Abstract
Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.
Highlights
Obesity is a predisposing factor for Type 2 diabetes (T2D), and the prevalence of obesity has significantly accelerated the rise of T2D in the past few decades
This review will focus on the roles of nicotinamide N-methyltransferase (NNMT) in obesity and T2D, as it has been found that the expression of this methyltransferase is elevated in the white adipose tissue and liver of obese people and diabetic mice and that NNMT knockdown protects against dietinduced obesity and insulin resistance [11]
Similar to NNMT overexpression, MNA-treated hepatocytes show a dose-dependent increase in glucose production, Sirt1 protein expression, glucose-6-phosphatase catalytic (G6pc) mRNA expression, and phosphoenolpyruvate carboxykinase 1 cytosolic (Pck1) mRNA expression compared to controls and these changes caused by MNA treatment can be abolished by Sirt1 knockdown [14]
Summary
Obesity is a predisposing factor for T2D, and the prevalence of obesity has significantly accelerated the rise of T2D in the past few decades. The mechanism linking obesity and the development of T2D is complex and unintelligible, but it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles [3]. The increase in the circulatory free fatty acid (FFA) concentration in plasma and the elevation of lipid deposition in skeletal muscles caused by abnormal lipid metabolism are the important signs of insulin resistance and T2D [4]. An increase in the NEFA level in plasma is observed in patients with obesity and T2D and is significantly associated with insulin resistance [6, 7]. It is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in linking obesity and T2D, the actual mechanisms are still unclear because not all obese people are insulin resistant or at high risk of diabetes [9]. This review will focus on the roles of NNMT in obesity and T2D, as it has been found that the expression of this methyltransferase is elevated in the white adipose tissue and liver of obese people and diabetic mice and that NNMT knockdown protects against dietinduced obesity and insulin resistance [11]
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