Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2...

Area of Science:

• Endocrinology
• Metabolic Diseases
• Molecular Biology

Background:

• Progressive decline in functional beta cell mass is central to type 2 diabetes development.
• Elevated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is linked to beta cell failure, yet its precise effects are unclear.
• eNAMPT exists in monomeric and dimeric forms, with dimerisation crucial for NAD-biosynthesis, while monomers may have distinct NAD-independent roles.

Purpose of the Study:

• To fully characterize the structure-functional effects of eNAMPT on pancreatic beta cell functional mass.
• To elucidate the role of eNAMPT in beta cell failure associated with type 2 diabetes.

Main Methods:

• Utilized CD-1 mice and human islets, generating recombinant monomeric and wild-type eNAMPT.
• Assessed beta cell function via insulin secretion and calcium microfluorimetry.
• Analyzed NAD-biosynthetic capacity, islet cell number, apoptosis, and inflammatory markers.

Main Results:

• eNAMPT exhibits bimodal, concentration- and structure-dependent effects on beta cell mass.
• Low physiological eNAMPT concentrations (dimeric form) enhance beta cell function via NAD-dependent mechanisms.
• High eNAMPT concentrations (~5 ng/ml, monomeric form) induce beta cell dysfunction, reduced identity, increased apoptosis, and inflammation via NAD-independent pathways.

Conclusions:

• A novel mechanism for type 2 diabetes beta cell dysfunction involving eNAMPT structure-function changes is identified.
• Dimeric eNAMPT maintains beta cell function at low levels, while elevated monomeric eNAMPT in type 2 diabetes induces a diabetic phenotype.
• Targeting monomeric eNAMPT presents a potential therapeutic strategy for type 2 diabetes.