Researchers reverse diabetes in mice: Discovery opens door to new treatment strategies
Researchers at The Hospital for Sick Children (SickKids), the University of Calgary and The Jackson Laboratory (Bar Harbor, Maine) said on Friday that nerve cells in the pancreas may be a cause of type-1 diabetes in mice.
Their research demonstrated that diabetes is controlled by abnormalities in the sensory nociceptor (pain-related) nerve endings in the pancreatic islet cells that produce insulin. This discovery, a breakthrough that has long been the elusive goal of diabetes research, has led to new treatment strategies for diabetes, achieving reversal of the disease without severe, toxic immunosuppression.
In their experiments, diabetic mice became healthy virtually overnight after researchers injected a substance to counteract the effect of malfunctioning pain neurons in the pancreas.
Their claim that the body’s nervous system helps trigger diabetes, if true, could open the door to a potential cure for millions of people who are affected by the disease world-wide. The discovery has stunned even the scientists at a Toronto hospital participated in the study.
Studies have focused on the immune system as the sole offender and research into the fundamental mechanisms of the disease have been overdue. Pancreatic islet cells, the cells responsible for the production of pancreatic hormones such as insulin, play a key role in the disease. In diabetes, islets become inflamed and are ultimately destroyed, making insulin production impossible. Insulin deficiency is fatal and current insulin replacement therapies cannot prevent many side effects such as heart attacks, blindness, strokes, loss of limbs and kidney function.
Defective nerve endings may attract immune system proteins that mistakenly attack the pancreas, destroying its ability to make insulin—it is this destruction is what causes diabetes. The defective nerve endings did not secrete enough of the peptides to keep enough insulin flowing. Recently, the group found an unsuspected control circuit between insulin-producing islets and their associated sensory or pain nerves. This circuit sustains normal islet function.
In an interview, Dr. Michael Salter, co-principal investigator, senior scientist at SickKids, professor of Physiology and director of the Centre for the Study of Pain at the University of Toronto, responded: “I couldn’t believe it…mice with diabetes suddenly didn’t have diabetes any more.”
Dr. Hans Michael Dosch of the University of Toronto, study principal investigator, senior scientist at SickKids and professor of Pediatrics and Immunology at the University of Toronto, said,
“I’ve never seen anything like it.... In my career, this is unique. We started to look at nervous system elements that seemed to play a role in Type 1 diabetes and found that specific sensory neurons are critical for islet immune attack in the pancreas.... These nerves secrete insufficient neuropeptides which sustain normal islet function, creating a vicious circle of progressive islet stress.”
Using diabetes-prone NOD mice, the gold-standard diabetes model, the research group learned how to treat the abnormality by supplying neuropeptides and even reversed established diabetes.
Dr. Salter said,
“The major discovery was that removal of sensory neurons expressing the receptor TRPV1 neurons in NOD mice prevented islet cell inflammation and diabetes in most animals, which led us to fundamentally new insights into the mechanisms of this disease…. Disease protection occurred despite the fact that autoimmunity continues in the animals. This helped us to focus our studies on finding the new control circuit in the islets.”
Strikingly, injection of the neuropeptide substance P cleared islet inflammation in NOD mice within a day and independently normalized the elevated insulin resistance normally associated with the disease. The two effects synergized to reverse diabetes without severely toxic immunosuppression. In lay terms, injecting a piece of protein, or peptide, to repair the defect cured diabetic mice "overnight," Dosch said. "It is very effective in reversing diabetes."
Type-1 diabetes, still commonly called “Juvenile Diabetes,” is the most serious form of the illness that typically first appears in childhood, affects two million Americans and 200,000 Canadians. There is no known way of preventing it.
The study’s conclusions have upset conventional wisdom that Type 1 diabetes was solely caused by auto-immune responses—the body’s immune system turning on itself.
The team will soon begin clinical studies on people whose family history suggests they are at risk of developing Type-1 diabetes to see if their sensory nerves work well. Trials could then begin injecting peptides into patients with diabetes or those at high risk. It could take a number of years, Dosch said.
The researchers are now setting out to confirm that the connection between sensory nerves and diabetes holds true in humans. If it does, they will see if their treatments have the same effects on people as they did on mice. If they do not, Dosch said, that would suggest the bad nerve endings were a cause of diabetes, not only an effect as has been widely assumed.
Dr. Dosch had concluded in a 1999 paper that there were surprising similarities between diabetes and multiple sclerosis, a central nervous system disease. His interest was also piqued by the presence around the insulin-producing islets of an “enormous” number of nerves, pain neurons primarily used to signal the brain that tissue has been damaged.
Suspecting a link between the nerves and diabetes, he and Dr. Salter used an old experimental trick—injecting capsaicin, the active ingredient in hot chili peppers, to kill the pancreatic sensory nerves in mice that had an equivalent of Type 1 diabetes.
“Then we had the biggest shock of our lives,” Dr. Dosch said. Almost immediately, the islets began producing insulin normally. “It was a shock…really out of left field, because nothing in the literature was saying anything about this.”
It turns out the nerves secrete neuropeptides that are instrumental in the proper functioning of the islets. Further study by the team, which also involved the University of Calgary and the Jackson Laboratory in Maine, found that the nerves in diabetic mice were releasing too little of the neuropeptides, resulting in a “vicious cycle” of stress on the islets.
Next, they injected the neuropeptide “substance P” in the pancreases of diabetic mice, a demanding task given the tiny size of the rodent organs. The results were dramatic.
The islet inflammation cleared up and the diabetes was gone. Some have remained in that state for as long as four months, with just one injection.
The studies were extended to Type 2 (obesity-associated) diabetes, in which insulin resistance is even more severe, using a number of additional model systems, thus generating strong evidence that treating the islet-sensory nerve circuit can work to dramatically normalize insulin resistance in models of Type 2 diabetes. The discovery that their treatments curbed the insulin resistance that is the hallmark of Type 2 diabetes, and that insulin resistance is a major factor in Type 1 diabetes, suggesting the two illnesses are quite similar.
Dr. Pere Santamaria, study collaborator and professor of Microbiology and Infectious Diseases at the University of Calgary, said:
“This discovery opens up an entirely new field of investigations in Type 1 and possibly Type 2 diabetes, as well as tissue selective autoimmunity in general.... We have created a better understanding of both Type 1 and Type 2 diabetes, with new therapeutic targets and approaches derived for both diseases.”
“We are now working hard to extend our studies to patients, where many have sensory nerve abnormalities, but we don’t yet know if these abnormalities start early in life and if they contribute to disease development,” added Dosch.
He said the findings might also hold promise for Type-2 Diabetes -- which affects about 10 times as many people as Type-1 -- though the results were not as strong.
The researchers found that the peptide injections lowered resistance to insulin, which is used to move blood glucose to the body's cells.
People with Type-2 diabetes often are obese. By lowering insulin resistance, it might be possible to prevent further obesity and damage from diabetes.
Dosch said,
"Whether we can reverse the process, I don't know. But I think we can certainly impact on the major physiological problem, and that's insulin sensitivity.... So if these people then have normal insulin, then a little activity, then a little walking would actually help lose weight, and then you stop the vicious circle."
The researchers caution they have yet to confirm their findings in people, but say they expect results from human studies within a year or so. “There is a great deal of promise,” Dr. Salter said. Any treatment to help at least some patients would likely be years from hitting the market.
They also conclude that there are far more similarities than previously thought between Type 1 and Type 2 diabetes, and that nerves likely play a role in other chronic inflammatory conditions, such as asthma and Crohn’s disease.
Insulin replacement therapy is the only treatment of Type 1, and cannot prevent many of the side effects, from heart attacks to kidney failure.
In Type 1 diabetes, the pancreas does not produce enough insulin to shift glucose into the cells that need it. In Type 2 diabetes, the insulin that is produced is not used effectively—something called insulin resistance—also resulting in poor absorption of glucose. The problems stem partly from inflammation—and eventual death—of insulin-producing islet cells in the pancreas.
While pain scientists have been receptive to the research, immunologists have voiced skepticism at the idea of the nervous system playing such a major role in the disease. Editors of Cell put the Toronto researchers through vigorous review to prove the validity of their conclusions, though an editorial in the publication gives a positive review of the work.
“It will no doubt cause a great deal of consternation,” said Dr. Salter about his paper.
The “paradigm-changing” study opens “a novel, exciting door to address one of the diseases with large societal impact,” said Dr. Christian Stohler, a leading U.S. pain specialist and dean of dentistry at the University of Maryland, who has reviewed the work. “The treatment and diagnosis of neuropathic diseases is poised to take a dramatic leap forward because of the impressive research.”
The excitement over the conclusions of the team’s research has been described as “palpable.”
Here is the team’s executive summary as published in the Medical Journal, “Cell:”
In type 1 diabetes, T cell-mediated death of pancreatic β cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1+ pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and β cell stress of prediabetic NOD mice are prevented when TRPV1+ neurons are eliminated. TRPV1NOD, localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1−/− mice, whereas insulitis/diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1+ sensory neurons in β cell function and diabetes pathoetiology.
The following medical researchers and scientists participated in the study—and have my personal vote for the Nobel Prize, just for the progress they’ve already made in their quest to find a cure for diabetes:
Rozita Razavi: lead author
Yin Chan
Dr.F. Nikoo Afifiyan
Dr.Xue Jun Liu
Dr. Xiang Wan
Jason Yantha
Hubert Tsui
Dr. Lan Tang from www.sickkids.ca. (SickKids is committed to healthier children for a better world).
Sue Tsai from the University of Calgary
Pere Santamaria, professor of Microbiology and Infectious Diseases at the University of Calgary
Dr.John P. Driver, The Jackson Laboratory, Bar Harbor, Maine
Dr.David Serreze, The Jackson Laboratory, Bar Harbor, Maine
Michael W. Salter: a pain expert at the The Hospital for Sick Children, Research Institute, University of Toronto
H.-Michael Dosch: immunologist at The Hospital for Sick Children, Research Institute, University of Toronto and a leader of the studies
For the full report, CLICK HERE
Cell Article
SickKids: SickKids is committed to healthier children for a better world.
National Post Article
Juvenile Diabetes Research Foundation International
