Effects of fructose feeding on mice with dual knockout of the insulin and insulin‐like‐growth factor, type 1 (IGF1) receptors from proximal‐tubule

Abstract

The proximal tubule (PT) metabolizes fructose. How insulin and/or IGF1 regulate this metabolism is unclear. We bred mice with dual knockout (KO) of receptors for insulin and IGF1 from PT by Cre‐lox recombination using a g‐glutamyl transferase promoter. Wild‐type (WT) and KO mice (n = 5‐7/genotype) of both sexes were fed control (C) or high fructose (Fr) diet (60%) for 4 weeks in 2 studies. Data for males and females were combined except when sex differences were found. In Study 1 (young mice, 3‐4 month‐old) semi‐fasting blood glucose (BG) was significantly higher in KO (20‐30%, p = 0.007, by 2‐way ANOVA), but not affected by fructose. In Study 2 (mid‐aged, 6‐10 month‐old), BG was increased by fructose, but only in KO mice (significant interaction). Western blotting of whole kidney homogenates (WKH) in Study 2 revealed that Fr increased band density for IGF1R over 2.5‐fold, but only in WT mice. In contrast, KOFr mice actually showed a reduction in band density with fructose (~30% of KOC, p <0.001 for interaction). Similarly, ketohexokinase (KHK), the first enzyme in fructose metabolism, was significantly increased in expression by fructose (2‐fold p <0.014) in WT mice, but decreased in KO (significant interaction, p = 0.022). In contrast the expression of GLUT5, a fructose transporter, was significantly increased by Fr (6‐20%) in both genotypes (p = 0.007 for diet). These studies suggest IR or IGF1R may have a role in mediating fructose metabolism by the PT. Furthermore the absence of the receptor(s) in PT may predispose individuals to hyperglycemia. Whether metabolism of fructose in PT affects gluconeogenesis at this site is in need of further study.