Endocrinology, Diabetes, and Metabolism Commons^™

Pskh1 Kinase Activity Is Differentially Modulated Via Allosteric Binding Of Ca2+ Sensor Proteins, Christopher R Horne, Toby A Dite, Samuel N Young, Lucy J Mather, Laura F Dagley, Jared L Johnson, Tomer M Yaron-Barir, Emily M Huntsman, Leonard A Daly, Dominic P Byrne, Antonia L Cadell, Boaz H Ng, Jumana Yousef, Dylan H Multari, Lianju Shen, Luke M Mcaloon, Gerard Manning, Mark A Febbraio, Anthony R Means, Lewis C Cantley, Maria C Tanzer, David R Croucher, Claire E Eyers, Patrick A Eyers, John W Scott, James M Murphy

Children’s Nutrition Research Center Staff Publications

Protein Serine Kinase H1 (PSKH1) was recently identified as a crucial factor in kidney development and is overexpressed in prostate, lung, and kidney cancers. However, little is known about PSKH1 regulatory mechanisms, leading to its classification as a “dark” kinase. Here, we used biochemistry and mass spectrometry to define PSKH1’s consensus substrate motif, protein interactors, and how interactors, including Ca2+ sensor proteins, promote or suppress activity. Intriguingly, despite the absence of a canonical Calmodulin binding motif, Ca2+-Calmodulin activated PSKH1 while, in contrast, the ER-resident Ca2+ sensor of the Cab45, Reticulocalbin, Erc55, Calumenin (CREC) family, Reticulocalbin-3, suppressed PSKH1 catalytic activity. In …

Regulating Chemoresistance And Cancer Stemness: The Cdh17-Yap Pathway In Distinct Cellular States Of Lung Cancer Ctc Clusters, Zujun Que, Dan Qi, Yun Yang, Wang Yao, Jiajun Liu, Yan Li, Yuanyuan Yu, Luyao Wang, Fangfei Li, Ge Zhang, Erxi Wu, Jianhui Tian

Children’s Nutrition Research Center Staff Publications

Background: Drug resistance in metastatic lung cancer significantly contributes to patient mortality. This study explores the role of circulating tumor cells (CTCs), the precursors to metastasis, in driving this resistance. We aim to delineate the unique biological traits of CTC clusters in lung cancer and elucidate the mechanisms underlying their resistance to chemotherapy.

Methods: We used an ultralow adsorption plate to establish a CTC suspension culture system. Comparisons between adherent and suspension cultures of CTC-TJH-01 cells were made via Cell Counting Kit-8 (CCK-8), western blot, immunofluorescence, and flow cytometry assays to evaluate cell proliferation, drug resistance, and cancer stemness. The …

Erythritol, Erythronate, And Cardiovascular Outcomes In Older Adults In The Aric Study, Layla A Abushamat, Bing Yu, Ron C Hoogeveen, Caroline Sun, Chao Cheng, Sean M Hartig, Mark A Herman, Ashok Balasubramanyam, Jane Eb Reusch, Elizabeth Selvin, Chiadi E Ndumele, Vijay Nambi, Christie M Ballantyne

Faculty, Staff and Student Publications

BACKGROUND: Circulating erythritol, an endogenously produced metabolite and an artificial sweetener, is associated with cardiovascular outcomes.

OBJECTIVES: The authors assessed associations of erythritol and its downstream metabolite, erythronate, with cardiovascular risk factors and events in older adults in the ARIC (Atherosclerosis Risk In Communities) study (visit 5, 2011-2013).

METHODS: We included 4,006 participants without prevalent cardiovascular disease and with metabolomic profiling. Erythritol and erythronate were measured by mass spectrometry. We analyzed associations of log-transformed erythritol and erythronate with cardiovascular risk factors and events using Cox proportional hazard models.

RESULTS: Participants in the highest tertiles of erythritol or erythronate were older, …

Biguanides Antithetically Regulate Tumor Properties By The Dose-Dependent Mitochondrial Reprogramming-Driven C-Src Pathway, Jun Hyoung Park, Kwang Hwa Jung, Dongya Jia, Sukjin Yang, Kuldeep S Attri, Songyeon Ahn, Divya Murthy, Tagari Samanta, Debasmita Dutta, Meron Ghidey, Somik Chatterjee, Seung Yeop Han, Diego A Pedroza, Abha Tiwari, Joyce V Lee, Caitlin Davis, Shuting Li, Vasanta Putluri, Chad J Creighton, Nagireddy Putluri, Lacey E Dobrolecki, Michael T Lewis, Jeffrey M Rosen, José N Onuchic, Andrei Goga, Benny Abraham Kaipparettu

Faculty, Staff and Students Publications

The biguanide metformin attenuates mitochondrial oxidation and is proposed as an anti-cancer therapy. However, recent clinical studies suggest increased proliferation and fatty acid β-oxidation (FAO) in a subgroup of patients with breast cancer (BC) after metformin therapy. Considering that FAO can activate Src kinase in aggressive triple-negative BC (TNBC), we postulate that low-dose biguanide-driven AMPK-ACC-FAO signaling may activate the Src pathway in TNBC. The low bioavailability of metformin in TNBC xenografts mimics metformin's in vitro low-dose effect. Pharmacological or genetic inhibition of FAO significantly enhances the anti-tumor properties of biguanides. Lower doses of biguanides induce and higher doses suppress Src …

The Unfolding Story Of Protein Misfolding Causing Alzheimer Disease In Recipients Of Human Pituitary Growth Hormone, Evan G. Graber, Sayed M. Hadi Hosseini, Darrell M. Wilson, Alan D. Rogol

Division of Endocrinology, Diabetes and Metabolic Diseases Faculty Papers

Human growth hormone (hGH) has been in clinical use for children with GH deficiency (GHD) since the late 1950s. The original formulations were considered very safe with few adverse events reported. That changed remarkably in 1985 when the first patients with GHD, who had been treated with cadaveric hGH, were diagnosed with Creutzfeldt-Jakob disease (CJD). Fortunately, that same year a robust supply of recombinant hGH was released to the market whose adverse event profile did not include CJD. Patients who had received National Hormone and Pituitary Program hGH have been continuously followed since 1985. It is clear that prions are …

Glycemic Variability And Migraine: New Insights From Glucose Monitoring, Christina A. Nelson, Kyle Reavely, Matthew Jennings, Brandon Burger, Jackson Nielsen, Amanda Page, Alexander Kim, David Sant, Kyle Bills

Annual Research Symposium

No abstract provided.

Divergence In Cellular Markers Observed In Single-Cell Transcriptomics Datasets Between Cultured Primary Trabecular Meshwork Cells And Tissues, Alice Tian, Sangbae Kim, Hasna Baidouri, Jin Li, Xuesen Cheng, Janice Vranka, Yumei Li, Rui Chen, Vijaykrishna Raghunathan

Faculty, Staff and Students Publications

The trabecular meshwork within the outflow apparatus is critical in maintaining intraocular pressure homeostasis. In vitro studies employing primary cell cultures of the human trabecular meshwork (hTM) have conventionally served as surrogates for investigating the pathobiology of TM dysfunction. Despite its abundant use, translation of outcomes from in vitro studies to ex vivo and/or in vivo studies remains a challenge. Given the cell heterogeneity, performing single-cell RNA sequencing comparing primary hTM cell cultures to hTM tissue may provide important insights on cellular identity and translatability, as such an approach has not been reported before. In this study, we assembled a …

A Systematic Review Of Persisting Tissue Health Challenges Amid Insulin Delivery System Advancements: Continuous Subcutaneous Insulin Infusion (Csii) And Lipohypertrophy In Diabetic Patients, Marlena Muszynska, Emily Awdish

Annual Research Symposium

No abstract provided.

Pediatric Diabetes Education, Trisha Williams, Tobie O'Brien, Amanda Williams

Advanced Practice Perspectives Podcast: For Nursing Contact Hours

Join us as we delve into the groundbreaking changes in the diagnosis and treatment of type 1 diabetes in children. Amanda Williams shares insights on new staging processes and the FDA-approved drug teplizumab, which adds years of quality life to young patients.

Click here to stream the podcast episode.

A Deep Learning-Based System For Automatic Detection Of Emesis With High Accuracy In Suncus Murinus, Zengbing Lu, Yimeng Qiao, Xiaofei Huang, Dexuan Cui, Julia Y H Liu, Man Piu Ngan, Luping Liu, Zhixin Huang, Zi-Tong Li, Lingqing Yang, Aleena Khalid, Yingyi Deng, Sze Wa Chan, Longlong Tu, John A Rudd

Children’s Nutrition Research Center Staff Publications

Quantifying emesis in Suncus murinus (S. murinus) has traditionally relied on direct observation or reviewing recorded behaviour, which are laborious, time-consuming processes that are susceptible to operator error. With rapid advancements in deep learning, automated animal behaviour quantification tools with high accuracy have emerged. In this study, we pioneere the use of both three-dimensional convolutional neural networks and self-attention mechanisms to develop the Automatic Emesis Detection (AED) tool for the quantification of emesis in S. murinus, achieving an overall accuracy of 98.92%. Specifically, we use motion-induced emesis videos as training datasets, with validation results demonstrating an accuracy of 99.42% for …

Effect Of Vitamin K Supplementation On Insulin Resistance: A Review, Samantha Mccord, Rebecca Willier, Kaitlyn Kirby, Kaylin Mahoney, Lance Dillon, Rileigh Rahrig, Brianna Lu, Joshua Honaker, Emily Eddy

Pharmacy and Wellness Review

Insulin resistance is one of the pathological hallmarks that leads to the development of type II diabetes mellitus (T2DM). Around 40% of people aged 18 to 44 living in the United States have insulin resistance. Recent research, coupled with a better understanding of how vitamin K functions in the body, suggests that this vitamin could potentially help reduce insulin resistance. Vitamin K is not included in the American Diabetes Association (ADA) guidelines for the treatment of insulin resistance, but it has been shown to have some benefits in patients with T2DM. It may also serve as a treatment option for …

Lifestyle Attitudes And Habits In A Case Series Of Patients With Cancer And Metabolic Syndrome, Kimberly Siu, Isabel Martinez Leal, Natalia I Heredia, Jessica T Foreman, Jessica P Hwang

Faculty, Staff and Student Publications

Metabolic syndrome (MetS) is associated with increased cancer risk and poor cancer prognosis. The current study applied a mixed methods approach to better understand attitudes about making lifestyle changes and current dietary and physical activity behaviors among cancer patients with MetS at a cancer center and to explore the suitability of brief lifestyle questionnaires to help providers understand their patients' lifestyle attitudes and habits. Qualitative interviews were used to obtain patients' perspectives about lifestyle changes, and 3 quantitative questionnaires-the Readiness Ruler, Rate Your Plate, and the International Physical Activity Questionnaire-Short Form (IPAQ-SF)-were used to measure patients' readiness for lifestyle change, …

Antidiabetic Properties Of Prickly Pear (Opuntia Ficus-Indica) Fruit Extract, Kenzy Aidan Joseph Mckay

The Undergraduate Research Journal

Diabetes mellitus is a metabolic disorder that claims 1.5 million lives annually. Opuntia ficus-indica, commonly known as the prickly pear, has been commonly used in traditional folk medicine for its hypoglycemic properties. It has been claimed that it has antimicrobial and antioxidant properties as well. The plant is native to Mexico and is commonly found in the middle east and India and folk medicine from all of these areas have been using prickly pear medicinally for years. To test these claims an extract of locally sourced Opuntia ficus-indica was prepared using the flesh and seeds of the fruit. The …

The Misalignment Of Incentives In Academic Publishing And Implications For Journal Reform, Jennifer S Trueblood, David B Allison, Sarahanne M Field, Ayelet Fishbach, Stefan D M Gaillard, Gerd Gigerenzer, William R Holmes, Stephan Lewandowsky, Dora Matzke, Mary C Murphy, Sebastian Musslick, Vencislav Popov, Adina L Roskies, Judith Ter Schure, Andrei R Teodorescu

Children’s Nutrition Research Center Staff Publications

For most researchers, academic publishing serves two goals that are often misaligned-knowledge dissemination and establishing scientific credentials. While both goals can encourage research with significant depth and scope, the latter can also pressure scholars to maximize publication metrics. Commercial publishing companies have capitalized on the centrality of publishing to the scientific enterprises of knowledge dissemination and academic recognition to extract large profits from academia by leveraging unpaid services from reviewers, creating financial barriers to research dissemination, and imposing substantial fees for open access. We present a set of perspectives exploring alternative models for communicating and disseminating scientific research. Acknowledging that …

Seroprevalence And Associated Factors For Hepatitis B And Hepatitis C Viral Infection Among Patients With Diabetes Mellitus In Northern Tanzania, Doreen T. Eliah, Nyasatu G. Chamba, Abid M. Sadiq, Amos Mwasamwaja, Faustini C. Kimondo, Cuthbert D. Matay, Eliada B. Nziku, Tumaini E. Mirai, Ibrahim Ali Ibrahim Muhina, Fuad H. Said

Internal Medicine, East Africa

Background: The coexistence of viral hepatitis with diabetes mellitus (DM) significantly escalates the risk of severe outcomes. This study aimed to determine the seroprevalence and associated factors of hepatitis B (HBV) and hepatitis C (HCV) viral infections among DM patients in northern Tanzania.

Materials and methods: Conducted between February 2023 and May 2023, this hospital-based cross-sectional study enrolled 189 patients with DM from the Diabetic Clinic of Kilimanjaro Christian Medical Centre. A structured questionnaire captured relevant clinical information, and plasma blood sample was assessed for hepatitis B surface antigen and anti-hepatitis C antibody seropositivity. Data analysis employed SPSS v26, and …

Bilirubin Bioconversion To Urobilin In The Gut-Liver-Kidney Axis: A Biomarker For Insulin Resistance In The Cardiovascular-Kidney-Metabolic (Ckm) Syndrome, Zachary A. Kipp, Olufunto O. Badmus, David E. Stec, Brantley Hall, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies …

Leptin Receptor Neurons In The Dorsomedial Hypothalamus Require Distinct Neuronal Subsets For Thermogenesis And Weight Loss, Marie Francois, Laura Kaiser, Yanlin He, Yong Xu, J Michael Salbaum, Sangho Yu, Christopher D Morrison, Hans-Rudolf Berthoud, Heike Münzberg

Children’s Nutrition Research Center Staff Publications

The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHALepr neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHALepr neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable …

Association Between Maternal Stress And Child Sleep Quality: A Nationwide Echo Prospective Cohort Study, Sarah Dee Geiger, Aruna Chandran, Marie L Churchill, Maxwell Mansolf, Cai Zhang, Salma Musaad, Courtney K Blackwell, Stephanie M Eick, Dana E Goin, Susan Korrick, Akram Alshawabkeh, Patricia A Brennan, Carrie V Breton, Jose F Cordero, Sean Deoni, Viren D'Sa, Anne L Dunlop, Amy J Elliott, Assiamira Ferrara, Arlene Keddie, Monique Lebourgeois, Kaja Z Lewinn, Daphne Koinis-Mitchell, Maristella Lucchini, Sara S Nozadi, Thomas O'Connor, Yeyi Zhu, Emily Zimmerman, Susan L Schantz

Children’s Nutrition Research Center Staff Publications

Background: Childhood sleep quality is associated with physical, cognitive, and behavioral health and predicts later sleep quality; it has many determinants, including developmental exposures.

Objectives: To examine associations between maternal stress during pregnancy and childhood sleep quality and determine whether postnatal stress mediates the association.

Method: Data from the Environmental Influences on Child Health Outcomes cohort were used. Perceived Stress Scale (PSS) T-scores were the exposure measure. Outcome measures were preschool Child Behavior Checklist (CBCL) sleep syndrome scale and Patient-Reported Outcomes Measurement Information System Sleep Disturbance Parent Proxy short form 4a (PSD4a) T-scores at ages 4-8 years. Linear mixed-effects regression …

Spock2 Controls The Proliferation And Function Of Immature Pancreatic Β-Cells Through Mmp2, Katarzyna Blaszczyk, Anna P Jedrzejak, Natalia Ziojla, Ekaterina Shcheglova, Karolina Szarafin, Artur Jankowski, Christine A Beamish, Jolanta Chmielowiec, Omaima M Sabek, Ashok Balasubramanyam, Sanjeet Patel, Malgorzata Borowiak

Faculty, Staff and Students Publications

Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. Although mitogens could in theory be used to expand β-cells, adult β-cells very rarely replicate. In contrast, newly formed β-cells, including SC-β-cells, display higher proliferative capacity and distinct transcriptional and functional profiles. Through bidirectional expression modulation and single-cell RNA-seq, we identified SPOCK2, an ECM protein, as an inhibitor of immature β-cell proliferation. Human β-cells lacking SPOCK2 presented elevated MMP2 expression and activity, leading to β-integrin-FAK-c-JUN pathway activation. Treatment with the MMP2 protein resulted in pronounced short- and long-term SC-β-cell expansion, significantly increasing glucose-stimulated insulin …

Testosterone Modulation Of Muscle Transcriptomic Profile During Lifestyle Therapy In Older Men With Obesity And Hypogonadism, Viola Viola, Tagari Samanta, Maria Liza Duremdes Nava, Alessandra Celli, Reina Armamento-Villareal, Ngoc Ho Lam Nguyen, Georgia Colleluori, Yoann Barnouin, Nicola Napoli, Clifford Qualls, Benny Abraham Kaipparettu, Dennis T Villareal

Faculty, Staff and Students Publications

Background: Testosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight-loss-induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.

Objective: To investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high-risk older population.

Methods: Among 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26-week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.

Results: Despite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (-2% vs. -4%, respectively; p = …