Type 2 diabetes mellitus (T2D) is a major public health concern and is characterized by sustained hyperglycemia due to insulin resistance and destruction of insulin-producing š· cells. One pathological hallmark of T2D is the toxic accumulation of human islet amyloid polypeptide (hIAPP) aggregates. Monomeric hIAPP is a hormone normally co-secreted with insulin. However, increased levels of hIAPP in prediabetic and diabetic patients can lead to the formation of hIAPP protofibrils, which are toxic to š· cells. Current therapies fail to address hIAPP aggregation and current screening modalities do not detect it. Using a stabilizing capping protein, monoclonal antibodies (mAbs) can be developed against a previously nonisolatable form of hIAPP protofibrils, which are protofibril specific and do not engage monomeric hIAPP. Shown here are two candidate mAbs that can detect hIAPP protofibrils in serum and hIAPP deposits in pancreatic islets in a mouse model of rapidly progressing T2D. Treatment of diabetic mice with the mAbs delays disease progression and dramatically increases overall survival. These results demonstrate the potential for using novel hIAPP protofibril-specific mAbs as a diagnostic screening tool for early detection of T2D, as well as therapeutically to preserve š· cell function and target one of the underlying pathological mechanisms of T2D.
Type 2 DiabeTesIn article number 2202342, Ronald J. Parchem and co-workers describe two hIAPP protofibrilspecific antibodies which prevent Ī² cell toxicity in type 2 diabetes (t2d). Treatment with mAbs increases survival in a mouse model of severe t2d, and pancreatic islets from treated mice show decreased Ī² cell death and macrophage infiltration, comparable to healthy wild-type animals, as depicted in the photo.
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