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Glucagon and the liver-alpha-cell axis

Source: vignettes/articles/glucagon-liver-alpha-cell-axis.Rmd
glucagon-liver-alpha-cell-axis.Rmd

Where the beta cell secretes insulin, the pancreatic alpha cell secretes glucagon. glucagon_release() and glucagon_resistance() summarize alpha-cell output and its regulation from fasting and OGTT glucagon values. This article explains the biology those indices are meant to capture.

The liver-alpha-cell axis

Glucagon and hepatic amino-acid metabolism form a feedback loop known as the liver-alpha-cell axis. Circulating amino acids stimulate glucagon secretion and alpha-cell proliferation; glucagon, in turn, drives hepatic amino-acid catabolism and ureagenesis. In health, an oral glucose load suppresses glucagon, limiting hepatic glucose output.

Glucagon resistance describes a breakdown of this loop, seen with hepatic steatosis and type 2 diabetes: the liver responds less to glucagon, amino acids and glucagon both rise (hyperglucagonaemia), and glucose fails to suppress glucagon normally. Non-suppression of glucagon after glucose is a recognized early feature of dysglycaemia.

Indices

Glucagon release (glucagon_release())

Index Definition Meaning
Fasting_glucagon Glucagon0 Basal alpha-cell tone; elevated in glucagon resistance.
Glucagon_auc trapezoidal AUC over 0, 30, 120 min Total glucagon exposure during the OGTT.

The area under the curve uses the trapezoidal rule: 0.5 x ((Glucagon30 + Glucagon0) x 30 + (Glucagon120 + Glucagon30) x 90).

Glucagon resistance (glucagon_resistance())

Index Definition Meaning
Glucagon_suppression_ratio Glucagon120 / Glucagon0 Below 1 = normal suppression after glucose; at or above 1 = failed suppression, a signature of glucagon resistance.
Glucagon_insulin_ratio Glucagon0 / I0 Fasting alpha-to-beta balance; tracks whole-body insulin sensitivity and beta-cell function.

For both ratios, glucagon and insulin should be supplied in a consistent molar unit (for example pmol/L).

Worked example 

data(example_data)
res <- glucagon_release(example_data)
res <- glucagon_resistance(res)
round(head(res[, c("Fasting_glucagon", "Glucagon_auc",
                   "Glucagon_suppression_ratio",
                   "Glucagon_insulin_ratio")], 5), 3)
#>   Fasting_glucagon Glucagon_auc Glucagon_suppression_ratio
#> 1             3.33       372.15                      1.117
#> 2            13.71      1123.05                      0.505
#> 3             6.28       556.50                      0.729
#> 4            11.36      1087.65                      0.772
#> 5            11.98      1091.10                      0.798
#>   Glucagon_insulin_ratio
#> 1                  0.059
#> 2                  0.345
#> 3                  0.072
#> 4                  0.158
#> 5                  0.383

Rows with Glucagon_suppression_ratio at or above 1 are the ones that failed to suppress glucagon after the glucose load.

References

  • Chen X, Maldonado E, DeFronzo RA, Tripathy D (2021). Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function. J Clin Endocrinol Metab, 106(5), 1398-1409. https://doi.org/10.1210/clinem/dgab019
  • Wewer Albrechtsen NJ, et al. (2018). Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids. Diabetologia, 61(3), 671-680. https://doi.org/10.1007/s00125-017-4535-5
  • Suppli MP, et al. (2020). Glucagon Resistance at the Level of Amino Acid Turnover in Obese Subjects With Hepatic Steatosis. Diabetes, 69(6), 1090-1099. https://doi.org/10.2337/db19-0715