Exploring the Trigger of Type 1 Diabetes

6/15/19

Secondary necrosis is the eventual outcome of apoptosis when an apoptosing cell is not efferocytosed[1]. In my article, “Autoimmunity is a Protective Response to β Cell Damage in Type 1 Diabetes”, I discussed how secondary necrotic β cells trigger β cell specific autoimmunity, while primary necrotic or apoptotic β cells do not. The reason for this may be the unique damage associated molecular patterns (DAMPs) released by secondary necrotic cells, as I explored in the article. But I also suspect that the gradual release of β cell antigens and DAMPs in secondary necrosis allows adequate time and opportunity for autoreactive lymphocytes to meet their cognate antigen with costimulation.

Progression to secondary necrosis depends on two factors: the extent of apoptosis, and the rate of phagocytosis. A defect in phagocytosis will lead to an increased tendency towards secondary necrosis. But, sufficiently large amounts of apoptosis will at some extent overwhelm even a healthy phagocytic capacity, and also lead to secondary necrosis.

Evidence of innate immune activity and the appearance of metabolic stress markers precedes seroconversion to autoantibody positivity by a few months[2][3]. This likely reflects the inflammatory response to initial β cell damage, and gives an idea of the intensity and duration of the triggering insult needed to produce secondary necrosis.

After autoimmunity appears, it can take months to decades for overt diabetes to appear. In order for autoimmunity to be sustained for such lengths, it must be continually primed by secondary necrotic β cells[4]. Autoimmunity after tissue trauma, for example, resolves once the injured tissue is healed[5]. In my article I offered evidence that suggests that autoimmunity is a protective response and not the perpetrator of β cell demise. Therefore, I propose that another agent is perpetuating the damage, and it is reasonable to assume that the initiating insult would likely also be the perpetual one.

Additionally, as is evident in Type 2 diabetes, the metabolic dysfunction of diabetes can cause β cell demise[6], and could conceivably compound the damage as glucose tolerance progressively declines in the pathogenesis of Type 1[7]. But these metabolic factors in Type 2 are insufficient to produce a dramatic deficiency of β cells as is seen in Type 1 and thus another agent is needed to cause the near total deficiency.

Progression of β cell depletion is seen to occur in phases[8], and this could suggest fluctuations in either the magnitude of the threat or in the host’s vulnerability to the threat. When trying to narrow down suspects it will be prudent to consider that the threat could be of a fluctuating nature.

The nature of the initiating trigger has remained elusive. This may be why so much focus has been directed towards vilifying the more easily visible autoimmune response. If it were discovered that the triggering agent were perpetually present, would autoimmunity still be called upon as the primary culprit? If autoimmunity is indeed a protective response, then the damage is necessarily caused by something else.

According to the ideas presented here, the cause of Type 1 diabetes should fit within a few parameters. The agent of β cell damage should be sufficiently noxious to produce continual and relatively large amounts of apoptosis, relative to the phagocytic capacity, that will progress to secondary necrosis after a few months on average. It should be something that can then persist for months to decades of the prediabetic period, and perhaps beyond. And it should be either specifically targeted to β cells or affect a unique vulnerability in β cells that other cells do not have. These parameters will help narrow down the potential agents that could be responsible for killing off the β cells.

References

1. Silva, M.T., Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett, 2010. 584(22): p. 4491-9.

2. Kallionpaa, H., et al., Innate immune activity is detected prior to seroconversion in children with HLA-conferred type 1 diabetes susceptibility. Diabetes, 2014. 63(7): p. 2402-14.

3. Oresic, M., et al., Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med, 2008. 205(13): p. 2975-84.

4. Filippi, C.M. and M.G. von Herrath, Islet beta-cell death - fuel to sustain autoimmunity? Immunity, 2007. 27(2): p. 183-5.

5. Mackay, I.R., N.V. Leskovsek, and N.R. Rose, Cell damage and autoimmunity: a critical appraisal. J Autoimmun, 2008. 30(1-2): p. 5-11.

6. Oh, Y.S., et al., Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes. Front Endocrinol (Lausanne), 2018. 9: p. 384.

7. Zmyslowska, A., et al., Free fatty acids level may effect a residual insulin secretion in type 1 diabetes. Pediatr Endocrinol Diabetes Metab, 2011. 17(1): p. 26-9.

8. von Herrath, M., S. Sanda, and K. Herold, Type 1 diabetes as a relapsing-remitting disease? Nat Rev Immunol, 2007. 7(12): p. 988-94.