Gene and Protein Kinase Expression Profiling of Reactive Oxygen Species-Associated Lipotoxicity in the Pancreatic β-Cell Line MIN6

Wang, Xiaolin; Li, Hui; Leo, Domenica De; Guo, Wei; Koshkin, Vasilij; Fantus, I. George; Giacca, Adria; Chan, Catherine B.; Der, Sandy D.; Wheeler, Michael B.

doi:10.2337/diabetes.53.1.129

Cited by 87 publications

(70 citation statements)

References 60 publications

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“…However, whether oxidative stress plays a role in FFA-induced decrease in ␤-cell function is still unclear. The majority of studies have shown that FFAs generate ROS in islets (21) and ␤-cell lines (22,23), although in a recent paper, ROS were not increased by FFA in cultured islets. In the same paper, antioxidants did not prevent the FFA-induced defect in GSIS (24).…”

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confidence: 90%

Free Fatty Acid–Induced Reduction in Glucose-Stimulated Insulin Secretion

et al. 2007

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OBJECTIVE-An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease ␤-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in ␤-cell function. RESEARCH DESIGN AND METHODS-We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells.RESULTS-Forty-eight-hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (P Ͻ 0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose-stimulated insulin secretion ex vivo (P Ͻ 0.01) and induced oxidative stress (P Ͻ 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight-hour infusion of olive oil induced oxidative stress (P Ͻ 0.001) and decreased the insulin response of isolated islets similar to oleate (P Ͻ 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P Ͻ 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine. T ype 2 diabetes is characterized by both insulin resistance and defective insulin secretion (1). Obesity is the major predisposing factor for type 2 diabetes and is associated with excessive release of fatty acids from the expanded adipose tissue mass, leading to elevated plasma free fatty acids (FFAs), which are known to induce insulin resistance (2,3). Acute FFA exposure stimulates insulin secretion (4), but studies in vitro and in situ have shown that prolonged FFA exposure decreases glucose-stimulated insulin secretion (GSIS) (5). The effect of prolonged FFA elevation on ␤-cell function in vivo has been more controversial, as absolute GSIS was found to be increased (6 -8), unchanged (9,10), or decreased (11-13) by FFA. However, in most of these studies ␤-cell function was inadequate to compensate for FFA-induced insulin resistance (9 -13), at least in predisposed individuals (14). Although the mechanisms behind FFA-induced decrease in ␤-cell function are unclear, one possibility points toward oxidative stress. Pancreatic ␤-cells have low antioxidant defenses (15) and are thus susceptible to reactive oxygen species (ROS)-induced decrease in function and viability (16,17). Oxidative stress has been implicated in the decrease in GSIS induced by prolonged exposure to glucose (18,19), which is in many respects similar to that induced by prolonged exposure to FFA (4,20). However, whether oxidative stress plays a role in FFA-...

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confidence: 90%

Free Fatty Acid–Induced Reduction in Glucose-Stimulated Insulin Secretion

et al. 2007

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“…Islets (10/condition) were preincubated for two sequential 30-min periods in Krebs-Ringer HEPES buffer and for 2 h at the indicated glucose concentration (either 2.8 or 20 mM) (24). The supernatants of the cells were collected and centrifuged at 300 g ϫ for 10 min to remove cell debris for insulin secretion assessment, and the cell pellets were lysed with acid ethanol (75% ethanol containing 1.5% (v/v) HCl) for DNA quantification or insulin content assessment (21). The insulin concentration in the supernatant or cell lysate was measured by radioimmunoassay as described previously (28).…”

Section: Evaluation Of Insulin Secretion and Content In Min6 Cells Anmentioning

confidence: 99%

“…Purified RNA was converted to cDNA using SuperScript II reverse transcriptase, and real-time PCR was performed using an ABI PRISM 7900HT sequence detection system (Applied Biosystems, Foster City, CA) according to the same protocol described previously (21). Primer Express Version 2.0 (Applied Biosystems) was used to design primers for real-time PCR.…”

Section: Evaluation Of Insulin Secretion and Content In Min6 Cells Anmentioning

confidence: 99%

“…Although many studies have reported on the biological functions of VILIP-1 in neurons, very little information is available regarding physiological roles in other tissues. In MIN6 cells, however, expression profiling of fatty acid-responsive genes has shown that oleic acid can significantly induce expression of VILIP-1 (21). In this study, we identified VILIP-1 in mouse pancreatic islets, and using overexpression and small interfering RNA (siRNA) knockdown strategies, we determined that VILIP-1 can regulate insulin secretion and insulin gene transcription.…”

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The Neuronal Ca2+ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion

Dai

Zhang

Kang

et al. 2006

Journal of Biological Chemistry

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Visinin-like protein-1 (VILIP-1) is a member of the neuronal Ca 2؉ sensor protein family that modulates Ca 2؉-dependent cell signaling events. VILIP-1, which is expressed primarily in the brain, increases cAMP formation in neural cells by modulating adenylyl cyclase, but its functional role in other tissues remains largely unknown. In this study, we demonstrate that VILIP-1 is expressed in murine pancreatic islets and ␤-cells. To gain insight into the functions of VILIP-1 in ␤-cells, we used both overexpression and small interfering RNA knockdown strategies. Overexpression of VILIP-1 in the MIN6 ␤-cell line or isolated mouse islets had no effect on basal insulin secretion but significantly increased glucose-stimulated insulin secretion. cAMP accumulation was elevated in VILIP-1-overexpressing cells, and the protein kinase A inhibitor H-89 attenuated increased glucose-stimulated insulin secretion. Overexpression of VILIP-1 in isolated mouse ␤-cells increased cAMP content accompanied by increased cAMP-responsive element-binding protein gene expression and enhanced exocytosis as detected by cell capacitance measurements. Conversely, VILIP-1 knockdown by small interfering RNA caused a reduction in cAMP accumulation and produced a dramatic increase in preproinsulin mRNA, basal insulin secretion, and total cellular insulin content. The increase in preproinsulin mRNA in these cells was attributed to enhanced insulin gene transcription. Taken together, we have shown that VILIP-1 is expressed in pancreatic ␤-cells and modulates insulin secretion. Increased VILIP-1 enhanced insulin secretion in a cAMP-associated manner. Downregulation of VILIP-1 was accompanied by decreased cAMP accumulation but increased insulin gene transcription.

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“…Along the same line, it has been shown that the saturated stearic acid (C18:0) has proapoptotic properties unlike equivalent concentrations of the polyunsaturated linoleic acid (C18:2n6c) [15,29]. Concerning the monounsaturated oleic acid (C18:1n9c), contradictory results about its proapoptotic properties have been obtained [15,30].…”

Section: Introductionmentioning

confidence: 99%

Soybean oil treatment impairs glucose-stimulated insulin secretion and changes fatty acid composition of normal and diabetic islets

et al. 2007

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We investigated the effect of sub-chronic soybean oil (SO) treatment on the insulin secretion and fatty acid composition of islets of Langerhans obtained from Goto-Kakizaki (GK), a model of type 2 diabetes, and normal Wistar rats. We observed that soybean-treated Wistar rats present insulin resistance and defective islet insulin secretion when compared with untreated Wistar rats. The decrease in insulin secretion occurred at all concentrations of glucose and arginine tested. Furthermore we observed that soybean-treated normal islets present a significant decrease in two saturated fatty acids, myristic and heneicosanoic acids, and one monounsaturated eicosenoic acid, and the appearance of the monounsaturated erucic acid. Concerning diabetic animals, we observed that soybean-treated diabetic rats, when compared with untreated GK rats, present an increase in plasma non-fasting free fatty acids, an exacerbation of islet insulin secretion impairment in all conditions tested and a significant decrease in the monounsaturated palmitoleic acid. Altogether our results show that SO treatment results in a decrease of insulin secretion and alterations on fatty acid composition in normal and diabetic islets. Furthermore, the impairment of insulin secretion, islet erucic acid and fasting plasma insulin levels are similar in treated normal and untreated diabetic rats, suggesting that SO could have a deleterious effect on β-cell function and insulin sensitivity.

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Gene and Protein Kinase Expression Profiling of Reactive Oxygen Species-Associated Lipotoxicity in the Pancreatic β-Cell Line MIN6

Cited by 87 publications

References 60 publications

Free Fatty Acid–Induced Reduction in Glucose-Stimulated Insulin Secretion

Free Fatty Acid–Induced Reduction in Glucose-Stimulated Insulin Secretion

The Neuronal Ca2+ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion

Soybean oil treatment impairs glucose-stimulated insulin secretion and changes fatty acid composition of normal and diabetic islets

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