Proximal‐tubule‐select dual knockout of insulin and insulin‐like‐growth factor (type I) receptors in mice alters responses to dietary fructose

Abstract

The monosaccharide, fructose is a common dietary constituent, but metabolized quite differently from glucose. One site of fructose metabolism is the renal proximal tubule (PT). How and whether insulin or the related hormone, insulin‐like‐growth‐factor, type 1 (IGF1), modulate fructose metabolism at this site is not known. To address this, we bred mice with dual knockout (KO) of the insulin receptor (IR) and the IGF1 receptor (IGF1R) from PT by Cre‐lox recombination using a γ‐glutamyltransferase promoter. Male (M) and female (F) wild‐type (WT) and KO mice were fed control (C) or high fructose (Fr) diet (60%) for 4 weeks (n = 10–12/group). KO mice had marginally lower body and/or kidney weights. Fructose feeding did not affect final body weight. Glucose tolerance was significantly impaired by fructose feeding, but only in the WT mice. KO mice also had a phenotype suggesting renal tubular acidosis, i.e., with significantly elevated blood chloride levels, and decreased blood total CO2 levels. Plasma sodium was also reduced in male KO by fructose, but not in the WT or females. Western blotting of cortex homogenates revealed significantly reduced (2‐way ANOVA) band densities for IR, IGF1R, and NaPi‐2 (sodium phosphate cotransporter) in the KO mice. However, no genotype differences were found for band densities of the fructose transporter (GLUT5) and ketohexokinase (KHK), the first enzyme in fructose metabolism, although the abundances of these two proteins were significantly increased in males and in fructose‐fed animals. The sodium bicarbonate cotransporter (NBC) was reduced in KO, but not WT males by fructose‐feeding. Females, overall, had significantly lower levels of NBC. Overall, genotype differences in the metabolic responses to fructose suggest a role for PT IR/IGF1R expression as a modulator of PT metabolism and/or acid‐base homeostasis.Support or Funding InformationMarriott Cardiovascular Fellowship and Georgetown Internal funding