Nicotinamide Mononucleotide Prevents Free Fatty Acid-Induced Reduction in Glucose Tolerance by Decreasing Insulin Clearance.

Ashraf Nahle,Frankie Poon,Tejas Desai,Suman Asalla,Jamie W Joseph,Aleksandar Ivovic,Yusaku Mori,Harrison T Muturi,Simona S Ghanem,Emelien M Jentz,Sonia M Najjar,Sandra Pereira,Adria Giacca,Hilda E Ghadieh,Yemisi Deborah Joseph

doi:10.3390/ijms222413224

Abstract

The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on β cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced β cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased β cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.

Highlights

Type 2 diabetes mellitus (T2DM) is a growing health concern worldwide, in parallel to increased incidences of obesity
Mice co-infused with nicotinamide mononucleotide (NMN) + OLE had a substantial increase in glucose infusion rate (GINF), compared with the OLE and the SAL groups
Since we unexpectedly found a decrease in insulin clearance in the NMN + OLE ver-5 of 17 sus the OLE group, and in light of our previous finding that free fatty acids (FFAs) decrease the expression of CEACAM1 [14] that plays a key role in hepatic insulin clearance [14,15], we assessed hepatic CEACAM1 protein levels by Western blot analysis

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a growing health concern worldwide, in parallel to increased incidences of obesity. It is associated with insulin resistance in combination with decreased secretory pancreatic β cell function (i.e., decreased ability of β cells to compensate for insulin resistance). In overweight and obese individuals, who represent ~90% of T2DM patients [1], insulin resistance is partly caused by elevated levels of circulating free fatty acids (FFAs). We found that intravenous co-infusion of resveratrol (a SIRT1 activator [5]) partially protected against β cell dysfunction induced by a 48 h intravenous oleate infusion. We found that β cell-specific sirtuin 1-overexpressing (BESTO) transgenic mice are partially protected against oleate-induced β cell dysfunction in vivo [6]

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Conclusion