Pancreatic \u03b2-cells respond to fuel pressure with an early metabolic switch

Ronja M Malinowski,Jan H Ardenkjær-Larsen,Seyed M Ghiasi,Pernille R Jensen,Thomas Mandrup-Poulsen,Sebastian Meier,Mathilde H Lerche

doi:10.1038/s41598-020-72348-1

Abstract

Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. The β-cells are not able to control glucose uptake and they are therefore left vulnerable for endogenous toxicity from metabolites produced in excess amounts upon increased glucose availability. In order to handle excess fuel, the β-cells possess specific metabolic pathways, but little is known about these pathways. We present a study of β-cell metabolism under increased fuel pressure using a stable isotope resolved NMR approach to investigate early metabolic events leading up to β-cell dysfunction. The approach is based on a recently described combination of 13C metabolomics combined with signal enhanced NMR via dissolution dynamic nuclear polarization (dDNP). Glucose-responsive INS-1 β-cells were incubated with increasing concentrations of [U-13C] glucose under conditions where GSIS was not affected (2–8 h). We find that pyruvate and DHAP were the metabolites that responded most strongly to increasing fuel pressure. The two major divergence pathways for fuel excess, the glycerolipid/fatty acid metabolism and the polyol pathway, were found not only to operate at unchanged rate but also with similar quantity.

Highlights

Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage
In order to select conditions where β-cells are challenged by high fuel pressure before functional impairment, suitable exposure time and concentration of glucose need to be defined first
The metabolic conversion of pyruvate and DHAP both use NADH for subsequent reduction to lactate and glycerolphosphate, respectively (Fig. S5). These reactions have previously been shown to respond to redox changes in yeast and mammalian cancer cells[20,21]. Since these metabolic pathways are part of the strongly conserved central carbon metabolism we suggest that a similar mechanism might be used as defense mechanism in β-cells, as well

Summary

Introduction

Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. It is clear from a mere visual comparison of the 1D 13C NMR spectra that the metabolic fingerprint of β-cells responds to changes in glucose availability, and all measured metabolites increase with increased glucose availability (Fig. 3A). It was further investigated how the metabolic output changed with a 2–8 h incubation time, for the two glucose concentrations, 11.7 mM and 17 mM (Fig. 5A).

Results

Conclusion