Human islet amyloid polypeptide (IAPP): a culprit of Type 2 Diabetes Mellitus (T2DM) and T2DM neuropathy

Abstract

Diabetes Mellitus (DM) is one of the most prevalent global health challenges in the 21st century, impacting over 500 million individuals by 2021. Among its types, Type 2 diabetes mellitus (T2DM) accounts for more than 90% of all diabetes cases. A significant complication of T2DM is Diabetic Peripheral Neuropathy (DPN), affecting approximately half of all DM patients. DPN manifests with sensory function alterations, ranging from increased sensitivity to decreased sensation. While hyperglycemia has been traditionally implicated in DPN development, recent evidence suggests the involvement of additional factors. This thesis explores into the role of islet amyloid polypeptide (IAPP) in T2DM and its complications, particularly DPN. Initially considered solely a metabolic disorder, T2DM is increasingly recognized as an amyloid disease due to the formation of islet amyloid, primarily composed of the protein IAPP. Drawing parallels with other amyloid-related neuropathies, the research explores the potential contribution of aggregated human IAPP (hIAPP) to DPN in T2DM. Through a comprehensive investigation utilizing transgenic T2DM mouse models expressing hIAPP, the study elucidates the neuropathic effects of hIAPP aggregation. Findings demonstrate mechanical hypersensitivity, reduced intraepidermal nerve fiber density, and neurotoxicity associated with hIAPP. Importantly, these effects are mitigated when hIAPP aggregation is inhibited. Moreover, analysis of gene expression profiles in dorsal root ganglia (DRGs) highlights molecular pathways influenced by hIAPP, shedding light on its mechanisms in neuropathy development. Furthermore, therapeutic intervention with an amyloid oligomer-modifying compound, anle138b, proves promising in inhibiting hIAPP aggregation and ameliorating T2DM-associated pathology. Treatment of hIAPP transgenic mice with anle138b significantly reduces hyperglycemia, preserves pancreatic islet function, and mitigates neuropathic symptoms, underscoring its potential as a therapeutic agent for T2DM and its complications. In summary, this thesis unveils the intricate involvement of hIAPP in DPN development, emphasizing the significance of targeting hIAPP aggregation as a therapeutic strategy for T2DM and its associated DPN. These findings pave the way for novel therapeutic interventions aimed at preventing and managing T2DM and its debilitating sequelae.