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

posted on 15.06.2021, 19:22 by Steven E. Kahn, Kieren J. Mather, Silva A. Arslanian, Elena Barengolts, Thomas A. Buchanan, Sonia Caprio, David A. Ehrmann, Tamara S. Hannon, Santica Marcovina, Kristen J. Nadeau, Kristina M. Utzschneider, Anny H. Xiang, Sharon L. Edelstein, The RISE Consortium
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 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.

Results: 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.

Conclusions: 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.


RISE is supported by grants from the National Institutes of Health (U01DK-094406, U01DK-094430, U01DK-094431, U01DK-094438, U01DK-094467, P30DK-017047, P30DK-020595, P30DK-045735, P30DK-097512, UL1TR-000430, UL1TR-001082, UL1TR-001108, UL1TR-001855, UL1TR-001857, UL1TR-001858, UL1TR-001863), the Department of Veterans Affairs and Kaiser Permanente Southern California. Additional financial and material support from the American Diabetes Association, Allergan Corporation, Apollo Endosurgery, Abbott Laboratories and Novo Nordisk A/S is gratefully acknowledged.