Thursday, February 9, 2017
News From EASD (European Association to Study Diabetes)
Back in October 2016 was the European Association to Study Diabetes (EASD) conference, which is the largest scientific meeting on diabetes in Europe. Much like ADA, it covers both type-1 and type-2 diabetes. The Europeans are way ahead of the American in terms of on-line access. The EASD 2016 web site has recordings of many of the talks, and much more content than the ADA web site. You can see it here:
http://www.easdvirtualmeeting.org/
Clinical Trials Aimed at Curing Type-1 Diabetes
The only research which I saw which was directly aimed at curing type-1 diabetes was a talk and a poster given by Dr. Ali from the Cardiff Diabetes Vaccine Development Center (which is part of Cardiff University, Wales, UK). This is part of the ongoing work by Dr. Peakman and others.
Results of the Monopept1de Phase-I Trial of An Insulin Peptide
This research has been on-going for at least 10 years. Here is my previous blogging:
http://cureresearch4type1diabetes.blogspot.com/search/label/Proinsulin
The basic idea is to give people with type-1 diabetes an injection containing part of the insulin molecule, which will teach the body's immune system not to attack itself. The idea is vaguely similar to giving people tiny amounts of peanut protein to desensitize them from peanut allergies. It is important to remember that type-1 diabetes is NOT a classic allergy. The analogy is not perfect, but that's the general idea.
The study showed that the treatment was safe and did not trigger any serious adverse effects, or unexpected adverse effects of any kind. The success/outcome data was weaker. C-peptide production did NOT increase, but insulin usage went down, and H1c numbers showed a downward trend in treated people. None of this is strong data for effectiveness, but this trial was aimed at gathering safety data. The researchers think the safety data is plenty strong enough to support a phase-II study.
Poster: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage
11 Minute Talk: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage-203021b2-7c50-4239-81b8-84fe0d8a0291
Older Poster On The Same Research: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-type-1-diabetes-safety-data-of-a-first-in-new-onset-type-1-diabetes-phase-1b-trial--2
This same research group is working on another clinical trial called "MultiPepT1De", which is testing using several different proteins at once. The trial reported on here only used one. The MultiPepT1De trial was scheduled to finish in Feb-2017, but is running late:
https://www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=5462
https://clinicaltrials.gov/show/NCT02620332
Other Interesting Talks
Faustman
This was a 15 minute talk by Dr. Denise Faustman, where she discusses a particular chemical pathway (TNFR2):
http://www.easdvirtualmeeting.org/resources/in-vitro-tnfr2-agonism-for-correction-of-treg-activation-defect-in-type-1-diabetes-c96e016f-57c0-4432-9805-9918efcd364e
Viral Infections as Triggers
The talk in the next link discussed looking for viruses in the pancreases of 6 newly diagnosed adults. It is 30 minutes long and has 114 slides:
http://www.easdvirtualmeeting.org/resources/the-pathogenesis-of-type-1-diabetes-virus-involved-lessons-from-the-divid-study
These researchers are trying to answer the question "does a viral infection trigger type-1 diabetes", by looking at pancreases close to the time of diagnosis. They did find more viruses in people with type-1 diabetes, but it was low grade persistent infection, not an acute infection. They were all enteroviruses, no two of the same strain, and the exact virus could not be identified (due to low levels).
Also, they found that 36% of the islets were still producing insulin approximately 5 weeks after diagnosis, which is higher than previous estimates that I'm familiar with. This definitely comes down on the "viruses are involved in triggering type-1", but the study was a small pilot study, in need of follow up.
Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.
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4 comments:
Tolerogenic treatment with small doses of insulin may not help if the cause of type 1 diabetes lies not in some immunological disorder but rather, as some research suggests, in deformations of the pancreatic beta cells which cause them to be misidentified by the immune system as foreign tissue.
Identifying a particular viral trigger for type 1 diabetes may not be very useful in clinical practise, since avoiding viruses, which are ubiquitous, is impossible, and a vaccination, even if possible, would take many more years to develop. Most likely the autoimmune response causing type 1 diabetes is triggered by any kind of stressor, which can be any viral or bacterial infection, a cold, psychological tension and the resulting rise of stress hormones which alter the behavior of the immune system, physical trauma, etc. The fact that the peak onset of type 1 diabetes is coincident with the beginning of cold weather suggests that viruses are the most common trigger in genetically predisposed individuals, though I suspect any other source of stress would do just as well.
Pending a true cure, what about treating type 1 diabetics with c-peptide injections? There has been considerable research over the last 20 years, especially in Sweden, and there mainly by Professor Wahren, about its potential use in preventing diabetic complications. Since c-peptide is produced along with insulin, it will decline along with the decline of insulin output, and so what look like the complications of the hyperglycemia caused by lack of insulin may in fact result, at least in part, from the decline of c-peptide which parallels the rise in blood sugar. Giving insulin alone, which as it is now produced has no c-peptide in it, would not correct this problem, so it could be beneficial to supplement it with c-peptide.
Dr. Wahren has certainly been working on this for decades, but the results have been small. He reported his most recent results (2016) as follows:
"Once-weekly subcutaneous administration of long-acting C-peptide for 52 weeks did not improve SNCV, other electrophysiological variables, or mTCNS but resulted in marked improvement of VPT compared with placebo." [VPT is vibration perception threshold]
From: http://care.diabetesjournals.org/content/early/2016/02/11/dc15-2068
However, it is clear that the results were a failure, as described here:
http://www.medpagetoday.com/endocrinology/type1diabetes/56229
If you know of any C-peptide research with better results, please do post it. My memory is that C-peptide proponents started out hoping it would cure/prevent many type-1 complications, and tested it in many situations. Over time, none of these panned out, and now the only test still outstanding was for nerve damage, which was the clinical trial reported above.
The fact that type 1 diabetics with some residual beta cell function have a reduced level of complications, despite the inability of their small additional insulin production to make any significant difference in blood sugar levels, suggests that something else the beta cells are producing is making the difference. This could well be c-peptide, especially since it raises the production of nitric oxide in the diabetic vascular basement membrane, and many of the vascular complications of diabetes are thought to be due to a lack of NO at this target point, which cannot be corrected by administering NO orally. So the known physiological effects of c-peptide argue for its possible role in addressing the characteristic complications of diabetes.
In one recent study, J. Wahren, et al, "Long-Acting C-Peptide and Neuropathy," Diabetes Care, 39 (4) 596 (2016), 250 type 1 diabetics were followed for a year in an experiment showing a 25% improvement in the vibration perception threshold in the subgroup treated with c-peptide. This result is certainly significant, and could quite possibly have had much greater impact if a c-peptide analogue had been used instead. This is indicated by one recent study in mice, C. Jolivolt, et al, "Long-Acting C-Peptide Analogue Against Peripheral Neuropathy," Diabetes, Obesity, and Metabolism, 17 (8) 781 (2015), which found this slight modification of the c-peptide molecule significantly to improve nerve health.
Generally, there are too many c-peptide studies to run through even a significant sample of them, so review articles of its effects are the most useful sources. P. Luppi, et al, "Can C-Peptide Mediated Anti-Inflammatory Effects Retard the Development of Microvascular Complications of Diabetes," Diabetes/Metabolism Research and Reviews, 19 (9) 357 (2013) shows in one survey of experimental work the anti-inflammatory role of c-peptide, which may directly address what some believe is the main mechanism of diabetic complications, the inflammatory effect of hyperglycemia. J. Wahren, et al, Diabetes, 61 (4) 761 (2012) discusses both the physiological mechanisms by which c-peptide should logically interrupt the formation of diabetic complications and reviews experimental data showing that c-peptide reduces inflammation, the development of diabetic nephropathy, the causes of diabetic encephalopathy, the worsening of diabetic neuropathy, as well as promoting circulation and nitric oxide formation.
The real problem with using c-peptide is that it is only physiologically active for a few hours after administration, but now that long-acting forms have been developed, this hurdle has been overcome, and should allow more extensive human studies in the future. If c-peptide were to have significant effects against the development of complications, diabetes could be transformed from a disease characterized by perpetual blood sugar monitoring and a dangerous cultivation of a razor-thin margin between normal functioning and hypoglycemic shock, to one in which patients would only have to keep blood sugar below the hyperosmolar coma range, and could generally cultivate a more normal lifestyle. Type 1 diabetes would not be cured, but it would be tamed.
Maybe the subcutaneous route is the problem. Should refer this old idea to Mannkind Corp, makers of inhaled Afrezza insulin. Their technosphere delivery system would deliver C-pep to the lungs and then the bloodstream in minutes. SWorth a small pilot to determine effects and another to determine whether the sub cu route leads to degradation or alteration that limits effects?
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