Blunted glucagon but not epinephrine responses to hypoglycemia occurs in youth with less than 1 yr duration of type 1 diabetes mellitus

Abstract

Context: Glycemic control is limited by the barrier of hypoglycemia. Recurrent hypoglycemia impairs counterregulatory (CR) hormone responses to subsequent hypoglycemia.

Objective: To determine the glucagon and epinephrine responses to insulin-induced hypoglycemia in adolescents with recent-onset type 1 diabetes mellitus (T1DM).

Methods: We assessed the CR responses to hypoglycemia by performing a hyperinsulinemic (2.0 mU/kg/min), euglycemic (BG 90 mg/dL; 5.0 mmol/L)-hypoglycemic (BG 55 mg/dL; 3.0 mmol/L) clamp in 25 recent-onset (<1 yr duration) patients 9-18 yr old (mean ± SD: 13.4 ± 2.7) with T1DM and 16 non-diabetic controls 19-25 yr old (mean ± SD 23.3 ± 1.8). Twenty of the T1DM subjects were retested 1-yr (53 ± 3 wk) later.

Results: At the initial and 1-yr studies, peak glucagon (pGON) and incremental glucagon (ΔGON) during hypoglycemia were lower in the T1DM subjects [median pGON = 47 pg/mL (quartiles: 34, 72), ΔGON = 16 (4, 27) initially and pGON = 50 pg/mL (42, 70), ΔGON = 12 (9, 19) at 1-yr] than in controls [pGON = 93 pg/mL (60, 111); ΔGON = 38 pg/mL (19, 66), p = 0.01 and p = 0.004 for ΔGON at initial and 1-yr study, respectively]. In contrast, peak epinephrine (pEPI) and incremental epinephrine (ΔEPI) levels were similar in the T1DM (pEPI = 356 pg/mL (174, 797) and ΔEPI = 322 pg/mL (143, 781) initially and pEPI = 469 pg/mL (305, 595) and ΔEPI = 440 pg/mL (285, 574) at 1 yr) and in controls (pEPI = 383 pg/mL (329, 493) and ΔEPI = 336 pg/mL (298, 471) p = 0.97 and 0.21 for ΔEPI at initial and 1-yr study, respectively).

Conclusions: Even within the first year of T1DM, glucagon responses to hypoglycemia are blunted but epinephrine responses are not, suggesting that the mechanisms involved in the loss of these hormonal responses, which are key components in pathophysiology of hypoglycemia-associated autonomic failure, are different.

Keywords: children; counterregulation; epinephrine; glucagon; hypoglycemia; type 1 diabetes mellitus.

Figure 1

Boxplots of plasma glucose (A), glucagon (B) and epinephrine (C) concentrations during a hyperinsulinemic (2.0 mU ^· kg^{−1 ·} min⁻¹) euglycemic, hypoglycemic clamp in non-diabetic controls, T1DM children at beginning of the study, and T1DM children 1 year later. At both the initial and 1-year studies glucagon were lower in the T1DM subjects (p= 0.01) compared with controls during hypoglycemia. Glucagon (p=0.004), but not the epinephrine (p=0.21), response to hypoglycemia are blunted within the first year of T1DM diagnosis. The top and bottom of the boxes represent the 75^th and 25^th percentiles, respectively. The horizontal line within each box represents the median and the dot represents the mean.

Figure 2

Dot plots of incremental counterregulatory hormone response to hypoglycemia: Glucagon (ΔGlucagon) and Epinephrine (ΔEpinephrine) during hyperinsulinemic euglycemic hypoglycemic clamp in children with T1DM at initiation of the study, at 1 year of the study and in non-diabetic controls. The horizontal lines on data points represents the median.