Abstract / Summary
Background: The conventional definition of diabetes mellitus is based on the presence of hyperglycemia. However, growing evidence indicates that key pathophysiological processes—particularly β-cell dysfunction—occur well before any measurable increase in blood glucose. These early changes remain undetected by standard diagnostics but are clinically significant. Objective: This work introduces the proposed concept of normoglycemic diabetes, defined as a pathophysiological state in which conventional glucose criteria remain normal while measurable evidence of early β-cell dysfunction is already present. Particular emphasis is placed on intact proinsulin as a marker of impaired proinsulin processing and β-cell secretory stress. Methods: A staged model of declining functional β-cell mass is presented, ranging from compensated β-cell stress during normoglycemia to overt secretory failure and dysglycemia, incorporating genetic, epigenetic, and environmental influences. Diagnostic strategies, including extended OGTT assessment and intact proinsulin quantification, and their potential preventive implications are discussed. Results: Early impairment of functional β-cell mass can be detectable while fasting glucose, HbA1c, and conventional glucose tolerance criteria remain normal. Intact proinsulin and proinsulin-related ratios may provide information on impaired hormone processing and secretory stress before overt hyperglycemia develops. The proposed concept therefore identifies a biological state that may become a target for earlier, marker-guided prevention. Conclusions: Normoglycemic diabetes is proposed as an early pathophysiological disease concept complementary to established glucose-defined categories. It is distinct from diabetes prevention itself: the former describes measurable β-cell pathology during normoglycemia, whereas prevention describes interventions intended to delay or avoid progression to dysglycemia and overt type 2 diabetes. Prospective studies are required before this concept can be considered an established diagnostic entity.