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Tau also impacts pancreatic beta cell function and glucose homeostasis. Amyloid deposits composed of islet amyloid polypeptide (IAPP) are a pathological feature of type 2 diabetes (T2D). The current study investigates the role of human tau (hTau) in combination with human IAPP (hIAPP) as a potential mechanism connecting AD and T2D. Transgenic mice expressing hTau and hIAPP in the absence of murine tau were generated to determine the impact of these pathological factors on glucose metabolism. Co\u2010expression of hIAPP and hTau resulted in mice with increased hyperglycaemia, insulin resistance, and glucose intolerance. The hTau\u2010hIAPP mice also exhibited reduced beta cell area, increased amyloid deposition, impaired insulin processing, and reduced insulin content in islets. Tau phosphorylation also increased after stimulation with high glucose. In addition, brain insulin content and signalling were reduced, and tau phosphorylation was increased in these animals. These data support a link between tau and IAPP amyloid, which seems to act co\u2010ordinately to impair beta cell function and glucose homeostasis, and suggest that the combined pathological actions of these proteins may be a potential mechanism connecting AD and T2D. \u00a9 2021 The Pathological Society of Great Britain and Ireland. 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