Reduced insulin action in muscle of high fat diet rats over the diurnal cycle is not associated with defective insulin signaling

Lewin Small,Amanda E Brandon,Benjamin L Parker,Vinita Deshpande,Azrah F Samsudeen,Greg M Kowalski,Jane Reznick,Donna L Wilks,Elaine Preston,Clinton R Bruce,David E James,Nigel Turner,Gregory J Cooney

doi:10.1016/j.molmet.2019.04.006

Abstract

ObjectiveEnergy metabolism and insulin action follow a diurnal rhythm. It is therefore important that investigations into dysregulation of these pathways are relevant to the physiology of this diurnal rhythm. MethodsWe examined glucose uptake, markers of insulin action, and the phosphorylation of insulin signaling intermediates in muscle of chow and high fat, high sucrose (HFHS) diet-fed rats over the normal diurnal cycle. ResultsHFHS animals displayed hyperinsulinemia but had reduced systemic glucose disposal and lower muscle glucose uptake during the feeding period. Analysis of gene expression, enzyme activity, protein abundance and phosphorylation revealed a clear diurnal regulation of substrate oxidation pathways with no difference in Akt signaling in muscle. Transfection of a constitutively active Akt2 into the muscle of HFHS rats did not rescue diet-induced reductions in insulin-stimulated glucose uptake. ConclusionsThese studies suggest that reduced glucose uptake in muscle during the diurnal cycle induced by short-term HFHS-feeding is not the result of reduced insulin signaling.

Highlights

There is considerable research linking lipid-induced insulin resistance to defects in the canonical insulin signaling pathway
Energy metabolism in mammals is regulated by mechanisms that follow a clear diurnal rhythm both at the whole-body level and in metabolically important tissues
We decided to investigate the relationship between circulating insulin, insulin signaling, and glucose metabolism in vivo over multiple points of the normal diurnal cycle without infusing exogenous glucose or insulin to control glycemia and insulinemia

Summary

Introduction

There is considerable research linking lipid-induced insulin resistance to defects in the canonical insulin signaling pathway. We decided to investigate the relationship between circulating insulin, insulin signaling, and glucose metabolism in vivo over multiple points of the normal diurnal cycle without infusing exogenous glucose or insulin to control glycemia and insulinemia. This provided a situation where experimental animals only utilize substrates derived from digestion or energy stores at times that are relevant to their normal feeding/fasting behavior. By utilizing radioactive glucose tracers and collecting tissue samples over the diurnal cycle, we were

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Conclusion