Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not ...been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects.
Among the mechanisms implicated in the tumor-promoting effects of obesity, signaling by insulin-like growth factor-I (IGF-I) and insulin has received considerable attention. However, the emerging ...realization that obesity is associated with chronic inflammation has prompted other consideration of how the IGF-I axis may participate in cancer progression. In the present study, we used two mouse models of chronic (LID) and inducible (iLID) igf-1 gene deficiency in the liver to investigate the role of IGF-I in regulating the host microenvironment and colorectal carcinoma growth and metastasis in obese mice. Obese mice had a heightened inflammatory response in the liver, which was abolished in mice with chronic IGF-I deficiency (LID). In control animals changes to the hepatic microenvironment associated with obesity sustained the presence of tumor cells in the liver and increased the incidence of hepatic metastases after intrasplenic/portal inoculation of colon carcinoma cells. These changes did not occur in LID mice with chronic IGF-1 deficiency. In contrast, these changes occurred in iLID mice with acute IGF-1 deficiency, in the same manner as the control animals, revealing a fundamental difference in the nature of the requirement for IGF-1 on tumor growth and metastasis. In the setting of obesity, our findings imply that IGF-1 is critical to activate and sustain an inflammatory response in the liver that is needed for hepatic metastasis, not only through direct, paracrine effect on tumor cell growth, but also through indirect effects involving the tumor microenvironment.
Serum insulin-like growth factor (IGF) -1 is secreted mainly by the liver and circulates bound to IGF-binding proteins (IGFBPs), either as binary complexes or ternary complexes with IGFBP-3 or ...IGFBP-5 and an acid-labile subunit (ALS). The purpose of this study was to genetically dissect the role of IGF-1 circulatory complexes in somatic growth, skeletal integrity, and metabolism. Phenotypic comparisons of controls and four mouse lines with genetic IGF-1 deficits--liver-specific IGF-1 deficiency (LID), ALS knockout (ALSKO), IGFBP-3 (BP3) knockout, and a triply deficient LID/ALSKO/BP3 line--produced several novel findings. 1) All deficient strains had decreased serum IGF-1 levels, but this neither predicted growth potential or skeletal integrity nor defined growth hormone secretion or metabolic abnormalities. 2) IGF-1 deficiency affected development of both cortical and trabecular bone differently, effects apparently dependent on the presence of different circulating IGF-1 complexes. 3) IGFBP-3 deficiency resulted in increased linear growth. In summary, each IGF-1 complex constituent appears to play a distinct role in determining skeletal phenotype, with different effects on cortical and trabecular bone compartments.--Yakar, S., Rosen, C. J., Bouxsein, M. L., Sun, H., Mejia, W., Kawashima, Y., Wu, Y., Emerton, K., Williams, V., Jepsen, K., Schaffler, M. B., Majeska, R. J., Gavrilova, O., Gutierrez, M., Hwang, D., Pennisi, P., Frystyk, J., Boisclair, Y., Pintar, J., Jasper, H., Domene, H., Cohen, P., Clemmons, D., LeRoith, D. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism.
Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity
Shoshana Yakar 1 ,
Jun-Li Liu 1 ,
Ana M. Fernandez 1 ,
Yiping Wu 1 ,
Andrew V. Schally 2 ,
Jan Frystyk 3 ,
Steve D. Chernausek ...4 ,
Wilson Mejia 1 and
Derek Le Roith 1
1 Section on Cellular and Molecular Physiology, Cellular Endocrinology Branch, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
2 Veterans Affairs Medical Center and the Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
3 Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus, Denmark
4 Department of Endocrinology, Children’s Hospital Medical Center, Cincinnati, Ohio
Abstract
Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism.
To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I–deficient (LID) mouse model. The LID mice
show a marked reduction (∼75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LID mice show
a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control mice) and abnormal glucose clearance after insulin
injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their
control littermates. Thus, the high levels of circulating insulin enable the LID mice to maintain normoglycemia in the presence
of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation
of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID
mice. In contrast, IGF-I–induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle
of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of
the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing
hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of
circulating IGF-I as an important component of overall insulin action in peripheral tissues.
Footnotes
Address correspondence and reprint requests to Derek Le Roith, MD, PhD, Clinical Endocrinology Branch, NIDDK, NIH, Room 8D12,
Bldg. 10, Bethesda, MD 20892. E-mail: derek{at}helix.nih.gov .
Received for publication 27 July 2000 and accepted in revised form 29 January 2001.
GH, growth hormone; GHRH, growth hormone–releasing hormone; HPLC, high-performance liquid chromatography; IGF, insulin-like
growth factor; IGFBP, IGF-I–binding protein; IR, insulin receptor; IRS, insulin receptor substrate; LID, liver IGF-I–deficient;
NIH, National Institutes of Health; PI3′-K, phosphatidylinositol 3′-kinase; rh, recombinant human; RIA, radioimmunoassay;
TBS, Tris-buffered saline.
Proteins from the extracellular matrix of enamel are highly specific and necessary for proper enamel formation. Most proteins are removed from the matrix by enamel proteases before complete ...mineralization is achieved; however, some residual protein fragments persist in the mineralized matrix of erupted enamel. So far, only amelogenin peptides obtained by traditional bottom‐up proteomics have been recovered and identified in human permanent erupted enamel. In this study, we hypothesize that other enamel‐specific proteins are also found in human permanent enamel, by analysing human erupted third molars. Pulverized enamel was used to extract proteins, and the protein extract was subjected directly to liquid‐chromatography coupled to tandem mass spectrometry (LC‐MS/MS) without a previous trypsin‐digestion step. Amelogenin and non‐amelogenin proteins (ameloblastin and enamelin) were succesfully identified. The sequences of the naturally occurring peptides of these proteins are reported, finding in particular that most of the peptides from the amelogenin X‐isoform come from the tyrosine‐rich amelogenin peptide (TRAP) and that some were identified in all specimens. In conclusion, our LC‐MS/MS method without trypsin digestion increased the coverage of identification of the enamel proteome from a few amelogenin peptides to a higher number of peptides from three enamel‐specific proteins.
Age-related osteoporosis is accompanied by an increase in marrow adiposity and a reduction in serum insulin-like growth factor-1 (IGF-1) and the binding proteins that stabilize IGF-1. To determine ...the relationship between these proteins and bone marrow adiposity, we evaluated the adipogenic potential of marrow-derived mesenchymal stromal cells (MSCs) from mice with decreased serum IGF-1 due to knockdown of IGF-1 production by the liver or knock-out of the binding proteins. We employed 10-16-week-old, liver-specific IGF-1-deficient, IGFBP-3 knock-out (BP3KO) and acid-labile subunit knock-out (ALSKO) mice. We found that expression of the late adipocyte differentiation marker peroxisome proliferator-activated receptor γ was increased in marrow isolated from ALSKO mice. When induced with adipogenic media, MSC cultures from ALSKO mice revealed a significantly greater number of differentiated adipocytes compared with controls. MSCs from ALSKO mice also exhibited decreased alkaline-phosphatase positive colony size in cultures that were stimulated with osteoblast differentiation media. These osteoblast-like cells from ALSKO mice failed to induce osteoclastogenesis of control cells in co-culture assays, indicating that impairment of IGF-1 complex formation with ALS in bone marrow alters cell fate, leading to increased adipogenesis.
Literacies of Design Amy Wilson-Lopez, Eli Tucker-Raymond, Alberto Esquinca, Joel Alejandro Mejia / Amy Wilson-Lopez, Eli Tucker-Raymond, Alberto Esquinca, Joel Alejandro Mejia
05/2022
eBook
Though engineering design can tackle the world's most pressing
challenges, engineering-related courses and experiences are often
alienating, especially to people from minoritized groups.
Literacies ...of Design: Studies of Equity and Imagination in
Engineering and Making covers the latest pedagogical
theories-as well as case studies and practical tips-to support
diverse people in identifying problems and designing solutions
through engineering and making.
Engineers tackle a range of problems, big and small, from
climate change to viral transmission to improved handrails for
persons with disabilities. Inclusion and equity efforts include not
only preparing the next generation of engineers and makers, but
also creating and fostering spaces where youth can express their
ideas and bring forth their whole selves. This book offers theories
and real-life examples for educators and practitioners at every
level, from K-12 through higher education and beyond.
Nowadays, online judges are very important to improve programming skills for education and technology companies. For this reason, there are many online judges that include large sets of programming ...challenges. This creates an information overload problem that affects students due to their lack of expertise in choosing the correct challenge to solve, resulting in frustration and a loss of interest in this topic. To solve this scenario, recommender systems appear, but programming judges have not delved much into it. Consequently, this research aims to evaluate the performance of six selected collaborative filtering techniques via a cloud-based software architecture. To validate our experiments we used real online programming judges like CodeChef and NinjaCoding using cloud based architecture with Amazon Web Services, evaluated through Friedman and Wilcoxon statistical tests. The results indicated that Singular Value Decomposition is the best model evaluated with RMSE metric and the fastest in execution time with big datasets.
A soy protein-based supplement may optimize bone health, support physical growth, and stimulate bone formation. This study aimed to assess the effect of a daily soy protein supplement (SPS) on ...nutritional status, bone formation markers, lipid profile, and daily energy and macronutrient intake in children. One hundred seven participants (62 girls), ages 2 to 9, started the study and were randomly assigned to lunch fruit juice with (n = 57, intervention group) or without (n = 50, control group) addition of 45 g (230 Kcal) of a commercial SPS during 12 months; 84 children (51 girls, 33 boys) completed the study (45 and 39 intervention and control, respectively). Nutritional assessment included anthropometry and nutrient intakes; initial and final blood samples were taken; insulin-like growth factor-I (IGF-I), osteocalcin, bone specific alkaline phosphatase (BAP), insulin-like growth factor binding protein-3 (IGFBP-3), cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were analyzed. Statistically significant changes (p < .05) in body mass index and weight for age Z scores were observed between groups while changes in body composition were not. Changes in energy, total protein, and carbohydrate intakes were significantly higher in the intervention group (p < .01). Calorie intake changes were statistically significant between groups (p < .001), and BAP decreased in both groups, with values within normal ranges. Osteocalcin, IGFBP-3, and lipid profile were not different between groups. IGF-I levels and IGF/IGFBP-3 ratio increased significantly in both groups. In conclusion, changes in macronutrient and energy intake and nutritional status in the intervention group compared to control group may ensure harmonious and adequate bone health and development.
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