Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids.
Level 5 - mechanism / opinion, no new human data
Bench and animal research with no clinical human data.
PubMed 24755741 · doi:10.1096/fj.13-243634
What was done
Investigators evaluated the mechanism connecting AMP deaminase (AMPD) activation, uric acid, and AMP kinase (AMPK) regulation in hepatic gluconeogenesis using liver tissue from diabetic mice and human HepG2 cell culture models. They tested the effects of reduced intracellular phosphate on AMPD activation, assessed downstream TORC2 phosphorylation and gluconeogenic enzyme expression (PEPCK and G6Pc), and expressed resurrected ancestral hominid uricases in HepG2 cells.
What was found
The abstract reports no numerical values, confidence intervals, or sample sizes. AMPD was activated in diabetic mouse liver, paralleling reduced AMPK activity and increased glucose accumulation in HepG2 cells. Uric acid derived from AMPD inhibited AMPK, reduced TORC2 phosphorylation at Ser171, and upregulated PEPCK and G6Pc. Transfecting resurrected ancestral uricase into HepG2 cells reduced gluconeogenesis and restored AMPK activity.
Why it matters
This study defines a biochemical pathway linking uric acid to hepatic gluconeogenesis via AMPK suppression. It suggests that the evolutionary loss of uricase in hominids, which aided survival during starvation, may drive excessive glucose production in modern diabetic states.
Limits
Findings are limited to preclinical animal models and in vitro immortalized cell lines (HepG2) without human clinical verification. No quantitative data, effect sizes, or statistical parameters are provided in the abstract.
Cited by
- supports Primate ancestors developed uricase gene mutations 14 to 18 million years ago that resulted in elevated uric acid levels.