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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