Browsing by Author "Grice, Brian A."

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    An early, reversible cholesterolgenic etiology of diet-induced insulin resistance
    (Elsevier, 2023) Covert, Jacob D.; Grice, Brian A.; Thornburg, Matthew G.; Kaur, Manpreet; Ryan, Andrew P.; Tackett, Lixuan; Bhamidipati, Theja; Stull, Natalie D.; Kim, Teayoun; Habegger, Kirk M.; McClain, Donald A.; Brozinick, Joseph T.; Elmendorf, Jeffrey S.; Anatomy, Cell Biology and Physiology, School of Medicine
    Objective: A buildup of skeletal muscle plasma membrane (PM) cholesterol content in mice occurs within 1 week of a Western-style high-fat diet and causes insulin resistance. The mechanism driving this cholesterol accumulation and insulin resistance is not known. Promising cell data implicate that the hexosamine biosynthesis pathway (HBP) triggers a cholesterolgenic response via increasing the transcriptional activity of Sp1. In this study we aimed to determine whether increased HBP/Sp1 activity represented a preventable cause of insulin resistance. Methods: C57BL/6NJ mice were fed either a low-fat (LF, 10% kcal) or high-fat (HF, 45% kcal) diet for 1 week. During this 1-week diet the mice were treated daily with either saline or mithramycin-A (MTM), a specific Sp1/DNA-binding inhibitor. A series of metabolic and tissue analyses were then performed on these mice, as well as on mice with targeted skeletal muscle overexpression of the rate-limiting HBP enzyme glutamine-fructose-6-phosphate-amidotransferase (GFAT) that were maintained on a regular chow diet. Results: Saline-treated mice fed this HF diet for 1 week did not have an increase in adiposity, lean mass, or body mass while displaying early insulin resistance. Consistent with an HBP/Sp1 cholesterolgenic response, Sp1 displayed increased O-GlcNAcylation and binding to the HMGCR promoter that increased HMGCR expression in skeletal muscle from saline-treated HF-fed mice. Skeletal muscle from these saline-treated HF-fed mice also showed a resultant elevation of PM cholesterol with an accompanying loss of cortical filamentous actin (F-actin) that is essential for insulin-stimulated glucose transport. Treating these mice daily with MTM during the 1-week HF diet fully prevented the diet-induced Sp1 cholesterolgenic response, loss of cortical F-actin, and development of insulin resistance. Similarly, increases in HMGCR expression and cholesterol were measured in muscle from GFAT transgenic mice compared to age- and weight-match wildtype littermate control mice. In the GFAT Tg mice we found that these increases were alleviated by MTM. Conclusions: These data identify increased HBP/Sp1 activity as an early mechanism of diet-induced insulin resistance. Therapies targeting this mechanism may decelerate T2D development.
  • Thumbnail Image
    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, Raghu
    Insulin 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.
  • Thumbnail Image
    Item
    Excess membrane cholesterol is an early contributing reversible aspect of skeletal muscle insulin resistance in C57BL/6NJ mice fed a Western-style high-fat diet
    (American Physiological Society, 2019-08-06) Grice, Brian A.; Barton, Kelly J.; Covert, Jacob D.; Kreilach, Alec M.; Tackett, Lixuan; Brozinick, Joseph T.; Elmendorf, Jeffrey S.; Anatomy and Cell Biology, School of Medicine
    Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter (GLUT)4 regulation occurs early after high-fat feeding. We fed 6-wk-old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or a high-fat (HF, 45% kcal) diet for 1 wk. This HF feeding challenge was associated with an increase, albeit slight, in body mass, glucose intolerance, and hyperinsulinemia. Liver analyses did not reveal signs of hepatic insulin resistance; however, skeletal muscle immunoblots of triad-enriched regions containing transverse tubule membrane showed a marked loss of stimulated GLUT4 recruitment. An increase in cholesterol was also found in these fractions from HF-fed mice. These derangements were associated with a marked loss of cortical filamentous actin (F-actin) that is essential for GLUT4 regulation and known to be compromised by increases in membrane cholesterol. Both the withdrawal of the HF diet and two subcutaneous injections of the cholesterol-lowering agent methyl-β-cyclodextrin at 3 and 6 days during the 1-wk HF feeding intervention completely mitigated cholesterol accumulation, cortical F-actin loss, and GLUT4 dysregulation. Moreover, these beneficial membrane/cytoskeletal changes occurred concomitant with a full restoration of metabolic responses. These results identify skeletal muscle membrane cholesterol accumulation as an early, reversible, feature of insulin resistance and suggest cortical F-actin loss as an early derangement of skeletal muscle insulin resistance.
  • Thumbnail Image
    Item
    New aspects of cellular cholesterol regulation on blood glucose control- review and perspective on the impact of statin medications on metabolic health
    (2017-01-01) Grice, Brian A.; Elmendorf, Jeffrey S.; Cellular and Integrative Physiology, School of Medicine
    Cholesterol is an essential component of cell membranes, and during the past several years, diabetes researchers have found that membrane cholesterol levels in adipocytes, skeletal muscle fibers and pancreatic beta cells influence insulin action and insulin secretion. Consequently, it is thought that dysregulated cell cholesterol homeostasis could represent a determinant of type 2 diabetes (T2D). Recent clinical findings compellingly add to this notion by finding increased T2D susceptibility in individuals with alterations in a variety of cholesterol metabolism genes. While it remains imperfectly understood how statins influence glucose metabolism, the fact that they display an influence on blood glucose levels and diabetes susceptibility seems to intensify the emerging importance of understanding cellular cholesterol in glucose metabolism. Taking this into account, this review first presents cell system and animal model findings that demonstrate the negative impact of cellular cholesterol accumulation or diminution on insulin action and insulin secretion. With this framework, a description of how changes in cholesterol metabolism genes are associated with T2D susceptibility will be presented. In addition, the connection between statins and T2D risk will be reviewed with expanded information on pitavastatin, a newer statin medication that displays actions favoring metabolic health
  • Thumbnail Image
    Item
    Outcomes from a single-intervention trial to improve interprofessional practice behaviors at a student-led free clinic
    (Elsevier, 2019-12) Horbal, Steven R.; Grice, Brian A.; Evans, Alexandra; Kaplan, Kyle W.; Wright, Lauren; Bidulescu, Aurelian; Pfeifle, Andrea L.; Family Medicine, School of Medicine
    Background Interprofessional collaboration (IPC) is the practice of two or more healthcare professionals working together and learning from one another to improve health outcomes. IPC is important for quality training, typically improving individual and group level outcomes. Students value the opportunity for leadership and teamwork development when IPC is offered in their curriculum. The Indiana University Student Outreach Clinic (IUSOC) is a student run clinic that provides free primary care services to underserved residents residing in Indianapolis, Indiana. The IUSOC partner leaders identified a need to enhance knowledge about partner roles, scope of practice, and professional training with the hopes of improving quality of care through IPC and utilization of clinic resources. Methods A cluster randomized design consisted of education session days and control days. Participants had an equal selection probability. Student partners from ten different disciplines were involved. Two survey instruments were used for data collection: 1) The Interprofessional Socialization and Valuing Scale and 2) The Professional Consciousness Raising Questionnaire. The former measured the attitudes and beliefs that underlie interprofessional socialization, while the latter assessed pre/post student knowledge of the roles and responsibilities of each partner. Results The control arm of the study was composed of 167 student participants and the intervention arm had 170 participants. Participants in the intervention arm had greater scores for “ability to work with others”, “value in working with others”, and “comfort in working with others.” The intervention arm also had significantly increased odds of correctly identifying the roles responsibilities of the nursing, law, dental, and global health disciplines. Conclusions Results of this study demonstrate that administering a short interprofessional education exercise to healthcare professional students leads to improved IPC through increased interprofessional knowledge about other professions and change in beliefs and values toward the value of interprofessional collaboration among healthcare professionals.
  • Thumbnail Image
    Item
    The moderating role of the built environment in prenatal lifestyle interventions
    (Springer Nature, 2021) Phelan, Suzanne; Marquez, Fred; Redman, Leanne M.; Arteaga, Sonia; Clifton, Rebecca; Grice, Brian A.; Haire-Joshu, Debra; Martin, Corby K.; Myers, Candice A.; Pomeroy, Jeremy; Vincent, Eileen; Van Horn, Linda; Peaceman, Alan; Ashby-Thompson, Maxine; Gallagher, Dympna; Pi-Sunyer, Xavier; Boekhoudt, Trisha; Drews, Kimberly; Brown, Greg; LIFE-Moms consortium; Emergency Medicine, School of Medicine
    This study examined whether the neighborhood built environment moderated gestational weight gain (GWG) in LIFE-Moms clinical trials. Participants were 790 pregnant women (13.9 weeks’ gestation) with overweight or obesity randomized within four clinical centers to standard care or lifestyle intervention to reduce GWG. Geographic information system (GIS) was used to map the neighborhood built environment. The intervention relative to standard care significantly reduced GWG (coefficient = 0.05; p = 0.005) and this effect remained significant (p < 0.03) after adjusting for built environment variables. An interaction was observed for presence of fast food restaurants (coefficient=−0.007; p = 0.003). Post hoc tests based on a median split showed that the intervention relative to standard care reduced GWG in participants living in neighborhoods with lower fast food density 0.08 [95% CI, 0.03,0.12] kg/week (p = 0.001) but not in those living in areas with higher fast food density (0.02 [−0.04, 0.08] kg/week; p = 0.55). Interaction effects suggested less intervention efficacy among women living in neighborhoods with more grocery/convenience stores (coefficient = −0.005; p = 0.0001), more walkability (coefficient −0.012; p = 0.007) and less crime (coefficient = 0.001; p = 0.007), but post-hoc tests were not significant. No intervention x environment interaction effects were observed for total number of eating establishments or tree canopy. Lifestyle interventions during pregnancy were effective across diverse physical environments. Living in environments with easy access to fast food restaurants may limit efficacy of prenatal lifestyle interventions, but future research is needed to replicate these findings.