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.
Highlights
Diabetes is one of metabolic diseases characterized by chronic hyperglycemia resulting from a complex etiology, with insulin resistance being one of the most important causes [1]
At 8 weeks, comparing with the diabetic model group (DM) group without treatment of MNAM, we found that the MNAM high-dose group (MNAMH) group had significantly lower weight gain (Figure 1(b)) and decreased fasting blood glucose (Figure 1(d), P < 0:05 vs. DM)
We demonstrated that MNAM can regulate liver gluconeogenesis and insulin signaling pathways in obese type 2 diabetes mellitus (T2DM) mice, reduce liver tissue lipid deposition, and improve insulin resistance in obese T2DM mice, resulting in reduced fasting blood glucose
Summary
Diabetes is one of metabolic diseases characterized by chronic hyperglycemia resulting from a complex etiology, with insulin resistance being one of the most important causes [1]. Patients with type 2 diabetes mellitus (T2DM) account for about 90%-95% of all diabetes cases [2]. The main clinical characteristic of T2DM is insulin resistance accompanied by insulin secretion deficiency [3]. The insulin deficiency and tissue insulin resistance can cause metabolic disorders involving the metabolism of glucose, fat, protein, water, and electrolytes [4]. The clinical treatment of T2DM mainly targets insulin resistance and relative insulin secretion; glycemic control in diabetic patients is still hard. New therapeutic targets that improve insulin resistance and protect islet β-cell function are of great significance for the prevention and treatment of T2DM
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