We read with interest the article by Russell et al. (1) on the use of abatacept treatment for the delay of progression of type 1 diabetes (T1D) in individuals with stage 1 diabetes. T1D is an autoimmune disease characterized by immune-mediated destruction of pancreatic β-cells. T1D is a complex multifactorial disease in which both genetic susceptibility and environmental factors promote the autoimmune responses against β-cells. CD8+ cytotoxic T lymphocytes are the most common of the islet-infiltrating immune cells. However, we recently reviewed some of the abnormalities existing in T1D that are beyond β-cells and the immune system, such as dysfunction of glucagon-secreting α-cells and histological abnormalities of the exocrine pancreas, sympathetic islet neuropathy, vascular events and hemorrhages within pancreatic islets, acinar atrophy, fatty infiltration, pancreatic arteriosclerosis, and focal lesions of acute pancreatitis, and all these alterations to the exocrine pancreas might negatively affect islet neogenesis from endocrine progenitor cells residing within the periductal area (2). Furthermore, increased endoplasmic reticulum stress, reduced autophagy in β-cells, and increased serum dipeptidyl peptidase 4 (DPP-4) activity have been reported in autoimmune diabetes at levels even higher than those in patients with type 2 diabetes (2).
It seems obvious that therapies used for the prevention and treatment of T1D based only on autoimmunity will be doomed to failure over time. Trials with T1D in stages 1, 2, or 3 of the disease that used immunobiological agents such as abatacept, anti-CD3 antibody, specific human monoclonal antibody for tumor necrosis factor-α, anti-CD20 monoclonal antibody, among other drugs acting only in one pathway of the immune system, found that the agents only delayed the fall in C-peptide levels. However, the use of these agents did not change the underlying pathophysiology of the disease, because the islets are also diseased in T1D.
We believe that therapies aimed at interrupting the evolution of T1D should work together on the immune system and on the pancreatic islets (2). My group (3) and other authors have shown prolongation of the honeymoon phase and maintenance of C-peptide levels in T1D treated with dipeptidyl peptidase 4 inhibitors plus vitamin D3 (VIDPP-4i), with some patients not needing to be treated with insulin for up to 24 months. Promising results have been shown in NOD mice and humans treated with a combination of sitagliptin, γ-aminobutyric acid, and proton pump inhibitors, and some patients did not need to be treated with insulin for a long time (4). Verapamil delayed the progression of T1D for at least 2 years postdiagnosis, with normalization of levels of serum chromogranin A (a T1D autoantigen) as well as of proinflammatory cytokines. Verapimil also regulated the thioredoxin system and promoted an antioxidative, antiapoptotic, and immunomodulatory gene expression profile in human islets (5). Verapamil may be an excellent choice for combination with other drugs to treat T1D.
Therefore, clinical trials using drug combinations are needed to reposition these combinations in the treatment of T1D, as drug combinations seem more promising in the treatment of autoimmune diabetes.
See accompanying article, p. e210.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
