bluuebunny/crossref_metadata_2025 huggingface dataset:
2255-PUB: 5-Year SLGT2-inh Treatment in Uncontrolled Elderly Diabetic Patients: Safety, Efficacy, and Durability
Authors: TRESCOLI CARLOS , PALASI PILAR , PLATERO PATRICIA , TRESCOLI-GARCIA ANA , ESPINOSA BORJA , VERCHER MANUEL
Published: June 2020

SLGT-2 inh have cardiovascular and renal protection effect. Elderly diabetic patients are more prone to cardiovascular events but are frailer with more comorbidities and more prone to SLG2-inh adverse effects. These patients are not represented in RCT as they not fulfil inclusion criteria.

Aim: Evaluate long term safety and efficacy of adding SGLT2 inhibitors to Elderly DM2 patients with uncontrolled glycemia in real life experience.

Method: We studied 72 Elderly DM2 patients treated with SGLT2 inhibitors for more than 5 years in our Health Department. Efficacy, Safety and Durability data was collected from our computerized Primary and Hospital Medical Records at baseline and after 5 years.

Results: Patients’ basal data: mean age: 71,6 years, 42% women, mean period diabetes: 12,5 years. Prevalence Hypertension 79%, Dyslipidemia 81% Obesity 51% and previous cardiovascular events 42%. Antidiabetic Treatment: Metformin (78%), SU (31%) Gliptines (37%) Pioglitazone (12%), GLP-1A (13%) and Insulin (36%). Results Before and After 5-year SGLT2 inh Treatment: HbA1c. 8,5 vs. 7,2% (p < 0,05); (38% maintained HbA1c < 7.5%) Weight: 90.9 vs. 86.7 kg (p< 0,05); Systolic BP: 133.2 vs. 128.6 mmHg (P< 0,05) Albumin-Creatinine ratio (ACR): 58,7 vs. 36,2 mg/g (p< 0,05) There were no statistical significant changes in e-GFR, microalbuminuria, lipid profile and hematocrit. No falls, volume depletion, severe hypoglycemia or ketoacidosis were recorded. 17% were treated for urinary-genital infections and half of them withdraw SLGT2i. 22% had a new non-fatal cardiovascular events and 6% heart failure hospitalization. There was a 17% mortality mainly due to neoplasic causes.

Discussion: 5-year SGLT2 inh. treatment in Elderly DM2 patients was safe and effective as in RCT. They had a significant maintained reduction in HbA1c, weight, systolic BP and ACR. Genito-urinary infection, although not frequent, was the main cause of withdraw.

Disclosure

C. Trescoli: None. P. Palasi: None. P. Platero: None. A. Trescoli-Garcia: None. B. Espinosa: None. M. Vercher: None.
2257-PUB: The Prevalence of Sarcopenia in Chinese Type 2 Diabetes Patients
Authors: HE QINGHUA , GUO LIXIN
Published: June 2020

Objective: To examine the prevalence of sarcopenia in type 2 diabetes (T2DM) patients and to clarify the associated risk factors.

Methods: T2DM patients aged 50 years or older were included from nine research centers. Body composition was measured by bioimpedance analysis. Sarcopenia was defined by low muscle strength coexisted with low muscle mass. Low muscle strength was determined by grip strength below the lower quintile of the same sex subjects, the cutoff was below 29.5kg in men and 21.2kg in women. Low muscle mass was determined by the appendicular skeletal muscle index (ASMI) below the lower quintile of the homogeneity, same sex and healthy young group, the cutoff value was 7.18kg/m2 in men and 5.73kg/m2 in women.

Results: (1)A total of 1125 participants including 586 males(52%) and 539 females(48%) was analyzed. The average age was (62.6±8.3) years, BMI was (25.8±3.4) kg/m2, the diabetes duration was [10.36(5.32, 16.15)] years, FPG was (8.4±2.5)mmol/l, and HbA1c was (8.1±1.8)%. There were no statistical differences between male and female. (2)The detection rate of low muscle mass was 14.0%, male was significantly higher than female(18.3% vs. 9.3%); (3)The detection rate of low grip strength was 36%, male was significantly higher than female (50.3% vs. 20.4%);(4) The prevalence of sarcopenia in all participants was 8.5%, male was significantly higher than female (12.8% vs. 3.9%). (5)Logistic regression analysis showed men, low BMI, aging, high HbA1c were risk factors associated with sarcopenia. The risk of sarcopenia increased obviously in patients older than 75 years old(OR=4.992, 95%CI 2.448-10.179) or whose HbA1c was over 10%(OR=3.563, 95%CI 1.526-8.322).

Conclusion: T2DM was associated with increased risk of sarcopenia. Low BMI, aging, high HbA1c were risk factors associated with sarcopenia in T2DM.

Disclosure

Q. He: None. L. Guo: None.
2258-PUB: Impact of Cardiovascular (CV) Risk Factors during the Initial 6 Months of the First Large-Scale Longitudinal Nationwide Study on Management and Real-World Outcomes of Diabetes in India (LANDMARC)
Authors: GHOSH ROMIK , DAS ASHOK K. , JOSHI SHASHANK , MITHAL AMBRISH , KUMAR K.M. PRASANNA , KALRA SANJAY , UNNIKRISHNAN AMBIKA GOPALAKRISHNAN , THACKER HEMANT , SETHI BIPIN , MOHANASUNDARAM SENTHILNATHAN , MENON SHALINI K. , NAIR ARJUN , RAIS NADEEM , WANGNOO SUBHASH KUMAR , CHOWDHURY SUBHANKAR , ZARGAR ABDUL H.
Published: June 2020

Impact of cardiovascular (CV) risk factors in participants with T2D during the first 6-months of observational period were examined in this 3 year prospective study (LANDMARC; CTRI/2017/05/008452). CV risk factors (rate of hypertension, dyslipidemia, albuminuria, and family history of premature coronary disease) at baseline (V1) and 6 months (Visit 2 [V2]) were assessed and compared between subgroups. Overall, >50% of the participants who had A1C data available, had CV risks at both V1 (2385/4479; 53.2%) and V2 (2422/4479; 54.1%). More than half of the participants with obesity (BMI ≥25 kg/m2) had CV risks at V1 (2305/4150; 55.5%) and V2 (2340/4150; 56.4%). On comparing the insulin (N=1548) vs. insulin naïve (N=4688) subgroups, a higher proportion of participants on insulin had CV risks than those who were insulin naïve (V1: 60.1% vs. 50.1%; V2: 60.8% vs. 50.9%). At V2, hypertension and dyslipidemia were more predominant in those with BMI ≥23 kg/m2 than <23 kg/m2, with A1C ≥ 7% than <7%, and in men than women (Table). In India, CV risks may be increased in people with T2D who are overweight, have suboptimal glycemic control, or are men. The real-world trend of CV risks may offer insights and direction for risk factor modifications and treatment adjustments.

Disclosure

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

Funding

Sanofi India Limited
2267-PUB: 1,5-Anhydroglucitol X Glycated Hemoglobin A1c/100: A Potential Biomarker for Islet ß-Cell Function in Type 2 Diabetes Mellitus
Authors: MA XIAOJING , SU HANG , SHEN YUN , HE XINGXING , YING LINGWEN , ZHU WEI , WANG YUFEI , BAO YUQIAN , ZHOU JIAN
Published: June 2020

Aims: The goals of the current study were to explore the level of and changes in the AH index (AHI, defined as 1,5-anhydroglucitol × glycated hemoglobin A1c/100) associated with different glucose metabolism statuses, and to evaluate the islet function and insulin sensitivity of type 2 diabetes mellitus (T2DM) patients with different AHI levels.

Methods: A total of 3562 individuals were enrolled in the study. According to the 2010 American Diabetes Association (ADA) diagnostic criteria, 1697 subjects were diagnosed as T2DM. The disposition index (DI) was defined as the product of insulin sensitivity-related indexes and islet secretion function.

Results: The overall AHI level was 1.0 (0.7-1.3), while the AHI level of the T2DM group was 0.8 (0.5-1.2), which was significantly lower than that of the normal glucose tolerance group and the impaired glucose regulation group [both AHI 1.2 (0.9-1.5), and P < 0.01]. The T2DM group was further divided into four subgroups according to the quartile of AHI level. The results demonstrated that the homeostasis model assessment of insulin resistance (HOMA-IR) decreased with the increase of AHI level (P for trend < 0.01). However, other parameters [i.e., HOMA of β-cell function (HOMA-β), insulin generation index, insulin sensitivity index, and DI] increased while AHI level increased (all P for trend < 0.01). Multivariate logistic regression illustrated that the odds ratios for a low DI for increasing levels of AHI were 1.00, 0.22 (0.16-0.29), 0.16 (0.11-0.22), and 0.09 (0.06-0.13), respectively, showing a decreasing trend (P for trend < 0.01).

Conclusion: AHI could reflect the changes in the trend of glucose metabolism disorder and the function of islet β cells to some extent. The lower AHI was associated with worsening of the glucose metabolism disorder in recent years, and the islet β-cell function was correspondingly poor.

Disclosure

X. Ma: None. H. Su: None. Y. Shen: None. X. He: None. L. Ying: None. W. Zhu: None. Y. Wang: None. Y. Bao: None. J. Zhou: None.
2283-PUB: Metformin Treatment and Prostate Cancer Risk: Cox Regression Analysis with Time-Dependent Covariates of 150,000 Men with Incident Diabetes Mellitus
Authors: DANKNER RACHEL , MURAD HAVI , AGAY NIRIT , OLMER LIRAZ , FREEDMAN LAURENCE S.
Published: June 2020

Background: There is conflicting evidence regarding the association between metformin use and prostate cancer risk in diabetic men.

Objective: We investigated the association of metformin treatment, as a time dependent exposure, with prostate cancer incidence, in a population-based cohort of T2D incident men, while accounting for major time related biases, time-dependent confounding by glucose levels, and for use of other diabetes medications.

Methods: During 2002-2012, we followed a cohort of 145,617 incident diabetic men aged 21-87 years insured in the largest health maintenance organization in Israel. We used a discrete form of the weighted cumulative exposure to metformin to evaluate its association with prostate cancer incidence. This was implemented in a time-dependent covariate Cox model, adjusting for age, ethnic background, and socioeconomic status. Other diabetes medications were not found to be strongly associated with prostate cancer. To account for time- dependent confounding by glucose levels, we used Propensity Score weighting for receiving metformin at each time-point.

Results: There were 1,592 prostate cancer events occurring over a total of 910,000 person-years. We found a positive association of prostate cancer with metformin exposure in the previous year (hazard ratio (HR) for 1 defined daily dose = 1.66; 95%CI 1.23, 2.24), but a negative association with metformin exposure in the previous 2-7 years (HR=0.57; 95%CI 0.32, 1.02).

Conclusion: Our results do not support a clear causal effect of metformin treatment on the incidence of prostate cancer. The positive association with metformin given in the previous year could be due to reverse causation of the cancer raising glucose levels and causing increased prescription of metformin. The negative association with metformin given 2-7 years previously is of borderline statistical significance and requires further research.

Disclosure

R. Dankner: None. H. Murad: None. N. Agay: None. L. Olmer: None. L.S. Freedman: None.
2290-PUB: Donor HLA-DR4 Positivity and Islet Transplantation Outcomes
Authors: CHAVEZ CARMEN , FUENMAYOR VIRGINIA , BAIDAL DAVID , ALVAREZ ANA M. , PADILLA NATHALIA , RICORDI CAMILLO , ALEJANDRO RODOLFO
Published: June 2020

Islet transplantation (ITx) has demonstrated efficacy in improving glycemic control and abolishing severe hypoglycemia in patients affected with type 1 diabetes (T1D). Several factors account for graft loss and recurrence of autoimmunity has been suggested as a contributor to graft failure but remains controversial. We hypothesized that ITx recipients of HLA DR4+ donors could be at increased risk for recurrence of autoimmunity, as DR4+ is a well-known risk factor for T1D.

We evaluated 50 ITx recipients transplanted at the Diabetes Research Institute, University of Miami, who have been followed from 2000 to 2019. Out of the 50 subjects, 7 received islet after kidney transplantation and 43 islet transplantation alone. Subjects received an average of 2 islet infusions from 1 to 5 donors. The data was analyzed using Kaplan-Meier Survival Curves, along with log-rank and Wilcoxon tests statistics.

No significant association was found between Donor DR4+ and islet transplant outcomes (>0.05). However, our study is limited by the small sample size, use of multiple donors as well as differences in immunosuppression regimens and use of GLP-1 analogs and DPP-4 inhibitors which may have affected outcomes.

Our data suggests that donor DR4+ is not associated with transplantation outcomes in our study cohort. Further studies are required to validate these findings.

Disclosure

C. Chavez: None. V. Fuenmayor: None. D. Baidal: None. A.M. Alvarez: None. N. Padilla: None. C. Ricordi: None. R. Alejandro: None.

Funding

Diabetes Research Institute Foundation; State of Florida; JDRF; The Leona M. and Harry B. Helmsley Charitable Trust; University of Miami Clinical and Translational Science Institute
2292-PUB: Luminescent Assays Quantitate the Biology of Peptide Hormones
Authors: VIDUGIRIENE JOLANTA , LEIPPE DONNA M. , VALLEY MICHAEL
Published: June 2020

The interest in metabolic diseases like diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), continues to increase due to their growing impact on cell health. To facilitate studies and uncover novel drug targets, there is a significant need to develop disease relevant in vitro cellular models and robust, easy to use detection technologies. Here we demonstrate that luminescent assays coupling specific dehydrogenases to the production of NAD(P)H and generation of light can be used to study insulin biology and its effects on key metabolic pathways. Insulin stimulated glucose uptake was measured in 3T3-L1 MBX adipocytes with 10-fold assay window and the expected pharmacology using a glucose uptake assay. Using a glycerol detection assay, we showed 4-fold increase in lipolysis upon isoproterenol stimulation that was suppressed by insulin. Effects of insulin on gluconeogenesis was studied by measuring glucose production in liver microtissues, which are also a useful model for NAFLD studies and measurement of steatosis using a triglyceride assay. This assay does not require organic extraction and has the sensitivity required for quantitative triglyceride detection using low cell numbers (<1000 cells/per well). Pancreatic islets are critical for regulated glucose homeostasis and measuring hormone production and secretion is the most direct method for assessing the quality and function of islets. To facilitate those studies, we developed bioluminescent, in solution, no wash insulin and glucagon immunoassays that are significantly more rapid and cost-effective than current commonly used approaches. The assays show high sensitivity and wide dynamic range (10 pM to 8 nM for insulin and 0.5 pM to 1 nM for glucagon) and are amenable to miniaturization making them well suited for rapid measurements of large numbers of samples that are generated, for example, in perifusion or high throughput screening experiments.

Disclosure

J. Vidugiriene: None. D.M. Leippe: None. M. Valley: None.
2298-PUB: Estradiol Protects Female ApoE KO Mice against Nonalcoholic Steatohepatitis
Authors: MOREIRA GABRIELA V. , MATOS SANDRO L. , CAMARGO FELIPE N. , ARAUJO LAYANNE , MURATA GILSON M. , CARVALHO CARLA R.O. , CAMPOREZ JOAO PAULO
Published: June 2020

Lifestyle and increased consumption of high fat diets contribute greatly to the development of obesity, insulin resistance, type 2 diabetes (DM2), and cardiovascular diseases, which are less prevalent in young women than in men of the same age or postmenopausal women. One of the consequences of the Western lifestyle and high fat diet is Nonalcoholic Fatty Liver Disease (NAFLD) and its aggressive form, Nonalcoholic Steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular cancer (HCC) and is rapidly becoming the leading cause for end-stage liver disease or liver transplantation. Therefore, we evaluated if female mice were protected against Western Diet (WD)-induced NASH in apolipoprotein E (ApoE) KO animals. Female ApoE KO mice ovariectomized (OVX) or sham operated (SHAM) were fed a WD for 7 weeks. Whole-body fat was increased by ∼65% (P<0.001) in OVX mice associated with an increase of glucose intolerance of by ∼75% (P<0.01) and increased hepatic triglycerides (TAG) by 130% (P<0.01) compared with SHAM mice. OVX mice also displayed increased plasma ALT (∼130, P<0.001) and AST (∼65%, P<0.05) compared with SHAM mice. These data were associated with increased hepatic inflammation in OVX mice, demonstrated by an increased of F4/80 of by ∼70% (P<0.01). Hepatic fibrosis was also increased in OVX mice by ∼80% (P<0.001) compared with SHAM mice. Estradiol treatment of OVX mice reversed some of these effects, reducing whole-body fat (P<0.01), glucose intolerance (P<0.01), and hepatic TAG content (P<0.001). Taken together, these data support the hypothesis that estradiol protects OVX mice from WD-induced NASH and glucose intolerance, by protecting female mice against hepatic steatosis, inflammation and fibrosis.

Disclosure

G.V. Moreira: None. S.L. Matos: None. F.N. Camargo: None. L. Araujo: None. G.M. Murata: None. C.R.O. Carvalho: None. J. Camporez: None.

Funding

Fundação de Amparo a Pesquisa do Estado de São Paulo (2018/04956-5)
2309-PUB: Postprandial Thermogenesis Is Reduced in Obesity
Authors: VOSSELER ANDREAS , FRITSCHE LOUISE , HUMMEL JULIA , DANNECKER CORINNA , STEFAN NORBERT , BIRKENFELD ANDREAS L. , HAERING HANS-ULRICH , FRITSCHE ANDREAS , WAGNER ROBERT , HENI MARTIN
Published: June 2020

Background and Aims: Postprandial thermogenesis is thought to be important for the control of metabolism. This process could be reflected by minute changes in body temperature after glucose load. In this study, we measured body temperature before and its change during a glucose challenge and investigated the relationships with anthropometric and glycemic traits.

Methods: We prospectively studied 383 volunteers (251 females, 132 males) with a mean age of 46.6 (SD ± 16) years and a BMI of 27.9 kg/m2 (SD ± 5.9). All participants underwent a 75 g oral glucose tolerance test (OGTT) and repeated bilateral measurements of intra-auricular temperature at time points 0, 30 and 120 minutes during the OGTT using a tympanic thermometer (Covidien Genius 2).

Results: Baseline temperature was 0.17°C lower in males compared to females (p = 0.001) and inversely associated with age (p < 0.0001). During the OGTT, there was a significant increase in body temperature (0.18 ± 0.34°C). This response was present in females and males. BMI was negatively associated with the increase of temperature during the OGTT (p = 0.0147). Participants with higher BMI displayed higher fasting temperatures, but less increase of temperature during the OGTT. Body temperature was not associated with glycemia, insulin sensitivity or insulin secretion, neither in females nor males.

Conclusions: There is a robust increase in body temperature during a glucose load that can be captured by intra-auricular temperature measurements. We did not detect any associations of the body temperature with glucose metabolism, arguing against a major contribution of the variability of body temperature in the pathogenesis of diabetes. However, the rise in temperature in response to oral glucose is reduced in obesity and might therefore be involved in body weight regulation.

Disclosure

A. Vosseler: None. L. Fritsche: None. J. Hummel: None. C. Dannecker: None. N. Stefan: None. A.L. Birkenfeld: None. H. Haering: None. A. Fritsche: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S.

Funding

German Federal Ministry of Education and Research (01GI0925)
231-LB: Importance of Intestinal Environment and Cellular Plasticity of Beta Cells in the Development of Post-Pancreatectomy Diabetes
Authors: BOUCHI RYOTARO , FUKUDA TATSUYA , TAKEUCHI TAKATO , AMO-SHIINOKI KIKUKO , TANABE KATSUYA , TANIZAWA YUKIO , YAMADA TETSUYA , OGAWA YOSHIHIRO
Published: June 2020

To elucidate the pathogenesis of post-pancreatectomy diabetes (PPDM), we carried out a prospective observational study in patients without diabetes undergoing partial pancreatectomy, investigating the effects of gut microbiota, incretins, and short-chain fatty acids (SCFAs) on postsurgical glucose metabolism. In addition, we analyzed histologically the resected pancreas to investigate whether increased cellular-plasticity and expansion of the islets could predict the development of PPDM. Forty-eight patients without diabetes, who underwent either pancreatoduodenectomy (PD) (n=20) or distal pancreatectomy (DP) (n=28), were included. To assess the post-surgical glucose metabolism, 75-g oral glucose tolerance test (OGTT) was performed every 6 months. Microbiome composition and SCFAs in feces were examined before and 6 months after the surgery. We also underwent immunostainings of insulin, glucagon, and ALDH1A3 (a progenitor cell marker) in the resected pancreatic samples obtained from patients following DP. During the follow-up (median 2.50 years), 2 out of 18 patients with PD and 16 out of 28 patients with DP developed PPDM. Microbiota shifted to a higher relative abundance of Proteobacteria after PD. After PD, fecal butyrate and plasma GLP-1 concentrations were significantly increased, which were not increased after DP. In all patients, postsurgical change in butyrate was strongly correlated with increased GLP-1 secretion. In DP patients, expansion of both α- and β-cell areas in the resected pancreas were significantly associated with the development of PPDM, and HR (95% CI) of ALDH1A3 positive cells (%) for PPDM was 1.127 (1.000-1.270). This study demonstrates that incidence of PPDM is much lower after PD than that after DP, which may be explained by marked changes in intestinal environment after PD. On the other hand, high cellular-plasticity and expansion of the islets in the resected pancreas can predict the development of PPDM after DP.

Disclosure

R. Bouchi: None. T. Fukuda: None. T. Takeuchi: None. K. Amo-Shiinoki: None. K. Tanabe: None. Y. Tanizawa: None. T. Yamada: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Ogawa: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker’s Bureau; Self; Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation.

Funding

Ministry of Education, Culture, Sports, Science and Technology of Japan (15K19507); Japan Foundation for Applied Enzymology; Takeda Science Foundation; AstraZeneca
2310-PUB: Chronic Western Diets Initiate Fibrosis Progression in Nonalcoholic Fatty Liver of Male Mice Modifying the PPARγ Pathway via Mir-27b-5p Regulation
Authors: ZHANG JIAN , POWELL CATHERINE , KAY MATTHEW K. , SONKAR RAVI , MERUVU SUNITHA , CHOUDHURY MAHUA
Published: June 2020

Increased fructose intake in Western diets contributes to metabolic diseases. However, the epigenetic mechanisms are mostly unknown. Here, six week-old C57BL/6J male and female mice were fed with a low-fat diet (LFD), high-fat diet (HFD), and high-fat high-fructose diet (HFD-HF) for 20 weeks. We determined that HFD-HF or HFD mice experienced significant metabolic dysregulation compared to the LFD. Metabolic changes in male mice were significantly dysregulated compared to female mice. HFD-HF and HDF male-specific responses included physiological/metabolic changes such as significant increased body weight, increased liver size, increased fasting glucose levels and downregulated PPARγ (P < 0.001), SCD1 (P < 0.05 to P < 0.01), and FAS (P < 0.05) protein expression. In contrast, female mice were less affected by HFD and HFD-HF. Interestingly, none of the groups exhibited less insulin sensitivity after 20 weeks of feeding when compared to LFD. As miR-27b contains a seed sequence in PPARγ, it was discovered that these changes are accompanied by male-specific upregulation of miR-27b-5p, which is even more pronounced in the HFD-HF group (P < 0.01 vs. LFD) compared to the HFD group (P < 0.05 vs. LFD). Other miR-27 subtypes were increased but not significantly. Fat ballooning in hepatocytes were increased in HFD fed mice compared to HFD-HF fed mice, however, the HFD-HF liver showed an increase in the number of small cells. Here, we concluded that our chronic western diet-composition administered for 20 weeks surpassed the nonalcoholic fatty liver (NAFL) stage and initiated liver fibrosis via miR-27b-5p-induced PPARγ downregulation.

Disclosure

J. Zhang: None. C. Powell: None. M.K. Kay: None. R. Sonkar: None. S. Meruvu: None. M. Choudhury: None.

Funding

Morris L. Lichtenstein, Jr. Medical Research Foundation
2313-PUB: Alterations in Basal State of Insulin and mTOR-Dependent Signalings Closely Related to Impaired Incretin Profile and Type 2 Diabetes in Subcutaneous Adipose Tissue of Obese Patients
Authors: STAFEEV IURII , SKLYANIK IGOR , MICHURINA SVETLANA , SHESTAKOVA EKATERINA , YURASOV ANATOLIY , YAHYAEV KAMIL , KARMADONOV ANDREY , RATNER ELIZAVETA , MENSHIKOV MIKHAIL , VOROTNIKOV ALEXANDER V. , PARFYONOVA YELENA V. , SHESTAKOVA MARINA V.
Published: June 2020

Objective: In our study we have compared basal insulin and mTOR signaling in subcutaneous fat of obese T2DM vs. obese subjects with normal glucose tolerance (NGT). We have performed correlation analysis of phosphorylation’s parameters against clinical parameters of carbohydrate metabolism and incretin secretion profiles.

Methods: 22 patients with long (>10 years) and morbid (BMI > 35 kg/m2) obesity, 12 of which had NGT and 10 had T2DM were enrolled in this study. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to measure insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Amount of total and visceral fat was determined by bioelectrical impedance analysis. Subcutaneous fat biopsies were obtained during bariatric surgery for all patients and signaling state was analyzed by western blots.

Results: As assessed by western blots of insulin receptor substrate (IRS), Akt, Raptor, Rictor, mTOR and S6K1, the basal insulin signaling and mTORC activities were comparable in NGT and T2DM groups, whereas phosphorylation of AS160 (pAS160-S318) was significantly lower and serum and glucocorticoid-induced kinase (SGK; pSGK-S422) was significantly higher in T2DM group. Various correlations were found between the degree of insulin resistance and amount of visceral fat, changes in incretin profile, glucose metabolic parameters and phosphorylation level of AS160, incretin secretion profile and phosphorylated levels of AS160 or SGK1.

Conclusions: Altered phosphorylation of AS160 and SGK1 is associated with obese T2DM phenotype and impaired incretin profile. We think that AS160 and SGK1 phosphorylations can be important markers of the prediabetes-to-diabetes transition.

Disclosure

I. Stafeev: None. I. Sklyanik: None. S. Michurina: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. A. Karmadonov: None. E. Ratner: None. M. Menshikov: None. A.V. Vorotnikov: None. Y.V. Parfyonova: None. M.V. Shestakova: None.

Funding

Russian Science Foundation (17-15-01435)
2315-PUB: High Serum Ferritin Predicts Inferior Diabetes-Related Outcomes after Gastric Bypass but Not Sleeve Gastrectomy Bariatric Surgery
Authors: TONG JENNY , ALVAREZ RAFAEL , RUSSELL GREGORY B. , KHOURI ALEXANDER N. , SEELEY RANDY J. , MCCLAIN DONALD A.
Published: June 2020

Objective: Because higher iron level is associated with increased risk of type 2 diabetes and bariatric surgery is known to alter iron homeostasis, we examined the effects of tissue iron stores on glycemic outcome after bariatric surgery.

Research Design and Methods: We performed a retrospective analysis of glycemia outcomes after Roux-en Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG) in individuals with elevated hemoglobin A1c (HbA1c) as a function of serum ferritin before and after surgery, using two large and independent electronic health databases from the Carolinas Collaborative and University of Michigan.

Results: Improvement of HbA1c, weight, and alanine aminotransferase (ALT) was comparable between the two procedures 6-12 months after surgery. For gastric bypass procedures, however, the improvement in HbA1c and the chance of normalizing HbA1c were inversely proportional to preoperative ferritin, while no such relationship existed for gastrectomy. The improvement in ALT was correlated with the decrease in serum ferritin after surgery for both surgery types. Changes in hemoglobin were also related to preoperative ferritin.

Conclusion: Preoperative iron stores may modulate glycemic improvement after bariatric surgery differentially depending on procedure type. This has implications regarding the operation of choice in certain patient populations.

Disclosure

J. Tong: None. R. Alvarez: None. G.B. Russell: None. A.N. Khouri: None. R.J. Seeley: Consultant; Self; Ionis Pharmaceuticals, Inc., Kintai, Kintai, Novo Nordisk A/S, Sanofi, Scohia Pharma Inc. Research Support; Self; AstraZeneca, Novo Nordisk A/S, Pfizer Inc. Stock/Shareholder; Self; Redesign Health. D.A. McClain: None.

Funding

National Institutes of Health (R01DK097550)
2316-PUB: Lipidomic Profiling Reveals Distinct Differences in Plasma Lipid Composition in Overweight or Obese Adolescent Students
Authors: YIN RUILI , WANG XIAOJING , ZHAO DONG , YU KE , YANG LONGYAN
Published: June 2020

The relationship between dyslipidemia and obesity has been widely reported, but the global lipid profiles associated with the development of obesity remain to be clarified, especially in the East Asia teenage population. We recruited 90 adolescent participants, including 30 individuals with normal body mass index (BMI) (BMI: 16-20), 30 obesity students (BMI: 20-26), and 30 overweight students (BMI: 26-37). All participants were performed anthropometric measurement by using InBody 770. Mass spectrometry coupled with liquid chromatography was applied to detect the global lipidome in the fasting plasma. Clinical biochemical indicators were measured by Cobas Elecsys 601. Both qualitative and quantitative analyses revealed a gradual change in plasma lipid features with obesity students exhibiting characteristics close to overweight students, but they differed significantly from students with normal. The levels of triglyceride, 18-Hydroxycortisol, Isohumulinone A, and 11-Dihydro-12-norneoquassin were up-regulated in obesity group, while phosphatidylcholine (PC), phosphatidylethanolamine (PE), LysoPC, LysoPE, and Phosphatidylinositol were significantly down-regulated in obesity group than in control and overweight individuals. Then conducted venn diagram and selected 8 significant metabolites from the 3 paired comparisons. Most of the selected features significantly correlated with anthropometric measurement.

In conclusion, the altered plasma lipidome in Chinese obesity and overweight students suggested that lipid features may provide a basis for evaluating risk and monitoring obesity development.

Disclosure

R. Yin: None. X. Wang: None. D. Zhao: None. K. Yu: None. L. Yang: None.

Funding

National Natural Science Foundation of China (81800768)
2317-PUB: Levels of Vaspine and Omentine in Circulation and Topography of Adipose Tissue Deposition
Authors: KRAVCHUN NONNA , IEFIMENKO TETIANA , MISURA KATHERINE , ALHAMID MOHAMAD
Published: June 2020

Introduction: Vaspin and Omentin are adipokines that cause peripheral tissue sensitivity to insulin and are a link between type 2 diabetes and obesity. The question of the consequences of excess accumulation in visceral and glutemoral adipose tissue at the level of vaspin and omentin remains unclear today.

Objective: the content of vaspine and omentin in blood depending on the degree and topography of the deposition of adipose tissue in representatives of the Ukrainian population.

Materials and Methods: An enzyme-linked immunosorbent assay of vaspin and omentin levels was determined. Abdominal obesity was determined by the circumference of the waist: in women it was more than 0.80 m, in men - more than 0.94 m.

Results: A direct correlation was found between blood pressure and waist and a hip examination (r = 0.4314, (p <0.001) and r = 0.5130 (p <0.001), respectively). The presence of a relationship between the degree of deposition of adipose tissue on the anterior abdominal wall and the level of circulating omentin confirms the presence of an inverse correlation between this parameter and RT (r = -0.397; p <0.001). The degree of correlation between the level of circulating omentin and the hips was determined: it was higher than with the waist (r = -0.532, p <0.001). The latter indicates that not only visceral, but also gluteal-femoral adipose tissue is displayed at the level of circulating omentin.

Conclusion: The decisive role of abdominal obesity in pathological changes in the production of vaspin and omentin has been confirmed. At the same time, it was found that the circumference of the hips is an informative criterion for changes in the circulation of omentin and vaspin.

Disclosure

N. Kravchun: None. T. Iefimenko: None. K. Misura: None. M. Alhamid: None.
232-LB: Chronic Adrenergic Stimulation of Human Brown and White Adipose Tissue Increases Bile Acid Synthesis Enzyme Expression and Plasma Bile Acid Levels
Authors: ZHU KENNETH Y. , LEA HANNAH J. , CERO CHERYL , CYPESS AARON M.
Published: June 2020

Beyond enabling digestion of fats, bile acids (BA) are now known to be receptor ligands that improve glucose and lipoprotein metabolism. Classically, regulation of BA synthesis has thought to be exclusively hepatic, but emerging evidence in rodents indicates that BA production is influenced by sympathetic activation of brown and white adipose tissue (BAT and WAT). We recently showed that chronic activation of BAT and WAT in adult women with the β3-adrenergic receptor (AR) agonist mirabegron increased HDL cholesterol, insulin sensitivity, and total plasma BA. The largest increases were with the primary unconjugated cholic and chenodeoxycholic acids. We hypothesized that chronic adrenergic stimulation increased BA synthesis enzymes in adipose tissue, thus increasing flux through these pathways. We therefore measured expression levels of BA synthesis enzymes from patients undergoing elective surgery in the following tissues: subcutaneous WAT (scWAT), and from pheochromocytoma (pheo) patients who have chronic adrenergic activation, scWAT (PhW) and peri-renal BAT (PhB). These were compared to cadaveric liver. Liver had higher expression levels of BAAT, which conjugates BA. However, expression levels among liver, scWAT, PhW, and PhB were similar for the enzymes initiating BA synthesis (CYP7A1) and other intermediate enzymes (CYP7B1, AKR1D1, AMCAR). Furthermore, pheo patients had higher levels of CYP27A1, which initiates the acidic/alternative BA synthesis pathway. These data suggest that regulation of plasma BA is not exclusive to the liver. Rather, human BAT and WAT likely contribute to the BA pool, and chronic adrenergic activation may shift the equilibrium toward primary unconjugated species to improve glucose and lipoprotein metabolism.

Disclosure

K.Y. Zhu: None. H.J. Lea: None. C. Cero: None. A.M. Cypess: None.
242-OR: Rare Genetic Variants in the Islet Regulome Contribute to the Heritability of Type 2 Diabetes Risk
Authors: MANNING ALISA ,   TOPMED DIABETES WORKING GROUP
Published: June 2020

Genome-wide association studies of type 2 diabetes (T2D) show common variant heritability is enriched within gene regulatory regions of pancreatic islets. Whole genome sequence (WGS) data in cohorts allows us to determine the contribution of the complete spectrum of genetic variation to the heritability of T2D risk, including rare alleles that have recently arisen in the human population. A variant-based heritability analysis can partition disease risk into environmental and genetic components, and the genetic components can be further decomposed by variant frequency (a proxy of variant age) and pancreatic islets regulatory annotation (a proxy of functional relevance to T2D risk). We hypothesized that rare, non-protein coding variants would have a significant contribution to the heritability of T2D risk and that further restricting to gene regulatory regions active in pancreatic islets would also produce significant heritability estimates. We conducted a WGS heritability analysis (GREML method in GCTA software) of T2D risk in 15109 unrelated individuals (2215 with T2D; 12894 controls) of European ancestry from the NHLBI’s TOPMed study. We partitioned variants with allele count > 5 by minor allele frequency (MAF): rare variants [MAF<0.1%], and annotation: all non-coding variants, and non-coding variants in pancreatic islets regulatory regions. We further partitioned variants by linkage disequilibrium properties to reduce estimate bias. One of the rare, "all non-coding" variants sets showed a relatively large liability-scale heritability estimate (h2=0.6, P< 0.001). Further significant estimates in rare variants were from active transcription start sites (h2=0.1, P<0.01); active promoters (three variant sets with h2=0.07, 0.08 and 0.1, P<0.05, after body mass index adjustment) and active enhancers from promotor capture Hi-C models (h2=0.07, P<0.05). These findings show a role for rare, non-coding variants in the genetic architecture of type 2 diabetes.

Disclosure

A. Manning: None.

Funding

National Institutes of Health (K01DK107836)
249-OR: A Randomized, Double-Blind Phase 2 Trial of the CXCR1/2 Inhibitor Ladarixin in Adult Patients with New-Onset Type 1 Diabetes
Authors: BOSI EMANUELE , POZZILLI PAOLO , GIORGINO FRANCESCO , COSSU EFISIO , LINN THOMAS , ROSE LUDGER , KEYMEULEN BART , GILLARD PIETER , DAFFONCHIO LUISA , RUFFINI PIER A. , ALLEGRETTI MARCELLO , PIEMONTI LORENZO
Published: June 2020

In preclinical studies, the investigational CXCR1/2 inhibitor ladarixin was shown to prevent and reverse diabetes in NOD mice. On this basis, a multicenter clinical trial in adult patients with new onset type 1 diabetes (T1D) was conducted (NCT02814838).

Patients (Table 1) were randomized 2:1 to ladarixin (LDX) 400 mg BID or placebo (PLA) and randomized within 100 days from first insulin administration.

Patients received 3 treatment cycles, each consisting of 14 days on and 14 days off drug, and were then followed up for 12 months. The difference between LDX and PLA in mixed meal tolerance test (MMTT) AUC of C peptide was statistically significant neither at week 13 (primary endpoint, p=0.330) nor at week 26 (p=0.404). Conversely, at week 26 patients having HbA1c<7% and daily insulin requirements <0.50 IU/kg were 76.6% and 45.8% in LDX and PLA, respectively (p=0.0095).

In patients with baseline fasting C-peptide below the median value of trial population (prespecified subgroup analysis), the difference between LDX and PLA in MMTT AUC of C peptide trended at week 13 (p=0.111) and reached statistical significance at week 26 (p=0.041).

Adverse Reactions occurring in ≥10% of patients included dyspepsia (16% LDX vs. 0% PLA) and headache (16% LDX vs. 15.4% PLA).

Although primary endpoint was not met, secondary and subgroup analyses suggest further investigation of LDX in new onset T1D may be warranted.

Disclosure

E. Bosi: Consultant; Self; Abbott, Eli Lilly and Company, Medtronic, Novartis AG, Roche Diabetes Care, Sanofi. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd. E. Cossu: None. T. Linn: Advisory Panel; Self; Dompe Pharmaceuticals. L. Rose: None. B. Keymeulen: None. P. Gillard: None. L. Daffonchio: Employee; Self; Domp farmaceutici S.p.A. P.A. Ruffini: Employee; Self; Domp farmaceutici S.p.A., Domp farmaceutici S.p.A. M. Allegretti: Employee; Self; Domp Farmaceutici spa. L. Piemonti: Advisory Panel; Self; AstraZeneca, Roche Diabetes Care, Semma Therapeutics, Inc.
250-OR: Hypoproliferative CD8 Effector Memory (EM) Subsets Are Linked to Preservation of C-Peptide in Alefacept-Treated Recent-Onset Type 1 Diabetes (T1D) Subjects
Authors: SERTI ELISAVET , DIGGINS KIRSTEN E. , MUIR VIRGINIA S. , LU TINGTING , BALMAS ELISA , NEPOM GERALD T. , LONG S. ALICE , LINSLEY PETER
Published: June 2020

In the ITN T1DAL trial, alefacept (LFA3-Ig fusion protein) preserved endogenous insulin production in 30% of recent onset T1D patients for two years after therapy. Although patients experienced immune alterations following treatment, including depletion of CD2hi effector T-cells and preservation of CD2lo regulatory T-cells, these effects were not predictive of overall response or outcome. However, using an unbiased approach and a combination of flow cytometry, RNA-sequencing, and CyTOF, we were able to identify a CD8 T-cell signature of response at ∼two years following treatment. Preservation of C-peptide was associated with a large transcriptional module (n= 738 genes; R= 0.4, p= 0.023) including activation and exhaustion-associated genes identified at two years following treatment using WGCNA. This module was further dissected into two distinct CD8 EM populations through correlation with hierarchically gated and clustered cytometry data. While both populations expressed multiple inhibitory receptors (IR) (TIGIT, KLRG1, T-bet, EOMES) and were hypo-responsive in in vitro proliferation assays, they were distinguished by higher expression either of markers seen in cytotoxic and terminally differentiated effector T cells (CD57+ Granzyme B+) or of PD-1. Gene expression signatures of both the CD57 and PD-1 subsets significantly overlapped with a previously identified partial exhaustion signature (p= 0.005, for both subsets). Our findings demonstrate an association of partially exhausted memory CD8 T-cells with beneficial clinical response to alefacept as we observed previously with teplizumab (anti-CD3) treatment. Our findings also demonstrate linkage of two phenotypically distinct IR-high, hypo-proliferative CD8 EM T-cell subsets with beneficial response. Together, our findings suggest that pathways regulating proliferation of EM CD8 cells may lead to successful immune interventions for T1D.

Disclosure

E. Serti: None. K.E. Diggins: None. V.S. Muir: None. T. Lu: None. E. Balmas: None. G.T. Nepom: None. S. Long: None. P. Linsley: Consultant; Self; Bristol-Myers Squibb.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases/National Institute of Allergy and Infectious Diseases (UM1AI109565)
252-LB: Insulin Secretion Pathway Genes Correlate with Markers Associated with Viral Infections in Human Islets
Authors: NELSON GRACE , LENCHIK NATALIYA I. , RODRIGUEZ-CALVO TERESA , BALCACEAN DIANA , GERLING IVAN C. ,   NPOD-V
Published: June 2020

Type 1 diabetes (T1D) is an autoimmune disease hypothesized, to be enhanced or triggered by viral infections. In this study we used organ donor pancreas to isolate islets that expressed known signs of viral infections, and subsequently investigated pathways that may be secondarily affected through analysis of gene expression profiles. Using samples provided by the Network for Pancreatic Organ Donors with Diabetes, (nPOD), islets were collected, by laser-capture, from nondiabetic donors (Control), autoantibody positive nondiabetic donors (AB+) and donors with T1D (T1D). Islets were categorized based on the presence of markers associated with viral infection (VIMs), HLA, Mx1, dsRNA, and PKR, identified via immunohistochemical staining. From each donor islets were pooled based on the number of VIMs (0 VIMs, 1 VIMs or ≥2VIMs). RNA was extracted, and microarray used to assess transcriptomes. GeneSpring software was used to generate a list of genes with differential expression between donors/VIMs. Using WebGestalt we identified pathways enriched by this list. A total of 383 genes with a fold change of ≥1.1 and p-value=0.001 had differential expression between islets with 0 VIMs and ≥1 VIMs. Pathway analysis showed strongest enrichment for genes in the insulin secretion pathway (p< 5.7E-5). As an example; CACNA1C and ABCC8 (important for the secretion of insulin), had lower expression in the islets with ≥1VIMs compared to 0 VIMs (p<0.03). CACNA1C also had lower expression in islets with 0 VIM vs. ≥1VIMs when only comparing samples from control donors (p=0.02). Islets selected for high expression for genes associated with viral infection had decreased expression of genes important for insulin secretion. This may suggest a pattern of dedifferentiation and/or functional impairment of beta cells in the setting of viral infection.

Disclosure

G. Nelson: None. N.I. Lenchik: None. T. Rodriguez-Calvo: None. D. Balcacean: None. I.C. Gerling: None.

Funding

JDRF; National Institute of Diabetes and Digestive and Kidney Diseases; Lebonheur Children’s Hospital
253-LB: A Novel Membrane Binding Domain in Conjunction with Golga5 Recruits the Secretory Granule Biogenesis Factor HID-1 to the Golgi
Authors: ASENSIO CEDRIC S.
Published: June 2020

Secretory granules (SGs) mediate the regulated release of neuropeptides and peptide hormones. HID-1 is a TGN localized peripheral membrane protein contributing to SG formation. Mice lacking HID-1 specifically in pancreatic β-cells are glucose intolerant and display impaired insulin secretion. However, there is no information about the structure or domain architecture of HID-1, and thus it remains unknown how HID-1 binds to the TGN and performs its function. We report that the N-terminus of HID-1 mediates membrane binding through a myristoyl group with a polybasic amino acid patch but lacks specificity for the TGN. Delineation of the minimal domain responsible for HID-1 targeting to the TGN reveals an interaction with the Golgi-localized protein Golga5. Finally, we identify the C-terminus as a novel membrane binding region and the functional domain of HID-1. This isolated domain, when tethered to the TGN, is also capable of rescuing the secretion and sorting defects observed in HID-1 KO cells. Finally, a point mutation within that domain, identified in patients with endocrine and neurological deficits, is not functional. We propose that HID-1 N-terminal and C-terminal domains, in cooperation with Golga5, ensure specific binding to Golgi membranes and functionality of HID-1.

Disclosure

C.S. Asensio: None.

Funding

American Diabetes Association (1-17-JDF-064); National Institutes of Health (GM124035, GM116096)