Characterizing Murine Diabetic Glucose Metabolism Under Conditions of Attenuated Renal Glucose Reabsorption

Abstract

While type 1 (T1DM) and type 2 (T2DM) diabetes mellitus differ in etiology, both are metabolic disorders characterized by chronic hyperglycemia; if left untreated, this can lead to serious complications including renal failure. Glucoregulation is critical to meeting tissues’ energy needs without exceeding adaptive glucose levels and involves several metabolic pathways including gluconeogenesis (occurring in the kidney and liver) and glycolysis, which are primarily regulated through certain rate‐limiting enzymes involved in the committed steps of each pathway. Beyond its metabolic contributions, the kidney also mediates glucoregulation through the process of glucose reabsorption in the proximal tubules (PT); crucial symporters known as sodium glucose cotransporters (SGLTs) move glucose into PT epithelial cells to facilitate its return to the bloodstream rather than excretion in the urine. Inhibiting renal glucose reabsorption via the modulation of SGLTs has been linked to improved diabetic outcomes, yet the impacts of this intervention on whole body glucose metabolism have not been fully characterized. Thus, we aimed to determine if SGLT modulation alters expression of rate‐limiting glucometabolic enzymes under conditions of T1DM and T2DM. Firstly, we compared renal and hepatic tissues isolated from nondiabetic and type 1 diabetic Olfactory Receptor 1393 (Olfr1393) knockout (KO) and wild type mice; Olfr1393 is a GPCR that has been previously demonstrated to impact localization of glucose transporters, and Olfr1393 KO mice exhibit improved diabetic phenotypes (Shepard et al., 2019; Schiazza et al., 2021). Secondly, hepatic tissues from T2DM TallyHo (TH) mice fed a milk fat diet with or without the SGLT2 inhibitor Empagliflozin were analyzed. Initial analysis of qPCR and Western blot data from each condition reveals diabetic differences in glucometabolic enzyme expression within each group; under conditions of T1DM, gluconeogenesis (via expression of glucose 6‐phosphatase) appears to be decreased in both the kidney and liver. In addition, we noted reciprocal regulation of glycolytic enzymes PKM 1 and 2; in the kidney, T1DM decreases PKM1 expression but upregulates PKM2. However, the data collectively suggest that SGLT modulation does not alter renal or hepatic glucose metabolism. Further in vivo exploration may elucidate patterns of similar or differential glucoregulation that will contribute to our current understanding of the body’s dynamic glucometabolic profile in the context of diabetes and the efficacy and whole body impacts of applying SGLT inhibition in the treatment of these disorders.