Hepatic insulin resistance is a key feature of type 2 diabetes, and the consequent dysregulation of glucose and lipid output from the liver are important contributors to the observed hyperglycemia and hyperlipidemia. While excessive lipid accumulation (1) and defective signaling by protein kinase C (2) have been implicated in the past, the full panoply of molecular mechanisms involved is still not defined. Deeper insights would therefore be welcome in the quest to identify new therapeutic approaches to the disease (3).

Mitochondrial metabolism and its dysfunction are well-known to contribute to metabolic dyshomeostasis in type 2 diabetes, with impaired glucose oxidation resulting from a failure to fully activate the intramitochondrial pyruvate dehydrogenase (PDH) complex (4). Originally described as sites for the exchange of phospholipids between organelles (5), mitochondria-associated membranes (MAMs) represent close contact sites through which endoplasmic reticulum (ER) communicates with mitochondria supporting the transfer not only of lipids but also the exchange of calcium (Ca2+) ions and other species. MAMs play important roles in several signal transduction pathways and the relevance of the ER–mitochondria interface to human diseases, including Alzheimer disease, cancer, and lysosomal storage disease (6), is slowly emerging. In this issue, Tubbs et al.(7) demonstrate the potential importance of MAM integrity in insulin action and resistance in hepatocytes. The association between ER and mitochondrial homeostasis and insulin signaling has recently been a topic of intense investigation and debate (8–10). Importantly, a reduction in ER-mitochondrial cross talk, achieved by liver-specific ablation of the regulator of mitochondrial fusion, mitofusin (Mfn2), causes mitochondrial dysfunction, insulin resistance, and impaired glucose tolerance