Abstract
Glucose and palmitate synergistically stimulate insulin secretion, but chronically elevated they induce apoptotic β-cell death. The glucotoxic effect has been attributed, at least partly, to the upregulation of the oxidative stress marker thioredoxin interacting protein (TXNIP). Palmitate downregulates TXNIP expression, the functional significance of which is still under debate. This study examines the mechanism and consequence of palmitate-mediated TXNIP regulation in insulin secreting cells. Palmitate (600 μM) reduced TXNIP mRNA levels in isolated human and mouse islets independently of FFAR1/GPR40. Similar effects of palmitate were observed in INS-1E cells and mimicked by other long chain fatty acids. The lowering of TXNIP mRNA was significant already 1 h after addition of palmitate, persisted for 24 h and was directly translated to changes in TXNIP protein. The pharmacological inhibition of palmitate-induced phosphorylation of AMPK, ERK1/2, JNK and PKCα/β by BML-275, PD98059, SP600125 and Gö6976, respectively, did not abolish palmitate-mediated TXNIP downregulation. The effect of palmitate was superimposed by a time-dependent (8 h and 24 h) decline of TXNIP mRNA and protein. This decline correlated with accumulation of secreted insulin into the medium. Accordingly, exogenously added insulin reduced TXNIP mRNA and protein levels, an effect counteracted by the insulin/IGF-1 receptor antagonist linsitinib. The inhibition of PI3K and Akt/PKB increased TXNIP mRNA levels. The histone deacetylase (HDAC1/2/3) inhibitor MS-275 completely abrogated the time-dependent, insulin-mediated reduction of TXNIP, leaving the effect of palmitate unaltered. Acute stimulation of insulin secretion and chronic accentuation of cell death by palmitate occurred independently of TXNIP regulation. On the contrary, palmitate antagonized glucose-augmented ROS production. In conclusion, glucose-induced TXNIP expression is efficiently antagonized by two independent mechanisms, namely via an autocrine activation of insulin/IGF-1 receptors involving HDAC and by palmitate attenuating oxidative stress of β-cells.
Highlights
Obesity-dependent type-2 diabetes is associated with chronically elevated blood glucose and with an elevation of serum non-esterified fatty acids (NEFAs) concentration [1]
We examined whether the inhibitory effect of palmitate on thioredoxin interacting protein (TXNIP) mRNA levels applies to human islets (Fig 1A)
These results suggest that the palmitatemediated downregulation of TXNIP mRNA occurs independently of G-protein coupled receptor 40/fatty acid receptor 1 (FFAR1) activation
Summary
Obesity-dependent type-2 diabetes is associated with chronically elevated blood glucose and with an elevation of serum non-esterified fatty acids (NEFAs) concentration [1]. Both glucose and NEFAs acutely stimulate insulin secretion, chronically elevated, they exert a negative effect on the β-cell function [2]. Glucotoxicity has been linked to increased oxidative stress and mitochondrial dysfunction resulting in apoptosis [3,4,5]. Multiple cellular defense mechanisms in form of superoxide dismutase, catalase, glutathione peroxidase, peroxiredoxin, glutathione Stransferase and thioredoxin can detoxify the endogenous oxidants and reduce oxidative stress [10]. The antioxidative capacity of thioredoxin is antagonized by the cellular protein thioredoxin interacting protein (TXNIP) [11]
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