Autophagy is a cellular defense mechanism conserved from yeasts to mammals that plays an important role in recycling substance and energy for cell survival. Besides this default function, autophagy fulfills many other tasks necessary for maintaining cell metabolism. As the regulation of autophagy intensity is tightly connected with proper sensing of nutrient deprivation or excess, any disturbances associated with metabolic disorders such as insulin resistance or type 2 diabetes (T2DM) significantly disarray normal autophagy regulation and may contribute to the diabetes-associated pathologies. This chapter focuses on the main mechanisms that are involved in the autophagy (dys)regulation in the context of insulin resistance - nutrients and growth factors (especially mTOR signaling axis), energy status (AMPK kinase), ER stress, and Forkhead box O (FoxO) transcription factors. Attention is further concentrated on the role of autophagy in insulin sensitive tissues (liver, pancreatic β-cells, adipose tissue, hypothalamus, myocardium, skeletal muscle) in physiological conditions and in the pathological metabolic environment. The involvement and contribution of particular regulatory pathways in different tissues are discussed in detail.