Research Article: Osteopontin Affects Insulin Vesicle Localization and Ca2+ Homeostasis in Pancreatic Beta Cells from Female Mice

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Anna Wendt, Inês G. Mollet, Anki Knutsson, Victor S. Bolmgren, Anna Hultgårdh-Nilsson, Maria F. Gomez, Lena Eliasson, Kathrin Maedler.


Type 2 diabetic patients suffer from insulin resistance and reduced insulin secretion. Osteopontin (OPN), a versatile protein expressed in several tissues throughout the body including the islets of Langerhans, has previously been implicated in the development of insulin resistance. Here we have investigated the role of OPN in insulin secretion using an OPN knock out mouse model (OPN-/-). Ultra-structural analyzes of islets from OPN-/- and WT mice indicated weaker cell-cell connections between the islet cells in the OPN-/- mouse compared to WT. Analysis of the insulin granule distribution in the beta cells showed that although OPN-/- and WT beta cells have the same number of insulin granules OPN-/- beta cells have significantly fewer docked granules. Both OPN-/- and WT islets displayed synchronized Ca2+ oscillations indicative of an intact beta cell communication. OPN-/- islets displayed higher intracellular Ca2+ concentrations when stimulated with 16.7 mM glucose than WT islets and the initial dip upon elevated glucose concentrations (which is associated with Ca2+ uptake into ER) was significantly lower in these islets. Glucose-induced insulin secretion was similar in OPN-/- and WT islets. Likewise, non-fasted blood glucose levels were the same in both groups. In summary, deletion of OPN results in several minor beta-cell defects that can be compensated for in a healthy system.

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Osteopontin (OPN) was originally discovered in bone [1], but has since then been detected in various tissues including the islets of Langerhans [2]. OPN is mainly known as a secreted extracellular matrix protein although an intracellular version of the protein also exists. It is believed that extracellular and intracellular OPN serves different biological roles [3]. In rodents, all major islet cells including the beta cells express OPN [4, 5]. The role of OPN in islets is not fully established but OPN seems to prevent apoptosis and stimulate proliferation of islets and insulin producing cells, suggesting an overall islet protective role [4, 6, 7]. However, Serum OPN has been reported to be predictive of cardiovascular disease in patients suffering from type 1 diabetes [8] and in a recent study by Barchetta, type 1 diabetic patients displayed higher serum OPN levels than the control group [9]. Interestingly, in the latter study high OPN levels correlated with a negative metabolic profile including higher blood pressure and body mass index, and lower HDL levels.

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Osteopontin is a versatile protein found in many tissues throughout the body. Extracellular OPN exerts its effects by binding to cell surface receptors. Intracellular OPN is less well studied and if and how it affects cell physiology is largely unknown. Mouse pancreatic beta cells express OPN [7]. The pancreatic beta cells have been assigned the important task of producing and secreting insulin. Insulin is the major blood glucose lowering hormone in the body and as such its production and release is under tight regulation by a multitude of mechanisms. In this study we asked what role OPN plays in beta cell physiology with a special focus on insulin secretion.