A decade or so ago, when a child suddenly woke up with a raging thirst, matched by an equal urge to urinate, the doctor diagnosed those symptoms as juvenile diabetes. That label distinguished the early onset disease from adult, or maturity-onset, diabetes. Nowadays, the preferred monikers are Type I and Type II diabetes mellitus, respectively.
Both age-related versions reflect the body’s inability to make insulin (Type I) or to utilize the insulin it can generate (Type II) but can’t use to control hyperglycemia, or sugar in the blood. Type I, which afflicts 10 percent or more of the U.S. diabetic population, is now better described as insulin-dependent, in contrast to Type II insulin-independent.
That Type I dependency on insulin is the treacherous work of antibodies in the immune system that literally chew up and spit out the million or so insulin-secreting islets of Langerhans that stud the pancreas. Each islet harbors two cells, alpha and beta. The beta cells are selectively destroyed before they can churn out the doomed insulin. Replacing that lost hormone condemns its youthful patients to daily insulin injections for life.
“About 30 years ago the field of immunology came into the field of diabetes,” said transplant surgeon Ali Naji, at the University of Pennsylvania in Philadelphia. “A group in England found out that the blood of people with Type I diabetes harbored antibodies that specifically stained islets in the pancreas. So they named them islet-cell autoantibodies. Since then, with the progress of basic research in immunology,” Naji continued, “we determined that Type I is an autoimmune disorder, in which the immune system’s T cells and B cells inappropriately target insulin-producing beta cells and kill them.”
Naji is senior author of a paper in the April 2002 Nature Medicine titled: “Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic [NOD] mice.”
“The NOD mouse,” he told BioWorld Today, “is an ideal animal for mimicking Type I diabetes. Researchers in the 1980s were trying to raise mice to model some other disease, and accidentally came up with spontaneous diabetes in the NOD mouse. Their metabolism is disregulated much like that in human Type I diabetes,” Naji pointed out. “They also harbor insulin autoantibodies prior to becoming overtly diabetic. To survive, NOD mice need insulin every day.”
Do Mouse Moms Co-Confer Diabetes?
“We developed some NOD mice,” Naji recounted, “whose antibodies are produced by their B lymphocytes. Then we generated a transgenic NOD line, which lacked those B cells. These mice unlike normal NODs did not become diabetic spontaneously because they didn’t have any antibodies. So we took advantage of this scenario to ask Does the maternal transmission of these autoantibodies to the susceptible fetus predispose them to diabetes?’
“Our aim,” Naji explained, “was to find out whether autoantibodies contribute to the disease process a controversial question. We thought of the maternal source because we had a B-cell-lacking NOD mouse that doesn’t produce antibodies. As pregnant females, we found that there are two ways the antibody gets from mom to fetus. One is by placenta, two via mother’s milk. The gestation period in mice is 19 to 20 days,” he noted. “So during that time there is transplacental transmission of these anti-insulin autoantibodies. And after birth, if the progeny are being fostered by the same mom, obviously, they are getting it through her milk.
“The bottom line,” Naji confirmed, “is that in the offspring, where there was an opportunity for maternal transmission of autoantibodies, we found a high incidence of diabetes, compared to littermates where there was interruption of maternal transfer.”
Naji and his co-authors mounted a three-part in vivo experiment to verify their mom-based scenario.
“First, we had prevention of autoantibody transfer. Second, we restricted the mother to one species of antibody. The third really critical experiment asked what would happen if a NOD embryo is fostered within another surrogate mother who is totally non-diabetic and has nothing to do with autoimmunity or autoantibody production.
“So,” he went on, “we did a two-day embryo transfer of NOD embryos onto the diabetes-resistant normal mother mice. Our control experiment was to transplant NOD embryos back into NOD moms. When diabetes-susceptible NOD embryos were raised in an environment of diabetes-resistant normal mothers, they were markedly protected against diabetes, compared with the NOD embryos fetal stage and post-delivery fostered by the NOD moms. They had a significant potential for diabetes. It appears,” he summed up, “that in this system, the maternal passage of autoantibodies contributes as a critical environmental factor to the promotion of diabetes.”
Detecting Type I Diabetes Long Before Onset
Naji said, “Years before they are actually found to become clinically diabetic by a simple blood-sugar test potentially prediabetic individuals harbor a variety of autoantibodies against some of the putative target antigens of the beta cells. Some people think that a candidate antigen the immune system targets is a molecule called GAD glutamic acid decarboxylase.
“But more important,” he added, “is the insulin itself, which is very specific to beta cells. Somehow the serum of the prediabetic, completely asymptomatic individual carries these autoantibodies against insulin. We know from families that if you take these autoantibodies as markers of islet destruction, then you can follow these individuals over time and a good portion will ultimately become diabetic. We don’t really know if these marker antibodies are contributing to the cause of Type I diabetes, or just a side effect.
“The tragedy of Type I diabetes,” Naji observed, “is that it strikes the young. It’s a chronic devastating disease that produces a long range of complications blindness, cardiac disease, amputation at tremendous social-economic cost. Are autoantibodies symptomatic or causative? It appears that they contribute to the pathogenesis of Type I. But no one argues that the destruction of beta cells is mediated by T lymphocytes. There’s no question about that. The question is whether the antibodies also contribute to this process and they appear to be doing so. But I don’t think that they’re sufficient to do that all by themselves.
“The potential human moms who are autoantibody-positive,” Naji concluded, “may in fact have children and these offspring, if they are genetically susceptible, could incur the risks of becoming diabetic.”