Melbourne researchers uncover new diabetes syndrome

A Melbourne University study has thrown new light on a dangerous complication of insulin-dependent diabetes called hypoglycaemic unawareness, which can cause diabetics to lapse into an insulin-induced coma.

The study, led by Assoc Prof Margaret Morris, has linked hypoglycaemic unawareness to the disruption of a signalling system in the brain that, in non-diabetic individuals stimulates the appetite when blood glucose levels fall.

Morris and her colleagues have found that diabetic rats that have been injected with insulin develop abnormally low levels of neuropeptide Y (NPY) in the hypothalamus, the region of the brain that regulates body temperature and basic drives such as hunger, thirst, the desire for salt, and the sex urge.

Japanese researchers in the 1960s found that specialised neurons in the hypothalamus are sensitive to glucose, and switch on and off in response to changes in blood glucose levels.

Although the glucose-sensing system was assumed to be involved in signalling the pancreas to adjust its secretion of insulin, Morris said there was little research into the mechanism involved.

In 1999, another Japanese research group showed that when the glucose-sensing neurons switch on in response to low blood glucose, they secrete neuropeptide Y, which produces sensations of hunger; when the individual eats, blood glucose levels rise and they experience feelings of satiety.

Morris said untreated diabetics had elevated levels of neuropeptide Y in the brain, which may account for their symptoms of raging thirst and intense hunger.

Over the course of the day, multiple insulin injections produce a series of highs and lows in diabetics' blood-glucose levels. If the individual does not carefully monitor their blood glucose, too much insulin can cause hypoglycaemia.

Normally, diabetics can sense the onset of hypoglycaemia, and eat something sweet to raise their blood glucose levels. But research in recent years has indicated that repeated episodes of hypoglycaemia can desensitise the brain's glucose sensor.

Controversy surrounds claims by many diabetics that the switch from porcine insulin to a genetically engineered human insulin reduced their ability to sense the onset of hypoglycaemia.

Morris and her colleagues compared the brain responses of diabetic and normal rats to low glucose levels, and their recovery after hypoglycaemia.

In the diabetic rats, NPY secretion fell significantly during hypoglycaemia, but it remained unchanged in the normal rats.

The Melbourne University researchers made a surprising discovery when they compared how NPY levels in the diabetic and normal rats responded to insulin injections.

The normal rats, which have low levels of NPY, increased their NPY production, and displayed symptoms of hunger -- a predictable response to the low blood glucose levels induced by the insulin injection.

But in the diabetic rats, which have abnormally high levels of NPY, the response was just the opposite -- they experienced a fall in NPY levels.

The response was paradoxical, because low NPY levels normally inhibit appetite -- the opposite to what would be expected when the rats' blood glucose levels fall.

The abnormally low level of NPY observed when blood glucose levels fell in response to insulin in the diabetic rats would also explain why diabetics who have experienced repeated episodes of hypoglycaemia become insensitive to the physiological signs associated with the onset of hypoglycaemia -- they are no longer producing enough NPY to alert them to their condition.

Morris said the task was now to understand NPY's exact role in the glucose-sensing system and appetite, and to determine how it differs in diabetics.

She said hypoglycaemia was now recognised as one of the most serious complications of diabetes, and a priority area for research.

She said she doubted that her team's discovery would lead to any novel therapy for hypoglycaemic insensitivity -- the solution for diabetics is more likely to lie in advances in electronic or nanotechnology devices that will deliver insulin in a way that mimics the body's own systems.