N¹-Methylnicotinamide Improves Hepatic Insulin Sensitivity via Activation of SIRT1 and Inhibition of FOXO1 Acetylation

Abstract

Objective. To explore the effects of N1-methylnicotinamide (MNAM) on insulin resistance and glucose metabolism in obese type 2 diabetes mellitus (T2DM) mice and regulatory mechanisms of the NAD-dependent deacetylase sirtuin-1 (SIRT1)/forkhead box protein O1 (FOXO1) pathway. Methods. Blood glucose and insulin levels were examined in mice. HE and oil red O staining were used to observe the effects of MNAM on liver lipid deposition in ob/ob mice. Real-time PCR and Western blotting were used to detect expression of gluconeogenesis, insulin signaling-related proteins, and SIRT1/FOXO1 pathway-related proteins. L-O2 cells were cultured as a model of insulin resistance, and MNAM and SIRT1 inhibitors were administered in vivo. Residual glucose and insulin signaling-related proteins were detected and the mechanisms associated with the SIRT1/FOXO1 signaling pathway in insulin resistance explored. Results. MNAM can effectively reduce levels of fasting blood glucose and insulin, improve liver morphology, and reduce lipid accumulation in obese type 2 diabetes mellitus mice. MNAM also downregulates the key proteins in the gluconeogenesis pathway in the liver, upregulates Sirt1 expression, and reduces acetylation of the FOXO1 protein. In vitro, MNAM could promote the glucose uptake capacity of L-O2 cells induced by palmitic acid (PA), a saturated fatty acid that induces IR in various scenarios, including hepatocytes, improving insulin resistance. As Sirt1 expression was inhibited, the reduction of hepatocyte gluconeogenesis and the regulation of the insulin signaling pathway by MNAM were reversed. Conclusion. MNAM activates SIRT1 and inhibits acetylation of FOXO1, which in turn regulates insulin sensitivity in type 2 diabetic mice, leading to a reduction of hepatic glucose output and improvement of insulin resistance.

Nicotinamide N‐methyltransferase ameliorates renal fibrosis by its metabolite 1‐methylnicotinamide inhibiting the TGF‐β1/Smad3 pathway

“…In previous studies, MNAM attenuated insulin resistance and reduced lipid accumulation in type 2 diabetic mice. 23 MNAM may be used as a new predictive biomarker for acute kidney injury mortality and renal replacement therapy. 49 In animal and clinical trials, the antiatherosclerotic effects of MNAM were associated with improved endothelial function.…”

“…Increased activation of the NNMT‐MNAM pathway protects against oxidant stress by decreasing reactive oxygen species levels in skeletal muscle in subjects with chronic obstructive pulmonary disease 21,22 . In patients with type 2 diabetes, high NNMT and plasma MNAM levels are related to the degree of insulin resistance 23,24 . The levels of NNMT and MNAM are substantially increased in both cultured proximal tubular cells stimulated with palmitate‐albumin and the kidneys of free fatty acids‐albumin‐overloaded mice, and NNMT overexpression and MNAM protect against lipotoxicity‐induced kidney tubular injury 25 .…”

“…21,22 In patients with type 2 diabetes, high NNMT and plasma MNAM levels are related to the degree of insulin resistance. 23,24 The levels of NNMT and MNAM are substantially increased in both cultured proximal tubular cells stimulated with palmitate-albumin and the kidneys of free fatty acids-albumin-overloaded mice, and NNMT overexpression and MNAM protect against lipotoxicity-induced kidney tubular injury. 25 However, the role and underlying mechanism of NNMT and its metabolite MNAM in the development of TIF have not been completely elucidated.…”

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

“…While initially assumed to be an inactive catabolite, studies nearly two decades ago found that (MNA) has anti-inflammatory activity [115]. Subsequent research has shown that MNA can be protective in rodent models of atherosclerosis, thrombosis, diabetes, metabolic syndrome, polycystic ovary syndrome, Alzheimer's disease, depression, and age-related hearing loss [116][117][118][119][120][121][122][123][124]. These versatile benefits may be attributable, at least in part, to the ability of MNA to slow proteasomal catabolism of SIRT1, increasing its protein half-life [125].…”

Manual therapy regulates oxidative stress in aging rat lumbar intervertebral discs through the SIRT1/FOXO1 pathway

“…Alvarez et al [ 24 ] showed that decreasing FOXO1 expression led to cell senescence and tissue degeneration in IVDs, indicating that FOXO1 is an important regulator for maintaining IVD homeostasis during aging. As the upstream of FOXO1, SIRT1 can reinforce the resistance to oxidative damage of tissue and delay aging by inhibiting FOXO1 acetylation [ 25 ]. However, the functions of the SIRT1/FOXO1 pathway in the aging of NP cells (NPC) has not been well studied.…”