MECHANISMS IN ENDOCRINOLOGY: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism?

Type 2 diabetes (T2D) is associated with inhibition of autophagic and lysosomal housekeeping processes that detrimentally affect key organ functioning; a process likely to be exacerbated by conventional insulin-driven anabolic therapies. We propose that the cardio-renal benefits demonstrated with sodium-glucose cotransporter-2 inhibitor (SGLT2i) treatment in T2D partly may be explained by their ability to drive consistent, overnight periods of increased catabolism brought about by constant glucosuria. Key steps driving this catabolic mechanism include: a raised glucagon/insulin ratio initially depleting glycogen in the liver and ultimately activating gluconeogenesis utilizing circulating amino acids (AAs); a general fuel switch from glucose to free fatty acids (accompanied by a change in mitochondrial morphology from a fission to a sustained fusion state driven by a decrease in AA levels); a decrease in circulating AAs and insulin driving inhibition of mammalian target of rapamycin complex 1 (mTORC1), which enhances autophagy/lysosomal degradation of dysfunctional organelles, eventually causing a change in mitochondrial morphology from a fission to a sustained fusion state. Resumption of eating in the morning restores anabolic biogenesis of new and fully functional organelles and proteins. Restoration of diurnal metabolic rhythms and flexibility by SGLT2is may have therapeutic implications beyond those already demonstrated for the cardio-renal axis and may therefore affect other non-diabetes disease states.