Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes

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.

SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease

“…In this study, the expression of NAMN (precursor to the NAD+ de novo synthesis pathway) and niacinamide (NAM, precursor to the salvage synthesis pathway) was increased after EMPA treatment, indicating that these key enzymes may act as targets for EMPA to amend energy metabolism. In addition, most NAM is mainly produced by NAD+-consuming enzymes, including the superfamily members of sirtuins (SIRT), poly (ADP-ribose) polymerase (PARP) and CD38 [ 55 ]. However, in a study, canagliflozin treatment reversed the reduction in SIRT1 expression in db/db mice and improved local NAD+ metabolism in the kidney [ 56 ].…”

A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male

“…Similarly to NAD(H), maintaining homeostatic levels of NNMT is considered important for preserving human health. Aberrantly high expression of NNMT has been linked to the development of obesity [ 37 ], type 2 diabetes [ 38 ], various cancers [ 39 , 40 , 41 ], neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease [ 42 , 43 , 44 ], and pulmonary hypertension [ 45 ]. On the other hand, abnormally low serum levels of NNMT have been reported in bipolar mania patients [ 46 ], and higher incidents of familial schizophrenia have been correlated with lower expression of NNMT in the frontal cortex [ 47 ].…”

Diabetes Mellitus and Pregnancy: An Insight into the Effects on the Epigenome

“…However, the metabolic pathways in which this molecule participates have not been elucidated. NNMT activity has been observed to increase in patients with T2DM, who also exhibit a higher expression of NNMT [67]. Decreased methylation was linked to the increased expression of NNMT in obese patients in the following genes: collagen type XXIII alpha 1 chain (COL23A1), plectin (PLEC1), F-box protein 21 (FBXO21), STEAP3 metalloreductase (STEAP3), regulator of G protein signaling 12 (RGS12), immunoglobulin superfamily DCC subclass member 3 (IGDCC3), forkhead box K2 (FOXK2), and ORAI calcium release-activated calcium modulator 2 (ORAI2) [68].…”