and log-transformed liver stiffness (log kPa) after adjusting for demographic and clinical covariates. Results are presented as Z-standardized β and p-values.

Results: One hundred fifty-nine participants underwent TE, and 6 were excluded due to unreliable results. Overall, 25% had diabetes and 44% were obese, with median age of 52 years. In univariable analysis, liver stiffness was associated with log HbA1c (β = 0.24, p = 0.0027), controlled attenuation parameter (CAP; β = 0.22, p = 0.0033), waist circumference (β = 0.30, p < 0.0001), and with log insulin (β = 0.16, p = 0.0574). In multivariable analysis, log HbA1c was robustly associated (β = 0.18, p = 0.0260) with liver stiffness after adjusting for age, sex, CAP, waist circumference, and insulin levels.

Discussion: This study presents evidence of a relationship between glucose control and liver stiffness, independent of steatosis, in high-risk Mexican Americans sampled from a population-based study in the U.S. Our results suggest that HbA1c may be an important tool for prevention and management of liver disease. Longitudinal follow-up studies are needed to determine if glucose control over time modulates risk of liver-related morbidities.

Disclosure

G.P. Watt: None. M. Lee: None. J. Pan: None. M. Fallon: None. J.B. McCormick: None. S.P. Fisher-Hoch: None.
Characteristics and Impact Factors of Different Renal Glucose Thresholds in Patients with Type 2 Diabetes Mellitus in China
Authors: HUANG XIUTING , GAO XUEYING , CAI XIAOLING , JI LINONG
Published: June 2018

Background: The aim of this study was to assess the clinical features of different renal glucose threshold (RGT) groups with type 2 diabetes (T2DM) patients.

Methods: A total of 2123 Chinese patients with T2DM hospitalized from Jan 2012 to Sep 2017 was collected in the study, including 174 patients with high RGT(defined as the absence of glycosuria when fasting plasma glucose (FPG) > 10 mmol/L), 111 patients with low RGT(defined as a the absence of glycosuria when FBG < 8 mmol/L) and 1838 patients with normal RGT.

Results: Compared with normal RGT, patients with high RGT showed higher HbA1c, FPG, postprandial glucose (PPG) (P<0.001), triglycerides (TG) (P=0.008), total cholesterol (TC) (P=0.010) and urinary albumin creatinine ratio(UACR) (P=0.025), but lower Homeostatic Model Assessment of β cell (HOMA-β) (P=0.010), and were more likely to have diabetic peripheral neuropathy (DPN) (P=0.001). The high RGT group was composed of significantly more female patients (P<0.001). A logistic regression analysis showed that FPG and TG were negatively associated with normal RGT after adjusting for age, sex and BMI. Compared with normal RGT, low RGT patients showed lower FPG (P=0.023), and lower waist to hip ratio and uric acid(UA) (P<0.05) in female. A logistic regression analysis showed that FPG and UA were positively associated with normal RGT. Compared with low RGT, high RGT patients showed higher HbA1c, FPG, PPG, TG, TC (P<0.05) but lower HOMA-β(P=0.016), and were more likely to have DPN (P=0.010). The high RGT group was composed of significantly more female patients (P<0.001). A logistic regression analysis showed that FPG was negatively associated with low RGT.

Conclusions: Our results indicate that the presence of T2DM subtypes characterized by different RGT. Patients with high RGT have higher glucose, TG and UACR levels, but lower levels of HOMA-β. HbA1c, FPG, TG, and UA were associated with RGT.

Disclosure

X. Huang: None. X. Gao: None. X. Cai: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Eli Lilly and Company, Bristol-Myers Squibb Company, Novartis AG, Novo Nordisk A/S, Merck & Co., Inc., Bayer AG, Merck Sharp & Dohme Corp., Takeda Development Center Asia, Pte. Ltd., Sanofi, Roche Pharma, Boehringer Ingelheim GmbH. Research Support; Self; AstraZeneca, Roche Pharma, Sanofi, Merck Sharp & Dohme Corp., Novartis AG, Eli Lilly and Company, Bristol-Myers Squibb Company.
Low Income Predicts Mortality Independently from the Presence of Type 2 Diabetes and Preexisting Coronary Artery Disease
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN DANIELA , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2018

A low socioeconomic status has been associated with increased mortality. Whether low income predicts mortality risk independently from the presence of type 2 diabetes (T2DM) and preexisting coronary artery disease (CAD) is not known and is addressed in the present study. We assessed the annual net income through a standardized questionnaire in a consecutive series of 438 patients referred to coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Prospectively, we recorded mortality over a mean follow-up period of 10.0±2.3 years. Annual net income was <€20.000 in 58.0%, €20.000-35.000 in 33.1% and >€35.000 in 8.9% of our patients. It was significantly lower in women (<€20.000 in 70.4%, €20.000-35.000 in 25.6%, >€35.000 in 4.0%) than in men (<€20.000 in 53.0%, €20.000-35.000 in 36.1%, >€35.000 in 10.9%; p<0.001) but did not differ significantly between patients with T2DM (n=116) and nondiabetic subjects (p=0.147) nor between patients with CAD (n=353) and those who did not have CAD at angiography (p=0.391). During follow-up, mortality significantly increased with decreasing income: it was 7.7%, 17.9%, and 25.6% in patients with net incomes of >€35.000, €20.000-35.000 and <€20.000, respectively; p=0.009). Annual net income significantly predicted the incidence of cardiovascular events both univariately (HR 0.59 [0.41-0.85]; p=0.004) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension, BMI, waist circumference, T2DM and angiographically determined baseline CAD (HR 0.61 [0.40-0.96]; p=0.033). We conclude that a low net income predicts cardiovascular event risk independently from the presence of T2DM and preexisting CAD.

Disclosure

C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin: None. B. Larcher: None. A. Mader: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
Hypoglycemia and Glycemic Variability in Singaporean Subjects with Type 1 Diabetes
Authors: YUNG KOH ANGELA FANG , FUN SHARON N. , YEOH ESTER
Published: June 2018

Tight glycemic control in type 1 diabetes (T1D) is limited by hypoglycemia, while glycemic variability (GV) confers independent risk for the development of diabetes-related complications. We aimed to establish the values for indices of hypoglycemia and GV in T1D Singaporean subjects. One-hundred and thirty one subjects (73% Chinese, 11% Malay, 12% Indian; 48% male) were recruited from a single center. Eighty subjects submitted glucose records performed over 4 weeks. Ryan lability index and HYPO score were calculated in subjects with at least 3 glucose readings/day. Key characteristics, indices of hypoglycemia and GV are summarized in the table.

Hypo score and LBGI were significantly correlated (r=0.63). ADRR and mLI correlated with each other (r=0.79), and with LI (ADRR r=0.72, mLI r=0.93), S.D.(r=0.78 and 0.79), %CV (r=0.45 and 0.56) and HbA1c (r=0.53 and 0.44). LI correlated with S.D. (r=0.58) but not %CV or HbA1c

Our results indicate differences compared to other populations. There were fewer subjects with hypoglycemia than Edmonton (85%), or Korean T1D subjects (71%), with much lower Hypo scores in our cohort (90th percentile of 76 vs. 1047 in Edmonton and 377 in Korean subjects). Ryan LI was comparable to the Edmonton cohort, but ADRR, LI and mLI were lower than Korean T1D subjects. Population-specific values should be established, to determine appropriate cut-offs for access to treatments such as islet transplantation.

Clinical characteristics and glycemic indicesCharacteristicResultsGlycemic parametersResultsHypoglycemia awareness ScoresResultsGlycemic variability IndicesResultsAge of diagnosis, years19 (12 – 27)Average HbA1c (%)8.2 (7.3 – 9.2)Clarke score ≥424.6%Average daily risk range   (ADRR) (n=53)Median (Interquartile range), 90th percentile25.0 (17.7 – 37.0), 40.6Duration of diabetes, years14 (8 – 19)Average Glucose (mmol/L)9.2 (8.0 – 11.2)Gold score ≥428.3%Ryan lability index (n843)Median (Interquartile range), 90th percentile168.5 (93.3 – 333.6), 432.8Insulin use (units/kg/day)0.77 (0.61 – 0.91)S.D. (mmol/L)4.4 (3.5 – 5.2)Hypoglycemia IndicesRyan lability index/no. of BG readings/day (modified Li, mLI)Median (Interquartile range), 90th percentile44.6 (27.0 – 63.1), 83.7Type of insulin regimen (twice daily, 3 times/day, 4 or more/day, insulin pump) (%)6.5/17.7/59.7/16.1%CV37.9 (9.9 – 44.5)Ryan Hypo score (n=43)Median (Interquartile range), 90th percentile 13 (0 – 25), 76Low blood glucose index (LBGI) (n=80)Median (Interquartile range), 90th percentile1.1 (0.5 - 2.1), 3.5% patients with at least 1 episode of hypoglycemia < 3 mmol/L38.8

Disclosure

A. Koh: None. S.N. Fun: None. E. Yeoh: None.
The Exocyst Complex in Insulin-Stimulated Glucose Uptake in Skeletal Muscle Cells
Authors: FUJIMOTO BRENT , LEE AMANDA , WONG ADRIAN M. , CARTER LAMAR T. , FOGELGREN BEN , POLGAR NOEMI
Published: June 2018

Objectives: Skeletal muscle cells are responsible for 80-90% of the insulin-induced glucose uptake in the body. Insulin activation of muscle cells triggers a signaling cascade that results in the exocytosis of membrane-bound glucose transporter type 4 (GLUT4) to the plasma membrane. The eight-protein complex called the exocyst is recognized as having an essential role in the insulin-induced exocytosis of GLUT4 vesicles in cultured adipocytes. We hypothesize that Sec10, a central component of the exocyst complex, is essential for the insulin-induced exocytosis of GLUT4 vesicles in skeletal myoblasts and that the exocyst is a master regulator of glucose homeostasis in metabolic tissues.

Methods/Results: To analyze exocyst-mediated intracellular trafficking in skeletal muscle in vitro, we used L6 GLUT4-myc rat skeletal myoblasts, and CRISPR/Cas9 to create Sec10 knockout (Sec10-KO) clones from these cells. Immunofluorescent staining shows co-localization of exocyst Sec10 and GLUT4 upon insulin signal in L6 myoblasts. Cellular fractionation reveals that GLUT4 delivery to the plasma membrane in response to insulin is impaired in Sec10-KO cells. Also, glucose uptake rates are significantly decreased in Sec-10-KO L6 myoblasts compared to wild type cells upon insulin stimulus. We have also generated a tamoxifen-activated skeletal muscle-specific Sec10-knockout mouse strain to assess the exocyst’s role in glucose homeostasis in vivo. Sec10 knockout mice demonstrate impaired glucose tolerance compared to littermate controls.

Conclusion: Based on our findings, Sec10 and the exocyst are necessary for insulin stimulated glucose uptake in skeletal muscle. Ongoing work will further investigate the molecular mechanism of exocyst-mediated GLUT4 trafficking in skeletal muscle.

Disclosure

B. Fujimoto: None. A. Lee: None. A.M. Wong: None. L.T. Carter: None. B. Fogelgren: None. N. Polgar: None.
Association of ATF5 Gene with Metabolic Syndrome and Insulin Resistance in Mediterranean Populations
Authors: HAYDAR SARA , GRIGORESCU FLORIN , LAUTIER CORINNE , NORMAND CHRISTOPHE , HADI JEAN CHRISTOPHE , VINTILA MADALINA , GHEORGHIU MONICA , FOUNTAS ATHANASIOS , TSATSOULIS AGATHOCLES , COPOLA ANDREA , LAURO DAVIDE , YLLI DORINA , YLLI AGRON , BRUGNARA LAURA , HANZU FELICIA , GOMIS RAMON
Published: June 2018

Insulin resistance (InsR) characterizes the metabolic syndrome (MetS) for which many genes were involved by GWAS. To further explore genetic susceptibility involving rare SNPs with major effect we genotyped patients from MEDIGENE collection using Affymetrix MEDISCOPE chip. Screening of French, Romanians and Albanians in Italy and Greece (n = 605) for metabolic pathways detected a new SNP associated with MetS in exon 3/4 of ATF5 (activating transcription factor 5) gene (Chr19q13.33). Genuine association was completed by imputation (BEAGLE4.1) at 1000 Genome Project adding new 6 SNPs and submitted to sliding window (SW) procedure for haplotypes detection. The strong association signal was found for rs61742136 with MetS (P < 1.8x10-7, Bonferroni 2.7x10-6, OR 9.37, 95% CI[3.3-26.8]), InsR (P < 0.00049, OR 3.4, 95% CI[1.7-8.4]) and with HOMA index (P < 0.023). Among MetS components, the strongest association concerned high blood pressure (HBP) (P < 2.1x 10-4, OR 4.8, 95% CI[1.8-12.4]) while HDL, TG and obesity were associated with OR < 3. In women, MetS association signal was much stronger with OR 10.9, 95% CI[3.2-36.6] (P < 8.5x10-7). SW detected associated haplotypes between 3 to 8 SNPs, the best value being that of ATGGGGTC haplotype with OR 12.2, 95% CI[3.2-46.65] (P < 1.98 x10-7, Bonferroni 1.13x10-5). Association of rs61742136 was replicated in MEDIGENE cohort (n = 948) with MetS, albeit with P < 2.0x10-3 (Bonferroni 0.026) and solely with low HDL (P < 0.05). Other SNPs were associated with HBP (rs75273180 and rs1152230 with P < 0.03 and 0.04, respectively) and with potential interactions in Haploreg V4 database. Overall fixation index (Fst = 0.001) indicates a minimal differentiation suggesting adaptive selection in Mediterranean populations. This is a first time report of implication of ATF5 in MetS and gives a new insight on its pathogenesis in view of this CREB valine/leucine zipper transcriptional factor in stress-induced anti-apoptosis or neuroprotective effects.

Disclosure

S. Haydar: None. F. Grigorescu: None. C. Lautier: None. C. Normand: None. J. Hadi: None. M. Vintila: None. M. Gheorghiu: None. A. Fountas: None. A. Tsatsoulis: None. A. Copola: None. D. Lauro: None. D. Ylli: None. A. Ylli: None. L. Brugnara: None. F. Hanzu: None. R. Gomis: None.
HLA Genotype in Ketosis-Prone Type 2 Diabetes
Authors: SHIMADA AKIRA , OIKAWA YOICHI , SATOMURA ATSUSHI , HAISA AKIFUMI
Published: June 2018

In ketosis prone type 2 diabetes with A-beta+ phenotype (= autoantibodies absent, beta cell function present; KPD), we found insulin peptide reactive T cell response, and reported in ADA meeting 2017. This time, we examined not only T cell response but also HLA genotype because characteristics of HLA in KPD is unknown. This study was approved by institutional review board. Peripheral blood was obtained from enrolled subjects with informed consent, and stimulated with insulin peptides (insulin B9-23, B10-24, B11-25, B12-26) for 24 hours, then IFN-gamma spots were counted (duplicate). Forty three point three percent (13 out of 30) of KPD (28 male, 2 female, mean age 41.1 years, mean duration 2.6 years) was found to be positive for the spots; we confirmed the previous data even we increased the patient numbers. This was similar level in acute onset type 1 diabetes (=T1D, 45.3% (24 out of 53), 19 male, 34 female, mean age 45.7 years, mean duration 5.7 years), but only 1 out of 35 (0.03%) was positive in controls (26 male, 9 female, mean age 61.8 years). On the other hand, the frequency of susceptible HLA in Japanese type 1 diabetes (DRB1*04:or DRB1*09:01) examined was 39.1% in KPD, 89.4% in T1D, and 45.7% in controls (KPD vs. T1D, p<0.001). Moreover, frequency of protective HLA in type 1 diabetes (DRB1*15:01 or DRB1*15:02) was 21.7% in KPD, 2.1% in T1D, and 20.0% in controls (KPD vs. T1D, p<0.05). Therefore, although insulin peptide T cell response was detected in KPD as same degree in T1D, characteristics of HLA genotype in KPD was different from T1D. These results suggest that even though autoreactivity exists in KPD, “less susceptible” and “protective” HLA genotype of type 1 diabetes in KPD may contribute to the suppression of the disease progression, and may explain the different clinical course after onset of ketoacidosis between KPD and T1D.

Disclosure

A. Shimada: Speaker's Bureau; Self; Eli Lilly and Company, Sanofi-Aventis, Novo Nordisk A/S. Y. Oikawa: None. A. Satomura: None. A. Haisa: None.
Correlations of Type 2 Diabetes Mellitus with Gastrointestinal Related Tumor Markers and Tumor Recurrence Risk
Authors: CHEN MING , YANG SHAOLING , LI NAN , WANG YANRU , XU LU , DONG JIAQI , ZHOU XUE , LI HONG , QU SHEN
Published: June 2018

The relationship of type 2 diabetes mellitus (T2DM) with the prognosis of gastrointestinal (GI) tumor remains unclear. Here we studied the correlations of T2DM with GI related tumor markers and recurrence risk among 370 patients with gastric cancer and colorectal cancer underwent radical surgery in our hospital from 2011 to 2014. Recurrence was evaluated during postoperative follow-up till 2017. The differences in GI related tumor markers (CEA, CA199, CA724, CA50 and CA242) between T2DM and non-DM group were compared. The correlation of T2DM with GI tumor recurrence risk were analyzed using Cox regression analysis. Moreover, patients with T2DM were divided into subgroups according to duration (0-5 years, 6-10 years, and >10 years) and HbA1c (<6.5%, 6.5-7.49%, and ≥7.5%). Of 370 patients, 68 (18.4%) were type 2 diabetics. After a median follow-up time of 47 months, 76 cases (30.7%) had recurrence. The CEA (Ln-transformed, 1.89±1.37 vs. 1.06±1.20, P<0.001), CA199 (2.68±1.57 vs. 2.43±1.30, P=0.021) and CA724 (1.66±1.47 vs. 1.01±1.08, P=0.001) in T2DM group were remarkably higher than those in non-DM group, and no significant differences were observed in CA50 and CA242 between two groups (P>0.05); FPG was positively correlated with CEA (r=0.182, P<0.001) and CA199 (r=0.143, P=0.007). Univariate Cox regression analysis indicated that the recurrence risk was positively correlated with T2DM, age, BMI, CEA, CA199, CA724, TNM stages, lymphatic metastasis, perineural invasion (all P<0.05), which increased with the increases in T2DM duration (OR1=1.738, OR2=2.314, OR3=3.325, all P<0.05) and HbA1c (OR1=1.909, OR2=2.331, OR3=2.362, all P<0.05). Besides, multivariate analysis revealed that T2DM remained the independent risk factor of recurrence after adjusting the above confounding factors (OR=1.701, 95% CI: 0.980-2.951, P=0.039). Hence, T2DM contributes to higher levels of CEA, CA199, CA724 and increased recurrence risk of GI tumor in China.

Disclosure

M. Chen: None. S. Yang: None. N. Li: None. Y. Wang: None. L. Xu: None. J. Dong: None. X. Zhou: None. H. Li: None. S. Qu: None.
Deletion of REDD1 Prevents Hyperglycemia-Induced Reactive Oxygen Species Accumulation and Retinal Cell Death
Authors: MILLER WILLIAM P. , TORO ALLYSON , DENNIS MICHAEL D.
Published: June 2018

Apoptosis of retinal neurons is accelerated by diabetes and the onset of increased cell death occurs early in disease progression. The present study was designed to evaluate molecular defects that contribute to diabetes-induced neuroretinal apoptosis and visual dysfunction. We recently demonstrated that the stress response protein REDD1 is induced by hyperglycemia in the retina of diabetic mice in a manner that contributes to neuronal cell death and visual dysfunction. One potential mechanism whereby REDD1 promotes neuronal apoptosis is through upregulation of reactive oxygen species (ROS), as the protein forms a pro-oxidant complex. In the retina of streptozotocin-induced diabetic mice, ROS levels, neuronal cell death, and REDD1 expression were increased concomitant with attenuation of contrast sensitivity thresholds, as assessed by behavioral optomotry. In R28 retinal cells in culture, hyperglycemic conditions increased REDD1 expression, ROS levels, and cell death. However, addition of the antioxidant N-acetyl-L-cysteine (NAC) to culture medium was sufficient to prevent the increase in ROS and cell death in response to hyperglycemic conditions. Moreover, REDD1-deficient cells did not exhibit increased ROS or cell death in response to hyperglycemic conditions. Similarly, in REDD1-deficient diabetic mice, ROS levels and cell death in retina were similar to that observed in nondiabetic mice. Finally, oral administration of NAC improved contrast sensitivity in diabetic mice relative to vehicle treated diabetic controls, demonstrating a key role for ROS levels in diabetes-induced visual dysfunction. Overall, the findings support therapeutic approaches targeting REDD1 and ROS production in the prevention of diabetes-induced visual dysfunction.

Disclosure

W.P. Miller: None. A. Toro: None. M.D. Dennis: None.
Elevated Nonesterified Fatty Acids (NEFA) Are Associated with Blunted Hyperglycemia-Induced Increments in Brain Glucose Levels
Authors: LAM WAI , JIANG LIHONG , BUTRICO GINA MARIE , CLINE GARY , RANGEL ELIZABETH SANCHEZ , HAMZA MUHAMMAD , PARIKH LISA , BELFORT-DEAGUIAR RENATA , ROTHMAN DOUGLAS L. , MASON GRAEME F. , SHERWIN ROBERT , HWANG JANICE
Published: June 2018

Recently, we have demonstrated that obesity and T2DM are associated with blunted brain glucose transport capacity during acute hyperglycemia in humans, which was also associated with higher total NEFA levels. Palmitic acid has been shown in vitro to suppress brain glucose uptake by downregulating GLUT1 expression in brain endothelial cells. Thus, this current study was undertaken to determine whether specific NEFA composition is associated with blunted human brain glucose transport capacity. Plasma NEFA composition was assessed using Gas-Chromatography Mass-Spectroscopy in 8 healthy lean (HC) (4F/4M, age 33±11 years, BMI 23±2 kg/m2, HbA1C 5.0±0.2), 10 obese (OB) (6F/4M, age 34±11 years, BMI 39±6 kg/m2, HbA1C 5.3±0.3), and 6 T2DM individuals (5F/1M, age 52±5 years, BMI 33±2 kg/m2, HbA1C 9.5±1.3) at the end of a 2-hour hyperglycemic clamp (220mg/dl) and correlated with previously measured changes in intracerebral glucose levels. Blunted rise in brain glucose levels was observed in OB and T2DM vs. HC individuals (p<0.05). Plasma long-chain non-esterified fatty acids (LCFA) including saturated (myristic acid, palmitic acid, stearic acid), monounsaturated (palmitoleic acid, oleic acid) and polyunsaturated (linoleic acid, an essential fatty acid) were different across all 3 groups (p<0.05). Moreover, these LCFAs negatively correlated with hyperglycemia-induced change in brain glucose levels (myristic r=-0.45; p=0.03, palmitic: r=-0.49, p=0.02; stearic r=-0.44, p=0.04; palmitoleic r=-0.49, p=0.02; oleic r=-0.49, p=0.02; linoleic r=-0.41, p=0.05). Our results demonstrate an inverse relationship between elevated LCFA levels and blunted brain glucose uptake in humans, which appears to be non-specific for NEFA composition. As the ability to transport glucose into the brain is crucial for energy homeostasis, these findings highlight a potential role for NEFAs to modulate brain glucose transport and metabolism and in turn cognitive function.

Disclosure

W. Lam: None. L. Jiang: None. G. Butrico: None. G. Cline: None. E. Sanchez Rangel: None. M. Hamza: None. L. Parikh: None. R. Belfort-DeAguiar: Research Support; Self; GlaxoSmithKline plc.. D.L. Rothman: None. G.F. Mason: Consultant; Self; UCB, Inc., Sumitomo Dainippon Pharma Co., Ltd. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc.. J. Hwang: None.