Chromatin protein HMGB1 regulates hyperinsulinemia mediated insulin resistance: low‐dose naltrexone rescues insulin resistance associated with hyperinsulinemia

Abstract

Insulin secretion with compensatory hyperinsulinemia where pancreatic β-cells are forced to secrete more insulin is central hallmark of peripheral insulin resistance and type 2 diabetes (T2DM). Considerable data have suggested that hyperinsulinemia itself leads to inflammation and Toll like Receptor-4 (TLR4) activation is critical determinant for this process. We found that hyperinsulinemia increases circulatory HMGB1 (an endogenous TLR4 ligand) by ensuring its nuclear-to-cytoplasmic shuttling and release into the extracellular space extracellular via secretory lysosomes. Our observations suggest that hyperinsulin promotes the hyperacetylation of HMGB1 via the inhibition of SIRT1, which reduces HMGB1 release. Further, a hypo-acetylation mutant HMGB1 (K 28,29,30 R), reduces HMGB1 release in hyperinsulin-activated cells, indicating that the acetylation-dependent interaction between HMGB1 and SIRT1 is critical for hyperinsulin induced-redistribution of HMGB1 from the nucleus to the cytosol and/or secretion to the extracellular medium. Besides, hyperinsulinemia induce elevated serum HMGB1 promotes proinflammatory responses in rodents as well humans and plays a crucial role in modulating hepatic insulin signalling. We further showed that Low Dose of Naltrexone (LDN) abrogates hyperinsulinemia-mediated SIRT1 repression and prevents hyperinsulinemia induced HMGB1 release into extracellular milieu and reinstates insulin sensitivity both in in vitro and in vivo diet-induced hyperinsulinemic mouse model. Taken together the data presented provides a completely new regulatory mechanisms within the insulin-TLR4 signaling axis of great significance to human health and diabetes. Finally, in therapeutic standpoint, instead of silencing HMGB1 use of LDN to correct HMGB1 intracellular distribution and LDN treatment may provide a novel therapeutic approach against hyperinsulinemia-associated insulin resistance.