Pathobiology of Prediabetes: Understanding and Interrupting Progressive Dysglycemia and Associated Complications

Diabetes currently affects ∼37 million adults in the U.S. and 537 million people worldwide, with type 2 diabetes (T2D) accounting for 90%–95% of the diabetes burden. The transition from normal glucose regulation (NGR) to T2D is via an intermediate stage of prediabetes, characterized by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Prediabetes affects ∼98 million adults in the U.S.; worldwide, more than 541 million adults have IGT and 319 million adults have IFG. Prediabetes is associated with increased risks of developing vascular and neuropathic complications, besides the risk of progression to T2D. Discussed herein are the demographic, anthropometric, biobehavioral, biochemical, and molecular factors associated with the transition from NGR to prediabetes. The natural history of prediabetes predicts time-dependent progression to T2D, as sustained recovery from prediabetes is uncommon without intervention. Lifestyle modification and certain medications interrupt the progression to T2D and may restore NGR. The landmark intervention trials are discussed, with an interpretive focus on their limitations and the need for novel approaches for durable reversal of prediabetes. Article Highlights Prediabetes, an intermediate stage in the pathogenesis of type 2 diabetes (T2D), affects ∼98 million U.S. adults and 800 million people worldwide. Prediabetes shares common pathophysiological mechanisms with T2D and progresses to T2D at variable rates based on risk factor burden. Less well studied is the initial transition from normoglycemia to prediabetes. Discussed herein are behavioral, clinical, biochemical, and molecular factors associated with development of prediabetes. Current approaches to prediabetes management are discussed, with an interpretive focus on their limitations and the need for novel interventions for durable reversal of prediabetes and avoidance of related complications.