The number of individuals with prediabetes is expected to grow substantially and estimated to globally affect 482 million people by 2040. Therefore, effective methods for diagnosing prediabetes will be required to reduce the risk of progressing to diabetes and its complications. The current biomarkers, glycated hemoglobin (HbA1c), fructosamine, and glycated albumin have limitations including moderate sensitivity and specificity and are inaccurate in certain clinical conditions. Therefore, identification of additional biomarkers is being explored recognizing that any single biomarker will also likely have inherent limitations. Therefore, combining several biomarkers may more precisely identify those at high risk for developing prediabetes and subsequent progression to diabetes. This review describes recently identified biomarkers and their potential utility for addressing the burgeoning epidemic of dysglycemic disorders.

Highlights A 1-hour plasma glucose (1-h PG) threshold >155 mg/dl (8.6 mmol/L) during an oral glucose tolerance test (OGTT) may be a suitable biomarker for identifying normal glucose tolerant (NGT) individuals at risk for future type 2 diabetes (T2D). A one-hour, non-fasting, 50g Glucose Challenge Test (GCT) performed during a routine health care visit has potential for practical screening of glucose disorders. The shape of the glucose curve reflects the cumulative effect of insulin sensitivity and response on glucose concentrations with prospective studies warranted to evaluate its prognostic utility. The continuous glucose monitor (CGM) has facilitated insight into the pathophysiology of prediabetes and phenotypes of T2D and holds promise for detecting glycemic disorders. Metabolomic profiling including amino acids, lipids, carbohydrates and other metabolites may be useful for early diagnosis of glycemic disorders. Non-classical markers for assessing glycemic disorders including fructosamine, glycated albumin, and 1,5-anhydroglucitol that evaluate shorter periods of glucose exposure than HbA1c have potential use as adjunctive tools.

For over 100 years, the oral glucose tolerance test (OGTT) has been the cornerstone for detecting prediabetes and type 2 diabetes (T2DM). In recent decades, controversies have arisen identifying internationally acceptable cut points using fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and/or HbA1c for defining intermediate hyperglycemia (prediabetes). Despite this, there has been a steadfast global consensus of the 2-h PG for defining dysglycemic states during the OGTT. This article reviews the history of the OGTT and recent advances in its application, including the glucose challenge test and mathematical modeling for determining the shape of the glucose curve. Pitfalls of the FPG, 2-h PG during the OGTT, and HbA1c are considered as well. Finally, the associations between the 30-minute and 1-hour plasma glucose (1-h PG) levels derived from the OGTT and incidence of diabetes and its complications will be reviewed. The considerable evidence base supports modifying current screening and diagnostic recommendations with the use of the 1-h PG. Measurement of the 1-h PG level could increase the likelihood of identifying high-risk individuals when the pancreatic ß-cell function is substantially more intact with the added practical advantage of potentially replacing the conventional 2-h OGTT making it more acceptable in the clinical setting.

Identifying the earliest moment for intervention to avert progression to prediabetes and diabetes in high-risk individuals is a substantial challenge. As β-cell function is already compromised in prediabetes, attention should therefore be focused on identifying high-risk individuals earlier in the so-called pre-prediabetes stage. Biomarkers to monitor progression and identify the time point at which β-cell dysfunction occurs are therefore critically needed. Large-scale population studies have consistently shown that the 1-h plasma glucose (1-h PG) ≥ 155 mg/dl (8.6 mmol/l) during the oral glucose tolerance test detected incident type 2 diabetes and associated complications earlier than fasting plasma glucose or 2-h plasma glucose levels. An elevated 1-h PG level appears to be a better alternative to HbA1c [5.7-6.4% (37-47 mmol/mol)] or traditional glucose criteria for identifying high-risk individuals at a stage when ß-cell function is substantially more intact than in prediabetes. Diagnosing high-risk individuals earlier proffers the opportunity for potentially reducing progression to diabetes, development of microvascular complications and mortality, thereby advancing benefit beyond that which has been demonstrated in global diabetes prevention programs.