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Dominik H Pesta, Dimitrios N Tsirigotis, Douglas E Befroy, Daniel Caballero, Michael J Jurczak, Yasmeen Rahimi, Gary W Cline, Sylvie Dufour, Andreas L Birkenfeld, Douglas L Rothman, Thomas O Carpenter, Karl Insogna, Kitt Falk Petersen, Clemens Bergwitz, Gerald I Shulman
Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [(31)P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (VATP) and plasma inorganic phosphate (Pi) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in NaPi2a knockout mice (NaPi2a(-/-)) compared with their wild-type littermate controls...
June 23, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Chuhan Chung, Karl L Insogna
No abstract text is available yet for this article.
September 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Evelyn Hsieh, Liana Fraenkel, Yang Han, Weibo Xia, Karl L Insogna, Michael T Yin, Ting Zhu, Xinqi Cheng, Taisheng Li
OBJECTIVE: To examine longitudinal change in vitamin D binding protein (DBP) levels during the first year after initiation of tenofovir disoproxil fumarate (TDF)/lamivudine/efavirenz and compare these findings with concurrent changes in markers of skeletal metabolism. DESIGN: Secondary analysis of plasma samples collected from an ongoing multicenter clinical trial. METHODS: Plasma samples collected at 0, 24, and 48 weeks after initiation of TDF + lamivudine + efavirenz from 134 adult participants enrolled in a multicenter randomized trial were analyzed...
July 31, 2016: AIDS
M Tish Knobf, Sangchoon Jeon, Barbara Smith, Lyndsay Harris, Jane Kerstetter, A Siobhan Thompson, Karl Insogna
Bone loss is a significant clinical problem for female cancer survivors (FCS) and increases fracture risk. The aim of the Yale Fitness Intervention Trial (Yale FIT) was to determine the effects of a 12-month aerobic-resistance exercise intervention compared to a home-based physical activity group on bone outcomes [bone mineral density (BMD)] and biomarkers bone turnover). Early postmenopausal FCS (N = 154) were randomized to the exercise intervention (3 times/week) or to a home-based physical activity group...
February 2016: Breast Cancer Research and Treatment
Meiling Zhu, Ben-Hua Sun, Katarzyna Saar, Christine Simpson, Nancy Troiano, Sarah L Dallas, LeAnn M Tiede-Lewis, Erin Nevius, João P Pereira, Robert S Weinstein, Steven M Tommasini, Karl L Insogna
Rac1 and Rac2 are thought to have important roles in osteoclasts. Therefore, mice with deletion of both Rac1 and Rac2 in mature osteoclasts (DKO) were generated by crossing Rac1(flox/flox) mice with mice expressing Cre in the cathepsin K locus and then mating these animals with Rac2(-/-) mice. DKO mice had markedly impaired tooth eruption. Bone mineral density (BMD) was increased 21% to 33% in 4- to 6-week-old DKO mice at all sites when measured by dual-energy X-ray absorptiometry (DXA) and serum cross-linked C-telopeptide (CTx) was reduced by 52%...
April 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Jae Geun Kim, Ben-Hua Sun, Marcelo O Dietrich, Marco Koch, Gang-Qing Yao, Sabrina Diano, Karl Insogna, Tamas L Horvath
The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1(-/-)), mice also developed reduced bone mass...
October 6, 2015: Cell Reports
Ping-Chih Ho, Jessica Dauz Bihuniak, Andrew N Macintyre, Matthew Staron, Xiaojing Liu, Robert Amezquita, Yao-Chen Tsui, Guoliang Cui, Goran Micevic, Jose C Perales, Steven H Kleinstein, E Dale Abel, Karl L Insogna, Stefan Feske, Jason W Locasale, Marcus W Bosenberg, Jeffrey C Rathmell, Susan M Kaech
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca(2+)-NFAT signaling and effector functions by repressing sarco/ER Ca(2+)-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions...
September 10, 2015: Cell
Beatrice C Lupsa, Karl Insogna
Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue leading to decreased bone strength and an increased risk of low-energy fractures. Central dual-energy X-ray absorptiometry measurements are the gold standard for determining bone mineral density. Bone loss is an inevitable consequence of the decrease in estrogen levels during and following menopause, but additional risk factors for bone loss can also contribute to osteoporosis in older women. A well-balanced diet, exercise, and smoking cessation are key to maintaining bone health as women age...
September 2015: Endocrinology and Metabolism Clinics of North America
Sarah C Larocque, Jane E Kerstetter, Jane A Cauley, Karl L Insogna, Kristine Ensrud, Li-Yung Lui, Heather G Allore
More than 90% of hip fractures in older Americans result from a fall. Inadequate intake of dietary protein and vitamin D are common in older adults, and diets in low these could contribute to loss of muscle mass and strength or coordination, in turn increasing the risk of falling. The objective of the study was to evaluate the relationship between protein and vitamin D intake with the occurrence of falls in older women in the Study of Osteoporotic Fracture, a prospective cohort of more than 4000 postmenopausal women participating from January 1997 to September 1998...
2015: Journal of Nutrition in Gerontology and Geriatrics
Jessica Connor, Elizabeth A Olear, Karl L Insogna, Lee Katz, Suher Baker, Raghbir Kaur, Christine A Simpson, John Sterpka, Robert Dubrow, Jane H Zhang, Thomas O Carpenter
CONTEXT: Treatment of X-linked hypophosphatemia (XLH) with active vitamin D metabolites and phosphate can partially correct skeletal deformities. It is unclear whether therapy influences the occurrence of two major long-term morbidities in XLH: enthesopathy and dental disease. OBJECTIVE: The objective of the study was to investigate the relationship between treatment and enthesopathy and dental disease in adult XLH patients. DESIGN: The study was designed as observational and cross-sectional...
October 2015: Journal of Clinical Endocrinology and Metabolism
Xiaoping Zhang, Erik A Imel, Mary D Ruppe, Thomas J Weber, Mark A Klausner, Takahiro Ito, Maria Vergeire, Jeffrey Humphrey, Francis H Glorieux, Anthony A Portale, Karl Insogna, Thomas O Carpenter, Munro Peacock
In X-linked hypophosphatemia (XLH), serum fibroblast growth factor 23 (FGF23) is increased and results in reduced renal maximum threshold for phosphate reabsorption (TmP), reduced serum inorganic phosphorus (Pi), and inappropriately low normal serum 1,25 dihydroxyvitamin D (1,25[OH]2 D) concentration, with subsequent development of rickets or osteomalacia. KRN23 is a recombinant human IgG1 monoclonal antibody that binds to FGF23 and blocks its activity. Up to 4 doses of KRN23 were administered subcutaneously every 28 days to 28 adults with XLH...
February 2016: Journal of Clinical Pharmacology
Erik A Imel, Xiaoping Zhang, Mary D Ruppe, Thomas J Weber, Mark A Klausner, Takahiro Ito, Maria Vergeire, Jeffrey S Humphrey, Francis H Glorieux, Anthony A Portale, Karl Insogna, Munro Peacock, Thomas O Carpenter
CONTEXT: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. OBJECTIVE: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. DESIGN: Two sequential open-label phase 1/2 studies were done...
July 2015: Journal of Clinical Endocrinology and Metabolism
Jane E Kerstetter, Jessica D Bihuniak, Jennifer Brindisi, Rebecca R Sullivan, Kelsey M Mangano, Sarah Larocque, Belinda M Kotler, Christine A Simpson, Anna Maria Cusano, Erin Gaffney-Stomberg, Alison Kleppinger, Jesse Reynolds, James Dziura, Anne M Kenny, Karl L Insogna
CONTEXT: It has been assumed that the increase in urine calcium (Ca) that accompanies an increase in dietary protein was due to increased bone resorption. However, studies using stable Ca isotopes have found that dietary protein increases Ca absorption without increasing bone resorption. OBJECTIVE: The objective of the study was to investigate the impact of a moderately high protein diet on bone mineral density (BMD). DESIGN: This was a randomized, double-blind, placebo-controlled trial of protein supplementation daily for 18 months...
June 2015: Journal of Clinical Endocrinology and Metabolism
Jessica D Bihuniak, Karl L Insogna
Dietary protein is required for optimal skeletal growth and maturation. Although Recommended Dietary Allowances (RDAs) exist for global dietary protein intake, the level and sources of dietary protein that are optimal for skeletal health over the life continuum have not been established. This is partly due to the difficulty in quantifying the effects of variable levels of a nutrient's intake over a lifetime as well as the complex nature of the relationships between dietary protein and calcium economy. Areas of current uncertainty include the precise source and amount of dietary protein required for optimal skeletal accretion and maintenance of skeletal mass, as well as the site-specific effects of dietary protein...
July 15, 2015: Molecular and Cellular Endocrinology
Evelyn Hsieh, Liana Fraenkel, Elizabeth H Bradley, Weibo Xia, Karl L Insogna, Qu Cui, Kunli Li, Taisheng Li
UNLABELLED: Individuals with HIV are at increased risk for osteoporosis and fracture. Using the Health Beliefs Model, we identified key relationships between knowledge, self-efficacy and health beliefs pertaining to physical activity and dietary calcium intake, two key modifiable preventive measures for osteoporosis. PURPOSE: Individuals with HIV are at increased risk for osteoporosis and fracture. Few studies have systematically explored concerns related to osteoporosis prevention among this group...
2014: Archives of Osteoporosis
Chang Cao, Carrie E Thomas, Karl L Insogna, Kimberly O O'Brien
BACKGROUND: Dietary heme contributes to iron intake, yet regulation of heme absorption and tissue utilization of absorbed heme remains undefined. OBJECTIVES: In a rat model of iron overload, we used stable iron isotopes to examine heme- and nonheme-iron absorption in relation to liver hepcidin and to compare relative utilization of absorbed heme and nonheme iron by erythroid (RBC) and iron storage tissues (liver and spleen). METHODS: Twelve male Sprague-Dawley rats were randomly assigned to groups for injections of either saline or iron dextran (16 or 48 mg Fe over 2 wk)...
November 2014: Journal of Nutrition
Christine A Simpson, Anna Maria Cusano, Jessica Bihuniak, Joanne Walker, Karl L Insogna
The Vitamin D Standardization Program (VDSP) has identified ID-LC/MS/MS as the reference method procedure (RMP) for 25(OH) vitamin D and NIST Standard SRM2972 as the standard reference material (SRM). As manufacturers align their products to the RMP and NIST standard, a concern is that results obtained in aligned assays will be divergent from those obtained with pre-alignment assays. The Immunodiagnostic Systems Ltd., chemiluminescent, 25(OH) vitamin D iSYS platform assay, was recently harmonized to the RMP...
April 2015: Journal of Steroid Biochemistry and Molecular Biology
Thomas O Carpenter, Elizabeth A Olear, Jane H Zhang, Bruce K Ellis, Christine A Simpson, David Cheng, Caren M Gundberg, Karl L Insogna
CONTEXT: Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities. OBJECTIVE: The objective of the study was to suppress elevated PTH levels in XLH patients. DESIGN: This was a prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later. SETTING: PATIENTS were recruited from the investigators' clinics or referred from throughout the United States...
September 2014: Journal of Clinical Endocrinology and Metabolism
Mimi I Hu, Ilya G Glezerman, Sophie Leboulleux, Karl Insogna, Rasim Gucalp, Waldemar Misiorowski, Bennett Yu, Paul Zorsky, Diego Tosi, Alberto Bessudo, Arnaud Jaccard, Giuseppe Tonini, Wendy Ying, Ada Braun, Rajul K Jain
CONTEXT: Hypercalcemia of malignancy (HCM) in patients with advanced cancer is often caused by excessive osteoclast-mediated bone resorption. Patients may not respond to or may relapse after iv bisphosphonate therapy. OBJECTIVE: We investigated whether denosumab, a potent inhibitor of osteoclast-mediated bone resorption, reduces serum calcium in patients with bisphosphonate-refractory HCM. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm international study, participants had serum calcium levels corrected for albumin (CSC) >12...
September 2014: Journal of Clinical Endocrinology and Metabolism
Debayan Dasgupta, Mark J Wee, Monica Reyes, Yuwen Li, Peter J Simm, Amita Sharma, Karl-Peter Schlingmann, Marco Janner, Andrew Biggin, Joanna Lazier, Michaela Gessner, Dionisios Chrysis, Shamir Tuchman, H Jorge Baluarte, Michael A Levine, Dov Tiosano, Karl Insogna, David A Hanley, Thomas O Carpenter, Shoji Ichikawa, Bernd Hoppe, Martin Konrad, Lars Sävendahl, Craig F Munns, Hang Lee, Harald Jüppner, Clemens Bergwitz
Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH)...
October 2014: Journal of the American Society of Nephrology: JASN
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