A short history of Glucagon
At the very dawn of endocrinology, the idea of a single bihormonal metabolic regulator was first expressed by Lane in 1907 [1]. He reported that certain Langerhans islets cells contained alcohol-precipitable granules and named them alpha and beta cells.
Banting and Best were probably the first to observe the physiologic action of glucagon. Historic experiments in 1921, in which pancreas extracts were injected into depancreated dogs, immediate increases of blood glucose were reported. Because, in those days the goal was the discovery of insulin, Banting and Best did not investigate the observations thoroughly and these were misinterpreted as caused by epinephrin deliberation [2].
In 1923 similar observations were reported by Murlin and Kimball. They believed that this blood glucose increase was due to a glucoregulatory hormone, named “glucagon”, meaning “glucose-driving” [3]. However, since its discovery glucagon had not been considered seriously as a hormone that might play a role in diabetes for the better part of 5 decades.
Ferner was one of the few who supported the idea of a single bihormonal metabolic regulator, claiming the alpha and beta cells of the pancreatic islets were sources of the antagonistic hormones glucagon and insulin in 1953 [4].
However, it was not possible to overcome the challenges for the development of a radio-immunoassay for glucagon until 1959 [5]. The ability to measure glucagon was supported by the methodological breakthrough of Berson and Yalow pioneering the first radio-immunoassay for insulin [6].
Nevertheless, glucagon measurements could not be carried out reliably in the peripheral blood of animals and humans until 1967. This scientific achievement enabled the assessment of its physiological and pathophysiological roles and the discrimination between pancreatic and gastrointestinal glucagon [7,8]. Intestinal peptides were detected that cross-reacted partly with glucagon antibodies (glucagon-like immunoreactivity, GLI), increasing after an oral glucose load while pancreatic glucagon was suppressed [9]. It was only many years later that GLI peptides were identified as ‘glicentin’ and ‘oxntomodulin’; nowadays known as regulators of gastric acid and hydromineral intestinal secretions and oyntomodulin also recognized as involved in the control of food intake and energy expenditure [10].
It was at this time that fundamental knowledge of the antagonism between insulin and glucagon action and the role of cyclic AMP in the liver metabolism was provided by excellent in vitro studies of Exton and Park and Sokal and colleagues [11] [12] and in-vivo studies of Vranic [13] and Lilienquist et al. [14]. Based on this data reasonable concepts of alpha-beta cell function and malfunction could be developed.
For a long period of time it was believed that insulin resistance and decreased insulin secretion in response to hyperglycaemia were responsible for the pathogenesis of diabetes mellitus type 2. However, it was only in the following years that the secretion of glucagon from the gastric alpha cells [15], the participation of glucagon in hyperglycaemia, and its glycogenolytic, gluconeogenic and ketogenic characteristics could be established [16,17] [18,19,20]. In addition, abnormal pancreatic alpha cell function was described in first-degree relatives of people with diabetes [21].
In 1973 Guillemin and his colleagues achieved a further important discovery: the purification and synthesis of somatostatin [22], which was supported by the unexpected finding of glucagon suppression during an infusion of somatostatin identified by Koerker and her associates [23]. Thanks to means of these methodological tools a vast array of data concerning the physiology and pathophysiology of glucagon related to insulin action were created [24] [25,26].
Functional subdivision of endocrine islet cells in pancreatic tissue became possible by using immuno-staining technology [27]. At an ultrastructural level Orci and his associates were also able to demonstrate low-resistance pathways of intercellular communication (gap junctions) between the adjacent endocrine cell types [28]. This understanding helped to explain the remarkable glucoregulatory balance of glucose efflux and influx as a structural unit and a synctitial network firstly imaged by Lane more than 60 years ago [29].
Glucagon and its analogues today
In 1982 the discovery of proglucagon, the precursor of glucagon and several other components in the pancreas and intestine led to the detection of two glucagon peptide analogues, named glucagon-like-peptide GLP1 and GLP2 [30,31], derived from the transcription product of the proglucagon gene. So far it has been shown that the major source of GLP1 in the periphery is the intestinal L cells as a gut hormone and the nucleus of the solitary tract in the brain. GLP-1 is a potent anti-hyperglycaemic hormone, inducing the β-cells in the pancreatic islets of Langerhans to release the hormone insulin in response to rising glucose, while suppressing glucagon secretion. The known peripheral functions of GLP-1 include: increases in insulin-sensitivity in both alpha and beta cells and in beta cell mass and insulin gene expression including post-translational modification and secretion. Several physiological properties like the inhibition of gastric emptying, gastric acid secretion and pancreatic exocrine secretion have been found. It has also been shown that GLP 1 receptors have cardioprotective and cardiotropic effects [32]. Insulin-like effects on liver, skeletal muscle and adipose tissue [33] and anabolic effects on bone have also been reported [34].
The future of Glucagon research
Future scientific interest will follow the treatment of diabetes by glucagon suppression. Animal studies with leptin or monoclonal antibodies against the glucagon receptor showed normalised glucose levels and HbA1c levels. In addition, glucagon suppression resulted in improved insulin sensitivity and glucose tolerance [35, 36, 37].
Novel research fields are focussing on the central role of glucagon action in the brain by reducing hepatic glucose production and food intake [38], its acute action on hepatic metabolism, especially its effect on gluconeogenesis [39] and its key role in the development of diabetes [40].
In part 2 of this article we look at promising developments in new treatments for diabetes involving glucagon.
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