Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 432

Biochemistry

Spring 2009

Lecture Notes: 25 February

© R. Paselk 2006
 
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Metabolic Integration, cont.

Last time we looked at the availability of fuel and tissue fuel usage in a typical male human. Today I want to continue by looking at fuel usage in stavation.

For humans the brain uses about 20% of resting energy, regardless of whether its user is "vegging out" or studying like crazy. In the fed state the brain uses about 4 g/hr of glucose while the anaerobic tissues (e.g. red blood cells) use about 1.5 g/hr. This is a particular problem because the brain is quite restricted in what fuels it can use, while the anaerobic tissues are restricted to glucose alone.

Now we can look at what occurs in fasting. In Table 3, below, is some data on the varying concentrations of key fuels and insulin, the major metabolic regulatory hormone. Notice that glucose concentrations fall for a few days, but then stabilize at about 3.5 mM. Given that an average liver has about 100 g of glycogen, and that glucose usage in the fed state is about 9-10 g/hr an average man would run out of glucose in only ten hours if some other fuel source did not become available after feeding. In fact liver glycogen lasts for about 24 hours. So what's going on?

Table 3: Concentrations of Major Fuels During Starvation in Man
Substance 

Serum or plasma concentration (mM) 

 Days

Fed 1 2 3 4 5 6 7  28-42
Glucose 5.5 4.7 4.1 3.8 3.6 3.6 3.5 3.5  3.6
 Fatty acids 0.30 0.42 0.82 1.04 1.15 1.27 1.18 1.88  1.44
 Ketone bodies 0.01 0.03 0.55 2.15 2.89 3.64 3.98 5.34  7.32
Insulin* >40 15.2 9.2 8.0 7.7 8.6 7.7 8.3  6

 *Insulin concentration is expressed in muU/mL

Data from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. pp 338 & 539.

Looking at fasting from 24 hours to 24 days or so, we see

So how are these changes initiated and controlled?

Glucose/Fatty acid control cycle (muscle): During carbohydrate stress (liver glycogen stores are depleted, so serum [glucose] falls) the utilization of glucose by muscle falls as fatty acids are metabolized.

Glucose/Ketone body/Fatty acid control cycle (peripheral tissues, i.e. brain, kidney, intestine): When at rest the non-muscle peripheral tissues generally consume more glucose than muscle. So how do they respond to carbohydrate stress?

Metabolism in Exercise

(This discussion is based largely on material from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. and R.W. McGilvery (1979) Biochemistry: A Functional Approach. W. B. Saunders Company, Philadelphia)

Heavy exercise may also result in carbohydrate stress. There are two extreme situations:

First, if we look at athletes (human or animal) at these two extremes, there are significant difference in muscle types, thus for humans,

Let's look at the performance of world class runners as a function of distance (time). If we look at the figure below it appears that there are three processes (as shown by the three different best fit lines), indicating three different metabolic regimes corresponding to:

  1. The initial 20 seconds.
  2. The time from 20 to 200 seconds.
  3. Times exceeding 200 seconds.

Redrawn from R.W. McGilvery (1979) Biochemistry: A Functional Approach. W. B. Saunders Company, Philadelphia: p 704

Fuel Utilization in Prolonged Exercise

 

Fuel O2 utilization

 

Fuel Concentrations in Blood (mM)

  Blood-delivered Fuels
Exercise Time (min) Muscle Glycogen Glucose Fatty Acid Glucose Lactate Fatty Acid Glycerol
0       4.5 1.1 0.66 0.04
40 36% 27% 37% 4.6 1.3 0.78 0.19
90 22% 41% 37%        
180 14% 36% 50% 3.5 1.4 1.57 0.39
240 8% 30% 62% 3.1 1.8 1.83 0.48
Data from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. pp 370-372.

"Carbohydrate Stress" and Injury

FYI - Severe Injury

(This discussion is based largely on material from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY.)

We've looked at fasting as an example to demonstrate metabolic integration at both the pathway and organ level. As a second example we can follow up with a situation which mimics aspects of starvation with some major differences - severe injury.

A complicating aspect of severe injury is that it often leads to anorexia, and if surgery is involved in response to the injury, then the patient fasts beforehand. In either case fasting is the result, so we would expect to see a fasting response.

In fact much of the response seen in severe injury mimics fasting. Thus serum values of a variety of substances are similar:

  • Lactate increases
  • Free fatty acids increase
  • Ketone bodies increase
  • There is a negative nitrogen balance (nitrogen is released as proteins and amino acids are broken down).

But some important differences also occur:

  • Metabolic rate increases
  • Serum glucose increases (e.g. to about 7 mM compared to about 5mM fed and 3.5 mM fasting)
  • Rapid protein loss occurs

These changes are likely due to hormonal changes. Specifically catacholamines, glucocorticoids and glucagon are increased, while insulin decreases. This would be expected to lead to the increased glucose concentration in blood via gluconeogenesis and glycogenolysis in the liver, while increased cortisol can cause increased protein breakdown.

The massive breakdown of protein in severe injury appears maladaptive, and medications are often used to reduce general protein degradation in clinical situations. So why would evolution lead to such a situation? It may simply be that the system has been stressed past its recovery point, where in nature the chances of survival are minimal, so there has been no adaptation. After all it is a common occurrence for normally adaptive responses to disease (e.g. high fever to aid in overcoming infection) to be the actual cause of death under severe conditions.

 


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Last modified 25 February 2009