Ask anyone what "diabetes" is, and they will probably launch into a description of diabetes mellitus, or sugar diabetes.

But there also is another type of diabetes, known as diabetes insipidus and characterized by the inability to regulate water levels, which leads to excessive drinking and urination.

Diabetes insipidus is at its root a neurodegenerative disorder rather than a metabolic disease. It is caused by a mutation in the gene for vasopressin, a hormone produced by the hypothalamus that regulates water retention. The mutant protein (which is truncated by a stop codon in its midst) misfolds and accumulates in the endoplasmic reticulum of hypothalamic cells; ultimately, that induces autophagy and leads to the death of vasopressin-producing hypothalamic neurons.

"The name diabetes insipidus actually comes from a time when clinicians had few diagnostic tools, other than their tastebuds," said David Murphy, professor at the University of Bristol in the UK. "Diabetes just means you produce a lot of urine. Diabetes mellitus is sweet urine, and diabetes insipidus is tasteless urine. The two diseases actually have completely different causes."

Diabetes insipidus hardly presents the health threat of either diabetes mellitus or neurodegenerative diseases. It does not affect lifespan or produce secondary disabilities or health risks, provided the affected individual has access to sufficient drinking water.

However, "diabetes insipidus is a nice model because it's very easy to monitor noninvasively, since it is characterized by excess volumes of urine," Murphy told BioWorld Today. And while the condition itself is rare, knowledge gleaned from studying diabetes insipidus is applicable to other neurodegenerative diseases, such as Alzheimer's, Parkinson's or Huntington's.

Murphy is senior author on two papers published online back-to-back in the March 21, 2005, issue of the FASEB Journal Express. In the papers, Murphy and colleagues from the University of Bristol and Amedeo Avogadro University in Novaro, Italy, investigated the role of autophagy in diabetes insipidus.

Autophagy has been known for some time to be a feature of neurodegenerative diseases such as Huntington's and Parkinson's. The question is whether it is a harmful feature, or a protective one.

"There is a consensus emerging, from our research, as well as others, that it is both," Murphy said. "Our research suggests that autophagy is initially triggered as a survival mechanism, but ultimately kills the cells, as they are constantly exposed to secondary insults."

The researchers first introduced a mutated vasopressin gene into transgenic rats; that induced both autophagy and hypothalamic cell death, but did not shed light on whether the autophagy was causing or delaying the cell death.

Murphy and colleagues further investigated that question in cell culture. They found that while the transfection of cells with the mutant protein per se did not affect cell survival for at least eight days, pretreatment of infected cells with autophagy inhibitors led to a sharp increase in cell death, suggesting the autophagy itself was protective.

In a second paper, the scientists investigated whether autophagy, though it initially is protective for the cells, can have harmful long-term consequences. They focused on the effects of the neurotransmitter dopamine on cells with autophagy machinery that has been activated by mutant vasopressin protein.

In those experiments, done in cell culture, the researchers again transfected cells in culture with a mutant vasopressin gene, and then exposed them to dopamine, which is known to be toxic at high concentrations. In cells transfected with mutant vasopressin, dopamine increased cell death compared to controls; staining for specific proteins showed that the cell death was induced by apoptotic mechanisms.

The disadvantage of cell culture is that it is fairly short-lived; the researchers plan to take their findings back into transgenic rats to investigate the mechanisms underlying autophagy's switch from protection to pro-apoptotic mechanism.

The use of transgenic rats rather than mice is somewhat unusual, but Murphy noted that "the rat remains the species of choice in physiology and neuroscience research. Just because of its size, you can do so much more with it than with mice." Mice max out at about 50 grams, whereas a typical rat weighs closer to 300 grams.

"You can easily sample half a milliliter of blood from a rat and it won't notice," Murphy said. "A mouse would be severely hemorrhaged."