In experimental anaimals there are >700 ways to prevent/delay/postpone autoimmune diabetes, but none is good enough in human Type 1 diabetes. There are a number of therapies/immune interventions ( eg antiCD3, andiCD20, TNFalfa-inhibition, etc) with some, usually transient efficacy to preserve residual beta cell function in Type 1 diabetes. Autoantigens ( GAD, proinsulin, insulin..) may modulate the immune system and also have some efficacy to preserve beta cell function. Some other substances may be protective eg Nicotinamide, omega-3.fatty acids, vitamin D. ...but there is no good combination therapy och treatment regimen.
The situation was similar in the treatment of Acute leukemia in children in the end of the 60ies, and then in the 70ies there was a dramatic improvement of results, when schemes/programmes were built up. Combination of different cytostatics, steroids etc lead to tremendous progress.
What is YOUR suggestion regarding Type 1 diabetes? Should we start with.eg antiCD +..??..and then after x ? weeks give autoantigen, and parallell give..??.? and then add...? -Why? What is your argument?
I would be happy to get your suggestions, listen to your opinion, rationale.../ Johnny Ludvigsson
Thanks Prof. Johnny Ludvigsson for again initiating discussion on the interesting topic of beta cell preservation in Type 1 diabetes (T1D).
Preserving residual beta cell function after clinical onset of T1D is beneficial for glycemic control and long-term complications. However, since majority of the beta cells are already destroyed at the time of clinical onset, there is little possibility of reversing the disease manifestations. The current immunotherapeutic interventions can at best produce a slower decline of residual beta cell function, and hence are only partially successful.
The real chance of prevention of T1D is at a time when, even though the beta cell destruction has begun, but there is still sufficient beta cell mass present. Finding these "at risk" individuals is a challenge, but there is hope from the sibling studies. Our ability to characterize the "risk" and "prediction" of T1D has been showing improvement recently with the use of a combination of genetics, autoantibodies positivity and biomarkers for ongoing beta cell destruction (1). The combination therapies may thus become future protocols for saving the beta cells in "at risk" populations, possibly preventing the clinical onset of T1D in them. There will however be several ethical questions of using such interventions in otherwise yet asymptomatic individuals, so the characterisation of risk and prediction of progression to clinical disease has to reach a level of certainity before that.
Regarding the possible combinations, I feel, anti-CD Abs alongwith some form of 'induced Tregs' will probably be used initially followed by relatively harmless immunomodulators such as vitamin D (2, 3). Manipulation of gut microbiome is getting extensively studied, similar to modulation of the GALT, so these may find a role in future combined approaches (4).
References
Thanks. You did not mention autoantigens. Does that mean that you do not beleive autoantign treatment has any place? Why?
Dear Johnny Ludvigsson,
We believe that any preservation of C-peptide is beneficial in autoimmune diabetes, as it is already proven that dosable C-peptide reduces acute and chronic complications of diabetes. Insulin independence would be a bonus for these patients.
The ideal would be to find patients with type 1 diabetes in the preclinical phase.
Any combination to treat autoimmune diabetes must modulate the immune system as well as beta and alpha cells.
The safe combination of DPP4 inhibitors plus vitamin D would be an excellent combination for this purpose (I recommend reading our articles and lectures). This combination could also be used with Omega 3, anti-CD3, islet and stem cell transplantation, probiotics and autoantigens...
We have about 20 patients in prolonged remission, some without insulin for several years (1 to 10 years), including children under 7 years old. These cases are being prepared for publication. At this time, prospective and randomized clinical studies are needed to evaluate this combination, with positive results in LADA.
Dear Marcelo P: Very interesting! What age, HLA-type, auto-antibodies, C-peptide have those patients in long complete remission? Have they got only DPP4inhibitors + Vitamin D ( dose? and for how long time? Continuosly? )
Autoantigens, again may have a role in prevention, and during the preclinical phase.
Your work on GAD-alum about a decade back also indicated effect in only those who had low insulin requirement, which indirectly meant that this subgroup of patients had better residual beta cell function than others, and immunotherapy probably preserved the residual beta cells.
The bottomline is that combination therapy will work only if there is enough beta cell mass to sustain body's insulin needs.
Dear Johnny,
Our patients are heterogeneous in relation to HLA, antibodies and clinical profile.
Some patients have HLA at risk for T1DM. Some patients have only anti-GAD + and others with multiple antibodies, boys and girls aged 6 to 24 years.
The start of treatment is always before clinical disease or in the first weeks after diagnosis, with C-peptide levels above 0.20 ng / ml. The time to start treatment is essential for the success of the intervention. Most of the patients showed an increase in C-peptide levels after treatment, which we believe to be due to the improvement of glycotoxicity.