Metabolic adaptation of renal carbohydrate metabolism. IV. The use of site-specific liver gluconeogenesis inhibitors to ascertain the role of renal gluconeogenesis (¹)

Abstract

The in vitro and in vivo effects of several different inhibitors of carbohydrate metabolism have been studied. The in vitro addition of 5-methoxyindole-2-carboxylic acid (MICA), pent-4-enoic acid, and quinolinic acid to the perfusion medium significantly inhibited liver gluconeogenesis in 48-hour-starved rats (100% inhibition when MICA and quinolinic acid were added at 0.8 and 2.4 mM, respectively). In vivo the level of inhibition varied greatly depending upon whether MICA was administered by intragastric tube or intraperitoneal injection. In all cases the inhibitory capacity of MICA on liver gluconeogenesis was significantly higher when injected intraperitoneally. On the other hand, the administration of MICA produced a significant, dose-dependent, increase in renal gluconeogenesis in both fed and 48-hour-starved rats, more so when the inhibitor was administered by intraperitoneal injection.

Reexploring 5-methoxyindole-2-carboxylic acid (MICA) as a potential antidiabetic agent

“…It should be noted that MICA inhibition of the conversion of pyruvate to acetyl-CoA occurs not only just in the liver but also in many other tissues such as adipose, testis, brain, and kidney. 5 , 12 , 19 , 20 The establishment that MICA inhibits DLDH is based on the evidence that the cofactor lipoic acid instead of other cofactors such as thiamine and thiamine pyrophosphate can reverse MICA inhibition of DLDH. 14 …”

“…Additionally, as MICA targets nearly all tissues in the body and has a variety of effects on protein expression and cellular pathways in numerous experimental settings or disease models, 4 , 5 , 12 , 15 , 20 , 25 – 27 its potential effect on pancreatic β-cell function and insulin secretion in the context of diabetes should also be investigated. Moreover, a comprehensive evaluation of MICA on glucose metabolism, in particular, gluconeogenesis in cultured hepatocytes should also be performed.…”