Palmitate Impairs and Eicosapentaenoate Restores Insulin Secretion Through Regulation of SREBP-1c in Pancreatic Islets

Abstract

OBJECTIVE-Chronic exposure to fatty acids causes ␤-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis. RESEARCH DESIGN AND METHODS-We studied in vitro and in vivo effects of saturated and polyunsaturated acids on insulin secretion, insulin signaling, and expression of genes involved in ␤-cell functions. Pancreatic islets isolated from C57BL/6 control and SREBP-1-null mice and adenoviral gene delivery or knockdown systems of related genes were used.RESULTS-Incubation of C57BL/6 islets with palmitate caused inhibition of both glucose-and potassium-stimulated insulin secretion, but addition of eicosapentaenoate (EPA) restored both inhibitions. Concomitantly, palmitate activated and EPA abolished both mRNA and nuclear protein of SREBP-1c, accompanied by reciprocal changes of SREBP-1c target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-1-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-1c-mediated insulin secretion defect because adenoviral constitutively active Akt compensated it. Uncoupling protein-2 (UCP-2) also plays a crucial role in the palmitate inhibition of insulin secretion, as confirmed by knockdown experiments, but SREBP-1c contribution to UCP-2 regulation was partial. The palmitate-EPA regulation of insulin secretion was similarly observed in islets from C57BL/6 mice pretreated with dietary manipulations. Furthermore, administration of EPA to diabetic KK-Ay mice ameliorated impairment of insulin secretion in their islets.CONCLUSIONS-SREBP-1c plays a dominant role in palmitatemediated insulin secretion defect, and EPA prevents it through SREBP-1c inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity. Diabetes 57:2382-2392, 2008

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

“…Insulin secretion in pancreatic islets was found to be impaired by the addition of palmitate, a typical saturated fatty acid, and this effect was abolished in SREBP-1c-null islets (Takahashi et al, 2005;Kato et al, 2008;Hong et al, 2012). These findings established an association between SREBP-1c and lipid-induced beta-cell dysfunction.…”

“…It was upregulated by dietary intake of carbohydrates, sugars, and saturated fatty acids. This type of nutritional SREBP-1c regulation has recently been observed in both cultured beta cells and isolated islets of mice (Kato et al, 2008;Shao et al, 2009). Moreover, transgenic mice overexpressing the active form of SREBP-1c exhibited impaired glucose tolerance in vivo, indicating that activation of SREBP-1c could cause beta-cell dysfunction (Takahashi et al, 2005).…”

“…Besides Pdx-1, SREBP-1c, as a transcription factor, was also reported to regulate the expression of genes involved in the beta-cell function, including uncoupling protein (UCP) 2, a protein mediating the energy dissipation in mitochondria instead of ATP synthesis, insulin receptor substrate (IRS)-2, which was involved in the insulin/insulin-like growth factor-1 pathway, GTPase granuphilin related to insulin granules transport for exocytosis, and electrophysiological function-related factors (Kir6.2, Kv1.2, Syntaxin-1a, and Munc18-1) (Kato et al, 2008;Shao et al, 2009Shao et al, , 2010. However, it was unclear whether these effectors are associated with SREBP-1c-involved lipotoxicity (Fig.…”

Anti-diabetic activity of stigmasterol from soybean oil by targeting the GLUT4 glucose transporter

“…In our study, we choose KK-Ay mice as a model of metabolic disorders to evaluate the anti-diabetic effects of SMR. C57BL/6J is the genetic background of KK-Ay mice, so that it is commonly used as normal control group in antidiabetic researches when KK-Ay mice are used as type 2 diabetic model mice [27]. 8-week-old male diabetic KK-Ay mice and their isogenic line 8-week-old normal male C57BL/6J mice were all purchased from Beijing HFK Bioscience Co, Ltd. (Certification number: SCXK 2009-0015).…”

n-3 polyunsaturated fatty acids and insulin secretion

“…ALA and DHA supplementation of the culture medium enhanced glucose (22 mM)-stimulated insulin secretion (GSIS) in MIN6 mouse insulinoma cells (Itoh et al 2003). In both INS1 cells and cultured mouse islets, EPA supplementation restored saturated fatty acid (palmitate)-mediated inhibition of insulin secretion (Kato et al 2008, Shao et al 2010. The palmitate-induced mRNA and nuclear expression of a key transcription factor regulating lipogenesis, sterol regulatory element-binding protein 1c (SREBP1c), is inhibited by EPA (Kato et al 2008).…”