Endocrinology, Diabetes, and Metabolism Commons^™

The Circadian E3 Ligase Fbxl21 Regulates Myoblast Differentiation And Sarcomere Architecture Via Myoz1 Ubiquitination And Nfat Signaling, Bo Hu, Jian-Xing Ma, Adam S Duerfeldt

Faculty, Staff and Student Publications

Diabetic retinopathy and age-related macular degeneration are common retinal diseases with shared pathophysiology, including oxidative stress-induced inflammation. Cellular mechanisms responsible for converting oxidative stress into retinal damage are ill-defined but have begun to clarify. One common outcome of retinal oxidative stress is mitochondrial damage and subsequent release of mitochondrial DNA into the cytosol. This leads to activation of the cGAS-STING pathway, resulting in interferon release and disease-amplifying inflammation. This review summarizes the evolving link between aberrant cGAS-STING signaling and inflammation in common retinal diseases and provides prospective for targeting this system in diabetic retinopathy and age-related macular degeneration. Further defining …

Clinical Outcomes Of Immune Checkpoint Inhibitor Diabetes Mellitus At A Comprehensive Cancer Center, Rebecca Jeun, Priyanka C Iyer, Conor Best, Victor Lavis, Jeena M Varghese, Sireesha Yedururi, Veronica Brady, Isabella C Glitza Oliva, Ramona Dadu, Denai R Milton, Kristy Brock, Sonali Thosani

Faculty, Staff and Student Publications

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients.

Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020.

Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients.

Conclusion: Development of ICI-DM is associated with long-term insulin dependence …

Relationships Among Biochemical Measures In Children With Diabetic Ketoacidosis, Nicole S Glaser, Michael J Stoner, Maria Y Kwok, Kimberly S Quayle, Kathleen M Brown, Jeff E Schunk, Jennifer L Trainor, Julie K Mcmanemy, Leah Tzimenatos, Arleta Rewers, Lise E Nigrovic, Jonathan E Bennett, Sage R Myers, Mckenna Smith, T Charles Casper, Nathan Kuppermann

Faculty, Staff and Students Publications

OBJECTIVES: Investigating empirical relationships among laboratory measures in children with diabetic ketoacidosis (DKA) can provide insights into physiological alterations occurring during DKA. We determined whether alterations in laboratory measures during DKA conform to theoretical predictions.

METHODS: We used Pearson correlation statistics and linear regression to investigate correlations between blood glucose, electrolytes, pH and PCO2 at emergency department presentation in 1,681 pediatric DKA episodes. Among children with repeat DKA episodes, we also assessed correlations between laboratory measures at the first vs. second episode.

RESULTS: pH and bicarbonate levels were strongly correlated (r=0.64), however, pH and PCO2 were only loosely correlated (r=0.17). …

Clinical Features And Shared Mechanisms Of Chronic Gastritis And Osteoporosis, Tao Han, Yili Zhang, Baoyu Qi, Ming Chen, Kai Sun, Xiaokuan Qin, Bowen Yang, He Yin, Aili Xu, Xu Wei, Liguo Zhu

Faculty, Staff and Student Publications

Chronic gastritis (CG) and osteoporosis (OP) are common and occult diseases in the elderly and the relationship of these two diseases have been increasingly exposed. We aimed to explore the clinical characteristics and shared mechanisms of CG patients combined with OP. In the cross-sectional study, all participants were selected from BEYOND study. The CG patients were included and classified into two groups, namely OP group and non-OP group. Univariable and multivariable logistic regression methods were used to evaluate the influencing factors. Furthermore, CG and OP-related genes were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified …

Delay In Diagnosis Of Pd-1 Inhibitor Induced Secondary Adrenal Insufficiency, Olubunmi Oladunjoye, Ibiyemi Oke, Ian Garrahy, Adeolu O. Oladunjoye, Kyle Macaulay, Jeremy Ellis

Transformative Medicine

Introduction: Immune checkpoint inhibitors including PD-1 inhibitors, were initially approved for the treatment of metastatic melanoma but are now increasingly being used for different types of solid organ malignancies. Despite the important clinical benefits, they are associated with immune-related adverse events. The most critical endocrinopathy associated with PD -1 inhibitor is adrenal insufficiency (AI), which requires prompt diagnosis and management to avoid fatality.

Case presentation: We present the case of a 78-year-old woman with colon adenocarcinoma treated with Nivolumab (PD-1 inhibitor) after her pulmonary metastases progressed on chemotherapy. She presented to the hospital with progressive generalized weakness, fatigue, headache, lightheadedness, …

Residential Racial Segregation And Neighborhood Adversity: Associations With Hemoglobin A1c In Adolescents With Type 1 Diabetes, Zechariah Jean, April Carcone, Deborah Ellis

Medical Student Research Symposium

Black adolescents with Type 1 Diabetes (T1D) are at increased risk for disparities in health outcomes. More research is necessary on the effects of neighborhood characteristics such as residential racial segregation (RRS) and neighborhood adversity on health.

149 Black youth with T1D were recruited from seven pediatric diabetes clinics in Detroit and Chicago to participate in a clinical trial to improve diabetes management. RRS was calculated at the census block group level based on US census data using Location Quotients. LQs represented the ratio of patients to total population in the block group compared to the same ratio in the …

Impact Of End Stage Renal Disease On The Clinical Outcomes Of Diabetics Admitted For Heart Failure: Analysis Of National Inpatient Sample, Muhammad Usman Almani, Yaqi Zhang, Muhammed Hamza Arshad, Muhammad Usman, Muhammad Talha Ayub

Einstein Health Papers

Introduction: Patients with diabetes and heart failure (HF) can have varying outcomes depending on whether they also have End Stage Renal Disease (ESRD). This study aimed to compare the outcomes of patients with diabetes and HF with and without ESRD.

Methods: Data from the National Inpatient Sample (NIS) 2016-2018 was analyzed to find hospitalizations for patients with HF as the main diagnosis and diabetes as a secondary diagnosis, with and without ESRD. Multivariable logistic and linear regression analysis was used to adjust for confounding factors.

Results: In the total cohort of 12215 patients with a principal diagnosis of heart failure …

Use Of Dual Genomic Sequencing To Screen Mitochondrial Diseases In Pediatrics: A Retrospective Analysis, Teng-Hui Wu, Jing Peng, Li Yang, Yan-Hui Chen, Xiu-Lan Lu, Jiao-Tian Huang, Jie-Yu You, Wen-Xian Ou-Yang, Yue-Yu Sun, Yi-Nan Xue, Xiao Mao, Hui-Ming Yan, Rong-Na Ren, Jing Xie, Zhi-Heng Chen, Victor-Wei Zhang, Gui-Zhen Lyu, Fang He

Children’s Nutrition Research Center Staff Publications

Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged <  18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.

Data Mining Framework For Discovering And Clustering Phenotypes Of Atypical Diabetes, Hemang M Parikh, Cassandra L Remedios, Christiane S Hampe, Ashok Balasubramanyam, Susan P Fisher-Hoch, Ye Ji Choi, Sanjeet Patel, Joseph B Mccormick, Maria J Redondo, Jeffrey P Krischer

Faculty, Staff and Students Publications

Context: Some individuals present with forms of diabetes that are "atypical" (AD), which do not conform to typical features of either type 1 diabetes (T1D) or type 2 diabetes (T2D). These forms of AD display a range of phenotypic characteristics that likely reflect different endotypes based on unique etiologies or pathogenic processes.

Objective: To develop an analytical approach to identify and cluster phenotypes of AD.

Methods: We developed Discover Atypical Diabetes (DiscoverAD), a data mining framework, to identify and cluster phenotypes of AD. DiscoverAD was trained against characteristics of manually classified patients with AD among 278 adults with diabetes within …

Risk Of Diabetic Retinopathy Between Sodium-Glucose Cotransporter-2 Inhibitors And Glucagon-Like Peptide-1 Receptor Agonists, Tzu-Yi Lin, Eugene Yu-Chuan Kang, Shih-Chieh Shao, Edward Chia-Cheng Lai, Sunir J. Garg, Kuan-Jen Chen, Je-Ho Kang, Wei-Chi Wu, Chi-Chun Lai, Yih-Shiou Hwang

Wills Eye Hospital Papers

BACKGROUND: To compare risk of diabetic retinopathy (DR) between patients taking sodium-glucose cotransporter-2 inhibitors (SGLT2is) and those taking glucagon-like peptide-1 receptor agonists (GLP1-RAs) in routine care.

METHODS: This retrospective cohort study emulating a target trial included patient data from the multi-institutional Chang Gung Research Database in Taiwan. Totally, 33,021 patients with type 2 diabetes mellitus using SGLT2is and GLP1-RAs between 2016 and 2019 were identified. 3,249 patients were excluded due to missing demographics, age <40 >years, prior use of any study drug, a diagnosis of retinal disorders, a history of receiving vitreoretinal procedure, no baseline glycosylated hemoglobin, or no follow-up data. …

Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated With Diabetic Kidney Disease, Yang Pan, Xiao Sun, Xuenan Mi, Zhijie Huang, Yenchih Hsu, James E Hixson, Donna Munzy, Ginger Metcalf, Nora Franceschini, Adrienne Tin, Anna Köttgen, Michael Francis, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium Topmed Kidney Function Working Group, Jennifer A Brody, Bryan Kestenbaum, Colleen M Sitlani, Josyf C Mychaleckyj, Holly Kramer, Leslie A Lange, Xiuqing Guo, Shih-Jen Hwang, Marguerite R Irvin, Jennifer A Smith, Lisa R Yanek, Dhananjay Vaidya, Yii-Der Ida Chen, Myriam Fornage, Donald M Lloyd-Jones, Lifang Hou, Rasika A Mathias, Braxton D Mitchell, Patricia A Peyser, Sharon L R Kardia, Donna K Arnett, Adolfo Correa, Laura M Raffield, Ramachandran S Vasan, L Adrienne Cupple, Daniel Levy, Robert C Kaplan, Kari E North, Jerome I Rotter, Charles Kooperberg, Alexander P Reiner, Bruce M Psaty, Russell P Tracy, Richard A Gibbs, Alanna C Morrison, Harold Feldman, Eric Boerwinkle, Jiang He, Tanika N Kelly, Cric Study Investigators

Faculty, Staff and Students Publications

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between …

Population Pharmacokinetics And Exposure–Response Analysis For The Phase 3 Cosmic-311 Trial Of Cabozantinib For Radioiodine-Refractory Differentiated Thyroid Cancer, Neang S. Ly, Jing Li, Raffaella Faggioni, Lorin K. Roskos, Marcia S Brose

Kimmel Cancer Center Faculty Papers

Background and Objective

In the USA, cabozantinib was approved for the treatment of patients aged ≥ 12 years with radioiodine-refractory differentiated thyroid cancer (DTC) who progressed on prior vascular endothelial growth factor (VEGFR)-targeted therapy based on the Phase 3 COSMIC-311 trial, which evaluated cabozantinib 60 mg/day versus placebo. Approved dosing is 60 mg/day for adults and for pediatric patients aged ≥ 12 years with body surface area (BSA) ≥ 1.2 m2, and 40 mg/day for pediatric patients aged ≥ 12 years with BSA < 1.2 m2. This report describes a population pharmacokinetic (PopPK) and exposure–response analysis of COSMIC-311.

Methods

A PopPK model was developed using concentration-time data from COSMIC-311 and 6 other cabozantinib studies. The …

Child Weight Status: The Role Of Feeding Styles And Highly Motivated Eating In Children, Maria A Papaioannou, Thomas G Power, Teresia M O'Connor, Jennifer O Fisher, Nilda E Micheli, Sheryl O Hughes

Children’s Nutrition Research Center Staff Publications

Although parental feeding plays an important role in child eating and weight status, high food motivation among children may also be a factor shaping how feeding impacts child weight. This study explored whether individual differences in preschool children’s food motivation interacted with mothers’ feeding styles in predicting subsequent child weight status. Participants included 129 Hispanic Head Start mother/child dyads. Data were collected at ages 4–5 years (Time 1) and 7–9 (Time 3). Staff measured heights/weights and observed children in an eating in the absence of hunger task. Mothers reported on feeding styles/practices and children’s eating behaviors. A principal components analysis …

Taking A Load Off: User Perceptions Of Smart Offloading Walkers For Diabetic Foot Ulcers Using The Technology Acceptance Model, M G Finco, Gozde Cay, Myeounggon Lee, Jason Garcia, Elia Salazar, Tze-Woei Tan, David G Armstrong, Bijan Najafi

Center on Aging Staff Publications

People with diabetic foot ulcers (DFUs) are commonly prescribed offloading walkers, but inadequate adherence to prescribed use can be a barrier to ulcer healing. This study examined user perspectives of offloading walkers to provide insight on ways to help promote adherence. Participants were randomized to wear: (1) irremovable, (2) removable, or (3) smart removable walkers (smart boot) that provided feedback on adherence and daily walking. Participants completed a 15-item questionnaire based on the Technology Acceptance Model (TAM). Spearman correlations assessed associations between TAM ratings with participant characteristics. Chi-squared tests compared TAM ratings between ethnicities, as well as 12-month retrospective fall …

Mglu5 Inhibition In The Basolateral Amygdala Prevents Estrous Cycle-Dependent Changes In Cue-Induced Cocaine Seeking, Claire M. Corbett, Emily N. D. Miller, Jessica A. Loweth

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Drug associated cues are a common relapse trigger for individuals recovering from cocaine use disorder. Sex and ovarian hormones influence patterns of cocaine use and relapse vulnerability, with studies indicating that females show increased cue-induced craving and relapse vulnerability compared to males. In a rodent model of cocaine craving and relapse vulnerability, cue-induced cocaine seeking behavior following weeks of withdrawal from extended-access cocaine self-administration is higher in females in the estrus stage of the reproductive (estrous) cycle (Estrus Females) compared to both Males and females in all other stages (Non-Estrus Females). However, the neuronal substrates and cellular mechanisms underlying these …

Exposure To Pcb126 During The Nursing Period Reversibly Impacts Early-Life Glucose Tolerance, Brittany Breon Rice, Keegan W. Sammons, Sara Y. Ngo Tenlep, Madeline T. Weltzer, Leryn J. Reynolds, Cetewayo S. Rashid, Hollie I. Swanson, Kevin J. Pearson

Markey Cancer Center Faculty Publications

Polychlorinated biphenyls (PCBs) are persistent environmental organic pollutants known to have detrimental health effects. Using a mouse model, we previously demonstrated that PCB126 exposure before and during pregnancy and throughout the perinatal period adversely affected offspring glucose tolerance and/or body composition profiles. The purpose of this study was to investigate the glucose tolerance and body composition of offspring born to dams exposed to PCB126 during the nursing period only. Female ICR mice were bred, and half of the dams were exposed to either vehicle (safflower oil) or 1 μmole PCB126 per kg of body weight via oral gavage on postnatal …

Validation Of The Entrainment Signal Regularity Index And Associations With Children’S Changes In Bmi, Jennette P Moreno, Kevin M Hannay, Amy R Goetz, Olivia Walch, Philip Cheng

Children’s Nutrition Research Center Staff Publications

Objective: This study examined the validity of a novel metric of circadian health, the Entrainment Signal Regularity Index (ESRI), and its relationship to changes in BMI during the school year and summer.

Methods: In a longitudinal observational data set, this study examined the relationship between ESRI score and children's (n = 119, 5- to 8-year-olds) sleep and physical activity levels during the school year and summer, differences in ESRI score during the school year and summer, and the association of ESRI score during the school year and summer with changes in BMI across those time periods.

Results: The ESRI score …

Affinity Purification Of Serum-Derived Anti-Ia-2 Autoantibodies In Type 1 Diabetes Using A Novel Mbp-Ia-2 Fusion Protein, Thilini Mendis, Barbora Filipova, Jing Jing Wang, Massimo Pietropaolo, Michael W Jackson

Faculty, Staff and Students Publications

Autoantibodies targeting epitopes contained within the intracellular domain (IC) of the protein phosphatase-like islet antigen 2 (IA-2) are a common marker of autoimmune type 1 diabetes (T1D), however the isolation of genuine, serum derived anti-IA-2 autoantibodies has proven challenging due to a lack of suitable bioassays. In the current study, an ELISA format was developed for affinity purification of human anti-IA-2ic autoantibodies utilizing a fusion protein (FP) incorporating maltose binding protein and the full-length IA-2IC domain. Using a T1D patient cohort validated for anti-IA-2ic autoantibodies by commercial ELISA, we demonstrate the MBP-IA-2ic FP ELISA detects serum anti-IA-2IC autoantibodies from 3 …

Tfeb-Mediated Lysosomal Exocytosis Alleviates High-Fat Diet-Induced Lipotoxicity In The Kidney, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease, in both humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here, we found that palmitic acid strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 pathway in a Rag GTPase-dependent manner, though these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney …

Promoting Health Equity: Identifying Parent And Child Reactions To A Culturally-Grounded Obesity Prevention Program Specifically Designed For Black Girls Using Community-Engaged Research, Haley Allen, Chishinga Callender, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

The Butterfly Girls (BFG) Study is a culturally and developmentally appropriate online obesity prevention program for 8-10-year-old Black girls designed with key stakeholders in the Black community. This multi-methods investigation, conducted with parent-child dyads who participated in an outcome evaluation of the intervention, aimed to understand parent and child reactions to the program. We were particularly interested in understanding perceptions regarding its cultural and developmental appropriateness, relevance and acceptability. Program participation and survey data (demographics, parent and child write-in comments on process evaluation surveys) were analyzed. Participation data demonstrated high adherence in treatment and comparison groups. Descriptive statistics were calculated …