The Effects of Exercise Training on Insulin Supply and Demand in Breast Cancer Survivors

Elevated insulin concentrations may influence cancer and cardiometabolic disease onset and prognosis, and lower insulin levels after exercise may contribute to disease prevention and overall health. The effect of exercise training on systemic and tissue-specific insulin supply and demand in breast cancer survivors and adults at risk for cardiometabolic disease is unclear. The objective of this dissertation was to evaluate the effects of exercise training on postmeal insulin concentrations in breast cancer survivors, and identify mechanisms responsible for changes to insulin supply and demand following exercise training in breast cancer survivors and adults at risk for cardiometabolic disease. Study 1 investigated differences between systemic and tissue-specific responses to exercise training and/or the anti-diabetes drug metformin in adults with prediabetes. Fasting proinsulin concentrations were lower following combined exercise and metformin (-24%), and insulin clearance was higher in the metformin and combined exercise and metformin groups (+19% and +17%). There were no differences in the exercise or placebo group, and taken together with previous work from our lab, suggests that exercise regulates insulin supply and demand systemically, while pharmacological adaptations may be tissue-specific. Study 2 evaluated the effects of physical activity on postmeal insulin concentrations in breast cancer survivors. Fifteen women completed 12 weeks of exercise training with pre- and post-intervention oral glucose tolerance testing. Insulin concentrations 120 minutes following glucose ingestion decreased (68.8±34.5 vs. 56.2±31.9 uU/ml, p Study 3 assessed the specific components of insulin supply and demand that may contribute to the blunted or absent postmeal insulin response observed in study 2. There was a significant increase in estimated skeletal muscle glucose uptake following exercise training (5.7±1.8 vs. 7.2 ±1.8, mmo*pmol*kg/m2

Nursing Poster - 2019

Nursing Posters - 2019https://scholarlycommons.libraryinfo.bhs.org/research_education/1007/thumbnail.jp

Pilot study of impact of a pedal desk on postprandial responses in sedentary workers

Physical inactivity has been linked to rates of obesity, diabetes, and heart disease through insulin resistance and other mechanisms. Although sedentary workplace environments have unintentionally contributed to the risk for chronic diseases, innovations in the workplace environment could potentially rectify this public and occupational health problem. Purpose: To evaluate the effects of light-intensity physical activity using a pedal desk (PD) compared with a standard desk (STD) in a pilot study on postprandial metabolic responses and work skills. Methods: Twelve overweight/obese full-time sedentary office workers (six men and six women; body mass index, 28.7 +/- 3.6 kg m-2) were tested in two conditions: 1) PD, pedaling at self-selected light-intensity pace for 2 h and 2) STD, remaining seated for 2 h in a conventional workstation setup while performing scripted computer-based work tasks. Blood samples were analyzed for plasma glucose, insulin, and free-fatty acids in response to a standardized meal and work skills were evaluated. Paired samples t-tests were used to examine the differences in metabolic responses and work performance tasks between the conditions. Results: Pedal desk use required significantly less insulin to maintain glucose concentrations compared with STD condition (peak insulin concentration, 42.1 uU mL-1 vs 66.9 uU mL-1; P = 0.03; and area under the curve, 302.6 vs 441.8 uU min-1 mL-1; P 0.05). In addition, pedaling at a self-paced rate caused no adverse effects on work skills (P > 0.05). Conclusions: The PD resulted in lower postmeal insulin concentrations without an overall negative impact on work skills. Thus, the PD could have the potential to achieve public and occupational health goals in sedentary work environments.Peer reviewedCommunity Health Sciences, Counseling and Counseling Psycholog

cDNA sequence and genomic structure of EVI2B, a gene lying within an intron of the neurofibromatosis type 1 gene

The gene responsible for neurofibromatosis type 1 (NF1), one of the more common inherited human disorders, was identified recently, and segments of it were cloned. Two translocation breakpoints that interrupt the NF1 gene in NF1 patients flank a 60-kb segment of DNA that contains the EVI2A locus (previously reported as the EVI2 locus), the human homolog of a mouse gene, Evi-2A, implicated in retrovirus-induced murine myeloid tumors. EVI2A lies within an intron of the NF1 gene and is transcribed from telomere toward centromere, opposite to the direction of transcription of the NF1 gene. Here we describe a second locus, EVI2B, also located between the two NF1 translocation breakpoints. Full-length cDNAs from the EVI2B locus detect a 2.1-kb transcript in bone marrow, peripheral blood mononuclear cells, and fibroblasts. Sequencing studies predict an EVI2B protein of 448 amino acids that is proline-rich and contains an N-terminal signal peptide, an extracellular domain with four potential glycosylation sites, a single hydrophobic transmembrane domain, and a cytoplasmic hydrophilic domain. At the level of genomic DNA the EVI2B locus lies within the same intron of the NF1 gene as EVI2A and contains a 57-bp 5' exon that is noncoding, an 8-kb intron, and a 2078-bp 3' exon that includes the entire open reading frame. EVI2B is transcribed in the same direction as EVI2A; its 5' exon lies only 4 kb downstream from the 3' exon of the EVI2A locus. In the mouse the 5' exon of the homologous gene, Evi-2B, lies approximately 2.8 kb from the 3' end of Evi-2A, in the midst of a cluster of viral integration sites identified in retrovirus-induced myeloid tumors; thus, Evi-2B may function as an oncogene in these tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29439/1/0000521.pd

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

Elevated insulin levels following seven days of increased sedentary time are due to lower hepatic extraction and not higher insulin secretion

Higher insulin following sedentary behavior may be due to increased insulin secretion (IS), decreased hepatic insulin extraction (HIE), or a combination of both. Ten healthy adults completed glucose tolerance tests following seven days of normal activity and seven days of increased sitting. There were no differences in IS, however HIE 120 minutes post-ingestion (85.4±7.2% vs. 74.6±6.6%, pThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author