Lack of PanK1 improves insulin sensitivity and glucose tolerance by activating AMPK in skeletal muscle

Coenzyme A (CoA) is an essential cofactor required for complete oxidation of fatty acids, selected amino acids, carbohydrates, and ketone bodies. CoA levels are tightly regulated by feedback inhibition of pantothenate kinase (PanK), the rate‐limiting enzyme in CoA biosynthesis. PanK1α and 1β derive from alternative splicing of the Pank1 gene, and we generated a global Pank1 knockout (KO) mouse. The KO mice exhibit reduced fasting serum glucose, insulin and triglyceride levels, together with improved glucose tolerance and insulin sensitivity. Furthermore, the KO mice display decreased exercise capacity and isometric strength, pointing to skeletal muscle as one of the organs most critically affected by the lack of PanK1. The purpose of this study was to uncover alterations in this tissue that underlie the improved insulin sensitivity and glucose tolerance of the KO mice. In control quadriceps fasting caused a 3‐fold upregulation of the PanK1α transcript and a 2‐fold increase in total CoA. This response to fasting was absent in the KO mice. A robust increase in the AMPK‐P to AMPK ratio was observed in the KO mice suggesting that impaired mitochondrial fuel utilization might be the underlying cause for increased glucose uptake by the muscle. Thus, lower muscle CoA leads to AMPK activation and improved glucose tolerance similar to the effects of the antidiabetic drug metformin. Funding was from NIH grant GM062896 and ALSAC.