Hyperglucagonemia Does Not Explain the β-Cell Hyperresponsiveness and Insulin Resistance in Dysglycemic Youth Compared With Adults: Lessons From the RISE Study
Authors: Kahn Steven E. , Mather Kieren J. , Arslanian Silva A. , Barengolts Elena , Buchanan Thomas A. , Caprio Sonia , Ehrmann David A. , Hannon Tamara S. , Marcovina Santica , Nadeau Kristen J. , Utzschneider Kristina M. , Xiang Anny H. , Edelstein Sharon L. ,   RISE Consortium, Ehrmann David A. , Temple Karla A. , Rue Abby , Barengolts Elena , Mokhlesi Babak , Van Cauter Eve , Sam Susan , Miller M. Annette , Kahn Steven E. , Atkinson Karen M. , Palmer Jerry P. , Utzschneider Kristina M. , Gebremedhin Tsige , Kernan-Schloss Abigail , Kozedub Alexandra , Montgomery Brenda K. , Morse Emily J. , Mather Kieren J. , Garrett Tammy , Hannon Tamara S. , Lteif Amale , Patel Aniket , Chisholm Robin , Moore Karen , Pirics Vivian , Pratt Linda , Nadeau Kristen J. , Gross Susan , Zeitler Philip S. , Williams Jayne , Green Melanie Cree , Garcia Reyes Yesenia , Vissat Krista , Arslanian Silva A. , Brown Kathleen , Guerra Nancy , Porter Kristin , Caprio Sonia , Savoye Mary , Pierpont Bridget , Buchanan Thomas A. , Xiang Anny H. , Trigo Enrique , Beale Elizabeth , Hendee Fadi N. , Katkhouda Namir , Nayak Krishan , Martinez Mayra , Montgomery Cortney , Wang Xinhui , Edelstein Sharon L. , Lachin John M. , Hogan Ashley N. , Marcovina Santica , Harting Jessica , Albers John , Hill Dave , Savage Peter J. , Leschek Ellen W. 
Published: June 2021

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 &gt;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 &lt; 0.001) and lower insulin sensitivity (youth r = −0.228, P = 0.066; adults r = −0.324, P &lt; 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.