By David N. Leff

If Hippocrates (ca. 460-377 B.C.) was the founding father of modern medicine, a later Greek physician, Aretaeus of Cappadocia - who flourished circa 140 A.D. - was the founder of diabetes. He named the disease for the Greek word for "siphon," which described his patients' "liquifaction of the flesh and bones into urine, in such quantity that the kidneys and bladder do not cease emitting urine."

Aretaeus' writings were lost until rediscovered in 1554 A.D. A century later, British neurophysiologist Thomas Willis (1621-75) dubbed the disorder "diabetes mellitus" - the Latin term for "honey-sweet," because diabetic urine is freighted with unmetabolized glucose.

At the opposite urinary extreme from diabetes mellitus is diabetes insipidus, a disorder marked by grotesquely large amounts of pale, thin, tasteless (i.e., insipid) urine, and a raging thirst, never slaked by huge quantities of water.

"There is no relationship between diabetes mellitus and diabetes insipidus," observed neurobiochemist Marc Caron, a professor of cell biology at Duke University Medical Center in Durham, N.C. "What the hormone insulin is to the former, the hormone vasopressin [VP] is to the latter.

"Vasopressin," Caron explained, "is an antidiuretic [urine-concentrating] hormone, secreted by the pituitary gland in the brain, while its receptor is expressed in kidney cells. VP gets into the circulation, passes through the kidney, binds to its receptor, and activates a process that phosphorylates proteins in those kidney cells, which are called aquaporins or water channels.

"Once phosphorylated," he went on, "these vesicles get incorporated into a membrane of the kidney cells. And since they are water channels, they reabsorb water from the urine. This is the normal process that goes on in healthy people."

The disease diabetes insipidus (DI) comes in several metabolic persuasions, of which the potentially life-threatening version is nephrogenic (kidney-generated) DI, or NDI.

Nephrogenic Diabetes Insipidus Can Be Fatal

"In patients with NDI," Caron observed, "the phenotype is that kids are born with certain mutations in their VP hormone receptors. They get in trouble because they constantly pass as many as 20 liters of urine a day. So they are totally dehydrated. Nowadays, pediatricians know to screen for this condition. Once NDI is diagnosed, they supplement this loss by requiring patients to drink lots of fluid, which can partially counteract it. But in the old days - and not so long ago - these infants would develop mental retardation and other disabilities not compatible with life in adulthood.

"NDI is a genetic disease," Caron pointed out. "Its VP receptor gene sits on the X chromosome, so it's Y-linked - mostly transmitted through the father. One might acquire it from two different classes of mutation: The first is that a patient might have several mutations in his VP receptor. That is, the receptor is nonfunctional. If you inject VP into a normal individual, it will concentrate the urine tremendously. In NDI patients you cannot do this. They are VP resistant, just as Type I diabetics are insulin resistant.

"The second way you can get NDI," he noted, "is if you have mutations in the acquaporin molecule - the water channel. So far, more than 60 different mutations have been found to occur naturally in the VP receptor, and probably just as many in acquaporin. So if you have mutations in the receptors you don't respond to the VP hormone, or if you have mutations in the acquaporin - which means the water channel cannot uptake water - then you pass too much water in your urine, and you get NDI.

"NDI is a rare disease, but a rather common one," he pointed out, "because of the fact that so many mutants have been found. It affects less than a fraction of 1 percent of the population. Although rare, it's not hard to diagnose."

Caron, a Howard Hughes Medical Institute investigator, is senior author of an article in the Proceedings of the National Academy of Sciences (PNAS), dated Jan. 2, 2001. Its title: "Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus."

"The significance of this finding," Caron told BioWorld Today, "is that there are many G protein-coupled receptors out there that may cause a disease - because the tissue, for example, is resistant to hormonal stimulation. The reason for this is that the receptor has a mutation in it that makes it desensitized too much, and that's why it's turned off. Our discovery that this phenomenon happens may explain a loss of function of receptors, or hormone resistance, in other human conditions. So if you're capable of inhibiting this constitutive [inherent] desensitization process, you may be able therapeutically to correct or manage the condition. That a receptor can be, in a sense, turned off - its function eliminated because it is constitutively desensitized - has never been shown before.

"With respect to NDI," Caron suggested, "it's nice because for these few families in the world that have this particular mutation, we know why they have this disease. If we could find a way to inhibit the desensitization process, maybe these few families that have this mutation would be helped. But beyond diabetes insipidus, the significance of this is really to have observed that this phenomenon explains a loss of function in general. So now people can say this phenotype of loss of function - a receptor that when you express it inside a cell's cytoplasm appears to be nonfunctional, may not only be because it's incapable of sending a signal, but maybe that it generates too much, and is turned off by another mechanism - such as arrestin."

Receptor Key: Location, Location, Location

"Now people can start looking," he foresees, "for whether these naturally occurring mutations have receptors that have lost their function because they are too much constitutively desensitized, and not really at the right place on the cell surface to send the signal.

"We're trying to identify some of these naturally occurring mutants," he observed, "trying to see whether this is a general phenomenon - to prove that what we have shown has this specific meaning. So animal models engineered to carry mutations like this would be great for testing some of these prospective therapeutics."

The university has patents pending, and Caron is in active touch with biotech companies, as well as potential academic collaborators.