β-cell metabolic alterations under chronic nutrient overload in rat and human islets
| Autor: | Theresa Weber, Stephanie Vernier, Timothy McPherson, Phuong Nguyen, Andrew S. Greenberg, Joseph Schober, Connie A. Marshall, Michael L. McDaniel, Mark Luer, Nidhi Rohatgi, Angela Chiu, Guim Kwon, Paul E. Wanda |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Endocrinology Diabetes and Metabolism medicine.medical_treatment lipid droplets time lapse studies mTORC1 Fatty Acids Nonesterified human islets Rats Sprague-Dawley chemistry.chemical_compound Endocrinology Lipid droplet Insulin-Secreting Cells Microscopy Phase-Contrast ADRP geography.geographical_feature_category TOR Serine-Threonine Kinases Islet Immunohistochemistry Insulin oscillation Research Paper medicine.medical_specialty endocrine system insulin Blotting Western Biology Mechanistic Target of Rapamycin Complex 1 Perilipin-2 Downregulation and upregulation Internal medicine medicine Animals Humans Triglycerides Sirolimus geography Triglyceride nutrient overload Cell growth rapamycin Insulin Membrane Proteins Proteins Rats Glucose chemistry Diabetes Mellitus Type 2 Multiprotein Complexes |
| Zdroj: | Islets |
| ISSN: | 1938-2022 1938-2014 |
| Popis: | The aim of this study was to assess multifactorial β-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of lipid droplets in β-cells in a time- and concentration-dependent manner. Glucose and FFAs synergistically stimulated the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1). A potent mTORC1 inhibitor, rapamycin (25 nM), significantly reduced triglyceride accumulation in rat islets. Importantly, lipid droplets accumulated only in β-cells but not in α-cells in an mTORC1-dependent manner. Nutrient activation of mTORC1 upregulated the expression of adipose differentiation related protein (ADRP), known to stabilize lipid droplets. Rat islet size and new DNA synthesis also increased under nutrient overload. Insulin secretion into the culture medium increased steadily over a 4-day period without any significant difference between glucose (10 mM) alone and the combination of glucose (10 mM) and FFAs (240 μM). Insulin content and insulin biosynthesis, however, were significantly reduced under the combination of nutrients compared with glucose alone. Elevated nutrients also stimulated lipid droplet formation in human islets in an mTORC1-dependent manner. Unlike rat islets, however, human islets did not increase in size under nutrient overload despite a normal response to nutrients in releasing insulin. The different responses of islet cell growth under nutrient overload appear to impact insulin biosynthesis and storage differently in rat and human islets. |
| Databáze: | OpenAIRE |
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