Abstract
Aims/hypothesisNicotinamide-N-methyltransferase (NNMT) was recently shown to be upregulated in mouse models of insulin resistance and obesity. So far, it is unknown whether NNMT is regulated in human disease. We have explored the hypothesis that white adipose tissue (WAT) NNMT expression and plasma 1-methylnicotinamide (MNA) concentration are increased in human insulin resistance and type 2 diabetes.Methods NNMT expression and plasma MNA were analysed in three groups of individuals: (1) 199 patients undergoing abdominal surgery; (2) 60 individuals on a 12-week exercise programme and (3) 55 patients on a two-step bariatric surgery programme.ResultsPatients with manifest type 2 diabetes have a significantly (approximately twofold) higher NNMT expression both in omental and subcutaneous WAT compared with controls. Notably, plasma MNA correlated significantly with WAT NNMT expression in patients with type 2 diabetes (women, r = 0.59, p < 0.001; men, r = 0.61, p < 0.001) but not in healthy control individuals. In insulin-resistant individuals, there was an inverse correlation between insulin sensitivity and plasma MNA (r = 0.44, p = 0.01) or adipose tissue NNMT mRNA (r = 0.64, p < 0.001). The latter association was confirmed in a second cohort (n = 60, r = 0.78, p < 0.001). Interventions improving insulin sensitivity—exercise and bariatric surgery—were associated with a significant (p < 0.001) reduction in WAT NNMT expression. Bariatric surgery was also associated with a significant decrease in plasma MNA.Conclusions/interpretationWe demonstrate that WAT NNMT expression is regulated in human insulin resistance and type 2 diabetes and that plasma MNA correlates with increased tissue NNMT expression and the degree of insulin resistance, making it a potential biomarker for loss of insulin sensitivity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3490-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Increased abdominal adiposity, especially expansion of visceral adipose tissue, has been identified as a major risk factor for the development of insulin resistance, type 2 diabetes and cardiovascular disease [1,2,3]
Conclusions/interpretation We demonstrate that white adipose tissue (WAT) NNMT expression is regulated in human insulin resistance and type 2 diabetes and that plasma MNA correlates with increased tissue NNMT expression and the degree of insulin resistance, making it a potential biomarker for loss of insulin sensitivity
This study demonstrates for the first time that NNMT mRNA in adipose tissue and circulating levels of the product of NNMT, MNA, were higher in humans with insulin resistance or type 2 diabetes and correlated with the extent of insulin resistance
Summary
Especially expansion of visceral adipose tissue, has been identified as a major risk factor for the development of insulin resistance, type 2 diabetes and cardiovascular disease [1,2,3]. Individuals at risk of type 1 diabetes who were treated with nicotinamide at a dose of 2 g per day for 2 weeks showed a significant decrease in systemic insulin sensitivity, which was reversible after treatment stopped [7]. It was observed in the HPS2-THRIVE study (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) that, in patients with cardiovascular disease, chronic treatment with a combination of extended-release niacin and laropiprant led to a significant increase in new-onset diabetes and disturbed glucose control in patients with established type 2 diabetes at baseline [8]. We explore the hypothesis that elevated nicotinamide-N-methyltransferase (NNMT) expression and activity may play a role in the development of human insulin resistance
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