Does DM not go into complete remission by a short time of drug therapy?
Except in some special cases, DM patients are clarified into two major categories according to their clinical cause: type 1 DM by autoimmunity and type 2 DM by insulin resistance. Both types may have different etiologies, in contrast, they share the same features of persistent hyperglycemia and the appearance of the same vascular and organ complications. Until now, DM treatment has mainly focused on blood glucose control to inhibit DM progression and new manifestations of complications. Is it impossible to develop a convenient method that can cure DM completely after only a short period of use?
The mystery of DM mouse with streptozotocin (STZ)
In this study, STZ-diabetic mice were used as a model of DM with persistent hyperglycemia. In this model, pharmacological doses of STZ specifically destroy about 95% of all β-cells and DM develops due to insulin deficiency; unlike autoimmune destruction of β-cells as in NOD mice, the destruction of β-cells in STZ diabetic mice should theoretically be transient and not lifelong. In practice, however, this is not the case.
The construction of a vascular niche is thought to be important for organ regeneration. Indeed, in normal islets, both in mice and humans, pericytes function as the islet niche 2. When β cells are lost due to aging or transient injury, it is thought that new β cells are formed from progenitor cells bordering the islet niche to compensate for the loss of β cells 3. However, when acute and massive islet destruction by STZ occurs, the absolute amount of insulin secretion decreases, and hyperglycemia persists.
Does hyperglycemia directly inhibit islet regeneration?
To answer this question, we attempted to suppress blood glucose levels by continuously supplying the same amount of insulin externally as was deficient in mice. However, islet regeneration did not occur even after 4 weeks of this treatment. Histological analysis revealed the important abnormal finding that the islets of STZ diabetic mice had lost most of the pericytes necessary for β-cell proliferation and differentiation.
Erase whole body bad memory!
We have identified the cell fraction that contained abnormal HSCs is VCAM-1-positive short-term HSCs (Vcam-1+ST-HSCs) 4. The cells may lose an appropriate differentiation program. The abnormal HSCs seen in diabetic mice were removed from this abnormal fraction normalized abnormalities not only in bone marrow but also in the thymus. Interestingly, in a diabetic model in which the thymus had been resected beforehand, the simultaneous treatment of HDAC inhibitor (HDACi) and insulin had no therapeutic effect. This indicates that normalization of the thymus is also essential for complete remission of DM since both B cells produced in the bone marrow and T cells produced in the thymus have hematopoietic stem cells in their ancestors (see Figure 1).
Clinical impact
Will the treatment of HDACi with insulin performed on STZ mice result in the complete remission of DM in humans as well? The answer to this question will not be known until clinical trials are conducted. But we must also remember the following reality. Even if DM goes into complete remission, the "causes of DM" - obesity, lack of exercise, and autoimmunity - will reappear, and if they are not prevented, the patient will surely revert to DM again.
Figure 1. The path to complete diabetes remission.
Until now, it has been believed that once diabetes mellitus develops, it never fully recovers. In this study, we demonstrated that persistent hyperglycemia generates hematopoietic stem cells with abnormal histone deacetylase expression in the bone marrow and that cells derived from these cells migrate to the islets and inhibit β-cell regeneration (Road with No-Entry). Both histone deacetylase inhibitor (HDACi) and insulin treatment were simultaneously applied to these abnormal cells to prevent the development of newly formed abnormal stem cells (Road with the hospital). As a result, the β cells of the STZ mice regenerated and their diabetes went into complete remission.
References
- https://diabetesatlas.org/atlas/tenth-edition/
- Tang, S. C., Jessup, C. F., & Campbell-Thompson, M. The Role of Accessory Cells in Islet Homeostasis. Curr Diab Rep 28, 117 (2018).
- Shiue-Cheng, Tang. et al. Plasticity of Schwann cells and pericytes in response to islet injury in mice. Diabetologia 56, 2424-2434 (2013).
- Katagi, M. et al. Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion. Commun Biol 4 (2021).