Wednesday, February 24, 2010

Big Brains Make Big Demands.

Brains are demanding organs; big brains dominate the biology of life-forms that develop them.
Like computers, brains must have an uninterrupted power supply, and a constant environment.
Unlike computers, brains cannot be switched off and rebooted.

Glucose is the energy source of the human brain. Our brains must have an uninterrupted supply of glucose, and lots of it. The brain is permanently damaged within a few minutes if the flow of glucose fails. This why hypoglycaemia - blood glucose below 3 mMolar - is dangerous, and below 1 mMolar, an emergency.

But hyperglycaemia - too much glucose in the blood - is also damaging to the brain, but in a different way, over a much longer time, and to kidneys, retinae, heart and other organs as well. 
Glucose is an aldehyde, it is chemically active, it has toxicity. In particular its aldehyde reacts with amine groups, forming Schiff bases, a process called glycosylation. Proteins have amine groups, and are vulnerable.
Blood glucose values persistently above 10 mMolar increase the glycosylation of basement membrane proteins, so damaging capillaries, especially in the retina and kidney.
In clinical practice the percentage glycosylation of haemoglobin is a useful guide to the severity of a patient's diabetes, and the degree of control achieved.

In normal human blood the glucose concentration is between 3.5 and 10 mMolar for at least 95% of the time. Values sustained above 10 mean diabetes mellitus. That normal range is presumably a biological trade between glucose concentrations needed to fuel the brain, and keeping glycosylation within safe limits.
Glucose concentrations are important, but glucose flow into brain and other organs is what matters, and that is much more difficult to evaluate.

On a conventional British diet most blood glucose comes from starch. Regulation of blood glucose is a function of the liver in particular, controlled by insulin secreted by the islet cells in the pancreas. Other hormones affect the blood glucose, notably glucagon, adrenaline and corticosteroids, but insulin is the most powerful.

Increasing blood glucose stimulates insulin secretion into the portal vein, to go straight to the liver. The liver extracts maybe a third of all insulin secreted.
Insulin directs the liver to take up glucose from the blood, for storing in liver cells as glycogen, 'animal starch', a polymer of low solubility. In a well-nourished person liver glycogen may be as much as 10% of liver weight.

Insulin secretion ceases if blood glucose concentrations fall. Without insulin the liver breaks down glycogen, to release glucose into the blood and prevent hypoglycaemia. As liver glycogen is depleted the liver begins to make glucose from protein, a process called gluconeogenesis. If glycogen is exhausted then gluconeogenesis is vital to maintain glucose flow to the brain.

The brain does not need insulin. It takes glucose from the blood as it requires, and presumably under its own control. It cannot store glucose in any quantity - it lives in an enclosed space.

Muscle needs insulin to take up glucose, and can store limited amounts as glycogen in muscle cells. Muscle glycogen is for muscle only: it cannot be excreted from muscle to support blood glucose in times of need. In starvation muscle is an important source of protein for liver gluconeogenesis.
Reduced muscle sensitivity to insulin is an important factor in type 2 diabetes mellitus.

Fat also needs insulin to take up glucose, but metabolizes it to fat components. As with muscle, glucose uptake by fat is irreversible.

The distribution of glucose between liver, brain, muscle and fat varies with diet, exercise and other factors, but the brain has priority in glucose disposal.

Carnivores must depend on gluconeogenesis to supply their brains with energy. Food protein is limited, so thrifty animals will be at a selective advantage. Maybe that is why cats sleep a lot, conserving resources for intense brain work during hunting, or defending territory.

Dolphins have large brains, and depend on fish protein for gluconeogenesis. It is interesting that they develop a transient diabetic state while fasting, with increased blood glucose. It may be they can adjust muscle insulin sensitivity in response to feeding. Well fed their livers  deliver glucose enough for the big hungry brain and muscle; while fasting the brain has priority, glucose uptake in muscle is regulated down.

It would be interesting to know if other carnivores can do this, if indeed humans might do it under special circumstances. Could failure to regulate such a facultative state become type 2 diabetes?

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