Glucose metabolism is normally regulated by a feedback loop including islet Ξ² cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of Ξ²-cell response. If insulin resistance is present, Ξ² cells maintain normal glucose tolerance by increasing insulin output. Only when Ξ² cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although Ξ²-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and Ξ²-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of Ξ²-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease.