Regulation of the Cortisol Axis, Glucagon, and Growth Hormone by Glucose Is Altered in Prediabetes and Type 2 Diabetes

Context Insulin-antagonistic, counter-regulatory hormones have been implicated in the development of type 2 diabetes (T2D).Objective In this cross-sectional study, we investigated whether glucose-dependent regulation of such hormones differ in individuals with T2D, prediabetes (PD), and normoglycemia (NG).Methods Fifty-four individuals with or without T2D underwent one hyperinsulinemic-normoglycemic-hypoglycemic and one hyperglycemic clamp with repeated hormonal measurements. Participants with T2D (n = 19) were compared with a group-matched (age, sex, BMI) subset of participants without diabetes (ND, n = 17), and also with participants with PD (n = 18) and NG (n = 17).Results In T2D vs ND, glucagon levels were higher and less suppressed during the hyperglycemic clamp whereas growth hormone (GH) levels were lower during hypoglycemia (P < .05). Augmented ACTH response to hypoglycemia was present in PD vs NG (P < .05), with no further elevation in T2D. In contrast, glucagon and GH alterations were more marked in T2D vs PD (P < .05). In the full cohort (n = 54), augmented responses of glucagon, cortisol, and ACTH and attenuated responses of GH correlated with adiposity, dysglycemia, and insulin resistance. In multilinear regressions, insulin resistance was the strongest predictor of elevated hypoglycemic responses of glucagon, cortisol, and ACTH. Conversely, fasting glucose and HbA1c were the strongest predictors of low GH levels during hypoglycemia and elevated, i.e. less suppressed glucagon levels during hyperglycemia, respectively. Notably, adiposity measures were also strongly associated with the responses above.Conclusions Altered counter-regulatory hormonal responses to glucose variations are observed at different stages of T2D development and may contribute to its progression by promoting insulin resistance and dysglycemia.