In this chapter, we develop the hypothesis that type 2 diabetes may in part reflect altered autocrine interactions in the adipocytes and the β cells of the pancreatic islets of Langerhans, together with an impaired adipo-insular axis whereby adipokines, as well as metabolic products of triglyceride mobilization released from adipose tissue, adversely impact β-cell function, with emphasis on the roles of fatty acids, derived from the breakdown of stored lipid, the adipokines leptin and adiponectin and the cytokine TNFα. In addition, we discuss the idea that an inappropriate early life environment may be an important player in the metabolic maladaptations leading to type 2 diabetes via augmented FA release in combination with altered secretion or action of adipo/cytokines.