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Start Over Topic insulin resistance Publisher springer us
749 results

1. The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

Author

Tamás Tábi, István Vincze, Kamilla Varga, Fruzsina Bagaméry, Kitti Kecsmár, and Éva Szökő

Subjects
0301 basic medicine, medicine.medical_specialty, SH-SY5Y, endocrine system diseases, Cell Survival, Cellular differentiation, medicine.medical_treatment, Incretin, Tretinoin, Biochemistry, Streptozocin, 03 medical and health sciences, Cellular and Molecular Neuroscience, Glycogen Synthase Kinase 3, 0302 clinical medicine, Insulin resistance, Internal medicine, Cell Line, Tumor, medicine, Retinoic acid induced differentiation, Humans, Insulin, Phosphorylation, Glycogen synthase, GLP-1 analogue, Original Paper, biology, Chemistry, Streptozotocin, Cell Differentiation, General Medicine, medicine.disease, Glycogen-synthase kinase-3, Insulin receptor, 030104 developmental biology, Endocrinology, biology.protein, Exenatide, SH-SY5Y cell line, 030217 neurology & neurosurgery, medicine.drug, Signal Transduction
Abstract

Recently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

Published
2021

2. Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments

Author

Tobias Kroon, Neil D. Evans, Johan Gabrielsson, Mats Jirstrand, Robert Andersson, Joachim Almquist, Michael J. Chappel, Nicholas D. Oakes, and Publica

Subjects
0301 basic medicine, Male, medicine.medical_specialty, RM, medicine.medical_treatment, Turnover models, Adipose tissue, Pharmacology, Fatty Acids, Nonesterified, 030226 pharmacology & pharmacy, Models, Biological, Niacin, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Internal medicine, Lipolysis, Medicine, Potency, Animals, Insulin, Obesity, Dosing regimen, chemistry.chemical_classification, Original Paper, Dose-Response Relationship, Drug, business.industry, Fatty acid, medicine.disease, QP, Nonlinear mixed-effects (NLME), 3. Good health, Rats, Rats, Zucker, Meta-analysis, Disease Models, Animal, 030104 developmental biology, Endocrinology, Nicotinic agonist, Disease modeling, chemistry, Adipose Tissue, Insulin Resistance, business, Tolerance
Abstract

Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$I_{\text{max}}$$\end{document}Imax model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\upmu {\text{M}}}$$\end{document}μM, respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sim$$\end{document}∼2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures.

Published
2017