Type I diabetes has three rather more familiar aliases - juvenile-onset, insulin-dependent and diabetes mellitus. Insulin dependent means that the Type I diabetic patient must shoot up the hormone two or three times a day to control the blood's glucose level.

"Normal glucose is produced by insulin," explained endocrinologist/molecular biologist Denise Faustman at Harvard-affiliated Massachusetts General Hospital (MGH). "Insulin is produced by insulin-secreting Islets of Langerhans cells in the pancreas. Islets are clustered in 100 to 500 cell groups," she continued, "scattered throughout the pancreas. They produce insulin when prompted by the sugar glucose. The bad magic in glucose," Faustman went on, "is that you can have high-level glucose or low-level glucose.

"Low glucose levels ends you up in a diabetic coma. High levels cause the horrific diabetic complications of limb amputation, blindness, heart disease, kidney disease - really bad symptoms."

Faustman, director of immunobiology at MGH, is senior author of an article in the Nov. 14, 2003, issue of Science. Its title: "Islet regeneration during the reversal of autoimmune diabetes in NOD [non-obese diabetic] mice."

"Cells from an unexpected source - the spleen - appear to develop into insulin-producing pancreatic cells in adult mice," Faustman observed. "It has opened a potential new approach to replacing diseased organs and tissues using adult precursor cells."

"These exciting findings in a mouse model of Type I diabetes," said David Nathan, director of the MGH Diabetes Center, "suggest that patients who are developing this disease could be rescued from further destruction of their insulin-producing cells. In addition, patients with fully established diabetes possibly could have their diabetes reversed."

A New Job Assignment For An Old Organ

"The amazing thing," Faustman told BioWorld Today, "is that this is a new function for an old organ - the spleen. Definitely, the precursor cells [embryonic stem cells] that people didn't expect in the spleen as an adult are regenerating the adjacent pancreas organ, source of the insulin-making islets. This is a sort of Eureka!' The spleen has a new job assignment! How come nobody saw this before?"

In her own response, Faustman stated: "Embryologically, the spleen and pancreas develop in coordination. From Day 11 to Day 14 in a mouse, these two organs are developing together, intricately linked. So it's surprising to see that function continuing into adulthood when people thought it stopped at a very early time point.

"The significance of this finding," Faustman noted, "is threefold: One, we wanted to establish we can reverse end-stage Type 1 diabetes; two, we didn't need an islet transplant; and three, we can regenerate an adult organ in the insulin-secreting fraction of the pancreas. Once it regenerates, these model mice are stable over their entire life span."

Faustman is swamped with mail from Type II diabetics (insulin non-dependent), who are prescribed exercise and weight control. "What can you do for us?" they ask. "I want to keep eating my steak and fries. Do it for me." Faustman's answer: "We only know that in adult animals the precursor cells rapidly reform the islet cells.

"The card-carrying embryonic cloning people take exception to the term stem cells,'" Faustman went on, "because we haven't proven that this spleen cell can go into brain, liver, intestine, skin, hair, et cetera - that it's pluripotential. We've only proven that we can tweak our model to go into islet cells and hematopoietic [blood-forming] cells.

"It's great to reverse autoimmunity, the mark of Type I diabetes," Faustman noted, "but where does it get you? For some autoimmune diseases like rheumatoid arthritis or lupus, you're win-win, but if you don't have insulin you've got another hurdle. And the record of islets in animals shows that most therapies to prolong islets didn't prevent recurrent disease.

"So we set out in vivo experiments," Faustman recounted, "to test in a tough mouse model, attempts to reverse the disease. And we did islet transplants. The lab was elated that we had normoglycemic animals [the optimum level for glucose] for the first time. The little experiment we did to be thorough was to pick out the islets from their pancreatic origin - and the blood sugar went up. Because the animals are stable for 200 days, we finally got islets to go after autoimmune diseases. So we took out the islets and the blood glucose didn't go up."

Which Organ For Insulin: Kidney Or Spleen?

"It was as if we picked the wrong organ - a kidney instead of the spleen," she added. "The animals stopped eating. It wasn't on our radar screen to think that if we reversed autoimmunity, we'd get spontaneous regeneration. Once we had confirmed that in hundreds of animal models [we're up to 322 right now] we went on to study the regeneration mechanism. And we were using spleen cells with their educational complex to re-educate the immune system. When we used the complex alone without spleen cells, we needed the islet transplants.

"These NOD mice had spontaneous natural' diabetes," Faustman pointed out. "On the endpoint of their secreted islet cells in the pancreas, the blood sugars went up four to six times normal, and within two to three weeks after implant the mice were uniformly dead. That was the closest we could get to mimic the real Type I disease. Then we introduced splenocytes [spleen cells] from normal animals and gave them injections twice a week for 40 days. At stage zero we induced tumor necrosis factor at a high dose for a short time. We also did an islet transplant because the mice had severe hyperglycemia. We put the islet transplant underneath a kidney capsule. After 40 days, if we took out the kidney with the islet the animal stayed normoglycemic over their life span - cured.

"Our ongoing research," Faustman said, "goes back from mouse to human, mapping these defects in human diabetic cells. Our other major human patient project is trying to set up assays to detect and monitor those bad cells. I would hope we can start the first Phase I human clinical trial in the coming year. The MGH hospital is working diligently to patent and commercialize this technique. We plan on a 40-patient cohort, for starters," she concluded.