Progression to diabetes, remission to normality, and epidemiology

Abstract

Background: Prediabetes is a highly prevalent and heterogeneous condition. Its phenotypic characterization is crucial, as metabolic profiles determine both the individual risk of progression to type 2 diabetes mellitus (T2DM) and the potential for regression toward normal glucose tolerance (NGT). Variations in prevalence and metabolic trajectories depend on the diagnostic criteria used and geographic distribution.

Objectives: To analyze the epidemiological, phenotypic, and pathophysiological factors influencing prediabetes metabolic trajectories, evaluating the risk of progression to T2DM and the probability of regression to normoglycemia.

Materials and Methods: review and analysis of global, multiethnic epidemiological data, including subgroup behavior by sex and age, along with a syndromic analysis of 103 prospective cohort studies worldwide in individuals with intermediate hyperglycemia (IH). Variables such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), HbA1c, and 1-hour plasma glucose (1-h PG) were evaluated and correlated with reference standards like the hyperinsulinemic-euglycemic clamp.

Results: Data from the US suggest that local environmental factors override genetic predisposition in obesogenic environments, showing no significant differences in prevalence across ethnicities (Asian: 37.3%; Black: 39.2%; Hispanic: 35.4%; White: 38.7%). However, the progression rate from IGT to T2DM exhibits geographic variability, being higher in Asian Indians (18.3% annually) compared to Chinese (11.3% annually), American (11 per 100 person-years), and Finnish populations (6.0% annually). By sex, elevated 2-hour glucose levels in men and impaired fasting glucose in women were associated with higher progression.

The analysis of 103 cohorts showed that the combination of IFG/IGT and elevated HbA1c increases the cumulative incidence of T2DM, though without a defined linear increase over time; similarly, regression rates to normoglycemia fluctuated without a clear decreasing linear trend. Pathophysiologically, progressors to T2DM manifested beta-cell dysfunction before reaching prediabetic ranges, which worsened as glucose levels rose. Through the clamp technique, it was confirmed that the transition from normoglycemia to prediabetes is associated with lower baseline insulin sensitivity and a more pronounced decline over the years.

Finally, individuals with IFG and high 1-h PG presented a significantly higher risk of developing T2DM (11.4% vs. 1.8% in those with low 1-h PG). In patients with IGT, an elevated 1-h PG increased the risk of progression to 14%, whereas in those with low 1-h PG, the conversion risk was virtually zero.

The complex interaction of genetic, dietary, and socioenvironmental factors challenges a universal phenotypic categorization of prediabetes. It is imperative to implement accessible intervention programs that consider cultural and socioeconomic determinants. Personalized therapeutic strategies based on individual risk profiles and metabolic phenotypes are suggested, reserving close monitoring for low-risk patients, with the ultimate goal of achieving remission to NGT and preventing micro- and macrovascular complications.