Islet amyloid is a hallmark of human type 2 diabetes (T2D), due to the amyloidogenic propensity of human IAPP (hIAPP) in contrast to mouse IAPP (mIAPP). Because autophagy is important in the clearance of amyloid-like proteins, we studied the role of autophagy in the pathogenesis of human T2D employing transgenic mice expressing hIAPP in β-cells. β-cell-specific autophagy-deficient mice expressing hIAPP (hIAPP⁺Atg7 ^Δβ-cell mice) developed overt diabetes, while hIAPP⁺ or Atg7 ^Δβ-cell mice never did. hIAPP oligomer and IAPP amyloid accumulated in islets of hIAPP+Atg7 Δβ-cell mice, leading to increased death and decreased mass of β-cells. When prepro-hIAPP was expressed in vitro, the pro-hIAPP dimer was formed, which was absent or dramatically reduced when nonamyloidogenic prepro-mIAPP or mutant prepro-hIAPP was expressed. When autophagy was deficient, accumulation of the pro-hIAPP dimer markedly increased, and the pro-hIAPP trimer was additionally observed in the detergent-insoluble fraction. Trehalose, an autophagy enhancer, improved metabolic profile of hIAPP⁺ mice fed high-fat diet. These results suggest that autophagy is critical for the clearance of amyloidogenic hIAPP and autophagy deficiency due to genetic predisposition or aging could play a role in the pathogenesis of human T2D. Autophagy enhancers could be therapeutic agents against human T2D characterized by islet amyloid accumulation