Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes [Review]

Abstract

Abstract. Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes.

Fulminant Type 1 Diabetes Mellitus and Fulminant Viral Myocarditis

“…[27][28][29] A viral-induced immune reaction and cytokines are also suggested to play a role in the pathophysiology of the rapid destruction of pancreatic beta cells in FT1D, but there have been few reports on a specific role for IL-6 or IL-10 in the onset of FT1D. 30) These findings suggest that serial changes in serum cytokines in our patient might be partly explained by viral myocarditis. Additionally, although the underlying reasons were unclear, the decreases in IL-10 and IL-6 suggest that viral myocarditis accompanied by the onset of FT1D might become clinically evident with corrected ketoacidosis, even when ECG abnormalities are not detected before treatment of ketoacidosis.…”

Increased expression of IL-18 in the serum and islets of type 1 diabetics

“…al. analyzed enterovirus-infected pancreatic specimens from subjects with fulminant diabetes and found that β-cells as well as a population of non-β-cells express IL-18 [28, 46]. Moreover, IL-18 mRNA is constitutively expressed in islet β-cells harvested from mice and rats [47].…”

The effects of grape seed on apoptosis-related gene expression and oxidative stress in streptozotocin-induced diabetic rats

“…5 Islet beta cell apoptosis occurs especially in the form of immune-mediated (Type 1) DM. 11 These models demonstrated that long-term hyperglycemia impairs renal structure and function.…”