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Browsing by Author "Considine, Robert"
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Item Cellular & Molecular Mechanisms That Contribute to the Early Development of Skeletal Muscle & Systemic Insulin Resistance(2019-10) Grice, Brian A.; Elmendorf, Jeffrey; Considine, Robert; Herring, Paul; Mather, Kieren; Mirmira, RaghuInsulin resistance starts years before type 2 diabetes (T2D) diagnosis, even before recognition of prediabetes. Mice on a high fat diet have a similar early onset of insulin resistance, yet the mechanism remains unknown. Several studies have demonstrated that skeletal muscle insulin resistance resulting from obesity or high fat feeding does not stem from defects in proximal insulin signaling. Our lab discovered that excess plasma membrane cholesterol impairs insulin action. Excess cholesterol in the plasma membrane causes a loss of cortical actin filaments that are essential for glucose transporter GLUT4 regulation by insulin. Our cell studies further revealed that increased hexosamine biosynthesis pathway (HBP) activity increases O-linked N-acetylglucosamine modification of the transcription factor Sp1, leading to transcription of HMG-CoA reductase (HMGR), the rate-limiting enzyme in cholesterol biosynthesis. Our central hypothesis is that cholesterol accumulation mediated by HBP activity is an early reversible mechanism of high-fat diet-induced insulin resistance. We performed a series of studies and found that early high-fat feeding-induced insulin resistance is associated with a buildup of cholesterol in skeletal muscle membranes (SMM). Akin to the antidiabetic effect of caloric restriction, we found that high-fat diet removal fully mitigated SMM cholesterol accumulation and insulin resistance. Furthermore, using the cholesterol-binding agent methyl-β-cyclodextrin (MβCD), studies established causality between excess SMM cholesterol and insulin resistance. To begin to assess the role of the HBP/Sp1 in contributing to de novo cholesterol biosynthesis, SMM accumulation, and insulin resistance we treated high-fat fed mice with an Sp1 inhibitor, mithramycin. We found that mithramycin prevented SMM cholesterol accumulation and insulin resistance. This series of studies provide evidence that HBP/Sp1-mediated cholesterol accumulation in SMM is a causal, early and reversible mechanism of whole body insulin resistance.Item Design and baseline characteristics of the Cognitive and Aerobic Resilience for the Brain (CARB) study(Elsevier, 2023-08) Tam, Joyce W.; Khurshid, Kiran; Sprague, Briana; Clark, Daniel O.; Xu, Huiping; Moser, Lyndsi R.; Miller, Douglas K.; Considine, Robert; Callahan, Christopher M.; Garringer, Holly J.; Rexroth, Daniel; Unverzagt, Frederick W.; Pathology and Laboratory Medicine, School of MedicineBackground Treatments that delay progression of cognitive impairment in older adults are of great public health significance. This manuscript outlines the protocol, recruitment, baseline characteristics, and retention for a randomized controlled trial of cognitive and aerobic physical training to improve cognition in individuals with subjective cognitive dysfunction, the “Cognitive and Aerobic Resilience for the Brain” (CARB) study. Methods Community-dwelling, older adults with self-reported memory loss were randomly assigned to receive either computer-based cognitive training, aerobic physical training, combined cognitive and physical training, or education control. Treatment was delivered 2- to 3-times per week in 45- to 90-min sessions for 12 weeks by trained facilitators videoconferencing into subject's home. Outcome assessments of were taken at the baseline, immediately following training, and 3-months after training. Results 191 subjects were randomized into the trial (mean age, 75.5 years; 68% female; 20% non-white; mean education, 15.1 years; 30% with 1+ APOE e4 allele). The sample was generally obese, hypertensive, and many were diabetic, while cognition, self-reported mood, and activities of daily living were in the normal range. There was excellent retention throughout the trial. Interventions were completed at high rates, participants found the treatments acceptable and enjoyable, and outcome assessments were completed at high rates. Conclusions This study was designed to determine the feasibility of recruiting, intervening, and documenting response to treatment in a population at risk for progressive cognitive decline. Older adults with self-reported memory loss were enrolled in high numbers and were well engaged with the intervention and outcome assessments.Item Effect of Depression Treatment on Somatic Depressive Symptoms and Cardiometabolic Biomarkers among People without Diabetes(2022-05) Shell, Aubrey Lynn; Stewart, Jesse; Hirsh, Adam; Cyders, Melissa; Considine, RobertWhile depression is a risk factor for type 2 diabetes, little is known about the effect of depression treatment on diabetes risk markers. Using data from the recently completed eIMPACT trial (NCT02458690, supported by R01 HL122245), I examined if depression intervention improves diabetes risk markers and if improvements in somatic depressive symptoms mediate potential intervention effects. 216 participants (primary care patients ≥50 years with depression and elevated cardiovascular disease risk from a safety net healthcare system) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care intervention involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants; n=107) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and affiliated psychiatrists; n = 109). Given my focus on diabetes risk, I excluded participants who did not attend the post-treatment visit (n = 17) or who had a diabetes history at pre-treatment (n = 73), leaving a final sample of 126 (n=66 intervention, n=60 usual care; Mage = 58 years, 79% women, 50% Black, 47% with income <$10k/year). I computed depressive symptom severity variables from the Hopkins Symptom Checklist-20 (SCL-20) items: hyperphagia (“overeating” item), poor appetite (“poor appetite”), hypersomnia (“sleeping too much”), disturbed sleep (“sleep that is restless or disturbed”) and SCL-15 (mean of items not pertaining to appetite or sleep). I calculated insulin resistance from fasting plasma glucose and insulin using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)-2 calculator, body mass index (BMI) from measured height and weight, and plasma concentrations of high-sensitivity C-reactive protein (hsCRP), leptin, and ghrelin using ELISA kits. Parallel mediation analyses revealed that 12 months of modernized collaborative care for depression improved both directions of sleep symptoms but did not improve poor appetite or hyperphagia – the somatic symptom most consistently linked with increases in HOMA-IR, BMI, hsCRP, and leptin. Of the five cardiometabolic biomarkers examined, the eIMPACT intervention decreased only hsCRP and ghrelin. There were no intervention effects on HOMA-IR, BMI, or leptin. In addition, no somatic depressive symptoms mediated intervention effects on the cardiometabolic biomarkers, nor did race moderate any mediation effects. Further research is warranted to determine best practices for targeting hyperphagia and reducing cardiometabolic disease risk among people with depression.Item Effect of Experimental Change in Children’s Sleep Duration on Television Viewing and Physical Activity(Wiley, 2016) Hart, Chantelle N.; Hawley, Nicola; Davey, Adam; Carskadon, Mary; Raynor, Hollie; Jelalian, Elissa; Owens, Judith; Considine, Robert; Wing, Rena R.; Department of Medicine, School of MedicineBackground Paediatric observational studies demonstrate associations between sleep, television viewing and potential changes in daytime activity levels. Objective(s) To determine whether experimental changes in sleep lead to changes in children's sedentary and physical activities. Methods Using a within-subject counterbalanced design, 37 children 8–11 years old completed a 3-week study. Children slept their typical amount during a baseline week and were then randomized to increase or decrease mean time in bed by 1.5 h/night for 1 week; the alternate schedule was completed the final week. Children wore actigraphs on their non-dominant wrist and completed 3-d physical activity recalls each week. Results Children reported watching more television (p < 0.001) and demonstrated lower daytime actigraph-measured activity counts per epoch (p = 0.03) when sleep was decreased (compared with increased). However, total actigraph-measured activity counts accrued throughout the entire waking period were higher when sleep was decreased (and children were awake for longer) than when it was increased (p < 0.001). Conclusion(s) Short sleep during childhood may lead to increased television viewing and decreased mean activity levels. Although additional time awake may help to counteract negative effects of short sleep, increases in reported sedentary activities could contribute to weight gain over time.Item Randomized double-masked controlled trial of cognitive training in breast cancer survivors: a preliminary study(Springer, 2022) Von Ah, Diane; McDonald, Brenna C.; Crouch, Adele D.; Ofner, Susan; Perkins, Susan; Storey, Susan; Considine, Robert; Unverzagt, Fred; Radiology and Imaging Sciences, School of MedicinePurpose: To evaluate the acceptability, satisfaction, and preliminary efficacy of cognitive training for improving cognitive function and health outcomes in breast cancer survivors (BCS). Patients and methods: BCS enrolled in this 2-group randomized, double-masked controlled trial of cognitive training. Primary outcomes included the acceptability and satisfaction of the interventions. Secondary outcomes included examining the effect size and reliable improvement of perceived cognitive function and health outcomes, including work ability, health perception (status and change), and quality of life. Exploratory outcomes were performance on neuropsychological tests and plasma levels of brain-derived neurotropic factor (BDNF). Data were collected at baseline and immediately post-intervention. Using ANCOVA models, the intervention was compared to attention control while adjusting for covariates and baseline values. The effect sizes for differences in means and the reliable improvement percentage were reported. Results: Thirty-six BCS completed the study and were on average 57.6 (SD = 8.0) years old, 59.4% Caucasian, and had some college education (74.5%). Both programs were reported to be satisfactory and acceptable. Non-significant small effect sizes were noted for the intervention on cognitive abilities (d = 0.26) and cognitive concerns (d = - 0.32), with reliable improvement noted in 32% and 28% of BCS, respectively. Small to medium effect sizes were noted in improvement in work ability (d = 0.37) and health perception status (d = 0.30) and change (d = 0.60, p < 0.05). Conclusions: Cognitive training was acceptable to BCS and resulted in improvement in perceived cognitive function and perceptions of "real-world" health benefits. A larger randomized controlled trial is warranted to determine its effectiveness for objective cognitive performance.Item Stress-activated MIG6 compromises hepatic metabolism during diet-induced obesity(2016-07-25) Lutkewitte, Andrew John; Fueger, Patrick T.; Considine, Robert; Evans-Molina, Carmella; Tune, Johnathan; Elmendorf, JeffreyObesity-induced hepatic fat accumulation or nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States. Unfortunately, NALFD patients are at higher risk of cardiovascular disease and mortality. The development of hepatic steatosis is multi-factorial and leads to a variety of pathologies. Yet, the molecular mechanisms behind liver disease during hepatic fat accumulation remain unclear. Here, we describe novel mechanisms of impaired liver function in the context of obesity-induced hepatic stress. Using chemical- and fatty acid-induced endoplasmic reticulum (ER) stress, we discovered ER stress decreases the activation of the pro-growth, pro survival, receptor tyrosine kinase, epidermal growth factor receptor (EGFR) in vitro. Importantly, EGFR was inhibited during these stress conditions by the induction and stabilization of mitogen inducible gene 6 (Mig6). Furthermore, Mig6 knockdown in vitro enhanced EGFR signaling and promoted survival. We demonstrated that mice fed a high fat diet have decreased EGFR activation and increased Mig6 protein expression, likely due to obesity-induced ER stress. To determine the functional consequences of increased Mig6 expression, we generated Mig6 liver-specific knockout mice (Mig6 LKO) and subjected them to high fat feeding. During diet-induced obesity, Mig6 LKO mice had improved hepatic glucose tolerance despite no improvements in whole-body insulin sensitivity or insulin secretion. Hepatic insulin signaling, measured by AKT activation, was similar between Mig6 LKO and littermate controls. However, several insulin-sensitive genes involved in gluconeogenesis were altered in Mig6 LKO mice compared to controls. In addition, Mig6 LKO mice had higher plasma high density lipoproteins and triglycerides despite similar liver lipid content. Using RNA sequencing we discovered Mig6 regulates several metabolic pathways in liver. These findings indicated Mig6 not only controls hepatic growth and survival but also regulates metabolism. This work will help us to better understand how augmented growth factor signaling impacts metabolic regulation during pathological obesity.