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Type 2 diabetes (T2D), alike Parkinson's disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in beta -cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (alpha Syn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in beta -cells. Here we show that alpha Syn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, alpha Syn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of alpha Syn in hIAPPtg mice enhanced beta -cell amyloid formation in vivo whereas beta -cell amyloid formation was reduced in hIAPPtg mice on a Snca (-/-) background. Taken together, our findings provide evidence that alpha Syn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for alpha Syn in beta -cell amyloid formation.

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced beta cell stress, and promoted beta cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro-and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.