Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus.

Thomas A. Lutz,Elisa S. Roesti,Christina N. Boyle,Federico Storni,Daniel T. Zeman,Marcos Sande-Melon,Monique Vogel,Alexander Knuth,Martin F. Bachmann,Gustavo Cabral-Miranda

doi:10.3390/vaccines8010116

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.

Highlights

According to the International Diabetes Federation (IDF, 8th Edition 2017), approximately425 million people worldwide are suffering from diabetes, and type 2 diabetes mellitus (T2DM)accounts for approximately 90% of all cases
Human islet amyloid polypeptide (IAPP) assembles into oligomers and fibrils, thereby forming β-sheet stacks stabilized by hydrogen bonds [42] and supported by the IAPP core structure [43,44] consisting of an N-terminal peptide linked by a disulfide (s-s) bond followed by two parallel β-sheets and a final amidated
We investigated whether Qβ-N-term (s-s) vaccination-induced antibodies discern between monomeric and oligomeric human IAPP (hIAPP). We found that it recognizes IAPP oligomers/fibrils, but not monomeric IAPP, rodent IAPP or a negative control composed of amyloidogenic Aβ peptide (Figure 3a)

Summary

Introduction

According to the International Diabetes Federation (IDF, 8th Edition 2017), approximately425 million people worldwide are suffering from diabetes, and type 2 diabetes mellitus (T2DM)accounts for approximately 90% of all cases. T2DM is a chronic progressive disease characterized by obesity, insulin resistance and β-cell failure [2]. The onset of T2DM is mainly determined by a failure of the insulin-producing β-cells to secrete adequate levels of metabolically active insulin to maintain normoglycemia [3,4]. One hallmark of the disease is the occurrence of amyloid deposits in pancreatic islets [5,6], which is associated with β-cell apoptosis [7] and reduced β-cell mass [4,8]. The major constituent of amyloid deposits is the β-cell secretory product islet amyloid polypeptide (IAPP; known as amylin). IAPP is co-secreted with insulin in a ratio of approximately

Methods

Results

Conclusion