Glucagon is the chief secretory product of α cells and glucagon concentrations have been used as the principal measure of α- cell function in vivo and in vitro. With the possible exception of individuals treated with bariatric surgery, there is no evidence that tissues besides the islet α cell release glucagon into the circulation. Glucagon secreted from islets in the pancreas collects in the portal vein, where concentrations are higher than other major vascular systems, and the liver is the primary target of glucagon signalling. Circulating glucagon is cleared by the liver and kidney, with roughly equal contributions by each organ, and 20–40% hepatic clearance of portal venous content. Glucagon secretion is regulated by a complex interplay of nutrient, endocrine, paracrine, and neural factors (Figure 1). While there is convincing evidence to support this diverse control of α- cell secretion, how the system is integrated varies under different physiological states, and is altered by disease in ways that are still not well understood.

Fig1. Signals that integrate to regulate α- cell secretion of glucagon. The α cell receives input from multiple sources including neuronal, endocrine, and paracrine signals. The incretins are endocrine signals that regulate α- cell function both directly (GIP) and indirectly (GLP- 1). Paracrine signals within the islet originate from both the β cell and the δ cell. Activation of the β cell enhances these paracrine signals, directly inhibiting the α cell through factors such as insulin, γ-aminobutyric acid, or Zn2+, and indirectly by increase δ- cell activity through the urocortin 3 system. Increased activity of the δ cell inhibits glucagon secretion through somatostatin. The α cell also receives neuronal input through the sympathetic (SNS) and parasympathetic nervous systems (PNS), both of which increase glucagon secretion. CRHR2, corticotropin- releasing hormone receptor 2; GIP, glucose- dependent insulinotropic polypeptide; GLP- 1, glucagon- like peptide 1; SSTR2, somatostatin receptor 2.

Like the β- cell secretion of insulin, ambient glucose concentrations also regulate α- cell release of glucagon. Low glucose levels increase and high concentrations inhibit glucagon secretion, in part through changes in α- cell electrical activity involving KATP channels. It remains a curiosity that α and β cells have similarities in key aspects of glucose transport, metabolism, and KATP channel activity, yet opposite secretory responses to changes in ambient glucose. Differences in resting electrical characteristics and ion channel function downstream of KATP channel closure can explain much of the reciprocal pattern of glucagon and insulin secretion at relative hypo- and hyperglycaemia. Moreover, new findings suggest that α cells, but not β cells, express sodium glucose transporters (SGLTs) 1 and 2, and that reduced flux through SGLT- 2 increases glucagon secretion. It is unclear how SGLT function is integrated with other aspects of α- cell glucose metabolism, but observations that humans treated with SGLT- 2 inhibitors have increased plasma glucagon suggests that this is an active physiological mechanism. Beyond glucose, amino acids are another nutrient source that stimulates α cells. Protein meals or infusions of amino acids stimulate glucagon release, and arginine is commonly used to stimulate glucagon secretion in research studies. Among the amino acids alanine, glutamine, proline, and glycine are also potent α- cell secretagogues.

Substantial differences exist between glucagon release from isolated α cells and intact islets, suggesting that other islet cells have important roles in α- cell regulation. Endocrine cells in islets are exposed to high concentrations of local products and both insulin and somatostatin inhibit glucagon release, acting either through the microvasculature or by local cell- to- cell contact. Insulin contributes measurably to the suppression of glucagon after meals and during progressive hyperglycaemia. Other compounds released from β cells inhibit glucagon release, includ ing zinc, γ- amino- butyric acid , and glutamate , but the physiological relevance of these compounds is unclear. Exogenous somatostatin is a potent inhibitor of glucagon secretion, and somatostatin secreted from islet δ cells restrains α- cell secretion during exposure to circulating nutrients after meals. A final mechanism of intra- islet regulation of glucagon is autocrine, as recent work suggests that other α- cell products may regulate the α cells. The α cells from both primates and mice secrete glutamate and express ionotropic glutamate receptors (iGlutR). Glutamate stimulates glucagon release, and this seems to be important for the normal response to low plasma glucose, since inhibition of iGlutR impairs hypoglycaemic counter- regulation in mice.

The autonomic nervous system is critical for the regulation of glucagon secretion, particularly in the setting of hypoglycaemic counter- regulation. Activation of both the parasympathetic and sympathetic limbs of the autonomic nervous system increases glucagon release, and adrenal epinephrine has a similar effect that may be especially important when blood glucose is very low. Importantly, catecholaminergic signalling synergizes with low blood glucose to stimulate glucagon release, and genetic disruption of autonomic neurons in the islet predisposes mice to hypoglycaemia. The key regions in the CNS for sensing circulating blood glucose and initiating counter- regulation are located in the hypothalamus and hindbrain.

Similar to insulin, glucagon release is also affected by the actions of enteric peptides. Glucose- dependent insulinotropic polypeptide (GIP) stimulates glucagon release through direct actions on the GIP receptor expressed on α cells. It is of great importance that the other major Gcg peptide, GLP- 1, inhibits glucagon secretion, although there is debate over the mechanism whereby this occurs, since the majority of α cells do not express the GLP- 1 receptor. GLP- 1 increases the secretion of hormones from both β and δ cells, and so could act indirectly to reduce glucagon release, and this is currently considered to be the primary means by which GLP- 1 acts on the α cell. In addition, GLP- 1 affects electrical activity and secretion of α cells, even in the absence of changes in somatostatin or insulin.

Overall α- cell regulation is a complex, multilayered process with dense integration of control by nutrients and neural, endocrine, paracrine, and autocrine inputs to secretion. Because glucagon has a key role across a range of physiological settings, during fasting, exercise, hypoglycaemia, and following mixed- nutrient meals, α cells are subject to a diversity of controlling factors. While there appears to be some overlap in α- cell control, it seems likely that some regulatory factors also have specific roles as well. Further understanding the regulation of glucagon secretion, and adaptation of therapeutic approaches to control this process, has great potential for the treatment of metabolic disease.

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مواضيع ذات صلة

Glucagon actions in the liver: amino acid metabolism and the hepatic–α- cell axis

Glucagon actions in the liver: glucose and lipid metabolism

Regulation of insulin secretion by non- nutrients

Regulation of insulin secretion

Islet structure and function

الجلوكاجون Glucagon

هرمون الانسولين

المرض السكري (Diabetes Mellitus)

الغدة البنكرياسيةThe Pancreas