Promising developments in new treatments for diabetes involving glucagon
Role of glucagon action
Glucagon is secreted by the pancreatic alpha cells mainly stimulated by changes in local concentration of glucose, amino acids and insulin and through the autonomic (vegetative) nervous system. Recently, it has been demonstrated that sodium-glucose co-transporter 2 (SGLT-2) is expressed in pancreatic alpha cells, designated for an inhibitory effect on glucagon release in the range of physiological glucose concentrations [1]. The endocrine effects on the liver include the activation on the glucagon receptor (GCGR), a G-protein-coupled receptor (GPCR), and engagement of the GαS and β-arrestin pathways (signalling cascades). Glucagon initiates the increase in the export of glucose from the liver as a result of enhanced glycogenolysis and gluconeogenesis [2, 3, 4, 5].
Controversy remains regarding the relative importance of the acute metabolic and more long-term transcriptional actions of glucagon. There is little doubt of the robust increase in the transcription of ‘cAMP response element binding protein’ (CREB) target genes (intracellular production of cAMP and subsequent activation of protein kinase A) whose protein products are at potentially rate-controlling steps in the gluconeogenic pathway [6]. However, rapidity of glucagon response provides arguments against a transcriptional mechanism for gluconeogenic fluxes [7]. However, it remains likely that after prolonged fasting or in a setting of chronic hyperglucagonemia, such as diabetes, transcriptional regulation drives meaningful changes in hepatic metabolism.
Further scientific research showed also direct post-translational effects of hepatic metabolism (such as phosphorylation) to cover rapid glucagon related changes in systematic and hepatic metabolism [8]. Additional metabolic actions of glucagon have been identified, which are parts of its conserved role as a regulator of fasting metabolism. These actions include the ability to promote the amino acid catabolism to provide gluconeogenic precursors [9, 10, 11] and to promote an increase of mitochondrial oxygen consumption through enhanced mitochondrial calcium uptake which is required for glucagon`s stimulation of gluconeogenesis. [12, 13, 14].
The central role of glucagon action in the brain
The brain is increasingly being recognised as an important glucagon-sensitive organ. It has been demonstrated that in contrast to the systemic effect on glucose response, glucagon action in the mediobasal hypothalamus (MBH) site linked to the nervous system and endocrine system and the dorsal vagal complex (DVC) site located in the brainstem, known to regulate several autonomic functions actually reduces hepatic glucose production [15]. The central sites of the brain are also sensitive to circulating glucagon induced either by i.v. glucagon or high-protein meals to antagonise the hepatic action of glucagon. However, this central negative autoregulation for glucose homeostasis was lost following a three day high fat diet in rats [16]. In addition, the role of hypothalamic glucagon is also implicated in reducing food intake via differential signalling cascades [17, 18]. The body weight changes induced by glucagon may be partly explained by its effect on energy expenditure; it induces thermogenesis through the sympathetic nervous innervation of brown adipose tissue [19].
Glucagon Antagonism
The recent renewed interest in glucagon antagonism as a viable therapeutic approach mainly derived from preclinical results in rodents suggesting that reducing glucagon action or secretion by potent glucagon suppressor leptin and glucagon receptor antibodies suppressed all catabolic manifestations of diabetes during insulin deficiency [20, 21, 22,23, 24, 25, 26]. Glucagon antagonism as a sustainable therapeutic approach has shown impressive glucose lowering with small molecule glucagon receptor antagonists in diabetic type 2 individuals [27]. In addition, significantly lowered HbA1c and glucose levels with a low risk for hypoglycemia have been demonstrated. However, modest, reversible increases in serum aminotransferases were observed [28]. The latter had also been noted with other glucagon receptor antagonists, including a human glucagon receptor monoclonal antibody [21], other small molecules [29, 30,31], and an antisense glucagon receptor antagonist [32]. Further contribution of distinct glucagon effects on clinical efficacy and safety will be an important area of research.
Glucagon Polyagonists
Novel findings indicate that activation of glucagon receptors in conjunction with other G-protein-coupled receptors showed metabolical improvements in diabetes and obesity. Therefore, maintaining a sufficient glucagon action to activate the central glucagon system may be therapeutically beneficial. A series of single-molecule glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonists were generated using glucagon as a template sequence to which chemical modifications were introduced. The resulting peptides were of comparable structure to glucagon and GLP-1, but of balanced agonism at each receptor and comparable inherent potency to native hormones. This dual activation of GCGR and GLP-1R normalised glucose tolerance and reduced food intake in mice with diet-induced obesity [33, 34]. It had also been suggested that oxyntomodulin, another gut peptide involved in metabolic control, would potentially represent a therapeutic approach [35].
Oxyntomodulin is a dual agonist, acting at both the GLP-1R (enhanced glucose-stimulated insulin secretion and suppression of food intake) and the GCGR (suppression of food intake, increased energy expenditure and improved lipid metabolism) with similar potency. The metabolic improvements resulting from high body fat burning and weight loss, together with the known beneficial metabolic actions of GLP-1, have a stronger impact than the inherent diabetogenic property of glucagon agonism. The exact molecular action that governs the action profile of the dual agonist is still being investigated, as well as the relative advantage in accomplishing the mixed pharmacology in a single peptide.
One important component has already been discovered: glucagon activates the secretion of fibroblast growth factor 21 (FGF21), an endogenous protein acting at the level of the brain, liver, and adipose tissue to decrease body weight and improve dyslipidemia, which itself has demonstrated translational benefits as an anti-obesity therapy [36, 37].
Aiming to enhance the glycemic benefits of GLP-1, the structurally related second member of the two principle incretin hormones, glucose-dependent insulinotropic peptide (GIP), was selected as the second component in a new series of dual agonists. These dual GIP/GLP co-agonists exhibit superior in vivo efficacy in mice, rats, nonhuman primates, and humans when compared to equimolar monoagonists. In particular, insulin secretion and glucose tolerance improved and neither chronic hyperinsulinemia nor hypoglycemia was observed [38].
A triagonist aimed at simultaneous activation of GCG, GLP-1 and GIP receptors improved metabolic and glycemic profiles in obese and diabetic rodents. When specifically compared to the dual incretin co-agonists, these novel triple-acting peptides were superior in correcting the excess of adipose tissue mass, liver fat, food intake, and plasma cholesterol while demonstrating increased energy expenditure, improved glucose tolerance, and protection from glucolipotoxic pancreatic islet destruction [39].
Work on safety and efficacy clinical data will help to expand the knowledge about increased energy expenditure and decreased food intake and its hyperglycemic effects to be countered by the actions of GLP-1 and/or GIP.
However, the brain penetrance of these polyagonists and whether activation of central glucagon signalling plays a role in counteracting the diabetogenic effects of peripheral glucagon remain to be investigated.
Bihormonal Bionic Pancreas
A promising approach treating diabetes is the development of fully automated artificial/bionic pancreas systems that use both insulin and glucagon as intermittent mini-boluses to maintain euglycemia. Compared with an insulin pump, an automated, bihormonal, pancreas showed improved mean glycemic levels, with less frequent hypoglycemic episodes, among both adults and adolescents with type 1 diabetes mellitus [40]. In dual-hormone artificial pancreas short-term studies glucagon concentrations are considered to be nearly within the physiologic fasting ranges [41]. Furthermore, glucagon’s effects on reducing caloric intake and increasing energy expenditure could even be beneficial within the context of the growing prevalence of overweight and obesity in patients with diabetes. So far, a stable liquid glucagon formulation for longer use in the bihormonal pancreas is still under development [42]. Therefore, comprehensive long-term artificial pancreas studies using repeated micro glucagon doses are still lacking. Further research is needed to characterize the potential benefits and safety profiles of future chronic glucagon use.
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