Signaling Molecules Involved in Lipid-Induced Pancreatic Beta-Cell Dysfunction

Abstract

The increasing incidence of type 2 diabetes mellitus is partially due to the rising obesity rates and the elevated levels of free fatty acids (FFAs). It is known that FFAs are putative mediators of beta-cell dysfunction, which is characterized with impaired glucose-stimulated insulin secretion and increased apoptosis, being defined as lipotoxicity. To date, many factors and their related signal pathways have been reported to be involved in FFAinduced beta-cell dysfunction. However, the entire blueprint is still not obtained. Some essential and newfound effectors, including the sterol regulatory element-binding protein (SREBP)-1c, farnesoid X receptor (FXR), forkhead box-containing protein O (FoxO) 1, ubiquitin C-terminal hydrolase L (UCHL) 1, N-myc downstreamregulated gene (NDRG) 2, perilipin family proteins, silent information regulator 2 protein 1 (Sirt1), pituitary adenylate cyclase-activating polypeptide (PACAP), and ghrelin are described in this review, which may help to further understand the molecular network for lipotoxicity.

Rice bran water extract attenuates pancreatic abnormalities in high-fat diet-induced obese rats

“…Activation of SREBP-1c in response to various metabolic stimuli, including hyperinsulinemia, hyperglycemia and high FFA levels, results in the up-regulation of lipogenic genes [7,22]. The upregulation of this transcription factor in the pancreas was found in association with the accumulation of TG [6,23]. In the present study, histological examination of pancreatic acinar cells in HFD-induced obese rats revealed marked accumulation of fat droplets, indicating ectopic fat deposition in the pancreas.…”

“…Excessive lipid accumulation in the pancreas can promote insulin resistance, oxidative stress and apoptosis in tissues [21]. SREBP-1c has been proposed as a major lipogenic transcription factor in various tissues including the pancreas [6]. Activation of SREBP-1c in response to various metabolic stimuli, including hyperinsulinemia, hyperglycemia and high FFA levels, results in the up-regulation of lipogenic genes [7,22].…”

“…Pancreatic steatosis can occur in the presence of obesity [5]. Sterol regulatory element-binding protein-1c (SREBP-1c) is now well established as a key transcription factor in the regulation of lipogenesis in the pancreas [6]. A previous report has indicated that activation of SREBP-1c is essential for impaired insulin secretion and islet mass associated with the accumulation of triglycerides (TG) [7].…”

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

“…The advanced and terminal phases of T2DM are characterized with reduced beta cell mass and function due to cumulative cell damage and apoptosis. Beta cell apoptosis and demise at these stages, which result in severe hypoinsulinemia, often require parenteral insulin replacement therapy in these patients (Anuradha et al, 2014;Campbell, 2009;Johnson and Luciani, 2010;Montane et al, 2014;Oh, 2015;Shao et al, 2013;Thomas et al, 2009).…”

WISP1: Clinical Insights for a Proliferative and Restorative Member of the CCN Family

“…Of the seven mammalian homologues of Sir2 that include SIRT1 through SIRT7, SIRT1 plays a significant role in oxidative stress, cell metabolism, genomic stability, cell survival, neurodegenerative disease, infection, and cardiovascular disease [102–107]. In regards to cytoprotection, SIRT1 activation can prevent hypoxic injury in retinal ganglion cells [108], modulate cell longevity [109, 110], protect against high-fat diet-induced metabolic abnormalities [111, 112], increase cellular survival during anoxia and ischemia [113, 114], reduce Aβ toxicity [115], reverse impaired fat and glucose metabolism [12, 116–118], maintain mitochondrial processing and quality through autophagy [119], foster cellular protection against radiation [120], protect against renal cell aging [121], block apoptotic pathways in preadipocytes [122], and modulate forkhead mediated apoptotic pathways [53, 72, 96, 118, 123–126]. Yet, other studies suggest that to achieve cytoprotection through sirtuin pathways, the level of sirtuin activity may be critical [53, 72, 115, 127], since SIRT1 gene polymorphisms may affect protein expression during cardiovascular disease [105], SIRT1 activity can promote tumor growth [128, 129], and reduction in SIRT1 activity has been reported to enhance the cytoprotective effects of IGF-1 [130].…”