Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function

• Published in: Diabetologia 2011-12, Vol.54 (12), p.3083-3092
• Main Authors: Caton, P. W., Kieswich, J., Yaqoob, M. M., Holness, M. J., Sugden, M. C.
• Format: Article
• Language: English
• Subjects: Acute effects; Adipose tissue; Animals; Beta cells; Biological and medical sciences; Body fat; Cell Differentiation; Cells, Cultured; Cytokines; Cytokines - administration & dosage; Cytokines - blood; Cytokines - metabolism; Dentistry; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Diets; Differentiation; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Feeding; Fructose; Fructose - administration & dosage; Genotype & phenotype; Glucose; Human Physiology; Inflammation; Inflammation - metabolism; Insulin; Insulin - metabolism; Insulin resistance; Insulin Secretion; Interleukin 1; Interleukin-1beta - administration & dosage; Interleukin-1beta - metabolism; Internal Medicine; Islets of Langerhans; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic syndrome; Mice; Mice, Inbred C57BL; nicotinamide; Nicotinamide Mononucleotide - administration & dosage; Nicotinamide Mononucleotide - metabolism; Nicotinamide phosphoribosyltransferase; Nicotinamide Phosphoribosyltransferase - blood; Nicotinamide Phosphoribosyltransferase - metabolism; Sirtuin 1 - antagonists & inhibitors; Sirtuins; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - administration & dosage
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2288-0

Aims/hypothesis Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD + biosynthesis, exists as intracellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT). eNAMPT, secreted from adipose tissue, promotes insulin secretion. Administration of nicotinamide mononucleotide (NMN), a product of the eNAMPT reaction, corrects impaired islet function in Nampt +/− mice. One of its potential targets is the NAD + -dependent deacetylase sirtuin 1. We hypothesised that altered NAMPT activity might contribute to the suppression of islet function associated with inflammation, and aimed to determine whether NMN could improve cytokine-mediated islet dysfunction. Methods Acute effects of NMN on cytokine-mediated islet dysfunction were examined in islets incubated with TNFα and IL1β, and in mice fed a fructose-rich diet (FRD) for 16 weeks. Changes in iNAMPT, eNAMPT and inflammation levels were determined in FRD-fed mice. Results FRD-fed mice displayed markedly lower levels of circulating eNAMPT, with impaired insulin secretion and raised islet expression of Il1b . NMN administration lowered Il1b expression and restored suppressed insulin secretion in FRD-fed mice. NMN also restored insulin secretion in islets cultured with pro-inflammatory cytokines. The changes in islet function corresponded with changes in key markers of islet function and differentiation. The anti-inflammatory effects of NMN were partially blocked by inhibition of sirtuin 1. Conclusions/interpretation Chronic fructose feeding causes severe islet dysfunction in mice. Onset of beta cell failure in FRD-fed mice may occur via lowered secretion of eNAMPT, leading to increased islet inflammation and impaired beta cell function. Administration of exogenous NMN to FRD-fed mice corrects inflammation-induced islet dysfunction. Modulation of this pathway may be an attractive target for amelioration of islet dysfunction associated with inflammation.