Randle Cycle as Applied to Diabetes Mellitus Type 2 ‘Spruce the Basement before Dusting the Super-structure’

Randle cycle (1963) is about substrate competition between products of glycolysis and β–oxidation to capture the citric acid cycle for further oxidation. Acetyl –CoA, the end product of both the energy metabolisms, when  accumulates in mitochondrial matrix beyond the oxidative capacity of the citric acid cycle, far-reaching consequences take place than simple substrate competition, inhibition of pyruvate  dehydrogenase (PDH),  inhibition  of  glycolysis  and  preferential  passage  of  β-oxidation products through citric acid cycle, as conceived by Randle. It is shown that citric acid cycle is equally shut off for both products of energy metabolism initially. Hence, the question of substrate competition between  them  does  not  arise.  How  the  preferential  passage  of  β-oxidation  products  occurs  is explained by a different mechanism than what Randle put forward. The final common pathway to either of β-oxidation or lipogenesis is- acetyl CoA carboxylase (ACC)-malonyl- CoA-CPT 1. The final result depends on whether ACC is stimulated or inhibited. Inhibition of ACC  results in β-oxidation and stimulation results in lipogenesis. Randle’s  contention that the low ATP status due to substrate  competitive inhibition , stimulates AMPK ,which results in initiation and perpetuation of β -oxidation   is not true because, simultaneously, AMPK is also inhibited which inhibits, in turn, the β -oxidation The proposed  hypothesis  suggests  that  low  substrate  for  ACC  i.e.  Plasma  acetyl- CoA,  which  is carboxylated  to  malonyl- CoA  is  responsible  for  the  switch  of  energy  metabolism  to  β-oxidation independent of AMPK. To corroborate the proposed mechanism, a low pyruvate level, an additional block in the glycolytic pathway at the  level of Pyruvate kinase (PK) and involvement of hexose monophosphate shunt (HMP shunt) are proposed with objective evidence, supporting the same.

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