Phenotypes in type 2 prediabetes and their prognostic value for complications and progression to type 2 diabetes

Abstract

Prediabetes represents a markedly heterogeneous metabolic state in which a one-dimensional definition based exclusively on glycemic thresholds is insufficient to stratify the true risk of progression to type 2 diabetes (T2D) and the development of macro- and microvascular complications. Regarding intermediate hyperglycemia as a single, homogeneous entity may constrain or overdimension the necessary therapeutic approach.

Pathophysiologically, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) arise from entirely distinct mechanisms: IFG primarily reflects hepatic insulin resistance together with reduced first-phase insulin secretion, whereas IGT expresses predominant skeletal muscle insulin resistance with impairments in both early and late secretory phases. The presence of IGT alongside HbA1c in the prediabetic range confers the highest impact on cardiovascular morbidity and mortality, as well as T2D conversion rates.

Data-driven clustering models integrate physiological, genetic, and imaging variables to identify six reproducible subphenotypes, three of which concentrate adverse metabolic outcomes: betacell failure (cluster 3), fatty liver (cluster 5), and "slow progressors" (cluster 6). This latter subphenotype is conceptually disruptive, exposing a profound dissociation between the rate of glycemic deterioration and target organ damage. Despite maintaining modest glycemic elevations over many years, slow progressors accumulate the highest overall mortality and develop early chronic kidney disease (manifested as elevated albuminuria) well before crossing the formal biochemical threshold for diabetes.

Concurrently, subphenotyping has evolved from a purely prognostic assessment into a valuable predictive marker of therapeutic response. Extended 21-year analyses from the Diabetes Prevention Program (DPP) and mechanistic findings from the PLIS trial confirm that achieving prediabetes remission—returning to normal glucose regulation—constitutes a clinical preventive endpoint superior to isolated weight-loss goals. Furthermore, this remission is achievable without weight loss when a favorable adipose tissue redistribution occurs from visceral to subcutaneous depots.

Finally, a pragmatic, clinically applicable stratification scheme suitable for routine healthcare settings is proposed, substituting complex research assays with accessible surrogates: 1-h and 2-h OGTT, the waist-to-height ratio, the TG/HDL or glucose/triglyceride ratios, the FIB-4 index for hepatic fibrosis risk estimation, and the urinary albumin-to-creatinine ratio. This comprehensive approach enables the early detection of subclinical organ damage, redirects resources toward high-risk phenotypes, and establishes genuine precision medicine in the prevention of chronic complications.