Low-dose naltrexone rescues inflammation and insulin resistance associated with hyperinsulinemia

Abstract

The incidence of diabetes, obesity, and metabolic diseases has reached an epidemic status worldwide. Insulin resistance is a common link in the development of these conditions, and hyperinsulinemia is a central hallmark of peripheral insulin resistance. However, how hyperinsulinemia leads to systemic insulin resistance is less clear. We now provide evidence that hyperinsulinemia promotes the release of soluble pro-inflammatory mediators from macrophages that lead to systemic insulin resistance. Our observations suggest that hyperinsulinemia induces Sirtuin1 (SIRT1) repression and stimulates NF-κB p65 nuclear translocation and transactivation of NF-κB to promote the extracellular release of pro-inflammatory mediators. We further showed that low-dose naltrexone (LDN) abrogates hyperinsulinemia-mediated SIRT1 repression and prevents NF-κB p65 nuclear translocation. This, in turn, attenuates the hyperinsulinemia-induced release of pro-inflammatory cytokines and reinstates insulin sensitivity both in in vitro and in-vivo diet-induced hyperinsulinemic mouse model. Notably, our data indicate that Sirt1 knockdown or inhibition blunts the anti-inflammatory properties of LDN in vitro. Using numerous complementary in silico and in vitro experimental approaches, we demonstrated that LDN can bind to SIRT1 and increase its deacetylase activity. Together, these data support a critical role of SIRT1 in inflammation and insulin resistance in hyperinsulinemia. LDN improves hyperinsulinemia-induced insulin resistance by reorienting macrophages towards anti-inflammation. Thus, LDN treatment may provide a novel therapeutic approach against hyperinsulinemia-associated insulin resistance.

LDN Protects Bone Property Deterioration at Different Hierarchical Levels in T2DM Mice Bone

“…The possible reason is due to the serum leptin and serum IGF-I, which cannot be controlled by LDN. 6 It is generally noted that leptin increases in HFD-induced mice. 5 These data indicated that LDN can control the fracture toughness; however, it cannot protect to increase the bone size in the T2DM mice group (Figures 1 and 2).…”

“…Details of the mice preparations and other biological parameters related to T2DM conditions are described in our earlier research paper. 6 Based on diet and treatment, all mice were divided into four groups. In group 1 (NC-saline), all mice receive regular chow diet and water ad libitum up to 3 weeks and are subjected to normal saline (i.p) on the fourth and fifth week.…”

“…Recently, LDN showed enhanced glucose tolerance and insulin sensitivity in T2DM mice. 6 A recent study showed that naltrexone treatment increases the bone strength and energy absorbed in type 1 diabetic bone. 27 Similarly, some other studies also indicated the positive effect of naltrexone on bone mass 28,29 and bone formation 29 and prevent bone loss.…”

“…It has been observed that T2DM impacts bone structural and mechanical properties in mice bone . Recently, low-dose naltrexone (LDN) exhibited enhanced glucose tolerance and insulin sensitivity in HFD-induced T2DM mice . Although naltrexone was synthesized as an orally active competitive opioid receptor antagonist, LDN exhibits paradoxical properties, including analgesia and anti-inflammatory actions, where LDN simultaneously has an antagonist effect on nonopioid receptors (TLR4) which have not been reported at larger dosages. − Recently, we have identified that LDN can control Raman-based compositional bone quality parameters in T2DM mice bone .…”

“…A number of anti-diabetic drugs are used to control high blood sugar (for T2DM patients). Recently, LDN showed enhanced glucose tolerance and insulin sensitivity in T2DM mice . A recent study showed that naltrexone treatment increases the bone strength and energy absorbed in type 1 diabetic bone .…”