bluuebunny/crossref_metadata_2025_split huggingface dataset:
29-LB: Exercise Effects on ?3-AMPK Activity, Akt Substrate of 160 kDa Phosphorylation, and Glucose Uptake in Muscle of Normal and Insulin-Resistant Female Rats
Authors: WANG HAIYAN , ARIAS EDWARD B. , ZHENG AMY , KWAK SEONGEUN , ZHAO JIAHUI , DONG GENGFU , CARTEE GREGORY D. 
Published: June 2021

Background: Previous studies demonstrated that exercise can enhance insulin-stimulated glucose uptake (ISGU) concomitant with greater Akt Substrate of 160 kDa (AS160) phosphorylation in muscles from normal or insulin resistant, male rats. However, little is known about exercise effects on ISGU in insulin-resistant muscle from female rats. Our goal was to assess exercise effects on ISGU and key signaling proteins in muscles from female rats fed a low-fat or high-fat diet.
Methods: Female rats were randomly assigned to 2 diet-groups: standard chow (low-fat diet, LFD: 14% kCal fat) or high-fat diet (HFD: 60% kCal fat). After 2 weeks, rats from each diet-group either remained sedentary (LFD-SED or HFD-SED) or exercised (2h duration swim). At 3h post-exercise (3hPEX), paired epitrochlearis muscles were isolated and incubated with [3H]-2-deoxyglucose ±insulin to measure GU. Muscles were also assessed for γ3-AMPK activity and phosphorylated AS160 (pAS160; Ser588 and Thr642).
Results: HFD-SED vs. LFD-SED rats had lower ISGU. At 3hPEX in each diet group, ISGU exceeded their diet-matched, sedentary controls. ISGU for LFD-3hPEX was greater than HFD-3hPEX. LFD-3hPEX vs. LFD-SED had greater γ3-AMPK activity and insulin-stimulated pAS160 (Ser588 and Thr642). For HFD-3hPEX vs. HFD-SED, insulin-stimulated pAS160 Thr642 was increased. However, γ3-AMPK activity was not different between HFD-SED and 3hPEX. Insulin-stimulated pAS160 Ser588 and Thr642 at 3hPEX did not differ between diet-groups, but γ3-AMPK for LFD-3hPEX exceeded HFD-3hPEX.
Conclusions: These results indicated that prior exercise can enhance ISGU for LFD and HFD female rats, and suggested that the exercise-increase in ISGU for each diet-group may be related to greater pAS160. The elevated γ3-AMPK activity for LFD-3hPEX vs. LFD-SED, but not HFD-3hPEX vs. HFD-SED, raises the possibility that this difference may be relevant for the greater ISGU in LFD-3hPEX vs. HFD-3hPEX.

Disclosure
H. Wang: None. E. B. Arias: None. A. Zheng: None. S. Kwak: None. J. Zhao: None. G. Dong: None. G. D. Cartee: None.

Funding
National Institutes of Health (DK71771)
293-OR: IFN-a Evokes a Heterogeneous, Rapid ROS Response from a Subset of Human Islet Beta Cells in Situ
Authors: ARVIN MATTHEW , MURALIDHARAN CHARANYA , CONTEH ABASS M. , IRIZARRY MICHELLE M. MARTINEZ , ORR KARA , DUNN KEN W. , LINNEMANN AMELIA K. 
Published: June 2021

A large body of evidence reveals a web of complex, multifaceted genetic, and environmental factors that influences incidence of T1D. Among these, viral infection has been discussed as a factor implicated in onset. Production of type 1 interferons (IFN) is the archetypal immune response to viral infection. Indeed, at-risk children exhibit IFN-associated transcriptional profiles and IFN-stimulated genes are elevated in new onset T1D patients. IFN-α induces ER stress, substantial overexpression of HLA class 1, and insulitis in the islet. β-cells are known to be sensitive to reactive oxygen species (ROS) accumulation which may contribute to autoimmunogenicity in the IFN response. In order to detect the in vivo effects of IFN-α on the physiology of human islets, we conducted intravital microscopy studies of human islets transplanted in the mouse kidney - following transduction with a ratiometric fluorescent redox biosensor. These studies revealed that intravenous IFN-α elicited a mild overall accumulation of ROS in human islets, but rapid and pronounced accumulation of ROS in a subset of islet β-cells - a population of cells we termed, “ROSponders." Interestingly, the percentage of β-cells categorized as ROSponders was variable between donors (ranging from ~1% to 6% of all β-cells). Recent observations have drawn attention to the importance of β-cell expression and functional heterogeneity within the islet. Furthermore, recent work suggests that blockade of IFN-α signaling prior to clinical T1D manifestation may intercept autoimmunity and abort onset. Altogether, this work identifies novel heterogeneity of response to an inflammatory cytokine implicated in T1D onset and may inform future approaches to the treatment of T1D.

Disclosure
M. Arvin: None. C. Muralidharan: None. A. M. Conteh: None. M. M. Martinez irizarry: None. K. Orr: None. K. W. Dunn: None. A. K. Linnemann: None.

Funding
Human Islet Research Network (RRID:SCR_014393; UC4 DK104162); National Institutes of Health (3T32DK064466-18S1)
298-OR: Lipid Pattern in Men with Hypogonadism and Type 2 Diabetes Improves during Long-Term Treatment with Testosterone Undecanoate Injections (TU) in Comparison with an Untreated Control Group: Update of Real-World Registry Data
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD 
Published: June 2021

Background: Previous studies reported inconsistent effects of testosterone therapy on the lipid profile in men with hypogonadism.
Methods: Of 361 men with hypogonadism and T2DM, 183 received TU 1000 mg/12 weeks (T-group), 178 opted against treatment (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups.
Results: Mean follow-up 8.7±3.1, baseline age: 61.8±5.3 years. Total cholesterol (mmol/L for all lipids) decreased by 2.9±0.1 (unadjusted from 8.3±1.1 to 5.2±0.3) at 12 years in T-group and increased by 1.3±0.1 (7.1±1.2 to 8.2±1.4) in CTRL. (p&lt;0.0001 for both). HDL increased by 0.5±0.0 (1.0±0.4 to 1.6±0.4) in T-group and decreased by 0.3±0.0 (1.1±0.5 to 0.1±0.4) in CTRL (p&lt;0.0001 for both). The total cholesterol:HDL ratio decreased by 5.6±0.3 (9.7±4.3 to 3.4±0.7) in T-group and increased by 5.5±0.3 (8.0±3.9 to 12.1±6.1) in CTRL. (p&lt;0.0001 for both). LDL decreased by 1.9±0.1 (4.7±0.9 to 2.6±0.2) in T-group and increased by 1.0±0.1 (4.1±1.4 to 4.9±1.5) in CTRL (p&lt;0.0001 for both). Triglyceride decreased by 1.1±0.0 (3.5±0.6 to 2.2±0.1) in T-group and increased by 0.6±0.0 (3.1±0.6 to 3.7±0.5) in CTRL (p&lt;0.0001 for both). Non-HDL decreased by 3.4±0.1 (7.3±1.2 to 3.6±0.3) in T-group and increased by 1.6±0.1 (6.0±1.4 to 7.4±1.5) in CTRL (p&lt;0.0001 for both). Remnant cholesterol decreased by 1.5±0.1 (2.6±1.0 to 0.9±0.3) in T-group and increased by 0.6±0.1 (2.0±1.0 to 2.4±0.7) in CTRL (p&lt;0.0001 for both). The triglyceride:HDL ratio decreased by 5.3±0.4 (9.4±4.4 to 3.2±0.8) in T-group and increased by 5.7±0.4 (8.0±4.1 to 12.5±6.0) in CTRL (p&lt;0.0001 for both).
Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM progressively improved the lipid profile, which worsened in controls.

Disclosure
F. Saad: Consultant; Self; Bayer AG, Stock/Shareholder; Self; AbbVie Inc., Bayer AG, Novo Nordisk. K. S. Haider: Other Relationship; Self; Bayer AG. A. Haider: Other Relationship; Self; Bayer AG.

Funding
Bayer AG
31-OR: ACSL1 in Smooth Muscle Cells Regulates High-Fat Diet-Induced Obesity and Thermogenesis in Mice
Authors: REN GUANG , YOUNG MARTIN , KIM JEONGA 
Published: June 2021

Long-chain acyl-CoA synthetases (ACSL) are the enzymes that convert long-chain fatty acids to long-chain fatty acyl-CoAs that are utilized for various cellular processes, including triglyceride synthesis, energy metabolism, sphingolipid formation, and modification of lipids and proteins. Among five common isotypes (ACSL1, 3, 4, 5, and 6), ACSL1 is the predominant isotype in adipose tissue and essential for fatty acid oxidation during the cold adaption in brown adipose tissue. However, it is unknown whether ACSL1 is involved in brown adipocyte differentiation. Since the smooth muscle-like cells (mural cells) are the progenitors of brown adipocytes, we hypothesize that the ACSL1 in smooth muscle cells contributes to brown adipocyte differentiation and energy metabolism. We generated a smooth muscle-specific ACSL1 knockout mouse (ACSL1SM-/-) by breeding SM22α-cre mouse with ACSL1flox/flox mouse. ACSL1 deficiency in smooth muscle cells protected from high-fat diet (HFD)-induced obesity without changes in food intake and physical activity. Furthermore, HFD-fed ACSL1flox/flox mice were more glucose tolerant and insulin sensitive compared to HFD-fed wild-type mice. We also observed that cold adaptation, thermogenesis, was significantly impaired in ACSL1SM-/- mice. We isolated stromal vascular cells (SVCs) from inguinal and brown adipose tissues and then subjected them to adipocyte differentiation. We found that the adipocyte differentiation was impaired, and the expression of UCP1 was significantly reduced in the absence of ACSL1. These results suggest that ACSL1 in smooth muscle cells contributes to energy metabolism and glucose homeostasis by regulation of brown fat differentiation.

Disclosure
G. Ren: None. M. Young: None. J. Kim: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079626); National Heart, Lung, and Blood Institute (HL128695); National Institute on Aging (AG058078)
311-OR: Predicting Inadequate Early Glycemic Control among Adults with Younger-Onset Type 2 Diabetes
Authors: MISHRA PRANITA , ALEXEEFF STACEY , GRANT RICHARD W. , GOPALAN ANJALI 
Published: June 2021

The prevalence of type 2 diabetes (T2D) is increasing among individuals younger than 45 years, who are at an increased risk of T2D-related complications, making the lasting benefits conferred by early glycemic control particularly critical. The ability to proactively identify these younger-onset individuals at increased risk of inadequate early glycemic control could support more targeted and tailored initial care. The study sample was randomly split into training (70%) and validation (30%) sets to develop and test the model. We used logistic LASSO (Least Absolute Shrinkage and Selection Operator) regression to identify predictors of inadequate glycemic control (HbA1c ≥8%) at 1-year following diagnosis among adults ages 21-44. Potential predictors were assessed at diagnosis. We used terciles of predicted risk to stratify our cohort into low (LR), intermediate (IR) and high-risk (HR) groups and compared characteristics between them using chi-square and ANOVA tests. Of the 10,897 individuals with new T2D, the mean age was 37.9 ± 5.3 years and 33% were Latinx. The LASSO model selected 46 out of 97 candidate variables. The resulting model yielded a c-statistic of 0.73 and had good calibration. We observed differences in socioeconomic, clinical, and care utilization characteristics between the risk groups. Those in high-risk group were more likely to be Latinx (45% HR vs. 30% IR vs. 27% LR, p&lt;0.01), residents of deprived neighborhoods (33% HR vs. 23% IR vs. 22% LR, p&lt;0.01), and have an HbA1c ≥ 10% ( 74% HR vs. 9% IR vs. 0% LR, p&lt;0.01) but less likely to have received a flu shot ( 22% HR vs. 37% IR vs. 42% LR, p&lt;0.01) or be active users of the online patient portal (44% HR vs. 65% IR vs. 75% LR, p&lt;0.01). Using a machine-learning developed predictive model, we characterized adults &lt;45 years at low, intermediate or high risk for inadequate early glycemic control. Such models can support healthcare systems by leveraging EHR data to risk stratify younger-onset individuals and inform the intensity of initial T2D care.

Disclosure
P. Mishra: None. S. Alexeeff: None. R. W. Grant: None. A. Gopalan: None.
32-OR: Receptor-Mediated Gq Signaling in Adipocytes as a Critical Modulator of Systemic Glucose and Lipid Homeostasis
Authors: KIMURA TAKEFUMI , PYDI SAI PRASAD , WANG LEI , CUI YINGHONG , GAVRILOVA OKSANA , WESS JÜRGEN 
Published: June 2021

Objective: In obesity, decreased insulin action leads to the accelerated breakdown of triglycerides stored in adipocytes, causing peripheral insulin resistance, a hallmark of type 2 diabetes. In this study, we investigated whether selective activation of Gq signaling in adipocytes might cause similar metabolic effects as insulin.
Methods: We generated a novel mutant mouse strain that expressed a CNO-sensitive, Gq-coupled designer G protein-coupled receptor (Gq DREADD = QGD) selectively in adipocytes (adipo-GqD mice). DREADDs are stimulated by an exogenous agent (e.g., CNO) that is otherwise pharmacologically inactive. We also made another mouse strain that selectively lacked Galpha-q and -11 in adipocytes (adipo-Gq/11 KO mice). Both mutant mouse strains underwent a series of metabolic tests.
Results: CNO-mediated activation of adipocyte Gq signaling in the adipo-GqD mice significantly improved glucose homeostasis and suppressed lipolysis. In contrast, adipo-Gq/11 KO mice showed the opposite metabolic phenotypes, impaired glucose metabolism and enhanced lipolysis. Consistent with these findings, in vitro studies with cultured adipocytes demonstrated that activation of Gq signaling enhanced glucose uptake and inhibited lipolysis in an AMPK-dependent manner. To test the hypothesis that activation of adipocyte Gq signaling might counteract impaired insulin signaling in adipocytes, we generated adipo-GqD mice that carried only one copy of the insulin receptor (IR) gene in adipocytes (adipo-GqD-IR+/- mice). Interestingly, activation of adipocyte Gq signaling by CNO ameliorated the metabolic deficits displayed by adipo-GqD-IR+/- mice maintained on a high-fat diet.
Conclusion: Our data indicate that adipocyte Gq signaling represents an essential regulator of whole-body glucose and lipid homeostasis. This finding is likely to stimulate the development of novel drugs that can mimic the actions of insulin in the insulin-resistant state.

Disclosure
T. Kimura: None. S. Pydi: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.
330-OR: Geographic Disparities and Community Context: Associations of Abandoned Coal Mine Lands with New-Onset Type 2 Diabetes in Pennsylvania
Authors: BROWN EVANS , POLLAK JONATHAN S. , HIRSCH ANNEMARIE G. , SCHWARTZ BRIAN S. 
Published: June 2021

Differences in community features could help explain the geographic disparities found in type 2 diabetes (T2D). A growing literature documents that communities with abandoned industrial infrastructure, including coal mine lands with hazards such as spoil piles, open pits, and acid mine drainage, can adversely affect health through impacts on health-related behaviors and stress. We investigated the association between living near abandoned coal mine lands (AML) and new onset T2D through a case-control analysis using electronic health records from a health system in Pennsylvania. We identified cases as persons with new onset T2D (n = 15,888) and frequency-matched controls (5:1, n = 79,435) on sex, age and year of encounter. Residential addresses were geocoded using ArcGIS. We used the Abandoned Mine Land Inventory System database to obtain AML data in Pennsylvania and created variables to represent metrics of AML type and density. We performed logistic regression for each AML variable, adjusting for age, sex, race (white vs. non-white), ethnicity (Hispanic vs. non-Hispanic), and Medical Assistance (≥ 50% of time). The highest quartile (vs. the lowest) of multiple AML variables were associated (odds ratio, 95% confidence interval) with new onset T2D, including the density of physical hazards (1.20, 1.11-1.29), toxic contamination sites (1.17, 1.09-1.26), acid mine drainage impacted streams (1.12, 1.04-1.22), and the density of total mined area (1.18, 1.11-1.25). These findings contribute to the growing literature on geographic disparities in T2D. Further research is needed to investigate the physiologic mechanisms through which these associations may occur.

Disclosure
E. Brown: None. J. S. Pollak: None. A. G. Hirsch: None. B. S. Schwartz: None.

Funding
Centers for Disease Control and Prevention (DP006299); National Institutes of Health (T32HP10025)
347-P: Why Some Americans Use Health Care following Severe Hypoglycemia, and Why Some Do Not: Baseline Results of the iNPHORM Study
Authors: RATZKI-LEEWING ALEXANDRIA , BLACK JASON E. , RYAN BRIDGET L. , ZOU GUANGYONG , HARRIS STEWART B. 
Published: June 2021

Background: Individual and societal determinants can affect the need and propensity for healthcare utilization (HCU) following diabetes-related severe hypoglycemia (SH). This is the first US study to explore the real-world risk factors of HCU- versus non HCU-based SH.
Methods: Data were collected online from a generalized cohort of Americans (≥18 years old) with type 1 or type 2 diabetes (T1D, T2D) on insulin and/or secretagogues. Multivariable logistic regression using backward selection was performed to identify the socio-demographic/clinical risk factors of past-year HCU- versus non HCU-based SH (daytime/nocturnal SH resulting in hospital or paramedical services).
Results: Results are based on 642 (T1D: 22.7%; female: 46.3%) of 1694 baseline respondents who experienced ≥1 SH events (past year). People with T1D were 40.9 (SD:12.5) years old, while those with T2D were 45.4 (SD: 13.3) years old. Among T2D respondents, 42.5% were on insulin and secretagogues, 31.1% were on insulin alone, and 26.4% on secretagogues alone. Almost half (44.6%) of participants (T1D: 29.9%; T2D: 49.0%) reported ≥1 HCU-based SH events (past year). In the final backward logistic model, the odds of past-year HCU-based SH decreased significantly with female sex, increasing age, decreasing income, and suburban or rural (versus urban) living. Diabetes type did not have an independent effect. However, for individuals on combination insulin-secretagogue therapy, the adjusted odds of HCU-based SH were 2- and 3-times that of those on insulin alone and secretagogues alone, respectively. High A1C (versus &lt;7%) also positively correlated with HCU-based SH; though, this association was marginally insignificant (p=0.065).
Conclusion: Our study reveals several factors that can promote or reduce the odds of HCU-based SH. Therapeutic optimizations to mitigate non-essential HCU should prioritize patients on combination insulin-secretagogue therapy and those with poor glycemic control.

Disclosure
A. Ratzki-leewing: Consultant; Self; Eli Lilly and Company, Novo Nordisk, Other Relationship; Self; Sanofi. J. E. Black: None. B. L. Ryan: None. G. Zou: None. S. B. Harris: Advisory Panel; Self; Abbott Diabetes, Abvance Therapeutics, HLS Therapeutics Inc., Lilly Diabetes, Novo Nordisk A/S, Consultant; Self; Boehringer Ingelheim (Canada) Ltd., mdBriefCase, Other Relationship; Self; American Diabetes Association, AstraZeneca, Novo Nordisk Canada Inc., Sanofi.

Funding
Sanofi Global
349-P: Hospital Utilization for Hypoglycemia among Patients with Type 2 Diabetes Using Pooled Data from Six Health Systems
Authors: PILLA SCOTT J. , KRASCHNEWSKI JENNIFER L. , LEHMAN ERIK , KONG LAN , FRANCIS ERICA , POGER JENNIFER M. , BRYCE CINDY L. , MARUTHUR NISA M. , YEH HSIN-CHIEH 
Published: June 2021

Hypoglycemia is the most common serious adverse effect of diabetes treatment and a major cause of medication-related hospitalization. This study aimed to identify trends and predictors of hospital utilization for hypoglycemia among adults with type 2 diabetes. Using electronic health record data from six academic health systems, we performed a retrospective open cohort study including 532,323 patients aged ≥18 years with type 2 diabetes receiving regular care between 2009 and 2019. The primary outcome was the yearly event rate for hypoglycemia hospital utilization: emergency department visits, observation visits, or inpatient admissions for hypoglycemia identified using a validated ICD-9 algorithm. After the transition to ICD-10 in 2015, we used two ICD-10 code sets for hypoglycemia (limited and expanded) that were used in prior studies. We identified independent predictors of hypoglycemia hospital utilization using multivariable logistic regression analysis with data from 2014. We found that yearly rates of hypoglycemia hospital utilization decreased non-significantly from 3.4 to 2.6 events per 1,000 patients from 2009 to 2014. From 2016 to 2019, yearly event rates ranged from 15.5 to 16.5, or 21.1 to 21.8, using the limited and expanded ICD-10 code sets, respectively. The strongest independent risk factors for hypoglycemia hospital utilization were chronic kidney disease (OR 3.13, 95% CI 2.63-3.70), age 18-39 years (OR 3.00 vs. age 40-64 years, 95% CI 2.42-3.73), and insulin use (OR 2.61 vs. no diabetes medications, 95% CI 2.16-3.15). In this multicenter open cohort study, we found that rates of hypoglycemia hospital utilization were stable from 2009 to 2014 and varied considerably by clinical risk factors such that younger adults, insulin users, and those with chronic kidney disease were at especially high risk. There is a need to validate hypoglycemia ascertainment using ICD-10 codes, which detect a substantially higher number of events compared to ICD-9.

Disclosure
S. J. Pilla: None. J. L. Kraschnewski: None. E. Lehman: None. L. Kong: None. E. Francis: None. J. M. Poger: None. C. L. Bryce: None. N. M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. H. Yeh: None.

Funding
National Institutes of Health (KL2TR003099); Patient-Centered Outcomes Research Institute (1306-04912)
350-P: The Importance of Professional CGM Use in Clinical Care of Older Adults with Type 2 Diabetes on Insulin
Authors: SLYNE CHRISTINE , TOSCHI ELENA , MICHALS AMY , ATAKOV-CASTILLO ASTRID , SIFRE KAYLA , DEWAR RACHEL , DAVIS DAI’QUANN J. , MUNSHI MEDHA 
Published: June 2021

Background: In recent years, professional continuous glucose monitoring (CGM) has become a beneficial tool in pattern management in older adults with type 2 diabetes (T2D) on insulin, however the need for use of professional CGM in this population had not been shown.
Methods: We evaluated electronic health record (EHR) data of a tertiary diabetes center to identify the use of professional CGM in patients over the age of 65 years with T2D using insulin. Professional CGM data from this cohort were analyzed when a minimum of 70% of data was available (≥10 days).
Results: A total of 2,481 patients over the age of 65 years with type 2 diabetes using insulin were seen at the Joslin Diabetes Center from January 2017-March 2020. Average age of the total cohort was 72±7 yrs, A1c was 8.2±1.5% and diabetes duration was 21±10 years. Professional CGM was used in 169 older adults with T2D using insulin (7% of the total patients seen). CGM data from 139/169 was sufficient for analysis. The average age of this cohort (139 patients) was 77±8 yrs, A1c 8.0±1.5%, duration of diabetes 21±12 yrs. The mean duration of hypoglycemia was 80±92 min/day &lt;70 mg/dL and 32±51 min/day ≤54 mg/dL. A total of 86% of the cohort had ≥1 episode of hypoglycemia. The measure of high glycemic variability (CV &gt;36%) was seen in 59 (42%) of the cohort, with a high A1c (8.2±1.2%). When comparing those people with and without hypoglycemia on CGM, there was no difference in age, A1c, or duration of diabetes.
Conclusion: In the real world, a small percentage of older adults with T2D on insulin therapy received professional CGM. Our data shows a high burden of hypoglycemia in this population, despite suboptimal A1c. Broader use of professional CGM would be beneficial in recognizing hypoglycemia in this vulnerable population.

Disclosure
C. Slyne: None. E. Toschi: Consultant; Self; Medtronic. A. Michals: None. A. Atakov-castillo: None. K. Sifre: None. R. Dewar: None. D. J. Davis: None. M. Munshi: Consultant; Self; Sanofi.

Funding
National Institutes of Health (1DP3DK112214-01)