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

Abstract

<b>Objective</b>: 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. <p><b>Research Design and Methods</b>: In 66 youth and 350 adults with IGT or drug-naïve, recently diagnosed type 2 diabetes, we performed hyperglycemic clamps and 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 (AGR) and C-peptide (ACPR) responses at glucose >25 mmol/L.</p> <p><b>Results</b>: Fasting (7.63±3.47 vs 8.55±4.47 pmol/L; mean±SD; 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, 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 M/I, 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 M/I (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.</p> <p><b>Conclusions</b>: Youth with IGT or drug-naïve, recently diagnosed type 2 diabetes have hyper-responsive β-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared to adults. Thus, α-cell dysfunction does not appear to explain the difference in β-cell function and insulin sensitivity in youth versus adults.</p>