individuals with IFG have a 40% deficit in relative beta‐cell volume compared to obese individuals with NFG [30]. Additionally, the diabetes‐associated genetic variation in TCF7L2 is associated with impaired insulin secretion [31–33]. The inability of insulin secretion to compensate for a decline in insulin action results in hyperglycemia.
It is also essential to consider the role of hepatic extraction in the pathophysiology of prediabetes and DM [26]. The peripheral insulin concentration reflects portal insulin secretion, hepatic extraction, distribution, and degradation [34]. Hepatic extraction of secreted insulin has a direct relationship with disposition index. Reduced hepatic extraction in prediabetes and DM may be a compensatory measure to increase circulating insulin. Interestingly, insulin pulse characteristics influence hepatic extraction of insulin, and the diabetes‐associated genetic variation in TCF7L2 is associated with abnormal insulin pulse characteristics [33].
Furthermore, lack of glucagon suppression contributes to hyperglycemia in subjects with impaired insulin secretion [24]. The diabetes‐associated genetic variation in TCF7L2 is associated with impaired glucagon suppression [31, 35]. In a longitudinal study, defects in α‐cell function with elevated fasting glucagon concentrations were associated with a subsequent decline in β‐cell function [36].
Screening recommendations for prediabetes
The 2020 ADA Guidelines recommend screening asymptomatic overweight or obese adults for DM or prediabetes if at least one of the following risk factors is present: first‐degree relative with DM; high‐risk race/ethnicity (e.g. African American, Latino, Native American, Asian American, Pacific Islander); history of cardiovascular disease; hypertension; high‐density lipoprotein cholesterol < 35 mg/dL; triglyceride level > 250 mg/dL; presence of polycystic ovary syndrome; physical inactivity; or other clinical considerations associated with reduced insulin action such as acanthosis nigricans [1]. The 2020 ADA Guidelines further recommend that patients with prediabetes be tested yearly and that women with a history of gestational diabetes be tested lifelong at least every three years. For all other patients, screening should begin at age 45, and if results are normal, should be repeated at least every three years.
FIG 1.2 Postprandial and fasting glucose concentrations are determined by insulin secretion, hepatic insulin extraction, insulin action, glucagon suppression, glucose effectiveness, endogenous glucose production, and the rate of gastric emptying [23–29]. EGP = Endogenous Glucose Production.
Reproducibility, sensitivity, and specificity of glycemic measurements and the role of oral glucose tolerance testing in clinical practice
A study that analyzed data from the Second Examination of the Third National Health and Nutrition Examination Survey (NHANES) found that the within‐person coefficient of variation was 16.7% (95% CI 15.0–18.3) for 2‐h PG, 5.7% (95% CI 5.3–6.1) for FPG, and only 3.6% (95% CI 3.2–4.0) for HbA1c [37]. A study of non‐diabetic adults reported a reproducibility rate of 65.6% for a 75‐g OGTT repeated twice over a six‐week period [38].
HbA1c, FPG, and 2‐h PG during a 75‐g OGTT have different sensitivities and specificities in the diagnosis of prediabetes and DM [39]. An analysis of NHANES data from 2005–2010 examined adults without self‐reported DM at baseline with available measurements for HbA1c, FPG, and 2‐h PG [40]. Prediabetes and DM were defined according to the current ADA Guidelines [1]. Using HbA1c thresholds of ≥ 6.5% for DM and ≥ 5.7% for prediabetes resulted in low sensitivity (24.9% and 35.4%, respectively) and high specificity in identifying patients diagnosed with FPG and 2‐h PG. When FPG and HbA1c were used together for diagnosis, the false‐negative rate was 45.7% for DM and 9.2% for prediabetes.
Similar findings were reported in the Insulin Resistance Atherosclerosis Study (IRAS), which examined 855 subjects and defined DM and prediabetes in accordance with the 2020 ADA Guidelines (Tables 1.1 and 1.2) [1, 41]. HbA1c ≥ 6.5%, FPG ≥ 126 mg/dL, and 2‐h PG ≥ 200 mg/dL identified 32.3%, 44.8%, and 86.8% of individuals with DM, respectively. The combination of HbA1c ≥ 6.5% and/or FPG ≥ 126 mg/dL detected 52.2% of all individuals with DM. HbA1c between 5.7–6.4%, FPG between 100–125 mg/dL, and 2‐h PG between 140–199 mg/dL identified 23.6%, 69.1%, and 59.5% of all non‐diabetic subjects with prediabetes. The combination of HbA1c 5.7–6.4% and/or FPG 100–125 mg/dL detected 75.6% of all non‐diabetic subjects with prediabetes.
TABLE 1.1 The sensitivity of various indices of glycemia used to diagnose type 2 diabetes mellitus in the Insulin Resistance Atherosclerosis Study. Diabetes mellitus was defined according to the 2020 American Diabetes Association criteria. This data illustrates that omitting an oral glucose tolerance test leads to under‐diagnosis of diabetes mellitus, even when both fasting plasma glucose and hemoglobin A1c are measured concurrently. HbA1c = Hemoglobin A1c. FPG = Fasting Plasma Glucose. 2‐h PG = 2‐hour Plasma Glucose [41].
| Sensitivity | |
|---|---|
| HbA1c ≥ 6.5% | 32.3% |
| FPG ≥ 126 mg/dL | 44.8% |
| 2‐h PG ≥ 200 mg/dL | 86.8% |
| HbA1c ≥ 6.5% and/or FPG ≥ 126 mg/dL | 52.2% |
| FPG ≥ 126 mg/dL and/or 2‐h PG ≥ 200 mg/dL | 97.1% |
TABLE 1.2 The sensitivity of various indices of glycemia used to diagnose prediabetes in the Insulin Resistance Atherosclerosis Study. Prediabetes was defined according to the 2020 American Diabetes Association criteria. This data illustrates that omitting an oral glucose tolerance test leads to under‐diagnosis of prediabetes, even when both fasting plasma glucose and hemoglobin A1c are measured concurrently. HbA1c = Hemoglobin A1c. FPG = Fasting Plasma Glucose. 2‐h PG = 2‐hour Plasma Glucose [41].
| Sensitivity | |
|---|---|
| HbA1c 5.7–6.4% | 23.6% |
| FPG 100–125 mg/dL | 69.1% |
| 2‐h PG 140–199 mg/dL | 59.5% |
| HbA1c 5.7–6.4% and/or FPG 100–125 mg/dL | 75.6% |
| FPG 100–125 mg/dL and/or 2‐h PG 140–199 mg/dL | 95.8% |
Despite the limitations of the OGTT – including lower reproducibility and reduced patient convenience compared to FPG and HbA1c – the aforementioned studies suggest that the OGTT continues to have a role in clinical practice. An individual eating three daily meals will be in a postprandial state for 6–9 hours per day [42]. Therefore, it is logical that the knowledge gained from a standardized glucose load is clinically informative. The 2020 ADA Guidelines state that FPG, 2‐h PG during a 75‐g OGTT, and HbA1c are equally appropriate to test for prediabetes and DM [1]. Many