Type 2 Diabetes: When Does It Start?

Abstract

Objective: We aimed to clarify the onset of diabetes.

Design: Data from 27,392 nondiabetic health examinees were retrospectively analyzed for a mean of 5.3 years. Trajectories of fasting plasma glucose (FPG), body mass index (BMI), and the single point insulin sensitivity (Si) estimator (SPISE), an index of Si, 10 years before diagnosis of prediabetes (PDM; n = 4781) or diabetes (n = 1061) were separately assessed by a mixed effects model. Diabetes and PDM were diagnosed by the American Diabetes Association definition on the basis of FPG and glycosylated hemoglobin A1c values.

Results: In individuals who developed diabetes, mean FPG and BMI were significantly higher (P < 0.01 each) and SPISE lower than those who did not at -10 years: FPG 101.5 mg/dL vs 94.5 mg/dL, BMI 24.0 kg/m² vs 22.7 kg/m², and SPISE 7.32 vs 8.34, P < 0.01 each. These measurements, in subjects who developed prediabetes, were slightly but definitely different from those who did not, already at -10 years: FPG 91.8 mg/dL vs 89.6 mg/dL, BMI 22.6 kg/m² vs 22.1 kg/m², and SPISE 8.44 vs 8.82, P < 0.01 each. In both cases, the differences were progressively greater toward year 0, the time of diabetes, or PDM diagnosis.

Conclusions: FPG was significantly elevated in those who developed diabetes at least 10 years before diagnosis of diabetes, and this was also the case in those who developed PDM. Glucose dysregulation precedes diagnosis of diabetes at least for 20 years.

Keywords: Japanese; diabetes mellitus; prediabetes; starting point of diabetes; trajectory.

Figure 1.

Validation of the SPISE. The clamp-based Rd values (adjusted for body weight) strongly correlated with SPISE: Spearman ρ = 0.668, P < 0.01.

Figure 2.

Trajectories of FPG before (A) PDM and (B) diabetes and weighted cubic regression of the estimated marginal means of FPG trajectory before (A′) PDM and (B′) diabetes. (A and B) Values in the progressors and nonprogressors at each time point were all significantly different (P < 0.01). (A) PDM-Progressors (▪) and NGR-Nonprogressors (□); (B) DM-Progressors (●) and NDM-Nonprogressors (○). The axis scale was intentionally maintained the same to facilitate visual comparison. (A′ and B′) The sizes of the circles are proportional to the number of individuals. The lines are the best-fit cubic regression, and broken lines indicate 95% confidence intervals. Dx, diagnosis; n, number of participants examined each year; Yrs, years.

Figure 3.

Trajectories of BMI before diagnosis of (A) PDM and (B) diabetes. Symbols are the same as in Fig. 2. (A and B) Values in the progressors and nonprogressors at each time point were significantly different both in A and B (P < 0.01 for each). The axis scale was intentionally maintained the same to facilitate visual comparison. See Fig. 2A and 2B for the number of individuals examined each year.

Figure 4.

Trajectories of SPISE before (A) PDM and (B) diabetes. (A and B) The axis scale was intentionally maintained the same to facilitate visual comparison. See Fig. 2A and 2B for the number of individuals examined each year.