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.