Two diabetic patients in coma

Ms CG is profoundly hypoglycaemic; we have already seen in the exercise Poisoned by unripe ackee fruit that when plasma glucose falls below about 2 mmol /L it is not possible to maintain normal ion transport in the brain, and loss of consciousness results.

Non-esterified fatty acid and ketone body concentrations are inappropriately low for someone with a plasma glucose concentration of 1.4 mmol /L. These are concentrations that you would expect in the fed state, not in the fasting state.

It is likely that she injected insulin as usual (or perhaps by accident injected more than usual), but then did not eat.

The effect of injected insulin without a meal will be to lower blood glucose by stimulating its uptake into muscle and adipose tissue, and stimulating synthesis of glycogen (in liver and muscle) and fatty acids (in adipose tissue).

At the same time, insulin will suppress the secretion of glucagon, and so inhibit gluconeogenesis and glycogen mobilisation.

Insulin also down-regulates hormone-sensitive lipase in adipose tissue, so reducing the production of non-esterified fatty aids, and inhibits ketogenesis. This means that despite the low plasma concentration of glucose, non-esterified fatty acids and ketone bodies are not being made available as an alternative metabolic fuel.

If it is available, measurement of plasma insulin would confirm the diagnosis.

However, if the diagnosis is correct then you should not wait for the insulin measurement, but start an intravenous infusion of glucose immediately. If you were correct, she will regain consciousness within a few minutes. If you wait for the lab to return the insulin measurement she will probably die.

This is quite easy. Diabetics inject insulin about 30 minutes before a meal. If Ms CG were distracted after injecting insulin (say by a long phone call) then it is possible that she would begin to develop hypoglycaemia, and be very confused as a result of the effects of hypoglycaemia on brain metabolism before it became serious enough to cause loss of consciousness. In this state of confusion and disorientation she might well not know whether or not she had eaten, or indeed why she felt so unwell.

We can now consider the other unconscious diabetic, Mr GJ

Mr GJ is obviously hyperglycaemic, and also ketotic, with a very high plasma concentration of ketone bodies. Both of these will contribute to coma:

• The very high plasma concentration of glucose will cause increased osmolality and disturb solute balance in the brain (and other tissues).
• At the same time, there will be considerable loss of water from his body as a result of the high concentration of glucose, which is above the renal threshold. This means that he will not only be excreting glucose in his urine, but also that the glucose will prevent the reabsorption of water in the distal renal tubule.
• The very high concentration of ketone bodies (and also non-esterified fatty acids) means that his plasma pH will be below the normal range of 7.35 - 7.45. This shift in plasma pH will disrupt ion transport in the central nervous system.

The rapid breathing is a way of trying to raise blood pH, by breathing out carbon dioxide, so that the bicarbonate equilibrium is shifted to the left, so depleting hydrogen ions and raising plasma pH.

Vomiting will also help to raise plasma pH, since gastric juice is very acidic, and vomiting provides a way of removing acid from the body.

This is the classical emergency presentation of an insulin-dependent diabetic who has eaten, but not injected insulin.

There are two reasons for this marked hyperglycaemia:

• In the absence of insulin glucose will not be taken up into muscle and adipose tissue, and synthesis of glycogen in the liver will not be stimulated.
• More importantly, glucagon secretion will be high, because it is normally opposed by insulin. This means that there will be stimulation of glycogen breakdown in the liver, and also gluconeogenesis, both of which will lead to an increase in plasma glucose.

The lack of insulin means that hormone-sensitive lipase will be active, liberating non-esterified fatty acids from adipose tissue, and the unopposed glucagon action in the liver will stimulate ketogenesis.

The hyperglycaemia will respond to injection of insulin.

The acidosis will respond to intravenous infusion of bicarbonate. By providing bicarbonate, the equilibrium will be shifted to the left, permitting more carbon dioxide to be formed and exhaled, so raising plasma pH.

Although this type of hyperglycaemic keto-acidotic coma is relatively common in insulin-dependent diabetics who have missed an insulin injection, it is rare in type II diabetics.

In type I diabetes there is little or no synthesis of insulin, as a result of progressive auto-immune destruction of pancreatic beta-islet cells. The condition is called insulin-dependent diabetes because the patients are absolutely dependent on injection of insulin in order to survive.

In type II diabetes the problem is not with insulin production, but the sensitivity of tissues to insulin action. In the early stages of the disease, although there is hyperglycaemia, there is also hyperinsulinaemia.The pancreas secretes more insulin in order to overcome the resistance of tissues to insulin action. As the disease progresses, so the need for more insulin exceeds the capacity of the pancreas t synthesise and secrete it. At this stage most people with type II diabetes are prescribed insulin, in order to maintain glycaemic control as well as possible.

Although part of the hyperglycaemia in type I diabetics is due directly to lack of insulin to stimulate tissue uptake of glucose, a great part, and also the keto-acidosis, is the result of unopposed glucagon action. In type II diabetes there is always insulin present to oppose glucagon actions, even if not enough to maintain normal glycaemic control.

Would pancreatectomy be the answer for a patient with pancreatic cancer?

We can now return to consider Mr AB, who is an 80 year old man with metastatic cancer of the pancreas (You considered him in the exercise on Weight loss in a patient with advanced cancer.)

We have to wonder why his consultant did not recommend total pancreatectomy at an early stage in his disease, before widespread metastasis occurred.

The exocrine functions of the pancreas are the secretion of pancreatic juice into the duodenum. This contains both digestive enzymes (proteases, amylase, lipase, etc) and also bicarbonate to neutralise the acid of the chyme entering from the stomach.

It might be possible to compensate for loss of the pancreatic enzymes after pancreatectomy by giving enzyme preparations with each meal. However, these would have to be in an acid-proof capsule, to survive in the stomach, and would normally be released from the capsule by the action of one or other of the enzymes in the small intestine - enzymes that should have been secreted by the pancreas.

Equally, it is not certain that the alkaline secretion of bile would be adequate to neutralise the acidic chyme without the pancreatic bicarbonate. In any case, since the bile duct merges with the pancreatic duct before entry into the duodenum, it would be necessary to extend the bile duct into the duodenum.

This means that almost certainly some-one who had undergone total pancreatectomy would have to be fed on a diet of simple sugars, free amino acids and non-esterified fatty acids, as s/he would not be able to digest starches, proteins or triacylglycerol.

The disaccharidases are not secreted by the pancreas, but are in the brush border of the intestinal mucosal cells.

Neither insulin nor glucagon will be present at all. Although insulin replacement therapy, as in the treatment of type I diabetes is possible, glucagon replacement is more problematical. Insulin is required mainly in response to a meal, so that it is relatively easy to give insulin when it is about to be required. By contrast, glucagon is required at all times other than in the fed state, in order to maintain fine control over the supply of metabolic fuels. As a result of lack of glucagon he would suffer from:

• profound hypoglycaemia, with little or no mobilisation of liver glycogen or gluconeogenesis in the fasting state
• little or no release of non-esterified fatty acids from adipose tissue in the fasting state
• little or no synthesis of ketone bodies in the fasting state

In other words, he would probably not survive an overnight fast, but would require feeding (either by intravenous infusion or through a naso-gastric tube) through the night. This in turn would distort his need for insulin!

Key points from this exercise:

• Both hypoglycaemia and hyperglycaemia can lead to coma:
• hypoglycaemia leads to coma as a result of impairment of energy-yielding metabolism in the brain
• hyperglycaemia leads to coma as a result of increased osmolality of body fluids (both directly and as a result of the diuresis caused by excretion of glucose in the urine).
• Excessive administration of insulin (or excessive secretion by an insulin secreting tumour, an insulinoma) leads to profound hypoglycaemia; plasma non-esterified fatty acid and ketone body concentrations are abnormally low because both lipolysis in adipose tissue and ketogenesis in the liver are down-regulated in response to insulin.
• Failure to inject insulin in people with type I diabetes leads to hyperglycaemia with very elevated plasma concentrations of non-esterified fatty acids and ketone bodies. This is the result of the actions of glucagon, unopposed by insulin. Glucagon stimulates glycogenolysis and gluconeogenesis in the liver, so contributing to the hyperglycaemia. In the absence of insulin, hormone-sensitive lipase in adipose issue is active, leading to release of non-esterified fatty acids; glucagon stimulates ketogenesis in the liver.
• Hyperglycaemia with ketoacidosis is rare in people with type II diabetes because they do secrete insulin to counteract the actions of glucagon, but not enough to overcome the resistance of tissues to insulin action.
• Total pancreatectomy would have serious effects on the ability to digest starchs, proteins and triacylglycerols, as well as causing major disruption of the control over the supply of metabolic fuels in both the fed and fasting states.