bluuebunny/crossref_metadata_2025 huggingface dataset:
1043-P: Diabetic Cardiomyopathy: A Systematic Analysis of Epidemiological Studies
Authors: PERFETTI RICCARDO , SHENDELMAN SHOSHANA
Published: June 2021

Diabetic cardiomyopathy (DbCM) is a sequela of diabetes. DbCM is characterized by abnormal cardiac structure and/or performance in the absence of coronary artery disease or hypertensive, valvular or congenital heart disease. We aimed to determine the prevalence of DbCM in the United States and EU5. PubMed was queried for epidemiological studies on DbCM from 2010 onwards using the terms (“diabetes” AND “cardiomyopathy”) OR (“diabetic cardiomyopathy”) AND (“incidence” OR “prevalence”). 563 articles were identified, 40 of which were screened for full text review based on the abstract indicating the reporting of original data captured in a general diabetic population. Ten of these were used either directly or to inform our analysis. Four of these studies reported data on DbCM having made appropriate exclusions for atherosclerosis mediated heart failure. However, only 2 of these were ultimately included based on the representativeness of the study population and thus generalisability of results. Many studies were excluded due to heterogeneity in definition of DbCM. Some studies clearly stated DbCM as the indication of interest, taking appropriate measures to exclude cases with a history of atherosclerosis mediated precursors such as coronary artery disease, hypertension, or valvular heart disease. Other studies were not clear in the exclusion criteria and for this reason were excluded. Based on our review, estimates in the literature for DbCM in type 2 diabetes without stringent clinical diagnostic criteria range from 12% to 48%. Of the two studies included in our analysis which clinically define DbCM according to diagnostic guidelines, estimates ranged from 17% to 24%. Our final estimate based on an average of these two was 21%, with some imputations for variation by age. There are ~30 million diabetics in the United States alone and we estimate 21% of diagnosed diabetics also have DbCM, which represents a huge burden of disease for which there is very limited robust epidemiological data.

Disclosure

R. Perfetti: Stock/Shareholder; Self; Applied Therapeutics. S. Shendelman: Stock/Shareholder; Self; Applied Therapeutics.
1050-P: Rates, Characteristics, and Comparison of Readmissions for Diabetic Ketoacidosis in Patients with Psoriasis in the United States: A National Population-Based Study
Authors: EDIGIN EHIZOGIE , OJEMOLON PIUS E. , SHAKA HAFEEZ , ESEATON PRECIOUS O. , ALMANI MUHAMMAD USMAN , JAKHAR DEEPAK , ASEMOTA IRIAGBONSE R. , AKUNA EMMANUEL
Published: June 2021

Introduction: Psoriasis is known to increase the risk of type 1 diabetes mellites. This study aims to compare rates and outcomes of 30-day readmissions following admissions for type 1 diabetic ketoacidosis (T1DKA) in patients with and without psoriasis in the United States.

Methods: We analyzed the 2018 National Readmission Database. We included index hospitalizations for all patients (aged≥18 years) with a principal diagnosis of T1DKA using ICD-10 codes. We further sub-stratified this group into those with and with a secondary diagnosis of psoriasis. Chi-square tests and regression analysis were used to compare 30-day readmission rates and readmission outcomes between both groups. We excluded elective and traumatic readmissions.

Results: A total of 94,461 index hospitalizations for T1DKA, that were discharged alive, were included in the analysis. 357 (0.4%) of these, had co-existing psoriasis. 15,614 (16.5%) readmissions occurred within 30 days. Readmission rates were similar between psoriasis and non-psoriasis group (15.0% vs. 16.5%, p=0.663). The psoriasis group had a similar mean hospital length of stay (3.3 days vs. 2.9 days, p=0.077) and total hospital costs ($8,435 vs. $7,231, p=0.055) compared to the non-psoriasis group. Readmissions for T1DKA in psoriasis patients was associated with a total of 1,191 hospital days and $3,014,844 in-hospital costs. T1DKA without coma was the most common reason for readmission in both groups.

Conclusion: Psoriasis patients admitted for T1DM have similar 30-day readmission rates and readmission outcomes compared to non-psoriasis patients admitted for TIDM.

Disclosure

E. Edigin: None. P. E. Ojemolon: None. H. Shaka: None. P. O. Eseaton: None. M. Almani: None. D. Jakhar: None. I. R. Asemota: None. E. Akuna: None.
1056-P: High Prevalence of Fatty Liver Disease in Individuals with Diabetes and Subclinical Manifestations of Liver Disease
Authors: CLAYPOOL KAJAL , PATEL CHIRAG
Published: June 2021

The prevalence and markers of liver complications in the T2D population with poor glycemic control remains uncertain.

Using participant data from the National Health and Nutrition Examination Survey (NHANES), we examined the association of poor glycemic control with NAFLD using controlled attenuation parameter (CAP) obtained via FibroScan. We next examined 121 markers indicative of liver dysfunction associated with poor glycemic control (A1C > 7%). We tested the association of each marker with A1C > 7%, and used false discovery rate criteria to identify liver markers that are strongly associated with poor glycemic control. We determined the dose-response between clinical biomarkers as a function of different severity levels of poor glycemic control.

The survey-adjusted prevalence of self-reported liver disease in the diabetic population is 7.4% (95% CI: 6.4, 8.4) and it is 3.2% (95% CI: 2.8, 3.4) in the nondiabetes group. The prevalence of NAFLD in the diabetes population, in contrast, is 69.4%, 95% CI: [62.6%, 76.1%] with prevalence in the group with glycemic control at 60.3% (95% CI: 50.7, 70) and those with poor glycemic control at 82.7% (95% CI: 76.2, 89.3). In multivariate models (adjusted for sex, age, ethnicity, body mass index, the use of 0, 1, 2 or more antihyperglycemic medications and smoking), poor glycemic control (A1C above 7%) was associated with increased odds of NAFLD (OR = 3.28, 95% CI: 1.72 - 6.27, p = 0.02). We identified poor glycemic control (A1C above 7%) was associated with 13 markers of liver disease and identified a linear increase in dose-response for these markers with increased severity of poor glycemic control.

Poor glycemic control is associated with high prevalence of NAFLD in the United States. Liver dysfunction with poor glycemic control is comparable to cardiovascular and kidney dysfunction, highlighting the need for greater vigilance of liver disease in T2D patients especially in those with poor glycemic control.

Disclosure

K. Claypool: None. C. Patel: Consultant; Self; Doc. ai, Janssen Research & Development, LLC, Stock/Shareholder; Self; Xy Health, Inc.

Funding

National Institute of Allergy and Infectious Diseases (R01AI127250)
1061-P: Use of Nutrition and Behavioral Therapy for Obesity among Medicare Beneficiaries with Incident Diabetes, 2002-2016
Authors: ANDES LINDA J. , SIEGEL KAREN R. , WILLIAMS ALEXIS , IMPERATORE GIUSEPPINA , ROLKA DEBORAH B.
Published: June 2021

Nutrition and weight loss/maintenance are important for managing blood glucose and preventing complications among individuals with diabetes (DM), and counseling for these behaviors can be particularly effective in those with newly diagnosed DM. To encourage their use in older adults - who may lack other support and thus rely on health care provider counseling- Medicare covers three types of counseling: 1. Medical nutrition therapy (MNT); 2. DM self-management training (DSMT); and 3. Intensive behavioral therapy for obesity (IBTO). We used Medicare claims data to estimate use of these three types of counseling among beneficiaries with incident DM. We included individuals with at least a) 1 inpatient claim with a DM diagnosis code in the index year or preceding 2 years, or b) 1 outpatient DM claim and 1 inpatient or outpatient claim in the 2 years following the first claim. An incident case must have an initial two year “clean period” with zero DM diagnosis codes. Therefore, participants must be at least 67 years of age to be included in the study. Use of counseling was defined as having any claims with the appropriate procedure codes in the 365 days after the first claim date with a DM diagnosis code. Among 8.6 million beneficiaries with incident DM, MNT use increased from 1.2% in 2002 to 2.8% in 2006 and then decreased to 2.4% in 2016. In contrast, DSMT use decreased from a high of 5.9% in 2002 to 3.1% in 2016. IBTO coverage began in 2011 and by 2016, IBTO use increased to 0.8%. MNT, DSMT and IBTO are under-utilized among Medicare beneficiaries with incident DM, and there is much room for improvement. Increasing health care provider and patient awareness of these Medicare benefits may help to increase the likelihood of referrals to such counseling and subsequently its use.

Disclosure

L. J. Andes: None. K. R. Siegel: None. A. Williams: None. G. Imperatore: None. D. B. Rolka: None.
1105-P: Effects of Exercise on Glycemic Control and Insulin Resistance (IR) in Individuals with Type 1 (T1D) and Type 2 Diabetes (T2D) in the NHANES Dataset
Authors: SONI PRIYA Y. , TANG QING , ISMAIL HEBA M.
Published: June 2021

Introduction: The rise in T1D, T2D, and obesity make it increasingly important to understand the role of BMI and lifestyle on glycemic control and IR. While it is known that weight and exercise affect these, the extent to which the effects of exercise are direct versus mediated by BMI has not been determined.

Methods: We analyzed data from the 2013-2016 NHANES dataset in participants >18 yrs of age (n=1168). Those on glucose-lowering medications were classified as T2D and those on insulin only as T1D. Participant reports on physical activity intensity and duration were converted to metabolic equivalent of task (MET)-hours/week. HOMA-IR, a measure of IR, was calculated in participants with insulin measurements not receiving insulin (n=335). Linear regression models were fitted for mediation analyses to evaluate whether BMI mediated associations between MET and HbA1c or HOMA-IR.

Results: In participants with T1D (n=173) and T2D (n=995), the mean ± SE age (56.8 ± 0.8 and 61.1 ± 0.3 yrs), BMI (32.8 ± 0.8 and 33.1 ± 0.3), and MET-hours/week (38.8 ± 4.5 and 38.3 ± 3.8) were reported, respectively. Further, 48.7% and 46.3% were females and 51.3% and 53.7% were males, respectively. The majority (62.9%) were Non-Hispanic White. HbA1c was significantly different between participants with T1D (8.1 ± 0.2) and T2D (7.4 ± 0.1), p=0.0008. After adjusting for age, race, and sex, the independent effect of MET-hours/week on HbA1c was nonsignificant in both cohorts (p=0.384 and p=0.167, respectively), suggesting BMI mediation analysis was not appropriate. The same was true with the effect of MET-hours/week on HOMA-IR (p=0.265).

Conclusions: Our results show that there were no BMI mediated associations between MET and HbA1c or HOMA-IR. However, participants with high HbA1c could be actively engaging in more physical activity to improve glycemic control and there is potential for recall bias. A future prospective study with larger sample sizes may be needed.

Disclosure

P. Y. Soni: None. Q. Tang: None. H. M. Ismail: None.
1122-P: Comparing the Relative Frequency of Pediatric New-Onset Type 1 Diabetes since the Onset of COVID in the United States
Authors: ROWLAND DUSTIN , LEE NICOLE D.O. , ERGUN-LONGMIRE BERRIN
Published: June 2021

Background: There has been a well-documented link showing that pre-existing diabetes worsens outcomes in Covid-19 infection in adults. However, researchers have postulated that this relationship is reciprocal, where infection with Covid-19 may trigger new onset diabetes. Data on pediatric new onset type 1 diabetes mellitus (T1DM) and Covid-19 remains scarce. Furthermore, the results are conflicting; some studies showed increased rate of new onset T1DM in children with Covid-19 and the others did not find any difference in 2020 compared to previous years. The aim of this study is to elucidate the relationship between pediatric new onset T1DM and diabetic ketoacidosis (DKA) with Covid-19 infection in a single center.

Methods: We conducted a retrospective chart review of 50 pediatric diabetes cases admitted to the Bronson Children’s Hospital between March 2020 and December 2020.

Results: From the total of 50 patients, 42 had new onset T1DM. Of these 42, 33 (78.6%) presented with DKA, and 17 (40.5%) met hospital criteria for Covid-19 testing, with 16 of those producing a negative result. There was only 1 (5.9% of tested, 2.4% of T1DM cases) patient with new onset T1DM associated with a positive Covid-19 test.

Conclusion: The low number of positive cases identified in this study suggests that there may be no link between Covid-19 viral illness and new onset T1DM in the pediatric population. Major limitations include the single center localization of the study and inability to test all cases for Covid-19 at this facility. Due to the scarcity of test kits and lab personnel especially early during the pandemic, only patients that met symptomatic criteria were tested. It is possible and likely that some of the patients were infected with Covid-19 but remained asymptomatic.

Disclosure

D. Rowland: None. N. D. O. Lee: None. B. Ergun-longmire: None.
113-LB: The Role of “Osmotoxicity” in Type 2 Diabetes Mellitus: A Retrospective Comparative Analysis of the Effect of Pretreatment with IV 0.9% Saline on Glycemic Control in Subcritical Hyperglycemia
Authors: SURESHKUMAR PICHAKACHERI
Published: June 2021

Background: Experimental studies have shown that an increase in serum osmolality (Osm) of even 10 mOsm/kg significantly contributes to progressive hyperglycemia by increasing hepatic glucose output and suppressing peripheral glucose utilization. The Osm increases parallel to the increase in blood glucose (BG) and vice versa. This is not therapeutically exploited yet.

Aim: To assess the effect of pre-treatment with IV 0.9% saline (NS) on glycemic control and medication requirement in type 2 diabetes mellitus (T2DM) patients presenting with subcritical hyperglycemia (SCH) -hyperglycemia not amounting to DKA or HHS.

Method: A retrospective comparative data analysis of T2DM patients (198) with SCH, pre-treated with NS before diabetic specific therapy (group 1) and compared with those who were not pre-treated with NS (group 2). Differences in glycemic control and drug dosage were assessed.

Results: In group 1, 1500ml of NS administration reduced the BG from a baseline of 496.3±67.1 to 283.3±83.8 (mg/dL), p=0.000 with a mean reduction of 43% and reduced the Osm by 11mOsm/kg [313.8±8.1 to 302.9±8.5, p<0.001]. There was a significant correlation between BG and Osm (r=0.322, p=0.001). Fluid pre-treatment enabled a better reduction in BG during 4 weeks of follow up in group 1{[FBS- 298.9±73.7 to 158.9±58.7 in group 1 v/s 265.6±70.7 to 171.48±66.5 in group 2, p=0.00] and [RBS- 496.3±67.1 to 228.3±80.7 in group 1 v/s 450.5±47 to 282±112.4 in group 2, p=0.001]}. There was a general trend of decrease in the dosages of antidiabetic medications in group 1 and increase of the same in group 2.

Conclusions: IV fluid pre-treatment reduced the BG and the drug dosage in T2DM patients presenting with SCH and the benefit persisted for a minimum of 4 weeks.

Disclosure

P. Sureshkumar: None.
1139-P: CD36/FABP4/PPAR-d Axis-Induced Inflammation Is Dependent on ACSL1 under the Influence of Acute High-Fat Feeding
Authors: ALRASHED FATEMA , MADHOUN ASHRAF AL , SINDHU SARDAR T. , AL-SAYYAR AMNAH , ALMULLA FAHD , AHMAD RASHEED
Published: June 2021

Elevated levels of circulating inflammatory macrophages are associated with several metabolic syndrome (MetS) such as obesity and type II diabetes (T2D). The ingestion of high-fat meals was proven by several groups to act as a stimulus for systemic inflammatory responses via activation of peroxisome proliferator-activated receptors (PPARs). However, little is known about the lipid metabolism involved in macrophage-mediated inflammation under the influence of acute high fat feeding (AHFF). ACSL1 is a member of the long chain acyl-CoA synthetase (ACSL) family that plays key roles in fatty acid metabolism in various tissues. Our previous studies showed that attenuation of ACSL1 was sufficient to dampen inflammatory responses in macrophages challenged with TNF-α or LPS. In this study, we investigated the molecular mechanisms underlying AHFF-induced ACSL1 gene transcription in macrophages. In our work, we showed that four hours feeding of palmitic acid induced significant up-regulation of ACSL1 at both gene and protein levels. Both the inhibition and the deficiency of ACSL1, showed a significant impact on downregulating AHFF-induced inflammatory responses. Furthermore, the inhibition ACSL1 reduced mRNA levels of fatty acid uptake-related genes cluster of differentiation 36 (CD36) and fatty acid transport protein 4 (FATP4). However, inhibition of ACSL1 had no impact on lipogenesis related genes; SREBS, FAS and ACACA or fatty acid-oxidation genes; CPT-1a, CPT-1b and CPT2. Our data also showed that ACSL1 inhibition reduced PPARδ gene expression, while PPARα and PPARγ were not affected. Of note, macrophage intracellular lipid accumulation was attenuated during ACSL inhibition. Our findings suggest that targeting ACSL1 has a therapeutic potential to prevent AHFF-induced macrophage inflammation.

Disclosure

F. Alrashed: None. A. Al madhoun: None. S. T. Sindhu: None. A. Al-sayyar: None. F. Almulla: None. R. Ahmad: None.

Funding

Kuwait Foundation for the Advancement of Sciences (CB-2020-004)
1141-P: Short-Chain Fatty Acid Acetate Increases TNF-a-Induced MCP-1 Production in Monocytes via the ACSL-1/MAPK/NF-?B Axis: Significance for Inflammation and Insulin Resistance
Authors: AHMAD RASHEED , ALROUB AREEJ ABU , ALRASHED FATEMA , AL-SAYYAR AMNAH , AKHTER NADEEM , KOCHUMON SHIHAB P. , ALMULLA FAHD , SINDHU SARDAR T.
Published: June 2021

Short-chain fatty acids (SCFAs) are formed as by-products of dietary fiber metabolism by gut bacteria and have multiple immunomodulatory functions in different cells involved in the inflammatory and immune responses. In general, the anti-inflammatory role of SCFAs is well documented. Here, we investigated whether SCFAs could modulate the TNF-α-mediated induction of chemokine MCP-1 (also known as CCL2) in monocytes/macrophages; and if so, which mechanisms were involved. Monocytic cells were exposed to SCFAs including acetate, propionate, and butyrate, with or without TNF-α, and the release of MCP-1 was measured. We found that none of the SCFAs suppressed TNF-α-induced MCP-1 release in monocytes. However, challenge with acetate in combination with TNF-α resulted in substantially greater MCP-1 release from monocytic cells than challenge with TNF-α alone, indicating synergistic effects. Interestingly, such effects of acetate were not seen in macrophages. Synergistic upregulation of MCP-1 was mediated through the activation of acyl-CoA synthetase 1 (ACSL1). Acetate/TNFα induced phosphorylation of p38, ERK1/2, and NF-κB was observed during the secretion of MCP-1. Acetate/TNF-α mediated synergistic expression of MCP-1 was significantly reduced by the inhibition of p38 MAPK, ERK1/2 and NF-κB signaling pathways. Furthermore, inhibition of the ACSL1 activity also attenuates the TNF-α-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB. ACSL1 inhibition led to a lower induction of NF-κB/AP-1 activity in response to co-stimulation with acetate and TNF-α.

In conclusion, these data support the proinflammatory, rather than anti-inflammatory, effects of acetate on TNF-α-mediated MCP-1 expression in monocytes involving the ACSL1/MAPK/NF-kB axis. These findings point to the differential effects of SCFA acetate in the settings of obesity and metabolic inflammation/insulin resistance.

Disclosure

R. Ahmad: None. A. Abu alroub: None. F. Alrashed: None. A. Al-sayyar: None. N. Akhter: None. S. P. Kochumon: None. F. Almulla: None. S. T. Sindhu: None.
1149-P: A Comparison between One Month vs. Two Months on a High-Fat Diet on the Impact on Glucose Metabolism in Male and Female Liver Androgen Receptor Knockout Mice
Authors: OSEI-NTANSAH ADJOA , OLIVER TRINITEE R. , FALZARANO CLAIRE , LOFTON TAYLOR , ANDRISSE STANLEY
Published: June 2021

Previous research has indicated that a lipid-independent pathogenic mechanism plays a role in androgen-induced hepatic insulin resistance where liver androgen receptors may play a role in modulating disease. Consequently, this study aims to investigate the pathophysiology of high fat diet (HFD) induced dysglycemia and hepatic insulin resistance in male and female liver androgen receptor knockout (LivARKO) mice. We performed insulin tolerance tests (ITT), glucose tolerance tests (GTT), and pyruvate tolerance tests (PTT) on LivARKO male and female mice fed a high fat diet (HFD) or a control diet (CD) (from Research Diets Inc) during months 1 or 2 after starting the diet. Two-months on the CD showed significantly enhanced glucose tolerance (EGT) compared to 1-month on CD in both male and female LivARKO mice. This EGT phenotype was the same and equally as significant in males vs. females. Two-months on CD showed impaired insulin sensitivity (IIS) compared to 1-month on CD in male and female LivARKO mice. This IIS was significantly greater in female mice. Two-months on the CD displayed enhanced pyruvate tolerance compared to 1-month on the CD in male and female LivARKO mice. Two-months compared to 1-month on HFD displayed no significant difference in glucose tolerance in male and female LivARKO mice. Two-months on HFD showed impaired insulin sensitivity compared to 1-month in female but not male LivARKO mice. Pyruvate tolerance was not changed from 1- to 2-months on HFD in male or female LivARKO mice. In the CD mice, we see EGT but IIS. This suggests that insulin action is decreased. The enhanced pyruvate tolerance in CD mice suggests that the control diet lowers gluconeogenesis. Why the control diet is altering glucose metabolism from 1-2 months is still a question to be investigated.

In conclusion, we show that 1- vs. 2-months on HFD showed no change in glucose metabolism in male and a slight change in female LivARKO mice.

Disclosure

A. Osei-ntansah: None. T. R. Oliver: None. C. Falzarano: None. T. Lofton: None. S. Andrisse: None.

Funding

National Science Foundation (HRD-1931045); Robert Wood Johnson Foundation
116-OR: Lipocalin-Type Prostaglandin D2 Synthase Depletion Induces Adipose Tissue Dysfunction in Response to High-Fat Diet
Authors: SRIVASTAVA ANKITA , PALAIA THOMAS , HALL CHRIS , LEE JENNY , STEVENSON MATTHEW , RAGOLIA LOUIS
Published: June 2021

Adipose tissue dysfunction is the primary defect in obesity which contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease and some cancers. Previous study from our lab implicated the role of lipocalin-type prostaglandin D2 synthase (L-PGDS) in glucose intolerance and atherosclerosis. Our lab also showed the development of NAFLD in L-PGDS knockout mice on both low fat and high fat diet. In the present study, we examined the role of L-PGDS in adipose tissue in response to high fat diet. We found decreased expression of L-PGDS in visceral and subcutaneous white adipose tissue (WAT) of C57BL/6 mice after 12 weeks on high fat diet (HFD). Our study showed increased fat content in L-PGDS KO mice as compared to control C57BL/6 mice after 14 weeks on HFD. Histological analysis showed hypertrophied adipocytes in visceral WAT of L-PGDS KO mice as compared to control mice. Furthermore, we found increased expression of the lipogenesis genes LXRα, SREBP-1c and FAS in visceral WAT of L-PGDS KO mice after 14 weeks on HFD. L-PGDS KO mice showed reduced gene expression of adiponectin and PPARγ in visceral WAT on HFD. The plasma adiponectin level was also decreased in L-PGDS KO mice. We conclude that absence of L-PGDS has a deleterious effect on adipose tissue functioning which further reduces insulin sensitivity in adipose tissue. Thus, our study suggests L-PGDS as a novel therapeutic target for the treatment of obesity-associated metabolic syndrome.

Disclosure

A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.

Funding

American Heart Association (15GRNT22420001); George Link, Jr. Foundation Inc. (3500-7294)
1161-P: NOD1-JNK1 Axis Plays a Causal Role in Palmitate-Induced ß-Cell Dysfunction
Authors: YUNG JUSTIN HOU MING , IVOVIC ALEKSANDAR , CLARK ISABEL , LI FIONA , LIN BRIAN , TAN YAO , GIACCA ADRIA
Published: June 2021

Chronic elevation of free fatty acids (FFA) in obesity may cause ß-cell dysfunction leading to type 2 diabetes (T2D). Recent studies have focused on innate immunity receptors due to evidence implicating inflammation in obesity-induced T2D. While several of these receptors have been implicated in FFA-induced ß-cell dysfunction, the nucleotide-binding oligomerization domain (NOD) receptors have not been investigated. Our previous work showed that whole-body NOD1-null mice were protected from palmitate-induced ß-cell dysfunction in vivo. This may be due to lack of NOD1 in ß-cells and/or macrophages infiltrating islets. Also, islets of whole-body NOD1-null and JNK1-null mice were protected from ß-cell dysfunction induced by palmitate but not oleate in vitro, suggesting NOD1 activation is likely in ß-cells, is specific to saturated FFA and may cause ß-cell dysfunction via JNK1. Thus, we hypothesized that ß-cell NOD1 mediates palmitate-induced ß-cell dysfunction in vivo, and that JNK1 is downstream of NOD1 activation. Addition of an ethyl group on palmitate reduces toxicity of unbound palmitate, thus ethylpalmitate (EtPAL) was used. Ethyl esterases in mouse plasma hydrolyze EtPAL into palmitate and ethanol. ß-cell specific NOD1-null (ßKO) mice (using Ins1- and RIP-Cre) and their controls were infused with EtPAL or ethanol vehicle (Veh) for 48 hours, followed by a hyperglycemic clamp to evaluate ß-cell function in vivo from the disposition index (DI). Islets of JNK1-null and wildtype (WT) mice were isolated and treated with a NOD1 activator to investigate the NOD1-JNK1 axis. As expected, EtPAL infusion elevated plasma FFA. EtPAL decreased DI in control mice, while EtPAL-infused ßKO mice had similar DI to Veh-infused mice. Further, the NOD1 activator reduced insulin secretion in WT islets but not in JNK1-null islets. These data implicate ß-cell NOD1-JNK1 axis in palmitate-induced ß-cell dysfunction and reveal a novel pathway that could be targeted for manipulation in order to preserve ß-cell function.

Disclosure

J. Yung: None. A. Ivovic: None. I. Clark: None. F. Li: None. B. Lin: None. Y. Tan: None. A. Giacca: None.

Funding

Canadian Institutes of Health Research (CIHR50748)
1162-P: Proinsulin as a Biomarker for Beta-Cell Function in a Diverse Cohort
Authors: COUCH CATHARINE , GOWER BARBARA , PICCININI FRANCESCA
Published: June 2021

Declining beta-cell function is a key component in the development of type 2 diabetes (T2D). Early in disease progression, first-phase insulin secretion deteriorates, precipitating impaired glucose tolerance. Markers for early beta-cell decline could assist in identifying individuals at risk for disease progression, particularly among demographic groups at elevated risk for T2D. This study was designed to test the hypothesis that proinsulin concentrations would be inversely associated with first-phase beta-cell function, as reflected in the Disposition Index (DI), in a diverse cohort of young individuals without T2D. Participants were 117 men and women of African-American and European-American descent aged 19-45 years with normal glucose tolerance. An oral-glucose tolerance test (OGTT) was used to measure proinsulin concentrations and assess beta-cell function. Mathematical modeling was used to estimate insulin sensitivity (Si) and indices of beta-cell function specific to basal, first-phase, second-phase, and total insulin secretion (PhiB, PhiD, PhiS, PhiTot, respectively). First-phase DI (DId) was calculated as Si x PhiD and second-phase DI (DIs) as Si x PhiS. Proinsulin concentrations were normalized for C-peptide. Fasting and 2-h proinsulin concentrations were inversely associated with DId (r=-0.21, p=0.02 and r=-0.22, p=0.01, respectively). Neither fasting nor 2-h proinsulin concentrations were significantly associated with DIs. African-Americans, who as a group have an elevated prevalence of T2D, had 25% higher concentrations of fasting proinsulin and 18% higher concentrations of 2-h proinsulin compared to EA (p=0.001 and p=0.01, respectively). Proinsulin may be a practical biomarker for first-phase beta-cell function that could assist in identification of individuals at risk for T2D who would benefit from interventions to prevent deterioration of glucose metabolism.

Disclosure

C. Couch: None. B. Gower: Advisory Panel; Self; Abbott. F. Piccinini: Employee; Self; Medtronic.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096388); Nutrition Obesity Research Center (P30DK056336); Diabetes Research Center (P30DK079626); National Heart, Lung, and Blood Institute (T32HL105349)
1164-P: A Zebrafish Nonalcoholic Fatty Liver Disease Model Links Liver Inflammation with Pancreatic Inflammation and Hyperglycemia
Authors: IBRAHIM SARA , HAIDER ISRA , KULKARNI ABHISHEK , DOYCHEVA ILIANA , MIRMIRA RAGHAVENDRA G. , SIMS EMILY K. , ANDERSON RYAN
Published: June 2021

The spectrum of nonalcoholic liver disease (NAFLD) ranges from simple steatosis to steatohepatitis with the latter having the potential to irreversibly progress to cirrhosis. Compared with the general population, NAFLD is more frequently seen in patients with type 2 diabetes (T2D), and conversely, NAFLD is associated with increased incidence of T2D. Existing rodent models of NAFLD focus narrowly on certain stages of liver damage and insufficiently encompass all metabolic changes, limiting their utility.

The aims of this study were to develop a new model of NAFLD in young zebrafish and use it to probe the associations between liver inflammation and pancreatic islet function. We examined hepatopancreatic inflammation under three conditions: (1) in a zebrafish line (fabp10-CETI-PIC3) in which liver-specific expression of pro-inflammatory cytokines IL-1β, TNFα, and IFN-γ was induced by doxycycline treatment (M1); (2) in wild-type zebrafish fed a high-fat diet (M2); and (3) in a combination of these models (M3). All three conditions showed increased expression of inflammatory cytokines compared to Tg(fabp10:cre) control larvae, and when compared to controls, all three showed increased macrophage infiltration in the liver. Strikingly, staining with CellRox Deep Red to assess reactive oxygen species (ROS)-mediated stress in the liver revealed a 2-fold increase in the M3 combination model, but not in either M1 or M2. Further, although all models showed hyperglycemia, decreased insulin transcription without β cell death, and ROS accumulation in the pancreas, only the M3 condition demonstrated a significant increase in macrophage infiltration of the pancreatic islets as compared to controls. In sum, our novel zebrafish model of liver steatosis and steatohepatitis is a promising model in which to study the intricate associations between NAFLD and T2D, and may serve as an amenable platform for screening novel pharmaceutical interventions.

Disclosure

S. Ibrahim: None. I. Haider: None. A. Kulkarni: None. I. Doycheva: None. R. G. Mirmira: Advisory Panel; Self; Hibercell Inc., Sigilon Therapeutics, Inc., Veralox Therapeutics, Employee; Spouse/Partner; Beta Bionics, Inc. E. K. Sims: None. R. Anderson: None.
117-LB: Glucokinase Activator Dorzagliatin (HMS5552) Regulates GLP-1 Release in T2D Patients and Is Synergistic with Sitagliptin and Empagliflozin in Optimizing Beta-Cell Function
Authors: CHEN LI , ZHANG JIAYI , YANG RONG , FENG LINGGE , MEDICINE HUA
Published: June 2021

Glucokinase (GK) is a glucose sensor and plays a central role in glucose homeostasis through regulation of threshold of hormone release from α and β cell that controls blood glucose set point. Based on this concept, Dorzagliatin as a glucose sensitizer for the treatment of diabetes has completed pivotal registration trial in China with desirable outcome. GLP-1 is an important hormone involved in β cell secretory function and such plays an important role in glucose homeostasis. It has been debated over the last decade on whether GK is involved in GLP-1 secretion. The dominant reports support the GLP-1 secretory organ is intestine L cell and the secreted hormone traveled to pancreas regulating β cell secreting function. Others suggested β cell regulates GLP-1 secretion from α cell through paracrine and is mediated through GLP-1 receptor on β cell.

Here we report that a glucokinase activator Dorzagliatin stimulates GLP-1 release in T2D patients and is synergistic with Sitagliptin, a DDP-IV inhibitor, to increase circulating active GLP-1 in T2D patients with AUEC0-4h of 94.9% over Dorzagliatin. Increase of total GLP-1 was observed in the Dorzagliatin treatment with AUEC0-4h increase of 103.6% and Cmax increase of 141% compared with Dorzagliatin in combination with Sitagliptin. The effect on β cell function is also seen in patients taking Dorzagliatin together with Sitagliptin and Empagliflozin, a SGLT-2 inhibitor, in the OGTT study with increased C-peptide secretion AUEC0-4h of 46.6% (p < 0.01) and 20.4%, Cmax of 52.5% (p < 0.01) and 22%, respectively. Furthermore, the C-peptide secretion increased in combination treatment with AUEC0-4h of 30.3% (p < 0.05) and Cmax of 31%(p < 0.01), compared with Empagliflozin alone. In both combination studies with Sitagliptin and Empagliflozin, reduction of glucose AUEC0-4h is 33.1% and 37.6% with reduction glucose Cmax of 13.9% and 27.8% over Sitagliptin and Empagliflozin alone.

Disclosure

L. Chen: Board Member; Self; Hua Medicine. J. Zhang: Employee; Self; Hua Medicine. R. Yang: Employee; Self; Hua Medicine. L. Feng: Employee; Self; Hua Medicine. Hua medicine: n/a.
1176-P: Effects of GLP-1 Therapy on GDF15 Expression in Hepatocytes of MAFLD
Authors: GAN LU , LIN BEISI , XU WEN , YAN JINHUA , SU YANNA , CHEN YALAN , YANG DAIZHI , LIANG HUA , XU FEN
Published: June 2021

To explore the effects of glucagon-like peptide-1 therapy (GLP-1) on the expression of growth different factor 15 (GDF15) in hepatocytes of metabolic dysfunction-associated fatty liver disease (MAFLD). Patients with MAFLD and type 2 diabetes mellitus received a 26-week therapy of liraglutide, sitagliptin, or insulin glargine, respectively. The level of serum GDF15, intrahepatic lipid (IHL) and body mass index (BMI) were collected at baseline and week 26. C57BL/6J mice challenged with a high-fat diet (HFD) for 12 weeks were treated with GLP-1 receptor agonist exenatide (GLP-1 group) or normal saline by intraperitoneal injection for 8 weeks (HFD group). Another group with a chow diet was designed as normal control. Human HepG2 cells were incubated in medium containing 300 μM sodium palmitate (PA) and treated with Exendin-4 0nM, 1 nM, 20 nM, 100 nM, respectively. A total of 25 patients were analyzed (liraglutide group, 9; insulin glargine group, 8 and sitagliptin group, 8). The level of serum GDF15 increased significantly in the liraglutide group (742±279pg/mL vs. 920±265pg/mL, P=0.015), and IHL and BMI decreased significantly (18.3±7.4% vs. 12.2±5.5%, P=0.004; 29.0±2.2kg/m2 vs. 27.8±1.9 kg/m2, P= 0.01, respectively). No significant changes in the level of serum GDF15 were observed in the sitagliptin and insulin glargine groups after 26-week therapy. Furthermore, negative correlation was found between the change in serum GDF15 and IHL by in the liraglutide group (r=-0.676, P=0.045). Hepatic steatosis and inflammation in the liver, which were improved markedly in the HFD group, reduced in GLP-1 group. Relative mRNA levels of GDF15 in liver tissue of mice were remarkably higher in the GLP-1 group than those in HFD group and control group (P<0.05). In addition, Exendin-4 alleviated lipid deposition in HepG2 cells, which induced by PA, and elevate the expression and secretion of GDF15 in a dose-dependent manner (P<0.05). GLP-1 can alleviates hepatic steatosis of MAFLD and up-regulate the expression and secretion of GDF15.

Disclosure

L. Gan: None. B. Lin: None. W. Xu: None. J. Yan: None. Y. Su: None. Y. Chen: None. D. Yang: None. H. Liang: None. F. Xu: None.
1180-P: Short-Term Low-Protein Diet Ameliorates Metabolic Dysfunction in Diabetic Lipodystrophic Mice
Authors: MUNOZ MARCOS D. , MCCANN MAXIMILIAN A. , KIM PHILIP , LIEW CHONG WEE
Published: June 2021

Long-term ad libitum dietary restriction such as low-protein diet (LPD) improves metabolic health and extend the life spans of mice and possibly human. However, most studies conducted thus far have mainly focused on preventive rather than the treatment potential of LP diets. To determine whether dietary protein or caloric restriction could be used to treat preexisting metabolic symptoms, particularly in a more severely affected mouse model, we subjected hyperglycemic lipodystrophic IRFKO (adipose-specific insulin receptor knockout) mice to LPD (5.1% kcal from protein). Interestingly, postprandial blood glucose (BG) values of the IRFKO mice began to improve 10 days after the introduction of LPD. The IRFKO mice became normoglycemic 2 weeks after the onset of the LPD treatment. Activation of adaptive thermogenesis in brown (BAT) and beige adipose tissues promotes energy expenditure (EE) and utilization of BG and triglyceride (TG). A LPD has been previously shown to promote EE via the sympathetic nervous system (SNS). Consistent with previous study, we observed that a LPD acutely and sustainably upregulates EE in both the WT and IRFKO mice. This is likely due to LPD dramatically improves BAT functions by transforming the whitened unilocular lipid droplet BAT in the IRFKO mice into normal looking brown multi-locular lipid droplet BAT within 1 week of LPD treatment. This is further supported by significant increase in thermogenic markers expression in the BAT after LPD. Besides thermogenic markers, we also observed a time-dependent regulation of gene markers for fatty acid transport, oxidation and glucose metabolism in BAT after LPD. Together with changes in blood chemistry in the IRFKO mice, we think that glucose and lipid-lowering effects of LPD is the consequence of continuous activation of EE leading to utilization and depletion of systemic thermogenic fuels. Taken together, our data suggest that short-term LPD could be a potential strategy for the treatment of metabolic syndrome.

Disclosure

M. D. Munoz: None. M. A. Mccann: None. P. Kim: None. C. Liew: None.
1185-P: Erythrocyte Eicosapentaenoic and Docosahexaenoic Acid Are Reliable Biomarkers of Dietary Intake in Women of African Ancestry: The Federal Women's Study
Authors: COURVILLE AMBER B. , YANG SHANNA , MABUNDO LILIAN , CRAVALHO CELESTE K. , MATTA SAMANTHA , VILLALOBOS-PEREZ ALFREDO , DAWSON JOSHUA M. , LICHTENSTEIN ALICE H. , SUMNER ANNE E. , CHUNG STEPHANIE T.
Published: June 2021

To formulate precision nutrition prescriptions, it is essential to understand the relationship between dietary assessment, ethnicity and cardiometabolic disease. Erythrocyte (RBC) fatty acid (FA) profiles reflect long-term dietary fat intake but have not been rigorously compared with short-term FA intake in women of African ancestry who have paradoxically low triglycerides with high fat intake. We compared the type of dietary fat consumed (proportion of total fat) using food records with fasting RBC FA (mol%) determined by gas chromatography in 130 female, healthy, federal employees without diabetes (12% African Immigrants (AI), 47% African Americans (AA), 41% White Americans (WA)); mean age 43+10 y and BMI 30 + 6 kg/m2). Diet quality and home prepared meals were similar across ethnicities. AI reported the lowest energy intake. Regardless of absolute energy intake, macronutrient distributions were similar. Fat intake differed by ethnicity; WA had the highest saturated FA (SFA) and lowest eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and omega-3 index (EPA + DHA), while AI and AA had similar SFA, EPA and DHA intake. AI women had the highest RBC DHA and omega-3 index. Associations between FA intake and RBC profiles were significant for DHA (r=0.3, p<0.01), EPA (r=0.2, p<0.05) and the omega-3 index (r=0.2, p<0.01). Overall, RBC EPA and DHA were reliable biomarkers of dietary intake in women of African ancestry, consistent with data in predominantly white populations. These findings support the combined use of food records and RBC profiles for comprehensive dietary assessments. As RBC SFA and monounsaturated FA reflect both endogenous and exogenous sources, the discrepancies between intake and RBC profiles could reflect ethnic variations in nutrient metabolism. To enable precision nutrition prescriptions, exploration of population-specific biomarkers in concert with dietary assessment is needed.

Disclosure

A. B. Courville: None. S. T. Chung: None. S. Yang: None. L. Mabundo: None. C. K. Cravalho: None. S. Matta: None. A. Villalobos-perez: None. J. M. Dawson: None. A. H. Lichtenstein: None. A. E. Sumner: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
121-LB: Glucose- and Glucagon-Lowering Effect of a Single Oral Leptin Dose in Type 1 Diabetes Patients
Authors: KIDRON MIRIAM , PERLES SHARON , WEISS RAM
Published: June 2021

Recent understandings of the role of leptin in glucagon and glucose homeostasis, have flagged it as a target for management of type 1 diabetes (T1D). While historically thought to be involved in long-term regulation of appetite and energy expenditure, leptin is now known to regulate food absorption, mucus secretion, intestinal motility and inflammatory processes. Leptin was shown to directly inhibit glucose uptake and reduce glucagon levels and insulin requirements in NOD mice, to ameliorate hyperglycemia in a T1D mouse model, and reduce insulin requirements in patients with insulin-resistant diabetes. Leptin-based drugs are currently only available in injectable forms, and suffer from a short half-life in the circulation. ORMD-0701 is an oral leptin drug, specially formulated to protect the active ingredient from degradative forces in the gut and enhance its uptake across the intestinal mucosa. This first-in-human study assessed the short-term effects of a single ORMD-0701 dose (3 mg leptin) administered to fasting patients with T1D. Patients on an insulin pump and with glucose levels >100 mg% and <280 mg%, received an ORMD-0701 (n=7) or placebo (n=3) capsule. Basal insulin pump rates were then lowered to 50% of the regular program and blood glucose, glucagon and leptin levels were monitored for 3 h. Glucagon area under the curve 30-120-min post-treatment (AUC30-120) was 0.60 ng*min/L lower than baseline values, while it rose by 0.69 ng*min/L in the placebo group. Similar trends were recorded for glucose AUC30-120 measures, with an 0.43 mmol*min/L decrease from baseline AUC in the active group versus a 0.24 mmol*min/L increase in the placebo group. By the end of the monitoring period, glucose and glucagon levels returned to baseline levels in all patients. No significant changes in blood leptin levels were detected in either cohort. These preliminary findings set the stage for further assessment of oral leptin and its impact on normalizing the insulin-glucagon balance in patients with T1D.

Disclosure

M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc., Stock/Shareholder; Self; Oramed Pharmaceuticals, Inc. S. Perles: Employee; Self; Oramed Ltd. R. Weiss: Consultant; Self; Lilly Global Health Partnership, Medtronic, Speaker’s Bureau; Self; Novo Nordisk.
1211-P: The Mechanistic Role of Thymidine Phosphorylase in the Development of Obesity
Authors: YUE HONG , BELCHER ADAM M. , BICAK ADAM , LI WEI
Published: June 2021

Obesity is a major independent risk factor for the development of type II diabetes (T2DM), nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Consequently, controlling obesity constitutes a key strategy for reducing the prevalence of these diseases. The majority of drugs developed for treating obesity over the past 20 years have been withdrawn due to the increased risk of cardiovascular and psychiatric complications. Therefore, developing novel mechanism-mediated therapeutics for controlling obesity and its consequent complications is a top priority and urgently needed. Our studies indicate that thymidine phosphorylase (TYMP) could be a promising target. The traditional role of TYMP is to catalyze the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose-1 phosphate and maintain the homeostatic nuclear pool of these molecules. TYMP expression is increased in several diseased conditions, including obesity, T2DM, and NAFLD. However, whether TYMP plays a role in the development of these diseases is unknown. We found that Tymp-deficient (Tymp-/-) male mice exhibited significantly limited body weight gain as well as liver and perigonadal fat weight when fed either a western diet (TD.88137) or a prodiabetic high-fat diet (D12492) compared with the wild-type mice. Male Tymp-/- mice showed better glucose tolerance. TYMP-deficiency reduced expression of enzymes that confer glycolysis and de novo lipogenesis in the liver. TYMP-deficiency enhanced the sensitivity of primary hepatocytes to insulin as evidenced by the increase of AKT activation. Inhibition of TYMP with tipiracil, a selective, potent, and the FDA approved TYMP inhibitor, dramatically reduced western diet and high-fat diet-induced body weight gain. We conclude that TYMP plays a pivotal role in liver glucose and lipid metabolism, which promotes the development of obesity and T2DM. Targeting TYMP with tipiracil could be a new therapy for obesity.

Disclosure

H. Yue: None. A. M. Belcher: None. A. Bicak: None. W. Li: None.
1225-P: Prevalence of Obesity and Bariatric Surgery Use in T1DM
Authors: WEST WILLIAM A. , ROMO KARINA G. , UWAIFO GABRIEL I.
Published: June 2021

With the increased prevalence of obesity, the phenotype of T1DM has changed. The prevalence of obesity in pts with T1DM is increasing, but there is limited data on how it compares to pts with T2DM. Bariatric surgery is effective for glycemic, weight and cardiometabolic risk surrogate amelioration in T2DM with obesity. However, the role of bariatric surgery in T1DM with obesity is largely unexplored. Retrospective chart review was done of patients with T1DM seen in Ochsner clinic system from January 2015 to January 2018. Obesity prevalence was quantified. Pts with bariatric surgery (BS) history were identified and their cardiometabolic surrogates pre and post BS were obtained. This was compared to pts with T2DM over the same time period. More in depth chart analysis of 300 pts from this cohort of T1DM pts was done to better characterize features of these pts 10, 282 pts with T1DM were identified over the observation period vs. 146,617 pts with T2DM. The prevalence of obesity in the T1DM cohort was 48.3% vs. 59.7% in the T2DM cohort while the prevalence of morbid obesity was 14.5% vs. 19% in the T1DM vs. T2DM groups. The number of pts who had bariatric surgery was 25 vs. 307 in the T1DM vs. T2DM groups. The percentage utilization of bariatric surgery as an intervention for obesity was very low in both cohorts (0.5 vs. 0.35 % in the T1DM vs. T2DM groups). Of the 300 pts with detailed chart review, actual diabetes subtypes were 163 (54%) T1DM, 43 (14.3%) as LADA, 1 (0.3%) as maturity-onset diabetes of the young, 2 (0.7%) as type 1.5 (essentially LADA), 8 (2.7%) as type 1+2 (T1DM with obesity and insulin resistance), 11 (3.7%) deceased, 71 (23.7%) as T2DM that had been miscoded as T1DM. For subsequent analyses, T1DM, LADA, type 1.5, and type 1+2 were included in the T1DM cohort. The weight and cardiometabolic surrogate changes in T1DM subjects were inconsistent and less marked than in T2DM subjects. Obesity prevalence in T1DM is close to that in T2DM and the use of bariatric surgery as an intervention remains very low both in T1DM and T2DM pts with obesity.

Disclosure

W. A. West: None. K. G. Romo: None. G. I. Uwaifo: None.