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Heat-shock protein might sound like a hot new energy drink, but is in factthe focus of an experimental therapy to preserve beta-cell function inautoimmune diabetes.
In type 1 diabetes, the 60-kDa heat-shock protein (hsp60) triggers anattack from the immune system's T-cells. This autoimmune process destroys theinsulin-producing cells of the pancreas.
Researchers are investigating whether injections of p277 (DiaPep277,DeveloGen), a peptide fragment of hsp60, can be used to alter the immuneresponse to protect the beta-cells from destruction.
RE-EXAMINING DIABETES CLASSIFICATION
What does this have to do with the increasing number of patients presentingwith type 2 diabetes in primary care offices? Research has shown that there ismore autoimmunity than expected in some patients who typically have beencalled type 2, says endocrinologist Jerry P. Palmer, MD, of the University ofWashington in Seattle. About 10–30% of typical type 2 diabetes patientshave anti–islet cell antibodies similar to those found in type 1diabetes.1
In addition, the insulin resistance related to obesity that is seen in type2 diabetes may make the autoimmune attack on the beta-cells more severe,Palmer says. Patients who share characteristics of both type 1 and type 2diabetes are being tagged with the terms double diabetes, type 1.5 diabetes,or latent autoimmune diabetes of adults (LADA) (see Editor's note below).
Typically, if a primary care physician thinks about the etiology of type 2diabetes, it is insulin resistance that first comes to mind, although quite anumber of these patients will be affected by LADA or type 1.5 diabetes, saysGünther Karmann, PhD, CEO of DeveloGen AG, based in Göttingen,Germany.
"Insulin resistance is the prevailing condition in these patients,and therefore the autoimmune aspect may be overlooked," he says."Given that the disease progresses relatively fast—patients withLADA go to full insulin dependency within 6 years and decline rapidly over thefirst 2 years after diagnosis—proper diagnosis and intervention with animmunomodulatory agent would be of benefit to doctors and patients."
But there aren't a lot of clues that would alert a primary care clinicianto double diabetes or LADA, Palmer says.
"If you're following a patient over a number of years, and he isfailing different oral agents more rapidly than expected, or if there is afamily history of other autoimmune diseases, especially type 1 diabetes, youmight want to study for antibodies," Palmer says. "Really, theonly way to know is to measure the antibodies."
"There is a lot of evidence that testing is done more frequently whenyou know there is a therapeutic intervention," Karmann adds.
That's where studies of the heat-shock protein peptide come in.
TREATMENT TRIALS
A paper published in 2001 in The Lancet reports that a 10-monthtrial of 35 patients with newly diagnosed type 1 diabetes showed treatmentwith p277 halted disease progression, prevented further destruction of thebeta-cells, and prolonged patients' insulinproduction.2Patients who received injections of a p277 analog at entry, 1 month, and 6months required less injected insulin than those treated with placebo.
Palmer says these results raise the question: If p277 preserves beta-cellfunction in type 1 diabetes, will it do the same in patients with type 1.5,LADA, or double diabetes? He has written previously, "One would not beable to assume that any antigen-based therapy efficacious in type 1 diabeteswould also be efficacious in all patients with autoimmunediabetes."3The main reason to answer the question about p277, he says, is to determine"if we really should be identifying [these patients] early on andtreating them differently."
Palmer notes a pilot study from Japan of patients with LADA who wereassigned to either insulin therapy orsulfonylurea.4Patients on insulin therapy had better preservation of C-peptide and residualbeta-cell function. Some clinicians immediately put these individuals oninsulin based on this study, he says.
Palmer is the primary investigator of the Prevail-It study, a multicenter,phase 2 clinical trial currently recruiting patients to investigate p277'seffect on LADA patients.
"Depending upon how strongly you believe those studies pertain to andinfluence clinical care, then you would screen to identify patients with LADAor type 1.5 and preferentially put them on insulin or enroll them in theDiaPep study," he suggests.
In Prevail-It, Palmer and colleagues are looking for people >30 years ofage who have had diabetes up to 5 years and who, when assessed, have glutamicacid decarboxylase (GAD) antibodies and fasting C-peptide levels >0.9ng/ml. There is no body weight requirement. All patients in the trial aretreated with insulin, and in addition, every 3 months for 2 years, patientswill receive either an injection of DiaPep277 or placebo. Neither patients norinvestigators know who is getting which drug.
The peptide therapy has worked in the animal model, Palmer says. And themost important thing is the Lancet study "that validates thatit does work in humans with type 1 diabetes, and essentially there is notoxicity, unlike what we see in other immunomodulatory drugs."
THERAPEUTIC PIPELINE
Another study investigating immunomodulatory therapy is a phase IIplacebo-controlled, randomized trial that demonstrated long-term remission oftype 1 diabetes after a 6-day treatment with a nonmitogenic CD3-specificantibody.5 Eighteenmonths after treatment, insulin needs decreased significantly in theantibody-treated patients compared with control subjects.
Study of another antigen, the protein GAD65, is based on an approachsimilar to that of the tests of p277—using the antigen to buildtolerance in patients and shut off the immune response. A phase II clinicaltrial of GAD65 (Diamyd, Diamyd Therapeutics) showed positive results forclinical safety that "further support the clinical development of Diamydas a therapeutic to prevent autoimmune diabetes," according to theinvestigators.6
And in the works at DeveloGen is a program to test the building of newbeta-cells with growth factors. Although it is still in the preclinical phase,Karmann thinks the therapy has great potential.
"It seems like two sides of the same coin—keeping the beta-cellreservoir where it is [with p277] and building new beta-cells with growthfactor," he says. 
Footnotes
The Prevail-It trial of p277 in latent autoimmune diabetes of adults(LADA) is recruiting subjects at seven centers in states across the country(Alabama, Colorado, Kentucky, Missouri, New York, Texas, and Washington). Formore information about referring patients to the trial, call206-277-3823.
A major study of LADA in Europe, Action LADA, is recruiting 10,000adult patients recently diagnosed with non-insulin-requiring diabetes with thehope of obtaining 1,000 patients with LADA. The aims are to characterizegenetic, immunological, and metabolic features of patients affected by LADAand, through a double-blind intervention trial of p277, to prevent or delaydisease progression in LADA patients. More information is available online atwww.actionlada.org.
References
2. Raz I, Elias D, Avron A, et al.: Beta-cell function in new-onsettype 1 diabetes and immunomodulation with a heat-shock protein peptide(DiaPep277): A randomised, double-blind, phase II trial.Lancet 358:1749–1753, 2001.[Medline]
3. Palmer JP, Hirsch IB: What's in a name? Latent autoimmune diabetesof adults, type 1.5, adult-onset, and type 1 diabetes. DiabetesCare 26:536–538, 2003.
4. Kobayashi T, Nakanishi K, Murase T, et al.: Small doses ofsubcutaneous insulin as a strategy for preventing slowly progressive cellfailure in islet cell antibody-positive patients with clinical features ofNIDDM. Diabetes 45:622–626, 1996.[Abstract]
5. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al.: Insulin needsafter CD3-antibody therapy in new-onset type 1 diabetes. N Engl JMed 352:2598–2608, 2005.
6. Agardh C-D, Cilio CM, Lethagen A, et al.: Clinical evidence for thesafety of GAD65 immunomodulation in adult-onset autoimmune diabetes.J Diabetes Complications 19:238–246, 2005.[Medline]
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