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A 22- year-old diabetic comes to the Accident and Emergency department. She gives a 2-day history of vomiting and abdominal pain. She is drowsy and her breathing is deep and rapid. There is distinctive smell from her breath. She has been diagnosed with Diabetic ketoacidosis. Diabetic ketoacidosis is a complication of uncontrolled diabetes mellitus.

The TCA cycle in diabetes mellitus is suppressed and the excess Acetyl co A, resulting from fatty acid oxidation is channeled towards the pathway of ketogenesis.

Which of the following intermediates of TCA cycle is depleted in Type 1 Diabetes mellitus to suppress TCA cycle?

A) Succinate

B) Malate

C) α-Keto glutarate

D) Oxaloacetate

E) Pyruvate.

The correct answer is- D) – Oxaloacetate.

Two facts demand attention here-

1) TCA cycle suppression and

2) Basis of ketogenesis

In Diabetes mellitus, TCA cycle is in a state of suppression due to diminished availability of oxaloacetate which is channeled towards the pathway of gluconeogenesis.

The hyperglycemia in Insulin deficiency results from decreased utilization and excess pouring in of glucose. The processes of glucose utilization such as- Glycolysis, TCA cycle, HMP and glycogenesis occur at a diminished rate, whereas rates of gluconeogenesis and glycogen degradation are increased due to disturbed Insulin to Glucagon ratio in diabetes mellitus. Oxaloacetate is a common intermediate of  TCA cycle and gluconeogenesis. The utilization of oxaloacetate in the pathway of gluconeogenesis depletes the amount which is required for TCA cycle (Oxaloacetate acts as a catalyst; an optimum amount of oxaloacetate is required for the functioning of TCA cycle), therefore it undergoes in a state of suppression.

As glucose utilization is decreased in Diabetes mellitus, alternatively fatty acids are oxidized to compensate for the energy needs. Excess fatty acid oxidation results in:

i) Accumulation of NADH which further suppresses TCA cycle ( Excess of NADH decreases the catalytic activities of three NAD+ requiring enzymes of TCA cycle- Isocitrate dehydrogenase, Alpha ketoglutarate dehydrogenase and Malate dehydrogenase), and

Regulation of TCA cycle

Figure-1- Regulation of TCA cycle. Accumulation of NADH inhibits the activities of NAD + enzymes of TCA cycle, isocitrate dehydrogenase, Alpha keto glutarate dehydrogenase and Malate dehydrogenase. The activity of PDH complex is also decreased.

ii) Accumulation of Acetyl co A- The end product of fatty acid oxidation cannot be oxidized in TCA cycle at the same rate as that of its production, as a result , Acetyl co A is channeled either towards pathways of ketogenesis, or of cholesterol synthesis (figure-2).

TCA suppression

Figure-2- a) The rate of lipolysis is increased, fatty acids are oxidized to produce Acetyl CoA.

b) Due to non availability of oxaloacetate, which is diverted towards pathway of gluconeogenesis, TCA cycle is suppressed.

c) Acetyl co A is diverted towards pathway of ketogenesis. Acetone, acetoacetate and beta hydroxy butyrate are the three ketone bodies

d) Accumulated ketone bodies, (being acidic in nature and also as they deplete the alkali reserve) cause acidosis.

In Type 1 Diabetes mellitus, the onset of the disease is abrupt, which is why the body switches abruptly from glucose utilization to fatty acid oxidation for energy needs.  Acetyl co A resulting from excess fatty acid oxidation saturates TCA cycle and the other alternative pathways resulting in ketogenesis. This is the reason ketoacidosis is far more commonly found in type 1diabetes mellitus than type 2 diabetes.

The similar situation is observed in prolonged fasting or starvation. Diabetes mellitus and starvation depict a similar metabolic state, in both the conditions, the cells are deprived of glucose and switch to alternative fuels for their energy needs. The basis of ketosis is thus the same in both conditions.

As regards other options:

A) Succinate-Succinate is an intermediate of TCA cycle, but it is not depleted in Diabetes mellitus.

B) Malate- Similarly malate and C) α-Keto glutarate are also not depleted in Diabetes mellitus.

E) Pyruvate depletion does not directly affect the functioning of TCA cycle, of course pyruvate is also diverted towards glucose production, but there are other sources available, in any case TCA cycle activity is not affected.

Thus the most logical option is Oxaloacetate which is the most important regulator of TCA cycle, depletion of which suppresses TCA cycle.






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