Extra-cellular nicotinamide phosphoribosyltransferase (eNAMPT; also referred to as visfatin/PBEF) concentrations are elevated in serum of patients with type 2 diabetes (T2D). However, the relationship between abnormally elevated serum eNAMPT and the pathophysiology of T2D is unclear. eNAMPT circulates in functionally and structurally distinct monomer and dimer forms. eNAMPT-dimer exerts NAD-biosynthetic activity. The role of eNAMPT-monomer is unclear but may exert NAD-independent pro-inflammatory effects. However studies of eNAMPT in T2D have not distinguished between monomer and dimer forms. Since T2D is characterised by chronic inflammation, we hypothesized a selective role for eNAMPT-monomer in T2D pathophysiology.
Two experimental models were used to examine the role of eNAMPT-monomer in T2D; (A) diabetic high-fat fed mice (HFD; 10 weeks) were administered a neutralizing anti-eNAMPT-monomer antibody; (B) lean mice were administered recombinant eNAMPT-monomer daily for 14 days, to induce a serum concentration of 5 ng/ml, similar to levels in HFD mouse serum.
Serum eNAMPT-monomer levels were elevated in diabetic HFD mice, whilst eNAMPT-dimer levels were unchanged. Increased eNAMPT-monomer levels occurred in part due increased secretion from dysfunction visceral white adipose tissue and liver. Strikingly, neutralization of eNAMPT-monomer in HFD mice resulted in lowered blood glucose, amelioration of impaired glucose tolerance (IGT) and whole-body insulin resistance, improved pancreatic islet function and hepatic insulin sensitivity and reduced systemic and tissue inflammation. These effects were maintained at least 3 weeks post-dosing. Finally, eNAMPT-monomer administration induced a diabetic phenotype in mice, characterised by elevated blood glucose, IGT, whole-body insulin resistance, impaired pancreatic insulin secretion and presence of systemic inflammation. In contrast administration of eNAMPT-dimer led to a modest improvement in glycaemic control.
In summary, we demonstrate that chronic elevation of eNAMPT-monomer plays a crucial role in the pathogenesis of diet-induced T2D via pro-inflammatory mechanisms. These data provide proof-of-concept evidence that eNAMPT-monomer represents a novel therapeutic target for T2D.