Introduction 1 2 4 2 Here we present the concept that removal of fatty acids within white adipocytes by fatty acid-induced uncoupled mitochondrial β-oxidation protects the organism against fatty acid leakage out of adipocytes, thereby preventing fatty acid-induced insulin resistance in liver and muscle and lipotoxicity in pancreatic beta cells. A consequence of this concept is that mitochondrial dysfunction in adipocytes, either inherited or acquired, makes the organism more prone to develop insulin resistance and type 2 diabetes. Mitochondria and fatty acids + 2 2 + + 5 6 8 2 Mitochondrial uncoupling in adipocytes by fatty acids may protect the organism against fatty acid-induced insulin resistance and lipotoxicity 9 10 11 14 15 1 5 8 16 17 18 19 20 21 Fig. 1 18 Dotted arrows continuous arrows  Discussion 2 11 15 18 22 Fig. 2 46 23 36 37 39 40  23 24 24 25 8 26 29 2 30 33 34 35 23 36 37 38 36 39 40 36 41 42 43 LARS2 44 45 Our model of the pathogenesis of type 2 diabetes mellitus requires experimental verification of several points, and it certainly does not exclude the involvement of additional factors such as the coregulation of whole-body insulin action and insulin secretion through adipokines and the involvement of uncoupling proteins in setting the threshold for fatty acid-induced uncoupling of mitochondria. However, we see the way fatty acids interact with mitochondria in the cytosol of adipocytes as a major initiating event in the disease process leading to the metabolic syndrome and type 2 diabetes mellitus.