Altered glucose-dependent secretion of glucagon and ACTH is associated with insulin resistance, assessed by population analysis

Abstract

This study aimed to characterize how the dysregulation of counter-regulatory hormones can contribute to insulin resistance and potentially to diabetes. Therefore, we investigated the association between insulin sensitivity and the glucose- and insulin-dependent secretion of glucagon, adrenocorticotropic hormone (ACTH), and cortisol in non-diabetic individuals using a population model analysis. Data, from hyperinsulinemic-hypoglycemic clamps, were pooled for analysis, including 52 individuals with a wide range of insulin resistance (reflected by glucose infusion rate 20-60 min; GIR20-60min). Glucagon secretion was suppressed by glucose and, to a lesser extent, insulin. The GIR20-60min and BMI were identified as predictors of the insulin effect on glucagon. At normoglycemia (5 mmol/L), a 90% suppression of glucagon was achieved at insulin concentrations of 16.3 and 43.4 µU/mL in individuals belonging to the highest and lowest quantiles of insulin sensitivity, respectively. Insulin resistance of glucagon secretion explained the elevated fasting glucagon for individuals with a low GIR20-60min. ACTH secretion was suppressed by glucose and not affected by insulin. The GIR20-60min was superior to other measures as a predictor of glucose-dependent ACTH secretion, with 90% suppression of ACTH secretion by glucose at 3.1 and 3.5 mmol/L for insulin-sensitive and insulin-resistant individuals, respectively. This difference may appear small but shifts the suppression range into normoglycemia for individuals with insulin resistance, thus, leading to earlier and greater ACTH/cortisol response when the glucose falls. Based on modeling of pooled glucose-clamp data, insulin resistance was associated with generally elevated glucagon and a potentiated cortisol-axis response to hypoglycemia, and over time both hormonal pathways may therefore contribute to dysglycemia and possibly type 2 diabetes.

Keywords: metabolism; obesity.

Figure 1

Schematic picture of study designs of hypo- (A–C) and hyperglycemic clamps (D) in Abrahamsson and colleagues (12) (A), Almby and colleagues (21) (B), and Lundqvist and colleagues (11) (C, D). Black vertical arrows indicate the time of measurement of insulin, glucagon, ACTH (not Abrahamsson), and cortisol. Target glucose concentrations are shown at the top of each panel per study/arm. BSA, body surface area. *Neither cortisol nor ACTH sampled at this timepoint, **ACTH not sampled at this timepoint

Figure 2

Schematic picture of the final sub-models of glucagon, ACTH, and cortisol. Dark gray arrows indicate mass transfer while light gray arrows indicate the location of the stimulus for dynamics. k_secr, secretion rate; k_degr degradation rate constant; t_1/2, half-life of glucose delay, f₁(G,I|GIR_20–60min), the function of glucose and insulin affecting glucagon, where insulin effect is influenced by the glucose infusion rate at normoglycemia (GIR_20–60min); f₂(Ge|GIR_20–60min), the function of delayed glucose affecting ACTH, where the effect is influenced by GIR_20–60min; f₃(ACTH), the function of ACTH affecting cortisol.

Figure 3

Visual predictive check of glucagon (left), ACTH (middle), and cortisol (right) vs glucose concentrations. The top panels show the concentrations of variables, while the bottom panels show the proportion of measurements below limit of quantification (BLQ). The median (solid line) and 2.5th and 97.5th percentiles (dashed lines) of the observations (indicated with dots) are overlayed with the 95% confidence interval of the corresponding percentiles of the simulated data (shaded area, 1000 simulations). The gray horizontal line indicates the limit of quantification.

Figure 4

Visual predictive check of ACTH (top), cortisol (middle), and glucagon (bottom) in the studies by Lundqvist (11) (left), Almby (21) (middle), and Abrahamsson (12) (right) vs time, with time = 0 being the start of the hypoglycemia in each study. The median (solid line) and 2.5th and 97.5th percentiles (dashed lines) of the observations (indicated with dots) are overlayed with the 95% confidence interval of the corresponding percentiles of the simulated data (shaded area, 1000 simulations).

Figure 5

Secretion of glucagon (A), ACTH (B), and cortisol (C) vs glucose as well as glucagon secretion vs insulin (D), ACTH vs delayed glucose (E), and cortisol vs ACTH (F). Points represent individual model predictions, colored by GIR_20–60min and the solid colored, lines are smooths through the data, grouped by GIR_20–60min. The black dashed, vertical line indicates the median of the x-axis variable of individuals with BMI ≤ 25 kg/m² at baseline, that is 5.1 mmol/L glucose, 4.4 µU/mL insulin, or 2.7 pmol/L ACTH.

Figure 6

Inhibition of ACTH secretion by glucose, illustrated for insulin-sensitive (GIR_20–60min ≥ 10.8 mg/kg-LBM/min; green) and insulin-resistant (GIR_20–60min ≤ 4.6 mg/kg-LBM/min; blue) individuals. The blue and green solid lines indicate the medians and the 90% confidence interval is shown as a shaded area. The horizontal line indicates 90% inhibition.

Figure 7

Inhibition of glucagon secretion by insulin for (A) hypo-, (B) normo-, and (C) hyperglycemia as well as (D) the relationship between glucose and insulin for 90% inhibition of glucagon, illustrated for insulin-sensitive (GIR_20–60min ≥ 10.8 mg/kg-LBM/min; green) and insulin-resistant (GIR_20–60min ≤ 4.6 mg/kg-LBM/min; blue) individuals. The blue and green solid lines indicate the medians, and the 90% confidence interval is shown as a shaded area. The horizontal line indicates 90% inhibition.

Figure 8

Hypothesized contribution of general hyperglucagonemia and augmented ACTH/cortisol responses to the development of insulin resistance and type 2 diabetes. Created with Biorender.com.