Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice.
Level 5 - mechanism / opinion, no new human data
Animal model study with no human clinical data.
PubMed 37175762 · doi:10.3390/ijms24098056
What was done
Researchers used tetracycline-inducible Cre-lox recombination with a PAX8 promoter to conditionally knock out (KO) the insulin receptor (InsR) specifically from renal tubules in adult male (M) and female (F) C57BL/6 mice. They compared KO mice against wild-type (WT) controls, measuring kidney and body weights, proximal tubule (PT) and cortical collecting duct cell heights, renal transporter protein levels (ENaC subunits, NKCC2, SGLT1, SGLT2) via Western blotting, exogenous glucose clearance, and markers of renal gluconeogenesis.
What was found
Body weight did not change, but mean kidney weight fell by 13% in male KO (KOM) and 3% in female KO (KOF) relative to WT. PT cell height decreased by 25% in KOM and 5% in KOF; cortical collecting duct cell height decreased by 19% in KOM and 11% in KOF. Both KO sexes exhibited reduced β- and γ-ENaC and NKCC2 protein expression, but α-ENaC was upregulated in KOM and downregulated in KOF. Both sexes cleared exogenous glucose faster and showed lower semi-fasted blood glucose. However, KOMs exclusively demonstrated higher glucose-6-phosphatase, elevated PT glucose production, increased post-prandial blood glucose, and higher plasma insulin. In contrast, KOFs exhibited downregulation of SGLT2 and upregulation of SGLT1, changes not observed in KOMs.
Why it matters
This study demonstrates that renal tubular insulin receptor signaling modulates tubular structure, sodium transport pathways, and glucose homeostasis in a sex-dependent manner, identifying potential mechanisms relevant to sex differences in diabetes and insulin resistance.
Limits
The abstract does not state the sample size (n) or report variance, confidence intervals, or p-values. As an animal study using mouse-specific gene deletion, direct translation to human renal physiology and clinical metabolic disease is unverified.
Cited by
- supports Insulin promotes the reabsorption of sodium at the level of the kidney.