Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Whereas accurate measurement of glucagon in

    2021-10-15

    Whereas accurate measurement of glucagon in humans has been possible since the early 1950s proper measurements in rodents, have not. That said, plasma concentrations of glucagon have been reported in rodent studies [21] using C-terminal specific methods but what has been lacking is the secretory dynamics of glucagon to e.g. a glucagonotropic THZ531 such as arginine. We (led by professor Holst, University of Copenhagen) recently contributed to the development of a sensitive low-volume (10μL) sandwich ELISA, commercialized by Mercodia, which we validated in both rats and mice. Using this method we uncovered the secretory dynamics of glucagon in rodents and also demonstrated the extremely short half-life of glucagon [22]. This method furthermore, allow the clinician to discriminate between a ‘true glucagonoma’, which excretes excess number of glucagon molecules, compared to the tumors (primarily expressing prohormone convertase 1/3) with up to 1nmol/L (reference interval ∼1–5pmol/l at fasting) of active GLP-1 that results clinically in severe hypoglycemia [16]. As such this may guide us for stratified medicine in individuals with intractable glucagonomas: A patients with a primarily glucagon-secreting tumor may be treated with a glucagon receptor antagonist (GRA), and a patient with a GLP-1-and oxyntomodulin-producing tumor with exendin 9–39 (a GLP-1 receptor antagonist) as an addition to the standard care of somatostatin analogues.Therefore, accurate measurement of glucagon in a suitable assay is prerequisite for understanding the biology of glucagon in a variety of disease processes.
    The molecular heterogeneity of hyperglucagonemia To what extent the reported hypersecretion of glucagon in a variety of clinical conditions actually represents ‘true’ pancreatic glucagon is not well characterized [23]. The molecular heterogeneity of glucagon has primarily been investigated in subjects with glucagon producing tumors using radioimmunoassay and size-exclusion chromatography [24], [25], but also normal subjects were investigated with this technique [26]. In these studies glucagon, beside of the canonical proglucagon products: oxyntomodulin, glicentin, GLP-1, GLP-2, have been reported however also N-terminal elongated glucagon-like molecules have been shown to exist. A study by Kuku et al. showed that in subjects with chronic renal failure, a glucagon-like molecule (high molecular weight ∼9000Da) exists [27]. In addition, a plasma component with a similar molecular weight was observed in uremic pigs and identified by chromatography as PG 1-61 [28]. Recently, we have described the identification of ‘glucagon variants’, using state-of the art mass-spectrometry based plasma proteomics, to which PG 1-61 was the major component beside native glucagon in a wide range of clinical conditions [29]. Interestingly, PG 1-61 seems mainly to be formed and detected in our circulation when the body is challenged metabolically such as due to hyperglycemia (Type 2 Diabetes) (Fig. 2B). Although, PG 1-61 may serve as a biomarker for alpha cells stress [29] further studies are needed to confirm and extend these preliminary observations in large epidemiological cohorts.
    Differential processing of proglucagon in metabolic diseases Glucagon is traditionally thought to be produced by the pancreatic alpha cells and GLP-1 from the enteroendocrine L-cells [30]. In the last decade it has become evident that such a concept may hold true in healthy subjects in individuals whereas in metabolically challenged individuals such as in patients with type 2 diabetes, altered processing of proglucagon may result in alpha cell derived GLP-1 and L-cell derived glucagon (Fig. 1B) [31]. Furthermore, since the first studies, in pancreatectomized dogs in 1978, extrapancreatic glucagon has been reported in pancreatectomized humans [32], [33], [34], [35] and it may therefore not be surprising that a new conceptual ‘processing design’ is arising [31]. As an example, pancreatic derived GLP-1 in mice has been suggested to be of importance for the glucose lowering capability of GLP-1 [31].