Hyperglucagonemia Does Not Explain the β-Cell Hyperresponsiveness and Insulin Resistance in Dysglycemic Youth Compared With Adults: Lessons From the RISE Study

Abstract

Objective: To determine whether β-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release.

Research design and methods: In 66 youth and 350 adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (drug naive), we performed hyperglycemic clamps and oral glucose tolerance tests (OGTTs). From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11.1 mmol/L, and arginine-stimulated glucagon (acute glucagon response [AGR]) and C-peptide (ACPRmax) responses at glucose >25 mmol/L.

Results: Mean ± SD fasting glucagon (7.63 ± 3.47 vs. 8.55 ± 4.47 pmol/L; P = 0.063) and steady-state glucagon (2.24 ± 1.46 vs. 2.49 ± 1.96 pmol/L, P = 0.234) were not different in youth and adults, respectively, while AGR was lower in youth (14.1 ± 5.2 vs. 16.8 ± 8.8 pmol/L, P = 0.001). Significant age-group differences in insulin sensitivity, fasting C-peptide, steady-state C-peptide, and ACPRmax were not related to glucagon. Fasting glucose and glucagon were positively correlated in adults (r = 0.133, P = 0.012) and negatively correlated in youth (r = -0.143, P = 0.251). In both age-groups, higher fasting glucagon was associated with higher fasting C-peptide (youth r = 0.209, P = 0.091; adults r = 0.335, P < 0.001) and lower insulin sensitivity (youth r = -0.228, P = 0.066; adults r = -0.324, P < 0.001). With comparable fasting glucagon, youth had greater C-peptide and lower insulin sensitivity. OGTT suppression of glucagon was greater in youth.

Conclusions: Youth with IGT or recently diagnosed type 2 diabetes (drug naive) have hyperresponsive β-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared with those in adults. Thus, α-cell dysfunction does not appear to explain the difference in β-cell function and insulin sensitivity in youth versus adults.

Trial registration: ClinicalTrials.gov NCT01779362 NCT01779375 NCT01763346.

Figure 1

Plasma glucose (A), glucagon (B), and C-peptide (C) concentrations during the hyperglycemic clamps in 66 youth (red) and 350 adults (blue). Data are mean ± SEM. Peak values were observed 3 min after the arginine bolus (163 min: youth, 17.7 ± 0.79 pmol/L, and adults, 20.4 ± 0.57 pmol/L), with this difference being similar at the subsequent time points.

Figure 2

Plasma glucose (A), glucagon (B), and C-peptide (C) concentrations during the OGTT in 66 youth (red) and 350 adults (blue). Data are means ± SEM.

Figure 3

Relationship of fasting glucagon and insulin sensitivity (M/I) (A), the AGR and M/I (B), fasting glucagon and fasting C-peptide (C), and AGR and ACPRmax (D) in 66 youth (in red) and 350 adults (in blue). The correlation of fasting glucagon with M/I was similar in youth (r = −0.228, P = 0.066) and adults (r = −0.324, P < 0.001); the slopes did not differ between youth and adults (P_interaction = 0.944), while the intercepts did (P < 0.001). The correlation of AGR with M/I was significant in adults (r = −0.222, P < 0.001) but not in youth (r = −0.069, P = 0.588); again, the slopes were not significantly different in youth and adults (P_interaction = 0.680), but the intercepts differed (P < 0.001). The relation of fasting glucagon to fasting C-peptide was similar in adults (r = 0.335, P < 0.001) and youth (r = 0.209, P = 0.091), with no significant difference in the slopes in youth and adults (P_interaction = 0.514) and a significant difference in the intercepts (P < 0.001). The correlation of AGR and ACPRmax was significant in adults (r = 0.355, P < 0.001), but not in youth (r = −0.101, P = 0.423), with the interaction of the slopes being significant (P = 0.014).