Submitted to: Islets
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/30/2012
Publication Date: 11/1/2012
Citation: Vernier, S., Chiu, A., Schober, J., Weber, T., Nguyen, P., Luer, M., Mcpherson, T., Wanda, P.E., Marshall, C.A., Rohatgi, N., Mcdaniel, M., Greenberg, A., Kwon, G. 2012. Beta-cell metabolic alterations under chronic nutrient overload in rat and human islets. Islets. 4(6):379-392. Interpretive Summary: In this publication we investigated and found that when, islets- the cells that produce insulin, from rats were exposed to fat and glucose, they increased in size and deposited fat inside the cell. However, and more importantly, the amount of insulin synthesized by these cells decreased. Isolated human islets that were exposed to fat and glucose synthesized less insulin and did store fat but did not exhibit increase in size. These studies, which investigate how diet alters the cells that synthesize and secret insulin help us to understand how different nutrients regulate insulin production.
Technical Abstract: The aim of this study was to assess multifactorial Beta-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 Beta-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 Beta-cells but not in Alpha-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 mM). 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.