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Friday » December 15 » 2006

Diabetes breakthrough
Toronto scientists cure disease in mice

Tom Blackwell
National Post

Friday, December 15, 2006

In a discovery that has stunned even those behind it, scientists at a Toronto hospital say they have proof the body's nervous system helps trigger diabetes, opening the door to a potential near-cure of the disease that affects millions of Canadians.

Diabetic mice became healthy virtually overnight after researchers injected a substance to counteract the effect of malfunctioning pain neurons in the pancreas.

"I couldn't believe it," said Dr. Michael Salter, a pain expert at the Hospital for Sick Children and one of the scientists. "Mice with diabetes suddenly didn't have diabetes any more."

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. Any treatment that may emerge to help at least some patients would likely be years away from hitting the market.

But the excitement of the team from Sick Kids, whose work is being published today in the journal Cell, is almost palpable.

"I've never seen anything like it," said Dr. Hans Michael Dosch, an immunologist at the hospital and a leader of the studies. "In my career, this is unique."

Their conclusions upset conventional wisdom that Type 1 diabetes, the most serious form of the illness that typically first appears in childhood, was solely caused by auto-immune responses -- the body's immune system turning on itself.

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.

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."

About two million Canadians suffer from diabetes, 10% of them with Type 1, contributing to 41,000 deaths a year.

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.

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.

So 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.

They also discovered 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.

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 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.

Nothing is for sure, but "there is a great deal of promise," Dr. Salter said.

[ZucchiniFlower]

Substance P and Parkinson's:

: Brain Res. 1990 Feb 26;510(1):104-7.
Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease.



Centre for Neuroscience, Flinders Medical Centre, Bedford Park, Australia.

Using postmortem immunohistochemical analysis, we have identified degeneration of several different neuronal cell groups in the brainstem of patients dying with idiopathic Parkinson's disease.

We report the first chemically identified loss of presumed serotonin neurons in the median raphe nucleus of the pons and of substance P-containing preganglionic neurons in the dorsal motor vagal nucleus.


This evidence is concordant with other evidence that the primary neuropathological process is not confined either to a single pathway or to neurons containing a particular transmitter. Rather it appears that Parkinson's disease affects several classes of neurons in localized areas of the brainstem.

PMID: 1691042 [PubMed - indexed for MEDLINE]

***************************

"In PD striatum, the concentrations of GABA are generally above-normal (Fig. 7), especially in the posterior putamen, being inversely correlated with the severity of DA loss ( Kish et al., 1986). A trend towards above-normal GABA levels is also present in the external and internal globus pallidus. Similarly, glutamate concentrations are elevated in the PD striatum ( Fig. 7), with a statistically significant increase in the putamen, and a trend towards increased concentrations in the subthalamic nucleus.

In contrast to the elevated striatal GABA levels, the corresponding neuropeptides met-enkephalin and substance P are subnormal in PD basal ganglia. (However, the level of preproenkephalin has been reported to be above-normal in PD putamen.) ( Agid; Nisbet and Fernandez) Since in PD, the intrinsic neuronal cellularity of the basal ganglia is preserved, the observed changes in GABA, glutamate and neuropeptide levels are very likely the result of the changed functional state, in PD, of the respective neuronal components of the basal ganglia.

Full article:

Chemical neuroanatomy of the basal ganglia — normal and in Parkinson's disease

Oleh HornykiewiczCorresponding Author Contact Information

Institute for Brain Research, University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria

Received 7 September 2000; accepted 13 November 2000 Available online 18 July 2001.

http://www.sciencedirect.com/science...839d4bc3#toc15

[ZucchiniFlower]

Expert Opinion on Therapeutic Targets
October 2005, Vol. 9, No. 5, Pages 923-929
(doi:10.1517/14728222.9.5.923)

Vasoactive intestinal peptide family as a therapeutic target for Parkinson’s disease
Elena Gonzalez-Rey, Alejo Chorny, Amelia Fernandez-Martin, Nieves Varela & Mario Delgado*

Parkinson’s disease (PD) is a common neurodegenerative disorder with no effective protective treatment, characterised by a massive degeneration of dopaminergic neurons in the substantia nigra and the subsequent loss of their projecting nerve fibres in the striatum.

Because current treatments for PD are not effective, considerable research has been focused recently on a number of regulatory molecules that regulate inflammation characteristic of PD, induce neurotrophic and survival factors and reduce oxidative stress.

Vasoactive intestinal peptide (VIP), a neuropeptide with a potent anti-inflammatory, antiapoptotic and neurotrophic effect, has been found to be protective in several inflammatory disorders.

This review examines the putative protective effect of VIP and analogues in different models for PD. VIP emerges as a potential valuable neuroprotective agent for the treatment of pathological conditions in the CNS, such as PD, in which inflammation-induced neurodegeneration occurs.

[ZucchiniFlower]

Peptides. 2005 May;26(5):827-36.Click here to read Links
Brain mast cells and therapeutic potential of vasoactive intestinal peptide in a Parkinson's disease model in rats: brain microdialysis, behavior, and microscopy.


In the present study, the effect of systemically administered vasoactive intestinal peptide (VIP) (25 ng/kg i.p.) was investigated on drug-induced rotational behavior, extra-cellular dopamine levels and histology of corpus striatum in a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. After 15 days of 6-OHDA lesion, apomorphine-induced (0.05 mg/kg s.c.) rotational behavior of the animals significantly increased and extra-cellular dopamine levels of corpus striatum were significantly reduced.

VIP reversed the rotational deficits but did not alter the decrease in striatal dopamine levels. On the other hand, histological data indicate that VIP significantly reduced neuronal death and demyelination.

Electron microscopic appearance of mast cells showed ultra-structural variety between VIP-treated and 6-OHDA lesioned groups. VIP activates mast cells without any evidence of typical exocytosis, and possibly mast cells could participate in neuroprotection.

Our results suggest that systemically administered VIP can attenuate the motor response changes, neuronal cell death, and myelin sheet loss characteristically associated with 12 microg 6-OHDA administration into the rat striatum. Brain mast cells seem to participate in neuronal protection. Possibly, protective cues could be produced by brain mast cells.

PMID: 15808913 [PubMed - indexed for MEDLINE]
Full article:

http://www.sciencedirect.com/science...005e8e9d5bff6c

[paula_w]

the less we know...thanks for posting - the body is such a puzzle - fascinating.

paula

[mrsD]

ZucchiniFlower...you never cease to amaze me with these fabulous studies
that you find! This one is really remarkable.