Endocrinology, Diabetes, and Metabolism Commons^™

A Class Of Benzofuranoindoline-Bearing Heptacyclic Fungal Ripps With Anticancer Activities, Qiuyue Nie, Fanglong Zhao, Xuerong Yu, Mithun C Madhusudhanan, Caleb Chang, Siting Li, Sandipan Roy Chowdhury, Bryce Kille, Andy Xu, Rory Sharkey, Chunxiao Sun, Hongzhi Zeng, Shuai Liu, Dishu Zhou, Xin Yu, Kevin Yang, Sandra A C Figueiredo, Maria Zotova, Zichen Hu, Alan Y Du, Dongyin Guan, Rui Tang, Todd Treangen, Jin Wang, Pedro N Leão, Yang Gao, Junjie Chen, Peng Liu, Hans Renata, Xue Gao

Children’s Nutrition Research Center Staff Publications

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new pharmaceuticals, yet the therapeutic potential of fungal RiPPs remains largely underexplored. Here, we report asperigimycins as a distinct class of fungal RiPPs, featuring a unique heptacyclic scaffold consisting of a benzofuranoindoline core and three additional macrocycles, primarily assembled by six distinct fungi-specific DUF3328 oxidases. Inspired by the enhancement of anticancer activity through the N-terminal pyroglutamate in naturally occurring asperigimycins C and D, we chemically modify the inactive asperigimycin B with a series of lipid substitutions at its N-terminus. A derivative with a C-11 linear fatty …

Cognitive Frailty And Cardiometabolic Risk In Middle-Aged And Older Adults: Evidence From The Uk And China, Haiyang Yan, Jingjing Lang, Chengfeng Li, Samaneh Eftekhariranjbar, Guoyan Jiang, Jing Lei, Lixin Sun, Carlos J. Toro-Huamanchumo, Zhongyang Guan

Research outputs 2022 to 2026

Background: Cognitive frailty, a novel construct integrating cognitive and physical deficits, is increasingly recognized in aging research. Aims: This study aimed to examine the associations between cognitive frailty and cardiometabolic risk in two nationally representative cohorts from China and the United Kingdom. Methods: We analyzed data from 7,628 participants in the China Health and Retirement Longitudinal Study (CHARLS) and 4,703 participants from the English Longitudinal Study of Ageing (ELSA), all aged ≥ 50 years. Frailty was assessed using the frailty index (FI) in the main analysis. Cox proportional hazards models were applied to estimate hazard ratios (HRs) for incident cardiometabolic …

The Effect Of Prednisolone Ingestion And Acute Exercise On Lipocalin-2 And Its Variants In Young Men: A Pilot Randomised Crossover Study, Carlie Bauer, Rhiannon K. Patten, Qiyang Sun, Haoyun Li, Daniels Konja, Mary Woessner, Xuzhu Lin, Andrew Garnham, David L. Hare, Peter R. Ebeling, Marc Sim, Joshua R. Lewis, Yu Wang, Lewan Parker, Itamar Levinger

Research outputs 2022 to 2026

Lipocalin-2 (LCN2) has three main variants; polyaminated (hLCN2) and non-polyaminated (C87A and R81E). The polyaminated form is proposed to positively influence energy control, whereas the non-polyaminated forms negatively impact energy control in mice. Glucocorticoids negatively affect glucose regulation and exercise has a positive effect. We hypothesise that glucocorticoids will suppress, while exercise will increase hLCN2, and decrease C87A and R81E, which will be associated with improved insulin sensitivity. In a randomised crossover design, nine young healthy men (aged 27.8 ± 4.9 years; BMI 24.4 ± 2.4 kg/m2) completed 30 min of high-intensity aerobic exercise (90–95% heart rate reserve) after glucocorticoid …

Hypercalcemia Of Down Syndrome., Seth Lmb, Melissa Litao, Nasreen Talib, Jacob M. Redel

Manuscripts, Articles, Book Chapters and Other Papers

We present a case of hypercalcemia in a 12-month-old female with Down syndrome. The patient presented with significant weight loss (810 g since her 6-month visit) and severe growth failure (weight 5.8 kg, -4.5 SDs). Laboratory evaluation revealed severe hypercalcemia with appropriately suppressed PTH and 1,25-hydroxyvitamin D levels. Renal ultrasound confirmed medullary nephrocalcinosis. After excluding common etiologies, the patient was diagnosed with hypercalcemia of Down syndrome, also termed Abnormal Calcium, Calcinosis, Creatinine in Down syndrome. Treatment with intravenous fluids, calcitonin, and transition to a low-calcium formula (Calcilo XD) normalized serum calcium levels. The patient maintained normal calcium levels on restricted …

Cumulative Triglyceride-Glucose Index And Hypertension Risk: A Longitudinal Cohort Study, Zhaogui Wu, Dan Wu, Sichi Xu, Yan Borné, Yulong Lan, Shuohua Chen

Research outputs 2022 to 2026

Background: Prior research has established a positive association between the single-measured triglyceride-glucose (TyG) index and hypertension. Nevertheless, longitudinal studies addressing the enduring impact of TyG index on incident hypertension are lacking. This study sought to explore the association between cumulative TyG index (cum-TyG) and incident hypertension, especially obesity-related hypertension (ORHT). Methods: A total of 21,017 individuals [mean (SD) age: 48.5 ± 11.7 years, male (%): 14,544 (69.2)] without hypertension were recruited from the Kailuan Study. The cum-TyG was determined by multiplying the mean TyG index by the time intervals between successive visits. Multivariable Cox regression models were used to investigate …

Hypophosphatemia Across The Lifespan, Madhuni Herath, Richard Prince, Craig F. Munns, Albert Kim

Research outputs 2022 to 2026

No abstract provided.

Transcriptional Coregulator Zmiz1 Modulates Estrogen Responses That Are Essential For Healthy Endometrial Function, Sylvia C Hewitt, Frank Orellana, Ryan M Marquardt, Myeongjin Yi, Cynthia J Willson, Mark Y Chiang, Yong Song, Goutham Venkata Naga Davuluri, Christopher Day, Ramakrishna Kommagani, Joseph Rodriguez, Asgerally T Fazleabas, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

Estrogen is a critical regulator of endometrial health. Aberrant estrogen stimulation can result in infertility, endometrial cancer, and endometriosis. Here, we identified Zinc Finger MIZ-Type Containing 1 (Zmiz1) as a coregulator of uterine estrogen signaling. ZMIZ1 is colocalized with an estrogen receptor α–binding (ESR1-binding) super enhancer. ZMIZ1 mutations are found in endometrial cancer and its RNA levels trend toward reduction in endometrium of patients with endometriosis. ZMIZ1 is dynamically expressed in human endometrial tissues during the menstrual cycle. Disrupting ZMIZ1 in cultured human endometrial stromal cells resulted in impaired cell proliferation and decidual differentiation. Ablation of Zmiz1 using …

Barriers And Facilitators To Lifestyle Behavior Change And Goal Setting In Adolescents With Polycystic Ovary Syndrome., Manasa Gadiraju, Joy Y. Kim, Erin M. Green, Alexandra Macmillan Uribe, Honghui Chang, Tania S. Burgert, Melissa D. Olfert, Heidi Vanden Brink

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: To identify barriers and facilitators to lifestyle modifications and goal setting and characterize goal setting for adolescents with polycystic ovary syndrome (PCOS).

METHODS: Retrospective chart review of registered dietitian nutritionist (RDN) nutrition notes from 118 adolescents with PCOS 11-21 years evaluated at a multi-specialty PCOS clinic. Goals, barriers, and facilitators were coded using open coding and a priori objectives and characterized for emerging themes using qualitative content analysis.

RESULTS: Five major themes of barriers and facilitators to behavior change emerged: interest and motivation, family involvement, resources and food environment, taste preferences, and self-efficacy. RDNs set ≥3 goals with 52%, …

[Lele] Incorporating Physiological Constraints In Estimates Of Post-Prandial Insulin Secretion Rate, Justin K. Garrish, Christine L. Chan, Douglas Nychka, Cecilia Diniz Behn

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

Rare Case Of Visual Hallucinations In A 60-Year-Old Female With A Recurring Pituitary Macroadenoma, Angelica Alday, Farah Qureshi, Kayvan Mirhadi

Advances in Clinical Medical Research and Healthcare Delivery

Pituitary adenomas are the third most frequently occurring primary intracranial tumor and are benign neoplasms that can have profound clinical implications. While most of these masses cause hormone hypersecretion, they may also be clinically silent until they elicit symptoms of mass effect, including severe headaches and visual field defects such as bitemporal hemianopia. This report highlights an atypical presentation of a pituitary adenoma that could be valuable for internists to consider when forming a differential diagnosis for patients with hallucinations. We discuss a case of a 60-year-old woman with a recent history of multiple emergency department visits for ongoing urinary …

Mortality Among Transgender Persons: A Taiwan Matched-Population And Sibling-Comparison Cohort Study, Chih-Wei Hsu, Yang-Chieh Brian Chen, Liang-Jen Wang, Mu-Hong Chen, Yao-Hsu Yang, Chih-Sung Liang, Po-Yen Chen, Edward Chia-Cheng Lai

Children’s Nutrition Research Center Staff Publications

Background: Transgender persons have been reported to experience excess mortality, but evidence is dominated by Western cohorts and seldom addresses familial confounding.

Methods: We conducted a nationwide, retrospective cohort study using two prespecified comparison designs: matched population controls (1:4, matched on legal sex and birth date) and within-family cisgender sibling comparisons. Transgender persons were identified by ≥2 psychiatrist-recorded gender identity disorder diagnoses during 2001-2021; cohort entry required age ≥6 years. Participants were followed until death or December 31, 2022. We compared all-cause, external-cause (suicide and accidents), and internal-cause mortality using Cox regression adjusted for sociodemographics and medical comorbidity.

Findings: Among …

Concerns Regarding The Standard Deviation Of Individual Responses For Assessing Treatment Response Heterogeneity, Aaron R Caldwell, David B Allison, Andrew W Brown, Gary L Gadbury, Thirupathi Reddy Mokalla, R Drew Sayer, Andrew D Vigotsky

Children’s Nutrition Research Center Staff Publications

The estimation of treatment response heterogeneity (TRH) is increasingly important as medicine moves toward personalized approaches. While various statistical methods have been proposed to quantify TRH in parallel-group trials, the standard deviation of individual responses (SDIR) has gained prominence within physiological research. This method is intended to quantify individual response variation by comparing standard deviations of change scores between intervention and control groups. We acknowledge that SDIR represents an improvement over many other flawed approaches that often involve responder counting. However, SDIR has critical limitations: 1) it cannot overcome the fundamental problem of causal inference because the correlation between potential …

Prevalent Vertebral Fracture Is Associated With Incident Cardiovascular Disease Events In Older Individuals Referred For Bone Densitometry, John T. Schousboe, Barret A. Monchka, J. Michael Davidson, Douglas Kimelman, Syed Zulqarnain Gilani, Zaid Ilyas, Siobhan Reid, Joshua R. Lewis, William D. Leslie

Research outputs 2022 to 2026

Background: It is unknown if prevalent vertebral fracture (PVFx) captured on bone density vertebral fracture assessment (VFA) images predicts incident CVD events. Methods: 11,760 individuals (mean [SD] age 75.7 [6.8] years, 94 % female) had VFA contemporaneously with bone densitometry in Manitoba, Canada, between February 2010 and December 2017, of whom 1919 (16.3 %) had ≥1 PVFx. This cohort was followed over a mean (SD) 3.8 (2.3) years for Major Adverse Cardiovascular Events (MACE, composite of hospitalization for myocardial infarction, non-hemorrhagic stroke, or all-cause mortality) and other CVD events (hospitalization for coronary artery disease, congestive heart failure, peripheral vascular disease, …

Myeloid-Specific Camkk2 Deficiency Protects Against Diet-Induced Obesity And Insulin Resistance By Rewiring Metabolic Gene Expression And Enhancing Energy Expenditure, Andrea R Ortiz, Kevin Nay, Brittany A Stork, Adam M Dean, Sean M Hartig, Cristian Coarfa, Surafel Tegegne, Christopher Rm Asquith, Daniel E Frigo, Brian York, Anthony R Means, Mark A Febbraio, John W Scott

Faculty, Staff and Students Publications

Objective: Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity. …

Dysregulated Mitochondrial Energy Metabolism Drives The Progression Of Mucosal Field Effects To Invasive Bladder Cancer, Sangkyou Lee, Sung Yun Jung, Pawel Kuś, Jolanta Bondaruk, June Goo Lee, Roman Jaksik, Nagireddy Putluri, Khanh N Dinh, David Cogdell, Huiqin Chen, Yishan Wang, Jiansong Chen, Neema Navai, Colin Dinney, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Charles C Guo, Peng Wei, Marek Kimmel, Bogdan Czerniak

Faculty, Staff and Students Publications

Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from field effects. Analysis of the mutational landscape identified three types of mutations, referred to as α, β, and γ. Time modeling of the mutations revealed that carcinogenesis may span 30 years and can be divided into dormant and progressive phases. The α mutations developed in the dormant phase. The progressive phase lasted 5 years and was signified by expanding β mutations, but it was driven to invasive cancer by γ mutations. …

Glycerol-3-Phosphate Activates Chrebp, Fgf21 Transcription And Lipogenesis In Citrin Deficiency, Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner

Faculty, Staff and Students Publications

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms …

Risk Score Roulette: A Cautionary Tale Of Polygenic Risk Score Reliability, Diane Xue, Elizabeth E Blue, Alexis C Wood, Jerome I Rotter, Alison E Fohner

Children’s Nutrition Research Center Staff Publications

Genetic risk prediction for Alzheimer's disease (AD) has high potential impact, yet few studies have assessed the reliability of various polygenic risk score (PRS) methods at the individual level. Here, we evaluated the reliability of AD PRS estimates among 6338 participants from the Multi-Ethnic Study of Atherosclerosis. We compared four PRS models that have been previously associated with dementia risk. Despite similar population-level performance metrics, inter-model reliability of individual-level risk assessment was low, even among individuals classified in the top and bottom deciles. These findings raise serious concerns about the downstream application of PRS for guiding interventions for AD.

Scrotal Temperature Change During Running In Naked Humans, Yasuho Takii, Makoto Fukuda, Kazuyuki Kanosue, Tamae Yoda

Children’s Nutrition Research Center Staff Publications

Male reproductive organs are functionally affected by high body temperature. This study aimed to clarify the thermoregulation mechanisms of the human scrotum during running, and experiments were conducted to investigate temperature changes in the whole body and the scrotum. Eleven male long-distance runners performed treadmill running at 60%[Formula: see text] for 60 min in an indoor environment at 27 °C and 40% relative humidity. Immediately after the start of the run, the skin temperatures in areas other than the scrotum decreased or showed a tendency to decrease. In contrast, the scrotal temperature increased immediately after the start of the run. …

Factor Structure Of Food And Physical Activity Parenting Practices Among Us Fathers By Ethnicity And Survey Language: A Cross Sectional Study, Salma M A Musaad, Louise C Mâsse, Alicia Beltran, Oriana Perez, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

Background: Parenting practices contribute to children’s eating and physical activity behaviors, and thereby their risk of obesity and associated medical conditions. Fathers may engage in different parenting practices than mothers. The objective of this study was therefore to establish psychometrically sound tools in English and Spanish for measuring Physical Activity Parenting Practices (PAPP) and Food Parenting Practices (FPP) for Hispanic and non-Hispanic fathers of diverse races for use in future studies, such as evaluations of family-based obesity interventions targeted at fathers.

Methods: We conducted a preliminary assessment of the psychometric properties of a reduced version of the PAPP and FPP …

Biallelic Loss-Of-Function Variants In C19orf44 Lead To Retinal Degeneration, Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen

Faculty, Staff and Students Publications

Background: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.

Methods: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to …