Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: I. Observations Using the Hyperglycemic Clamp

Abstract

Objective: To compare insulin sensitivity (M/I) and β-cell responses in youth versus adults with impaired glucose tolerance (IGT) or drug-naïve, recently diagnosed type 2 diabetes.

Research design and methods: In 66 youth (80.3% with IGT) and 355 adults (70.7% IGT), hyperglycemic clamps were used to measure 1) M/I, 2) acute (0-10 min [first phase]) C-peptide (ACPR_g) and insulin (AIR_g) responses to glucose, 3) steady-state C-peptide and insulin concentrations at plasma glucose of 11.1 mmol/L, and 4) arginine-stimulated maximum C-peptide (ACPR_max) and insulin (AIR_max) responses at plasma glucose >25 mmol/L. The fasting C-peptide-to-insulin ratio was used as an estimate of insulin clearance.

Results: Insulin sensitivity was 46% lower in youth compared with adults (P < 0.001), and youth had greater acute and steady-state C-peptide (2.3- and 1.3-fold, respectively; each P < 0.001) and insulin responses to glucose (AIR_g 3.0-fold and steady state 2.2-fold; each P < 0.001). Arginine-stimulated C-peptide and insulin responses were also greater in youth (1.6- and 1.7-fold, respectively; each P < 0.001). After adjustment for insulin sensitivity, all β-cell responses remained significantly greater in youth. Insulin clearance was reduced in youth (P < 0.001). Participants with diabetes had greater insulin sensitivity (P = 0.026), with lesser C-peptide and insulin responses than those with IGT (all P < 0.001) but similar insulin clearance (P = 0.109).

Conclusions: In people with IGT or recently diagnosed diabetes, youth have lower insulin sensitivity, hyperresponsive β-cells, and reduced insulin clearance compared with adults. Whether these age-related differences contribute to declining β-cell function and/or impact responses to glucose-lowering interventions remains to be determined.

Trial registration: ClinicalTrials.gov NCT01779362 NCT01779375 NCT01763346.

Figure 1

Plasma glucose, C-peptide, and insulin concentrations during the hyperglycemic clamps in youth and adults in the three RISE protocols. A–C: Pediatric Medication Study (n = 66 [in red]), Adult Medication Study (n = 267 [in blue]) and Adult Surgery Study (n = 88 [in green]). D–F: Youth with IGT (n = 53 [in green]) and diabetes (n = 13 [in purple]). G–I: Adults with IGT (n = 251 [in green]) and diabetes (n = 104 [in purple]). Data are mean ± SEM. At all time points after commencement of the glucose infusion for the clamp, C-peptide and insulin concentrations were greater in youth than adults (all P < 0.001) as well as in IGT vs. diabetes (all P < 0.001).

Figure 2

Relationship of log-transformed M/I and log-transformed ACPR_g (A), steady-state (second phase) C-peptide concentration (B), ACPR_max (C), AIR_g (D), and AIR_max (E) in youth (n = 66 [in red]) and adults (n = 355 [in blue]). The axes are logged with the values on each being natural numbers. Lines were fit by linear regression on the log-log scale. The slopes relating the five β-cell response measures to M/I were all significant (P < 0.001), and the group differences were also all significant (all P < 0.001 except steady-state C-peptide [P = 0.047]). The slopes for youth and adults did not differ (all P ≥ 0.200).

Figure 3

Relationship of log-transformed M/I and log-transformed ACPR_g (A), steady-state (second phase) C-peptide concentration (B), ACPR_max (C), AIR_g (D), and AIR_max (E) in participants with IGT (n = 304 [in green]) and diabetes (n = 117 [in purple]). The axes are logged with the values on each being natural numbers. Lines were fit by linear regression on the log-log scale. The slopes relating the five β-cell response measures to M/I were all significant (P < 0.001). Slopes for M/I and ACPR_g in individuals with IGT or diabetes were significantly different (P = 0.031). For all other β-cell response measures, the slopes with M/I were not significantly different between participants with IGT or diabetes (all P > 0.200), and participants with IGT had higher β-cell responses across the range of M/I (all P < 0.001).

Figure 4

Relationship of fasting glucose and ACPR_g (A) and AIR_g (B), ACPR_max (C), and AIR_max (D) and fasting glucose and the ratio of fasting C-peptide to insulin in youth (n = 66 [in red]) and adults (n = 355 [in blue]) (E), and IGT (n = 304 [in green]) and diabetes (n = 117 [in purple]) (F). Lines were fit by linear regression of the log-transformed variables and then transformed back to the original scale for plotting. Prior to taking logs, a constant of 1.06 was added to ACPR_g and 10.0 to AIR_g because of negative values in these variables. Therefore, all plotted values appear greater than 0. The slopes relating the β-cell response measures to fasting glucose were all significant (all P < 0.001), and the group differences were also all significant (all P < 0.001). The slopes for youth and adults did not differ (all P ≥ 0.21). For the relation of the fasting C-peptide–to–insulin ratio to fasting glucose, there were no significant relationships. Youth had a ratio that was lower than adults across the fasting glucose range (P < 0.001), while there was no difference across the same glucose range between IGT and diabetes.