1618-P: Progression to Glucose Intolerance Is Characterized by Glucagon Secretion Inappropriate for Circulating Glucose

• Published in: Diabetes (New York, N.Y.) Vol. 73; p. 1
• Main Authors: Mohan, Sneha, Christie, Hannah E, Laurenti, Marcello C, Egan, Aoife M, Vella, Adrian, Dalla Man, Chiara
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01-06-2024
• Subjects: Beta cells; Body composition; Diabetes; Diabetes mellitus (non-insulin dependent); Fasting; Glucagon; Glucose; Glucose tolerance; Insulin secretion
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db24-1618-P

As part of a series of studies to understand the pathogenesis of prediabetes, we studied 96 nondiabetic individuals (54 ± 1.2 years; BMI 28.4 ± 0.4 Kg/M2) on 2 occasions, 3 years apart using an oral 75g glucose challenge. Weight and body composition were measured prior to each study. Fasting and 120-minute glucose were used to classify subjects' glucose tolerance at baseline, and at the 3-year visit. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Overall, 32 subjects progressed from normal to Impaired Glucose Tolerance (IGT) or from IGT to type 2 diabetes. Anthropometric variables were similar between progressors and those with stable glucose tolerance at baseline (BMI 28.1 ± 0.7 vs. 28.7 ± 0.6 Kg/M2, p = 0.50), and at 3 years (29.1 ± 0.8 vs. 29.3 ± 0.6 Kg/M2, p = 0.81). No significant differences in baseline fasting and nadir GSR or in Disposition Index (DI - 659 ± 98 vs. 885 ± 86 10-4 dl/kg/min per μU/ml, p = 0.11) were noted. Although, peak glucose concentrations differed significantly at baseline (11.4 ± 0.3 vs. 10.3 ± 0.2 mmol/l, p < 0.01), integrated concentrations did not (462 ± 47 vs. 402 ± 26 mmol/l per 6hr, p = 0.23). At 3-year follow-up, DI declined in the progressors (659 ± 98 vs. 451 ± 65 10-4 dl/kg/min per μU/ml, baseline vs. 3-years p = 0.04). This did not occur in the stable group (885 ± 86 vs. 893 ± 142 10-4 dl/kg/min per μU/ml, p = 0.94). α-cell suppression by glucose (fall in GSR (pmol/min)/glucose rise (mmol/l)) did not differ at baseline (1.3 ± 0.2 vs. 1.5 ± 0.1 nmol/min/L, p = 0.37) but was impaired at 3 years (1.0 ± 0.2 vs. 1.4 ± 0.1 nmol/min/L, p < 0.01) in those who progressed. Analysis of the entire cohort showed that our index of glucagon suppression was inversely correlated to increase in glycemic excursion (R2=0.14, p < 0.01). These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.