Sodium‐glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter‐organ crosstalk

Abstract

Aim: To investigate sodium-glucose cotransporter 2 inhibitor (SGLT2i)-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models.Materials and methods: Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/d by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/d by subcutaneous injection) or SGLT2i (25 mg/kg/d by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analysed.Results: In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium-dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycaemic conditions, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis. Conclusions:SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration. K E Y W O R D Santidiabetic drug, empagliflozin, sodium-glucose cotransporter 2 inhibitors

High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment

“…Consistent with this finding, the same pathways seemed to be up-regulated in T2DM patients with cardiovascular disease [43]. On the contrary, in the murine liver, kidney or intestine, dapagliflozin showed a ketogenesis increase [44]. In metabolomics studies including fast and feed situations, as well as the main metabolite available on each tissue, is important.…”

Effects of sodium–glucose cotransporter 2 inhibitors on non‐alcoholic fatty liver disease in patients with type 2 diabetes: A meta‐analysis of randomized controlled trials

“…Cotter's findings 34 suggest that ketogenesis might prevent fatty liver injury and hepatic steatosis through regulating hepatic acetyl coenzyme A metabolism, glucose metabolism and tricarboxylic acid cycle function. The latest research 35 shows that SGLT2 inhibitors could increase ketone body metabolism by upregulating ketogenic enzymes and transporters in the liver, which might be a significant part of the improvement of NAFLD.…”

Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study

“…There are several potential mechanisms for the pleiotropic role of ketone bodies in glucose metabolism. First, in the process of formation of ketone bodies, nuclear receptor peroxisome proliferator-activated receptor, alpha (PPARα) and one of its downstream targets, fibroblast growth factor 21 (FGF21), are strongly induced, and Hmgcs2 transcription is increased in the liver [35][36][37][38]. HMGCS2 may also induce Fgf21 gene expression [39].…”