Human IAPP is a driver of painful diabetic peripheral neuropathy

Abstract

Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet {beta}-cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. Transgenic hIAPP mice that have elevated plasma hIAPP levels without hyperglycemia developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intra-epidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice that have hyperglycaemia in combination with elevated plasma hIAPP levels had signs of neuropathy, although more aggravated. In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (Pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared to non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/471098v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@323953org.highwire.dtl.DTLVardef@15195feorg.highwire.dtl.DTLVardef@14e7311org.highwire.dtl.DTLVardef@16488bd_HPS_FORMAT_FIGEXP M_FIG C_FIG