Human islet amyloid polypeptide (IAPP)

Summary

Diabetes Mellitus (DM) is one of the most prevalent current global health challenges, with Type 2 Diabetes Mellitus (T2DM) comprising 90% of cases. Diabetic peripheral neuropathy (DPN) is one of the most frequent diabetic complications, characterized by pain, abnormal sensation, and loss of sensory function . How this complication develops is not fully understood. While T2DM is characterized by hyperglycemia other factors also contribute to DPN, because control of hyperglycemia does not reduce neuropathy in T2DM. T2DM is also characterized by amyloid formation within the islets of Langerhans in the pancreas, and islet amyloid polypeptide (IAPP) is the building block of this islet amyloid. 

This thesis explored the role of human IAPP (hIAPP) in DPN development. Using a transgenic T2DM mouse model, we showed that hIAPP is neurotoxic and contributes to painful neuropathy. The role of hIAPP in DPN was linked to hIAPP aggregation.

Further investigation revealed that hIAPP dysregulates genes and cellular pathways associated with pain regulation and peripheral neuropathy in sensory neurons innervating the skin. Notably, the AGE-RAGE signaling pathway emerged as a key player in hIAPP-associated peripheral neuropathy. In a hIAPP transgenic T2DM mouse model we showed that the compound anle138b inhibited hIAPP aggregation, preserved mitochondrial function, and improved glycemic control. Thus, targeting hIAPP aggregation may hold promise for treatment of T2DM and DPN.

In conclusion, this thesis uncovers a significant role of hIAPP in DPN development and demonstrates the potential of inhibiting hIAPP aggregation as a therapeutic strategy for T2DM and its complications.

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