More than 50 human trials have been conducted among those with new onset type 1 diabetes using many different immune therapies, which were successful in reversing diabetes in rodent models, but not in man. Making peace with the immune system by using an immune tolerance therapy is enough to reverse diabetes in rodents, but not in man (Ablamunits 2007).
Work by Ilic and Jovanovic (2000), Gabbe (1976) and others has been the model of regeneration with immunosuppression resulting in insulin independence in man, even those with a history of type 1 diabetes for 20 years. Jovanovic and Gabbe have published data among type 1 women who have remissions of their diabetes with no insulin requirements within 10 weeks of pregnancy. These remissions, in which no insulin injections are needed during pregnancy, are hypothesized to occur because 1) there is downregulation of the immune system in the mother to prevent rejection of the fetus who has 50% different DNA and 2) there is islet neogenesis from ductal progenitor cells in contrast to beta cells regeneration from existing beta cells within the pancreas of pregnant women, even those with type 1 diabetes (Johansson 2006). The downregulation of the immune system appears to be enough in some women to prevent attack on the new pools of beta cells within the newly formed islets. (See presentation below this article by Dr. Lois Jovanovic followed by a list of references.)
Based upon the distinct differences between islets that contain insulin-producing beta cells in rodents and man, type 1 diabetes in man is now considered by many scientists to be a disease of not only autoimmunity, but also the lack of beta cell regeneration even when immune tolerance therapy is used (Levetan 2013). It is hypothesized that insulin independence among type 1 diabetes patients will occur when there is both 1) new beta cell formation and 2) the new beta cells are protected from autoimmune destruction.
Of the immune agents used in type 1 diabetes studies, none have been as effective as cyclosporine in both slowing the decline in beta cell mass and resulting in the potential for insulin-free remissions. (Canadian-European Randomized Control Trial 1988, Eisenbarth 1989, Skyler 1992, Sobel 2010). More than 500 patients with new onset type 1 diabetes have been given cyclosporine and some studies have demonstrated as high as a 57% insulin-free remission rates. However, remissions were not sustained due to the lack of beta cell regeneration even in the face of an immune protectant to try to preserve the remaining few beta cells. (Feutren 1986, Bougneres 1988, Eisenbarth 1989, Sobel 2010). The data to date with immune therapies utilized suggests that in type 1 diabetes in man, in contrast to rodents, there is a substantial lack of beta cell regeneration, even when an immune agent is used.
The usage of cyclosporine in new onset type 1 diabetes was discontinued because over time, all patients required insulin; not because of side-effects or toxicity. Because cyclosporine is known for its potential side-effects, most notably in the kidney, all previous studies among type 1 patients have carefully monitored kidney function. Follow-up studies for up to 7-13 years among 285 type 1 patients utilizing 6.5 mg/kg/day of cyclosporine for 20 months did not demonstrate renal side effects. This study included follow-up renal biopsies (Assan 2002). Whereas, Parving (1999) found that 4/21 patients receiving 10 mg/kg/day developed microalbuminuria. Only those patients receiving cyclosporine in the Parving study and none of the control patients received renal biopsies for comparison.
For decades, it has been shown that patients who have increased gastrin production in the pancreas (Zollinger-Ellison Syndrome) form new islets (Bryant 1965, Meier 2006). Proton pump inhibitors have been shown to significantly increase gastrin levels which are associated with the ability to increase one’s own beta cells without the need for transplant of beta cells made in a lab. Proton pump inhibitors and higher gastrin levels have also been shown to be safe among patients with new onset type 1 diabetes for one year (Griffin 2014, Griffin Supplemental Appendix 2014).
Not only are proton pump inhibitors safe, they are also effective. Studies among diabetes patients utilizing proton pump inhibitors have shown the potential to increase one’s own beta cell mass by 40% by the transformation of ductal progenitor cells contained in the adult pancreas into new islets (Singh 2012, Griffin 2014). In a randomized trial for 12 weeks among 56 patients undergoing removal of the pancreas, those randomized to receive a proton pump inhibitor had significantly increased gastrin levels, higher insulin levels and improved endocrine function as measured by glucose tolerance testing and less pancreatic atrophy as measured by CT scans (Jang 2003).
The recently completed REPAIR T1D demonstrated the safety of a proton pump inhibitor when used among patients with new onset type 1 diabetes, but as equally important, underscored the importance for usage of an immune therapy with a regeneration therapy with a proton pump inhibitor among type 1 patients (Griffin 2014, Rigby 2014). Among type 1 diabetes, the development of one’s own new islets containing new beta cells is a trigger to the immune system because in type 1 diabetes, the immune system recognizes beta cells as foreign, similar as it would to an infection (Meier 2006). Thus, immunotherapy and regeneration therapy must be combined.
The combination of cyclosporine and a proton pump inhibitor has the potential to demonstrate both maintenance of remaining beta cells and regeneration of beta cells. This combination therapy provides the unique ability for type 1 patients to become insulin independent. This is the new paradigm for the treatment of new onset type 1 diabetes.
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