Mechanisms of insulin resistance, mitochondrial dysfunction and the action of the ketogenic diet in bipolar disorder. Focus on the PI3K/AKT/HIF1-a pathway

Over the past decade evidence from multiple research trajectories have converged to provide evidence that impaired glucose metabolism and mitochondrial dysfunction in the brain are the critical issues laying at the root of Bipolar Disorder (BD). These developments have been paralleled by increasing recognition of the systemic metabolic dysfunction accompanying mood disorders. Significant insulin resistance (IR) occurs in BD patients and this has been demonstrated to be related to illness severity independent of medication status. Preliminary evidence for a therapeutic effect of a Ketogenic Diet (KD) in BD and other neuropsychiatric conditions has recently refocused interest in the role of IR in BD pathogenesis. In this paper we review evidence of hyperinsulinemia in BD as the primary cause of mitochondrial dysfunction mediated by impairment of the PI3K/AKT/HIF1-a insulin signaling pathway. This cascade of dysfunction directly suppresses the Pyruvate Dehydrogenase Complex through HIF1-a mediated activation of Pyruvate dehydrogenase kinase 1 (PDK1) leading to the Warburg effect and mitochondrial dysfunction. We review evidence that the KD acts directly on each of these mechanisms and propose that a trial of KD in BD with a mechanistic component is needed to further investigate the role of IR in BD.