Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function

Abstract Aim To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. Methods Suppression of plasma glucagon was examined in 275 obese Hispanic Americans with varying glucose tolerance. All subjects received a 2-hour oral glucose tolerance test (OGTT) and a subset (n = 90) had euglycemic hyperinsulinemic clamp. During OGTT, we quantitated suppression of plasma glucagon concentration, Matsuda index of insulin sensitivity, and insulin secretion/insulin resistance (disposition) index. Plasma glucagon suppression was compared between quartiles of insulin sensitivity and beta-cell function. Results Fasting plasma glucagon levels were similar in obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D), but the fasting glucagon/insulin ratio decreased progressively from NGT to prediabetes to T2D (9.28 ± 0.66 vs 6.84 ± 0.44 vs 5.84 ± 0.43; P < 0.001). Fasting and 2-hour plasma glucagon levels during OGTT progressively increased and correlated positively with severity of insulin resistance (both Matsuda index and euglycemic hyperinsulinemic clamp). The fasting glucagon/insulin ratio declined with worsening insulin sensitivity and beta-cell function, and correlated with whole-body insulin sensitivity (Matsuda index, r = 0.81; P < 0.001) and beta-cell function (r = 0.35; P < 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = −0.47; P < 0.001 and r = −0.32; P < 0.001). Conclusion Insulin-mediated suppression of glucagon secretion in obese subjects is impaired with increasing severity of glucose intolerance and parallels the severity of insulin resistance and beta-cell dysfunction.