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At top: optimal ER mitochondria interactions are required for metabolic flexibility (left) and insulin signaling (right). Top left: increased organelle interactions at fasting state promote mitochondria fusion and maximal oxidative capacities to predominantly oxidize lipids. Top right: antidiabetic drugs improve both insulin sensitivity and organelle interactions in diabetic mice. At the bottom: ER mitochondria miscommunication is involved in metabolic inflexibility during nutritional transition (left) and in insulin resistance (right). Bottom left: high glucose levels reduce ER mitochondria interactions at post-prandial state, presumably leading to the storage of excess of glucose into lipids. 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