Metabolic Messengers: glucagon

Abstract

Plasma glucose is tightly regulated via the secretion of the two glucose-regulating hormones insulin and glucagon. Situated next to the insulin-secreting β-cells, the α-cells produce and secrete glucagon-one of the body's few blood glucose-increasing hormones. Diabetes is a bihormonal disorder, resulting from both inadequate insulin secretion and dysregulation of glucagon. The year 2023 marks the 100th anniversary of the discovery of glucagon, making it particularly timely to highlight the roles of this systemic metabolic messenger in health and disease.

Fig. 1 |. Timeline of important discoveries in glucagon research.

Banting and Best observed that transient hyperglycemia preceded a drop in plasma glucose following administration of pancreatic extracts (1921). In 1923, Murlin proposed that this effect reflected a contaminant with glucogenic capacity and he named this substance glucagon (glucose agonist), the existence of which was formally proven in 1935 by Bürger and Brandt. In 1948, it was demonstrated by de Duve and Sutherland that glucagon is secreted by α-cells of the pancreatic islets. Work in the 1950s led to the purification, crystallization and amino acid sequencing of glucagon (1955–1957)^,. This was followed by the establishment of a radioimmunoassay for glucagon by Unger (1961). Studies in the 1960s and 1970s demonstrated the role of cAMP as the intracellular second messenger and defined glucagon’s role in normal metabolism and in the etiology of diabetes^,. This eventually led to the appreciation of diabetes as a bihormonal disorder (1980s). The gene-encoding proglucagon was cloned in 1983, which led to the elucidation of the differential posttranslational processing in the gut and the pancreatic islets. This information eventually led to ‘sandwich’ assays that discriminate between the gut and islet glucagon. It is important to note that many pre-sandwich assays were essentially specific for glucagon. From the 2000s onwards, there has been an increased focus on pharmacological modulation of glucagon secretion and action. More recently, protocols for in vivo generation of stem-cell-derived human α-cells was reported.

Fig. 2 |. Tissue regulation by glucagon.

GCGRs are present in several tissues. GCGR gene expression is greatest in the liver, with more modest or low mRNA levels in the kidney, heart and pancreatic islets. As it is anatomically directly downstream of the pancreas, the liver is likely to be the physiologically most important target of glucagon. Most experimental studies have been conducted in experimental animals (mice and rats) but are supported by human data. In metabolic tissues (principally the liver), GCGR signaling increases fuel availability, leads to breakdown of glycogen and triglycerides, and promotes gluconeogenesis. In addition, GCGR signaling (directly or indirectly) influences energy expenditure, electrolyte transport, cardiac and smooth muscle, but it is uncertain whether these processes are influenced by physiological and circulating levels of glucagon. Stimulation and inhibition of highlighted processes are indicated by upward and downward arrows, respectively.

Fig. 3 |. Regulation of glucagon secretion.

a, High glucagon secretion at low glucose proceeds because K_ATP channels are under strong tonic inhibition by a high cytoplasmic ATP/ADP ratio (1). The resultant membrane depolarization (Ψ↓) triggers action potential (AP) firing through the opening of voltage-gated Na⁺ (Na_V) channels. This culminates in the opening of P/Q-type Ca²⁺ (Ca_P/Q) channels that are tightly associated with the glucagon-containing secretory granules (SGs) and the local increase in cytoplasmic Ca²⁺ ([Ca²⁺]_i↑) stimulates glucagon release. A high basal ATP/ADP ratio is maintained by a high rate of glucose metabolism (by the low-K_m hexokinase I (HK), following glucose uptake via plasmalemmal GLUT1/3 transporters) or β-oxidation of NEFAs, circulating or derived from lipolysis of endogenous triglyceride (TG) stores (2). Glucagon secretion in vivo may also proceed because of high-circulating amino acids (AAs), which depolarize the α-cell by electrogenic entry either as charged amino acids (AA⁺) or through co-transport with Na⁺ (3). Circulating hormones and locally released neurotransmitters such as AVP, GIP and adrenaline (via β-adrenergic receptors) also stimulate glucagon secretion(4). They act via activation of G_q/s and elevate [Ca²⁺]_i through mobilization of intracellular Ca²⁺ stores and/or stimulation of α-cell electrical activity. b, At high glucose, glucose metabolism is stimulated via high-K_m glucokinase (GCK), leading to a further elevation of the ATP/ADP ratio and complete inhibition of K_ATP channel activity (K_ATP channel = 0) (1). This leads to stronger membrane depolarization (Ψ↓↓) with resultant voltage-dependent inactivation of the Na_V channels (↓), reduced AP height, less activation of the Ca_P/Q channel (↓), a smaller increase in [Ca²⁺]_i and suppression (−) of glucagon exocytosis (glucagon↓). High glucose also inhibits voltage-gated Ca²⁺ entry (2) and lowers intracellular cAMP (3), with resultant inhibition (−) of glucagon release. Finally, paracrine regulators, including serotonin (5-HT) or somatostatin, inhibit glucagon release by receptor activation of inhibitory G proteins (G_i) (4). c, Plasma glucagon displayed against plasma glucose concentration in healthy (non-diabetic (ND)) people (black trace) and individuals diagnosed with T1D (red trace). Levels have been normalized to basal (~5 mM (red circle) and 9 mM (black square) in ND and T1D, respectively). Data sourced from refs. ^,. Because basal plasma glucose is much higher in T1D, glucagon should be ~ 50% lower in these patients than in the healthy controls. The finding that it is the same therefore suggests relative hyperglucagonemia (blue arrow).