Case study- Starvation

Case details

A 25 –year-old woman living alone became severely depressed after the termination of her engagement. Two months later, she was brought to the emergency room by a friend because of weakness and lethargy. She appeared thin and pale. Questioning revealed that she had not eaten for several weeks.

Analysis of a plasma sample indicated elevated levels of acetoacetate, β hydroxybutyrate, and blood urea nitrogen (BUN). However her plasma glucose concentration was within normal limits. She was hospitalized, given intravenous feeding and antidepressant medications and subsequently shifted to an 1800 Cal (7500 kJ) diet. Her recovery was uneventful.

During starvation muscle activity decreases, and muscle protein is broken down to provide a carbon source for the liver production of glucose via gluconeogenesis. Which of the following amino acids remains in the muscle cell to provide a source of energy for the muscle?

A. Alanine

B. Aspartate

C. Leucine

D. Glutamate

E. Threonine

Answer- The correct answer is C. Leucine. The muscle has a very active branched-chain amino acid metabolic pathway and uses that pathway to provide energy for its own use. The products of leucine metabolism are acetyl-CoA and acetoacetate, which are used in the tricarboxylic acid cycle. Acetoacetate is activated by succinyl-CoA (by thiophorase) and cleaved to two molecules of acetyl-CoA in the β-keto thiolase reaction. The other branched-chain amino acids, valine, and isoleucine, yield succinyl-CoA and acetyl-CoA as products of their catabolism.

In the absence of food the plasma levels of glucose, amino acids and triacylglycerols fall, triggering a decline in insulin secretion and an increase in glucagon release. The decreased insulin to glucagon ratio, and the decreased availability of circulating substrates, make this period of nutritional deprivation a catabolic state, characterized by degradation of glycogen, triacylglycerol and protein. This sets in to motion an exchange of substrates between liver, adipose tissue, muscle and brain that is guided by two priorities

(i) the need to maintain glucose level to sustain the energy metabolism of brain ,red blood cells and other glucose requiring cells and

(ii) to supply energy to other tissues by mobilizing fatty acids from adipose tissues and converting them to ketone bodies to supply energy to other cells of the body.

Even under conditions of starvation, the blood-glucose level has to be maintained above 2.2 mM (40 mg/dl). The first priority of metabolism in starvation is to provide sufficient glucose to the brain and other tissues (such as red blood cells) that are absolutely dependent on this fuel. However, precursors of glucose are not abundant. Most energy is stored in the fatty acyl moieties of triacylglycerols. Fatty acids cannot be converted into glucose, because acetyl CoA cannot be transformed into pyruvate. The glycerol moiety of triacylglycerol can be converted into glucose, but only a limited amount is available. The only other potential source of glucose is amino acids derived from the breakdown of proteins. However, proteins are not stored, and so any breakdown will necessitate a loss of function.

Thus, the second priority of metabolism in starvation is to preserve protein, which is accomplished by shifting the fuel being used from glucose to fatty acids and ketone bodies by cells  other than brain cells and the cells lacking mitochondria.

It is a biological compromise to provide glucose to these cells as a priority. During prolonged starvation, when the gluconeogenic precursors are not available, proteins are however broken down to use carbon skeleton of glucogenic amino acids for glucose production.

In muscle, most of the pyruvate is transaminated to alanine, at the expense of amino acids arising from breakdown of protein. The alanine, lactate and much of the keto-acids resulting from this transamination are exported from muscle, and taken up by the liver, where the alanine is transaminated to yield pyruvate. Pyruvate is a major substrate for gluconeogenesis in the liver.

Hence Alanine is not used at all by the muscle for energy needs; instead it is transported out acting as a carrier of amino groups of amino acids and of pyruvate.- (Figure)

Glucose - Alanine cycle

 

Figure- Glucose Alanine and Cori’s cycle

The other amino acids, enlisted are not branched chain amino acids, muscle preferentially utilizes branched chain amino acids during starvation.

Thus the most suitable option is leucine, the products of which can be directly used by the muscle for energy needs.

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