title: β-cell metabolic alterations under chronic nutrient overload in rat and human islets.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Southern Illinois University Edwardsville, Edwardsville, IL, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Vernier
authors.forename: Angela
authors.initials: A
authors.lastname: Chiu
authors.forename: Joseph
authors.initials: J
authors.lastname: Schober
authors.forename: Theresa
authors.initials: T
authors.lastname: Weber
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Mark
authors.initials: M
authors.lastname: Luer
authors.forename: Timothy
authors.initials: T
authors.lastname: McPherson
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wanda
authors.forename: Connie A
authors.initials: CA
authors.lastname: Marshall
authors.forename: Nidhi
authors.initials: N
authors.lastname: Rohatgi
authors.forename: Michael L
authors.initials: ML
authors.lastname: McDaniel
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
authors.forename: Guim
authors.initials: G
authors.lastname: Kwon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage* / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism; D008858:Microscopy, Phase-Contrast; D046912:Multiprotein Complexes; D000070780:Perilipin-2; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; C000602984:Plin2 protein, rat; D011506:Proteins; D014280:Triglycerides; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus