Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

Abstract

Abstract. Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy. Because p62 appears to play an important role in maintaining mitochondrial quality control, it is possible that the loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction, and thus leading to impaired glucose tolerance. In this study we investigated the physiological roles of p62 by inactivating p62 in a β-cell specific manner. We found that firstly, rat insulin-2 promoter-Cre (RIP-Cre)-mediated p62 inactivation did not cause body weight gain, although ubiquitous inactivation of p62 was previously shown to result in severe obesity. Secondly, we found no gross structural disorganization of the islets of p62-deficient mice. Consistent with normal islet morphology, no impairment in glucose tolerance was observed in mice with RIP-Cre-mediated p62 deletion. These results suggest that p62 is dispensable for normal islet organization and β-cell function.Key words: Islets, β cell, Diabetes, p62, Sequestosome 1 TYPE 2 DIABETES MELLITUS is a metabolic disorder characterized by hyperglycemia resulting from the complex interplay of multiple genetic and environmental factors, resulting in both decreased insulin action on target tissues and defective pancreatic β-cell insulin secretion in response to glucose [1]. The natural history of diabetes is strongly associated with the disability of pan-

Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis

“…LC3 has been shown to accumulate in insulin-positive cells in autoantibody-positive donors ( 149 ) and both LC3 and p62 in T2D human islets ( 150 , 151 ). However, deletion of the gene encoding p62 in β cells displays no overt phenotype, suggesting that p62 is dispensable during normal β-cell function ( 152 ). Global and β-cell–specific deletions of Parkin, a protein involved in mitochondrial degradation, show contrasting effects.…”