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

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.