Unraveling the endless complexities of diabetes is like explaining theins and outs of baseball, football and basketball _ all three _ to aMartian.
Not only how the games are played, on diamond, gridiron and court,but how they embroil players and owners in their running labor-management battles.
To appreciate the progress in diabetes research reported by threepapers in the March issue of Nature Genetics, out today, calls for ascore card: You can't tell the players apart without one.
For openers, diabetes comes in two leagues, the minor league ofdiabetes insipidus, and the major, diabetes mellitus. Diabetesinsipidus, the body's inability to manage its water balance, issomething of a misnomer. Its grotesque polydipsia and polyuria areetiologically unrelated to diabetes mellitus, the seventh largest causeof death in the U.S. today.
Diabetes mellitus describes the body's inability to metabolizeglucose, owing either to its autoimmune destruction of insulin-secreting beta cells (type 1 diabetes), or gradually acquired cellularresistance to insulin, (type 2).
Type 1, better known as juvenile-onset diabetes, and more preciselyas insulin-dependent diabetes mellitus (IDDM), divides into two sub-types, reflecting the location on the genome of its presumed causativegene alleles (parentally-bequeathed variants). IDDM1 defines alleleson human chromosome 6; IDDM2, those on chromosome 11, wherethe insulin gene abides.
Only Half Of Adult Diabetics Know They Have It
IDDM strikes its victims in childhood, peaking around age 12. Withan incidence of 10 percent of all diabetes cases, it numbers 1 millionpatients in the U.S.
Type 2 _ adult-onset or non-insulin-dependent diabetes mellitus(NIDDM) _ affects about 5 percent of the world's population."More than 14 million Americans," notes an editorial in today'sNature Genetics, "suffer from diabetes, although only half of themare aware of it."
Like so many diseases, diabetes mellitus involves interacting geneticand environmental (high-sugar intake, obesity, perhaps a virus)components.
Thus, molecular geneticist Philippe Froguel of France's Center forStudy of Human Polymorphisms reports that "A missense mutation inthe glucagon receptor gene is associated with non-insulin-dependentdiabetes mellitus."
Glucagon is the opposite-number hormone to insulin in the pancreasgland's islets of Langerhans. The islets' alpha cells secrete glucagon,which _ among many other functions _ increases the level ofglucose in the blood. The beta cells then pump out insulin, to keepthe glucose in balance with the body's ever-changing energy needs.
Froguel, with co-authors in Denmark and Germany, found that asingle amino-acid mutation, from glycine to serine, in the glucagonreceptor gene showed up specifically in French and Sardinianpatients with late-onset NIDDM. Moreover, he found linkage todiabetes in 18 sets of siblings from nine French extended families.
"This mutation," Froguel's study concluded, "results in a receptorwhich binds glucagon with a three-fold lower affinity compared tothe wild-type receptor."
Climbing On Diabetes Gene Research Bandwagon
Molecular biologist Wayne Kindsvogel, in the bio-pharmaceutical division of Seattle-based ZymoGenetics Inc., clonedthe glucagon receptor for this French study.
Other biotech companies are joining government laboratories andacademia in hot pursuit of diabetes' genetic roots. The editorial,which bears the title, "Diabetes' sweet little mystery," noted, "Furtheradvances are on the horizon, especially as the resources of genecompanies such as Millennium Pharmaceuticals Inc. [Cambridge,Mass.], Sequana Therapeutics [La Jolla, Calif.] and Myriad GeneticsInc. [Salt Lake City], which are targeting NIDDM or related diseases. . . come into play."
Molecular biologist Giulia Kennedy of Millennium and OxfordUniversity molecular geneticist John Todd have two back-to-backpapers in Nature Genetics on the sinister role of polymorphic mini-satellites, or tandem repeat variations, in the genomes of patients withIDDM2, the insulin-dependent, autoimmune form of the diseaseinvolving chromosome 11.
The IDDM2 gene locus encodes genetic susceptibility to Type 1diabetes. The insulin gene sits on the short arm of chromosome 11,flanked by a variable number of tandem repeats (VNTR) of whatused to be called "junk DNA." Todd's group mapped the IDDM2mutation embedded in a site inside the gene and adjoining stretch ofrepeats. "We present preliminary evidence," his paper concluded,"that the level of [insulin] transcription in vivo is correlated withallelic variation within the VNTR." He suggests that thisphenomenon "may play an important general role in human disease."
Kennedy told BioWorld Today, "The major import of our paper isthat we find there are differences among human beings in their abilityto conduct the first step of insulin production, which is transcription_ copying DNA into RNA."
Different Conclusions, But No Conflict
Her research found that "people who have a risk gene for type 1diabetes, IDDM2, which is the sequence in the insulin gene, have alower capability of transcribing insulin.
Todd's study looked not just at transcription, but the overallproduction of insulin RNA, and came to a different conclusion. Hisgroup found that the risk-related alleles were associated withincreased levels of insulin messenger RNA.
Kennedy said, "We are looking specifically at the very first step intranscription, whereas Todd et al. are looking at a downstream step.So it's not necessarily that our results are in conflict. We both agreethat there are differences in the human population with respect toparticular alleles. I think that's a major contribution by both ourstudies."
Why this risk gene should have anything to do with an autoimmunedisease," Kennedy said, "is a big open question right now. Nobodyknows why type 1 diabetics start an immune attack against their ownbeta cells. Something has to initiate that destruction. That's aquestion for future experiments."
She concluded, "Of course, in understanding what the risk gene does,one can come up with strategies of how we can alter its functionsunto our liking. It would be great if some day we could find a way toboost transcription of the insulin genes, and perhaps overcome thisrisk factor." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.