Miotto 2020 Am J Physiol Endocrinol Metab

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Miotto PM, Petrick HL, Holloway GP (2020) Acute insulin deprivation results in altered mitochondrial substrate sensitivity conducive to greater fatty acid transport. Am J Physiol Endocrinol Metab 319:E345-53.

» PMID: 32543943

Miotto PM, Petrick HL, Holloway GP (2020) Am J Physiol Endocrinol Metab

Abstract: Type 1 and type 2 diabetes are both tightly associated with impaired glucose control. While both pathologies stem from different mechanisms, a reduction in insulin action coincides with drastic metabolic dysfunction in skeletal muscle and metabolic inflexibility. However, the underlying explanation for this response remains poorly understood, particularly since it is difficult to distinguish the role of attenuated insulin action from the detrimental effects of reactive lipid accumulation which impair mitochondrial function and promote reactive oxygen species (ROS) emission. We therefore utilized streptozotocin to examine the effects of acute insulin deprivation, in the absence of a high lipid / nutrient excess environment, on the regulation of mitochondrial substrate sensitivity and ROS emission. The ablation of insulin resulted in reductions in absolute mitochondrial oxidative capacity, ADP-supported respiration, and reduced the ability for malonyl-CoA to inhibit carnitine palmitoyl-transferase I (CPT-I) and suppress fatty acid-supported respiration. These bioenergetic responses coincided with increased mitochondrial derived H2O2 emission and lipid transporter content, independent of major mitochondrial substrate transporter proteins and enzymes involved in fatty acid oxidation. Together, these data suggest that attenuated/ablated insulin signalling does not affect mitochondrial ADP sensitivity, while the increased reliance on fatty acid oxidation in situations where insulin action is reduced may occur as a result of altered regulation of mitochondrial fatty acid transport through CPT-I.

Keywords: ADP sensitivity, Insulin, Lipid metabolism, Mitochondria, Streptozotocin Bioblast editor: Plangger M O2k-Network Lab: CA Guelph Holloway GP

Labels: MiParea: Respiration  Pathology: Diabetes 

Organism: Rat  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS  Pathway: F, N, NS  HRR: Oxygraph-2k