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Alpha cell
Pancreatic islets (islets of Langerhans).
Alpha cells in red
Details
SystemEndocrine
LocationPancreatic islet
FunctionGlucagon secretion
Identifiers
THH3.04.02.0.00025
FMA70585
Anatomical terms of microanatomy

Alpha cells (α-cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.[1]

Discovery

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Islets of Langerhans were first discussed by Paul Langerhans in his medical thesis in 1869.[2] This same year, Édouard Laguesse named them after Langerhans.[3] At first, there was a lot of controversy about what the Islets were made of and what they did.[3] It appeared that all of the cells were the same within the Islet, but were histologically distinct from acini cells.[3] Laguesse discovered that the cells within the Islets of Langerhans contained granules that distinguished them from acini cells.[3] He also determined that these granules were products of the metabolism of the cells in which they were contained.[3] Michael Lane was the one to discover that alpha cells were histologically different than beta cells in 1907.[3]

Before the function of alpha cells was discovered, the function of their metabolic product, glucagon, was discovered. The discovery of the function of glucagon coincides with the discovery of the function of insulin. In 1921, Banting and Best were testing pancreatic extracts in dogs that had had their pancreas removed. They discovered that "insulin-induced hypoglycemia was preceded by a transient, rather mild hyperglycemia..."[4] Murlin is credited with the discovery of glucagon because in 1923 they suggested that the early hyperglycemic effect observed by Banting and Best was due to "a contaminant with glucogenic properties that they also proposed to call 'glucagon,' or the mobilizer of glucose".[4] In 1948, Sutherland and de Duve established that alpha cells in the pancreas were the source of glucagon.[4]

Anatomy

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Alpha cells are endocrine cells, meaning they secrete a hormone, in this case glucagon. Alpha cells store this glucagon in secretory vesicles that typically have an electron dense core and a grayish outer edge.[1] It is believed that alpha cells make up approximately 20% of endocrine cells within the pancreas.[1] Alpha cells are most commonly found on the dorsal side of the pancreas and are very rarely found on the ventral side of the pancreas.[1] Alpha cells are typically found in compact Islets of Langerhans, which are themselves typically found in the body of the pancreas.[1]

Function

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Alpha cells function in the maintenance of blood glucose levels. Alpha cells are stimulated to produce glucagon in response to hypoglycemia, epinephrine, amino acids, other hormones, and neurotransmitters.[5]

Glucagon Secretion and Control of Gluconeogenesis

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Glucagon functions to signal the liver to begin gluconeogenesis which increases glucose levels in the blood.[5] Glucagon will bind to the glucagon receptors on the plasma membranes of hepatocytes (liver cells). This ligand binding causes the activation of adenylate cyclase, which causes the creation of cyclic AMP (cAMP).[6] As the intracellular concentration of cAMP rises, protein kinase A (PKA) is activated and phosphorylates the transcription factor cAMP Response Element Binding (CREB) protein.[6] CREB then induces transcription of glucose-6-phosphatase and phosphoenolpyruvate carboxylase (PEPCK). These enzymes increase gluconeogenic activity.[6] PKA also phosphorylates phospho-fructokinase 2 (PFK2)/fructose 2,6-biphsophatase (FBPase2), inhibiting PFK2 and activating FBPase2.[6] This inhibition decreases intracellular levels of fructose 2,6-biphosphate and increases intracellular levels of fructose 6-phosphate which decreases glycolytic activity and increases gluconeogenic activity.[6] PKA also phosphorylates pyruvate kinase which causes an increase in intracellular levels of fructose 1,6-biphosphate and decreases intracellular levels of pyruvate, further decreasing glycolytic activity.[6] The most important action of PKA in regulating gluconeogenesis is the phosphorylation of phosphorylase kinase which acts to initiate the glycogenolysis reaction, which is the conversion of glycogen to glucose, by converting glycogen to glucose 1-phosphate.[6]

Alpha cells also generate Glucagon-like peptide-1 and may have protective and regenerative effect on beta cells. They possibly can transdifferentiate into beta cells to replace lost beta cells.[7]

Regulation of glucagon secretion

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There are several methods of control of the secretion of glucagon. The most well studied is through the action of extra-pancreatic glucose sensors, including neurons found in the brain and spinal cord, which exert control over the alpha cells in the pancreas.[5] Indirect, non-neuronal control has also been found to influence secretion of glucagon.[5]

Neuronal Control

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The most well studied is through the action of extra-pancreatic glucose sensors, including neurons found in the brain, which exert control over the alpha cells in the pancreas.[5] The pancreas is controlled by both the sympathetic nervous system and the parasympathetic nervous system, although the method these two systems use to control the pancreas appears to be different.[8]

Sympathetic control of the pancreas appears to originate from the sympathetic preganglionic fibers in the lower thoracic and lumbar spinal cord.[9] According to Travagli et al. "axons from these neurons exit the spinal cord through the ventral roots and supply either the paravertebral ganglia of the sympathetic chain via communicating rami of the thoracic and lumbar nerves, or the celiac and mesenteric ganglia via the splanchnic nerves. The catecholaminergic neurons of these ganglia innervate the intrapancreatic ganglia, islets and blood vessels..."[9] The exact nature of the effect of sympathetic activation on the pancreas has been difficult to discern. However, a few things are known. It appears that stimulation of the splanchnic nerve lowers plasma insulin levels possibly through the action of α2 adrenoreceptors on beta cells.[9] It has also been shown that stimulation of the splanchnic nerve increases glucagon secretion.[9] Both of these findings together suggest that sympathetic stimulation of the pancreas is meant to maintain blood glucose levels during heightened arousal.[9]

Parasympathetic control of the pancreas appears to originate from the Vagus nerve.[8] Electrical and pharmacological stimulation of the Vagus nerve increases secretion of glucagon and insulin in most mammalian species, including humans. This suggests that the role of parasympathetic control is to maintain normal blood glucose concentration under normal conditions.[8]

Non-neuronal Control

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Non-neuronal control has been found to be indirect paracrine regulation through ions, hormones, and neurotransmitters. Zinc, insulin, serotonin, γ-aminobutyric acid, and γ-hydroxybutyrate, all of which are released by beta cells in the pancreas, have been found to suppress glucagon production in alpha cells.[5] Delta cells also release somatostatin which has been found to inhibit glucagon secretion.[5]

Zinc is secreted at the same time as insulin by the beta cells in the pancreas. It has been proposed to act as a paracrine signal to inhibit glucagon secretion in alpha cells. Zinc is transported into both alpha and beta cells by the zinc transporter ZnT8. This protein channel allows zinc to cross the plasma membrane into the cell. When ZnT8 is under-expressed, there is a marked increase in glucagon secretion. When ZnT8 is over-expressed, there is a marked decrease in glucagon secretion. The exact mechanism by which zinc inhibits glucagon secretion is not known.[10]

Insulin has been shown to function as a paracrine signal to inhibit glucagon secretion by the alpha cells.[11] However, this is not through a direct interaction. It appears that insulin functions to inhibit glucagon secretion through activation of delta cells to secrete somatostatin.[12] Insulin binds to SGLT2 causing an increased glucose uptake into delta cells. SGLT2 is a sodium and glucose symporter, meaning that it brings glucose and sodium ions across the membrane at the same time in the same direction. This influx of sodium ions, in the right conditions, can cause a depolarization event across the membrane. This opens calcium channels, causing intracellular calcium levels to increase. This increase in the concentration of calcium in the cytosol activates ryanodine receptors on the endoplasmic reticulum which causes the release of more calcium into the cytosol. This increase in calcium causes the secretion of somatostatin by the delta cells.[12]

Somatostatin inhibits glucagon secretion through the activation of SSTR2, a membrane bound protein that when activated causes a hyperpolarization of the membrane. This hyperpolarization causes voltage gated calcium channels to close, leading to a decrease in intracellular calcium levels. This causes a decrease in exocytosis. In the case of alpha cells, this causes a decrease in the secretion of glucagon.[13]

Serotonin inhibits the secretion of glucagon through its receptors on the plasma membrane of alpha cells. Alpha cells have 5-HT1f receptors which are triggered by the binding of serotonin. Once activated, these receptors suppress the action of adenylyl cyclase, which suppresses the production of cAMP. The inhibition of the production of cAMP in turn suppresses the secretion of glucagon.[5] Serotonin is considered a paracrine signal due to the close proximity of beta cells to alpha cells.[14]

Glucose can also have a somewhat direct influence on glucagon secretion as well. This is through the influence of ATP. Cellular concentrations of ATP directly reflects the concentration of glucose in the blood. If the concentration of ATP drops in alpha cells, this causes potassium ion channels in the plasma membrane to close. This causes depolarization across the membrane causing calcium ion channels to open, allowing calcium to flood into the cell. This increase in the cellular concentration of calcium causes secretory vesicles containing glucagon to fuse with the plasma membrane, thus causing the secretion of glucagon from the pancreas.[5]

Medical significance

[edit]

High levels of glucagon secretion has been implicated in both Type I and Type II diabetes. In fact, high levels of plasma glucagon is considered an early sign of the development of both Type I and Type II diabetes.[15]

Type I Diabetes

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It is thought that high glucagon levels and lack of insulin production are the main triggers for the metabolic issues associated with Type I diabetes, in particular maintaining normal blood glucose levels, formation of ketone bodies, and formation of urea.[16] One finding of note is that the glucagon response to hypoglycemia is completely absent in patients with Type I diabetes.[16] Consistently high glucagon concentrations in the blood can lead to diabetic ketoacidosis,[16] which is when ketones from lipid breakdown build up in the blood, which can lead to dangerously low blood glucose levels, low potassium levels, and in extreme cases cerebral edema.[17] It has been proposed that the reason for the high levels of glucagon found in the plasma of patients with Type I diabetes is the absence of beta cells producing insulin and the reciprocal effect this has on delta cells and the secretion of somatostatin.[16]

Type II Diabetes

[edit]

Patients with Type II diabetes will have elevated glucagon levels during a fast and after eating.[18] These elevated glucagon levels over stimulate the liver to undergo gluconeogenesis, leading to elevated blood glucose levels.[18] Consistently high blood glucose levels can lead to organ damage, neuropathy, blindness, cardiovascular issues and bone and joint problems.[19] It is not entirely clear why glucagon levels are so high in patients with Type II diabetes. One theory is that the alpha cells have become resistant to the inhibitory effects of glucose and insulin and do not respond properly to them.[18] Another theory is that nutrient stimulation of the gastrointestinal tract, thus the secretion of gastric inhibitory polypeptide and Glucagon-like peptide-1, is a very important factor in the elevated secretion of glucagon.[18]

In other species

[edit]

There is much controversy as to the effects of various artemisinin derivatives on α-cell-to-β-cell differentiation in rodents and zebrafish.[43] Li et al., 2017 find artemisinin itself forces α⇨β conversion in rodents (via gephyrin)[45] and zebrafish[46] while Ackermann et al., 2018 find artesunate does not[48] and van der Meulen et al., 2018 find the same absence of effect for artemether[49] (although artemether does inhibit ARX).[50] (Shin et al., 2019 further finds no such effect for GABA in rhesus macaque, although GABA is not an artemisinin but has a related action.)[51] Both Eizirik & Gurzov 2018[33] and Yi et al., 2020[36] consider it possible that these are all legitimately varying results from varying combinations of substance, subject, and environment. On the other hand, a large number of reviewers[52] are uncertain whether these are separate effects, instead questioning the validity of Li on the basis of Ackermann and van der Meulen – perhaps GABA receptor agonists as a whole are not β-cell-ergic.[53] Coppieters et al., 2020 goes further, highlighting Ackermann and van der Meulen as publications that catch an unreplicatable scientific result, Li.[47]

See also

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References

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Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Alpha cell

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Alpha cells, also known as α-cells, are endocrine cells located within the of Langerhans in the , where they constitute approximately 33-46% of the total islet cell population in humans. These cells are primarily responsible for the production and secretion of the peptide hormone , which plays a pivotal role in maintaining blood glucose homeostasis by counteracting . secretion is triggered by low blood glucose levels, prolonged fasting, exercise, or high-protein meals, and it functions by binding to receptors on hepatocytes to stimulate —the breakdown of glycogen into glucose—and , the synthesis of glucose from non-carbohydrate precursors such as . In addition to their core function in glucose regulation, alpha cells interact closely with neighboring beta cells (which produce insulin) and delta cells (which produce ) within the islet architecture, forming a paracrine network that fine-tunes hormone release. Glucose directly inhibits glucagon secretion from alpha cells through mechanisms involving ATP-sensitive potassium (KATP) channels, ensuring that glucagon release is suppressed during to prevent excessive blood sugar elevation. Neural inputs, such as sympathetic stimulation via adrenaline, and other hormones like further modulate alpha cell activity, highlighting their integration into broader endocrine and autonomic regulatory systems. Dysfunction of alpha cells is implicated in metabolic disorders, particularly type 1 and type 2 diabetes, where impaired glucagon secretion can contribute to glycemic instability, including inappropriate hyperglucagonemia that exacerbates hyperglycemia. In type 1 diabetes, autoimmune destruction of islets primarily leads to beta cell loss, while alpha cells persist but become dysfunctional, resulting in both deficient counterregulatory responses during hypoglycemia and paradoxical hyperglucagonemia during hyperglycemia. In type 2 diabetes, alpha cell hyperactivity persists despite insulin resistance, underscoring the therapeutic potential of targeting alpha cell function for better glucose control. Normal circulating glucagon levels in humans range from 50 to 100 pg/mL, reflecting the precise balance required for metabolic health.

History

Discovery

The alpha cells of the pancreas were first identified in 1907 by Michael A. , a medical student at the , through detailed histological analysis of the islets of Langerhans. Employing selective staining methods, Lane differentiated two distinct cell populations within the islets: the alpha (A) cells, which appeared larger with more prominent granular cytoplasm, and the beta (B) cells, establishing alpha cells as a separate entity from the insulin-producing beta cells. This pioneering work provided the initial cytological characterization of alpha cells, highlighting their morphological differences and peripheral distribution in the islets. In the early 1920s, amid efforts to isolate insulin, researchers and Charles Best conducted extensive microscopic examinations of pancreatic tissue, further elucidating the morphology and distribution of alpha cells. By ligating pancreatic ducts in experimental animals to selectively degenerate acinar cells while preserving the islets, and Best observed the relative proportions and spatial organization of alpha and beta cells, noting alpha cells' tendency to cluster at the islet periphery. These observations, integral to their insulin discovery process, reinforced Lane's earlier findings and emphasized the structural heterogeneity of islet cells. Key milestones in alpha cell discovery span the 1907 introduction of techniques by and, in the 1920s, emerging connections to physiological phenomena such as symptoms following . Experiments on depancreatized dogs revealed that pancreatic extracts initially provoked prior to insulin-induced , indicating the presence of a counterregulatory hyperglycemic factor later identified as produced by alpha cells.

Key Developments

In 1923, Charles P. Kimball and John R. Murlin isolated a hyperglycemic factor from pancreatic extracts and named it , recognizing its role in elevating blood glucose in depancreatized animals. In 1948, Earl W. Sutherland and isolated the hyperglycemic-glycogenolytic factor from extracts of pancreatic tissue and demonstrated its specific association with through selective destruction experiments using , which targets these cells. This breakthrough separated from insulin's effects, establishing it as a distinct produced by alpha cells in the islets of Langerhans. During the and , the development of s revolutionized the measurement of levels, confirming its role as the primary hormone secreted by alpha cells. Roger H. Unger and colleagues pioneered the first for in 1961, enabling precise quantification in plasma and revealing its hyperglycemic effects, such as stimulating hepatic and to counteract insulin's actions. These assays also highlighted 's involvement in glucose , with elevated levels observed during fasting and , solidifying alpha cells' counterregulatory function. Advancements in electron microscopy during the 1970s provided unprecedented insights into the of alpha cell secretory granules, revealing their polymorphic, electron-dense cores often surrounded by a clear halo, which distinguished them from granules. Studies by Lelio Orci and collaborators utilized high-resolution techniques to depict these granules' maturation and packaging of within the Golgi apparatus, enhancing understanding of the secretory pathway in alpha cells. In the early , the cloning of the marked a pivotal molecular advance, allowing detailed of its expression and processing. Patricia K. Lund and colleagues isolated and sequenced the cDNA for pancreatic preproglucagon in 1982, uncovering two tandem glucagon-related coding sequences that encode the precursor protein processed into and other peptides. This work facilitated subsequent genetic studies on alpha cell-specific regulation and proglucagon biosynthesis.

Anatomy

Location and Distribution

Alpha cells are endocrine cells primarily located within the of Langerhans in the . In , these cells constitute approximately 33–46% of the total islet endocrine cell population. This proportion is notably lower in , where alpha cells account for 10–20% of islet cells. Within the , alpha cell density exhibits regional variation, with a higher proportion observed in the body and tail compared to the head. The body and tail regions, derived largely from the dorsal pancreatic bud during embryogenesis, show an increasing alpha cell fraction from the head toward the tail. In contrast, the head region, originating from the ventral bud, contains a greater abundance of (PP) cells rather than alpha cells. At the intra-islet level, alpha cells in are arranged in a mantle-like peripheral layer surrounding a core of beta cells. This organization facilitates distinct cellular interactions. In humans, however, alpha cells are more uniformly intermixed with beta cells throughout the , often aligning along blood vessels without a clear core-mantle structure. Such differences in distribution influence islet architecture and intercellular communication.

Cellular Structure

Pancreatic alpha cells exhibit a distinct characterized by the presence of electron-dense secretory granules, which are essential for storing and processing proglucagon-derived peptides. These granules measure approximately 250–300 nm in diameter and feature an electron-dense core surrounded by a less electron-dense halo, as observed through microscopy. Proglucagon, synthesized in the rough , is transported to these granules where it undergoes proteolytic cleavage primarily by prohormone convertase 2 (PC2) to yield mature , the predominant secreted by alpha cells. This processing ensures the granules contain bioactive peptides ready for regulated release. Key organelles in alpha cells include a prominent Golgi apparatus, which plays a critical role in the packaging and further modification of proglucagon en route to the secretory granules. The Golgi facilitates the sorting and concentration of precursors, contributing to the formation of dense-core vesicles characteristic of endocrine cells. Additionally, the plasma membrane of alpha cells expresses voltage-gated calcium channels, particularly P/Q-type channels, which are integral to the cell's excitability and support calcium influx necessary for cellular functions. Immunohistochemical identification of alpha cells relies on specific molecular markers, with strong glucagon immunoreactivity serving as the primary indicator of their identity due to the abundance of glucagon within the secretory granules. Alpha cells also co-express the aristaless-related homeobox gene (ARX), a that maintains alpha cell lineage specification and is detected alongside in immunohistochemical staining. These markers distinguish alpha cells from other islet endocrine cells at the molecular level.

Function

Glucagon Synthesis and Secretion

Glucagon is synthesized in pancreatic alpha cells through the transcription of the glucagon gene (GCG), located on the long arm of human chromosome 2 at position 2q24.2. This gene encodes preproglucagon, a 180-amino-acid precursor protein that undergoes signal peptide cleavage in the endoplasmic reticulum to form proglucagon (160 amino acids). In alpha cells, proglucagon is specifically processed via post-translational modifications by prohormone convertases 1/3 (PC1/3) and 2 (PC2), along with carboxypeptidase E, to yield mature glucagon—a 29-amino-acid straight-chain peptide hormone—as the primary product, with the intervening peptide (IP-1) and C-terminal extensions removed. This tissue-specific cleavage distinguishes alpha cell processing from that in intestinal L-cells, where proglucagon yields glucagon-like peptide-1 (GLP-1) instead. Mature glucagon is packaged and stored within large dense-core secretory granules in the of alpha cells, where it constitutes a significant portion of the cell's hormonal content, enabling rapid release upon stimulation. These granules, typically 200-300 nm in diameter, maintain in a crystalline core stabilized by calcium and other ions, poised for . of occurs primarily through calcium-dependent of these granules, triggered by alpha cell that opens voltage-gated calcium channels, leading to Ca²⁺ influx and fusion of granules with the plasma . Under basal conditions, such as during with normoglycemia around 5 mmol/L, alpha cells release at a steady rate, maintaining plasma concentrations typically below 20 pmol/L to support endogenous glucose production. Stimulated secretion, often in response to or certain , elevates these levels significantly—up to 2-3-fold or more—through increased frequency and Ca²⁺ entry, enhancing exocytotic events. Neuronal inputs, such as sympathetic activation, can further amplify this process by promoting .

Physiological Roles

Pancreatic alpha cells primarily function through the secretion of glucagon, which plays a central role in maintaining metabolic balance by elevating blood glucose levels during periods of fasting or hypoglycemia. Glucagon binds to its G-protein-coupled receptor on hepatocytes, activating adenylate cyclase to increase intracellular cyclic AMP (cAMP) levels, which in turn activates protein kinase A (PKA). This cAMP-PKA signaling pathway promotes hepatic glycogenolysis by phosphorylating glycogen phosphorylase kinase, leading to the breakdown of glycogen into glucose-1-phosphate and subsequent release of free glucose into the bloodstream. Simultaneously, the pathway stimulates gluconeogenesis by upregulating key enzymes, ensuring a sustained supply of glucose from non-carbohydrate precursors when glycogen stores are depleted. As a counter-regulatory hormone to insulin, opposes insulin's glucose-lowering effects by enhancing hepatic glucose output, thereby preventing and supporting energy demands during or stress. A critical aspect of this gluconeogenic action involves the upregulation of (PEPCK), a rate-limiting that converts oxaloacetate to phosphoenolpyruvate, facilitating glucose synthesis from substrates like lactate and ; this is mediated by PKA-induced activation of CREB and coactivators such as PGC-1α. Beyond glucose , contributes to by stimulating in adipocytes, particularly in where it activates hormone-sensitive via the cAMP pathway to release free fatty acids, though this effect is less pronounced at physiological concentrations in humans. Additionally, promotes hepatic amino acid catabolism by enhancing activity, including the rapid activation of carbamoyl-phosphate synthetase through increased N-acetylglutamate, thereby clearing circulating and supporting while reducing blood levels. Recent 2025 research has uncovered heterogeneity in human alpha cell populations, with differences in glucagon storage and secretion dynamics that enhance islet adaptability. Emerging evidence as of 2025 also indicates that alpha cells can produce and secrete active (GLP-1), contributing to local paracrine regulation of insulin secretion and glucose . Alpha cells' involvement in pancreatic regeneration, particularly through their potential to transdifferentiate into insulin-producing s under specific conditions. Post-2020 studies have demonstrated that targeted overexpression of transcription factors like PDX1 and MAFA in alpha cells can induce functional beta-like cells in murine models, restoring glucose and offering therapeutic promise for beta cell replenishment in . This plasticity underscores alpha cells' broader role in maintenance and adaptability beyond traditional glucagon-mediated functions.

Regulation

Neuronal Regulation

Alpha cells in the receive dense innervation from the , with sympathetic and parasympathetic fibers playing key roles in modulating secretion. Sympathetic endings, which constitute a significant portion of islet innervation, release norepinephrine that binds to β-adrenergic receptors on alpha cells, thereby stimulating glucagon release. This mechanism is particularly active during stress or conditions, where triggers sympathetic activation to promote counterregulatory hormone secretion and maintain blood glucose levels. Recent studies highlight the interplay between sympathetic and vagal pathways, with 2022 research emphasizing how norepinephrine signaling at β1- and β2-adrenergic receptors on alpha cells enhances glucagon output while balancing vagal influences for overall glycemic control. Parasympathetic innervation, mediated by postganglionic fibers, further regulates alpha cell function through release, which activates muscarinic receptors to enhance . This stimulation contributes to release in response to neural signals, including those during the postprandial phase, where parasympathetic activity supports metabolic adjustments following nutrient intake. In like mice, parasympathetic fibers directly contact alpha cells, underscoring their role in fine-tuning . Central nervous system integration coordinates these autonomic inputs via hypothalamic glucose-sensing neurons that detect blood glucose fluctuations and relay signals to the . Regions such as the arcuate nucleus, ventromedial , and lateral hypothalamic area express glucose-sensing enzymes like , enabling rapid responses to by activating sympathetic and parasympathetic outflows to alpha cells. Intra-pancreatic nerve endings, with vagal sensory fibers present in approximately 10% of rat islets, facilitate this integration by transmitting central signals directly to endocrine cells, ensuring precise modulation of secretion based on systemic glucose needs.

Paracrine and Endocrine Regulation

Alpha cells within the are subject to paracrine regulation primarily through inhibitory signals from neighboring beta and delta cells. Insulin secreted by beta cells acts in a paracrine manner to suppress release from alpha cells, particularly during periods of elevated glucose levels, thereby helping to fine-tune postprandial glucose . Similarly, released from delta cells inhibits alpha cell activity by binding to somatostatin receptors, reducing calcium influx and in alpha cells. Zinc ions co-released with insulin from beta cells may exert a paracrine inhibitory effect on secretion, though this role remains controversial based on knockout studies. Endocrine regulation of alpha cells involves systemic hormones that modulate glucagon secretion in response to metabolic needs. Adrenaline, released during stress or hypoglycemia, potentiates glucagon release by activating beta-adrenergic receptors on alpha cells, enhancing and through L-type calcium channels. In contrast, (GLP-1), an hormone, inhibits glucagon secretion in a glucose-dependent manner by engaging GLP-1 receptors on alpha cells, which promotes membrane hyperpolarization and reduces voltage-gated calcium entry. Glucose itself exerts direct endocrine-like control, with low concentrations (approximately 2-5 mM) stimulating glucagon secretion to counteract hypoglycemia, while higher levels suppress it, reflecting the alpha cell's role in glycemic counterregulation. Feedback loops involving further regulate alpha cell function, linking to output. Elevated circulating , such as , directly stimulate secretion from alpha cells, promoting amino acid in the liver to maintain energy balance during or high-protein states. This stimulation occurs via nutrient-sensing mechanisms, including the calcium-sensing receptor (CaSR), which responds to L-amino acids like and to trigger intracellular signaling pathways that enhance release.

Pathophysiology and Medical Significance

Role in Diabetes Mellitus

In mellitus (T1D), autoimmune destruction of leads to a significant reduction in alpha cell mass, estimated at approximately 50% relative to non-diabetic individuals, alongside the more profound loss of beta cells. This depletion impairs glucagon secretion, particularly the appropriate response to falling blood glucose levels, resulting in defective glucose counterregulation. Consequently, patients with T1D experience heightened vulnerability to insulin-induced , as the absence of glucagon-mediated hepatic glucose production fails to restore euglycemia effectively. This dysfunction contributes to hypoglycemia unawareness, where symptomatic thresholds shift, increasing the risk of severe hypoglycemic events by up to 25-fold during intensive insulin therapy. Recent therapeutic advancements have explored glucagon suppression strategies to mitigate these risks in T1D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as , have demonstrated potential as adjuncts to insulin therapy by inhibiting inappropriate release, thereby improving glycemic stability and reducing incidence without exacerbating hypoawareness. These agents leverage paracrine mechanisms within the to restore partial counterregulatory balance, highlighting alpha cell modulation as a complementary approach to traditional insulin management. In mellitus (T2D), alpha cell dysfunction manifests as hyperglucagonemia, with fasting levels significantly elevated compared to non-diabetic controls, directly contributing to hepatic glucose overproduction and fasting . This dysregulation arises from , which diminishes the intra-islet suppression of secretion by insulin, leading to persistent alpha cell hyperactivity even in the presence of . Postprandially, levels in T2D patients remain elevated, failing to suppress adequately as observed in healthy individuals, thereby exacerbating meal-related glucose excursions. These alterations underscore the biphasic alpha cell defect in T2D, where impaired inhibition amplifies the metabolic burden of .

Implications in Other Conditions

Alpha cells play a critical role in counterregulatory responses to in various syndromes, including idiopathic , where impaired alpha cell function contributes to exaggerated insulin responses and subsequent glucose instability. In non-diabetic , such as that associated with insulinomas or post-bariatric states, suppressed glucagon secretion from alpha cells fails to adequately counteract low blood glucose, exacerbating the condition. Similarly, in beyond diabetic contexts, such as alcoholic or starvation-induced forms, elevated from alpha cells promotes hepatic and , worsening despite low insulin levels. Glucagonomas, rare neuroendocrine tumors arising from pancreatic alpha cells, are characterized by alpha cell and excessive glucagon secretion, leading to a distinct syndrome with , , and weight loss; their incidence is approximately 1 in 20 million population per year. This disrupts normal architecture and amplifies glucagon's catabolic effects, contributing to severe and thromboembolic complications in affected patients. Emerging research highlights alpha cell dysfunction in , where altered secretion may promote through enhanced and energy expenditure, independent of tumor . Post-2020 studies have further linked non-alcoholic (NAFLD) to alpha cell stress, with hepatic impairing the liver-alpha cell axis and leading to hyperglucagonemia that sustains dysregulation and accumulation. This axis disruption exacerbates NAFLD progression by reducing 's regulatory feedback on hepatic catabolism. Therapeutically, (GLP-1) receptor agonists suppress pathological alpha cell activity by inhibiting release in a glucose-dependent manner, offering benefits in conditions with hyperglucagonemia such as postprandial states in metabolic disorders. Additionally, inducers like promote conversion of alpha cells to insulin-producing s, with a completed phase 1 trial as of 2025 demonstrating increased beta cell mass in human islets without significant adverse effects when combined with GLP-1 agonists. These approaches target alpha cell plasticity for regenerative therapies in endocrine deficiencies.

Comparative Biology

In Non-Human Mammals

In models, such as mice and rats, exhibit a distinct mantle-core , with beta cells predominantly forming a central core and alpha cells localized to the peripheral mantle. This structured arrangement contrasts with the more intermixed distribution observed in s and facilitates detailed studies of alpha cell function and plasticity, including potential. Alpha cells constitute approximately 10-30% of the endocrine cell population in islets, lower than the 30-40% typically found in islets, reflecting species-specific differences in islet composition. The mantle-core structure in has proven advantageous for investigating alpha-to- , a process where alpha cells convert into insulin-producing beta-like cells under stress or pharmacological intervention. Seminal research from 2016 demonstrated that , an antimalarial derivative, promotes this in mouse models by enhancing GABA signaling and suppressing the Arx, leading to improved beta cell mass and glycemic control in diabetic conditions. Subsequent studies between 2017 and 2020 built on these findings, exploring artemisinin's mechanisms in islets, though controversies arose regarding the extent of versus transient functional changes. These insights from models have informed therapeutic strategies for regeneration, leveraging the clear spatial separation of cell types for lineage tracing and . In non-human , such as cynomolgus monkeys, alpha cells display an intermixed distribution within similar to that in , differing from the segregated pattern in and enabling more translational studies of dynamics. High-fat diet-induced models showing altered signaling that exacerbates and informs dual-agonist therapies targeting GLP-1R and GCGR. This similarity in islet organization and receptor responsiveness makes non-human primates valuable for bridging rodent findings to . Experimental knockouts in mice have revealed the resilience of alpha cell function; targeted of approximately 98% of alpha cells results in near-complete survival (with most mice living into adulthood) but induces glucose dysregulation, including postprandial and impaired counterregulation. These studies underscore alpha cells' non-essential role for immediate survival in yet highlight their critical contribution to fine-tuned glucose , with compensatory mechanisms like elevated activity partially mitigating effects.

In Non-Mammalian Species

In zebrafish (Danio rerio), a model non-mammalian vertebrate, alpha cell homologs express the gluca gene within the principal islet, the initial endocrine structure that forms around 24 hours post-fertilization from the dorsal pancreatic bud. These alpha cells secrete glucagon to regulate glucose levels, mirroring mammalian function but with distinct developmental dynamics. Post-2018 studies, including single-cell RNA sequencing and lineage tracing with gcga:Cre lines, reveal that zebrafish alpha cells exhibit robust transdifferentiation into beta cells following beta-cell ablation, driven by glucagon-derived peptides and IGF signaling pathways, demonstrating greater regenerative plasticity than observed in adult mammals. This enhanced potential underscores evolutionary conservation of alpha cell identity while highlighting adaptive flexibility in teleost fish for rapid islet regeneration. In birds and reptiles, alpha cell equivalents produce and related peptides that primarily maintain , often at higher baseline levels than in mammals due to constitutively active glucagon receptors and elevated pancreatic content—5–10 times greater per unit mass in birds. The endocrine pancreas in these species features a relatively compact structure with scattered islets, where the endocrine portion comprises approximately 1–2% of total pancreatic mass, lower than in some mammalian models and emphasizing exocrine dominance. In reptiles like and , alpha cells (often equal in proportion to beta cells). These roles provide evolutionary context for glucagon's diversification from metabolic counterregulation to broader physiological adaptation in ectothermic and avian lineages. Invertebrates lack true alpha cells but possess analogous neuroendocrine cells producing hyperglycemic hormones, such as adipokinetic hormone (AKH) in insects like locusts (Locusta migratoria), which mobilizes trehalose (the insect blood sugar equivalent) from fat body stores during stress or flight. AKH functions as a glucagon homolog, activating similar G-protein-coupled receptors in the conserved glucagon receptor superfamily, despite low sequence similarity in ligands. Evolutionary analyses reveal conserved motifs in the prohormone processing and receptor signaling domains of the GCG-related gene family, tracing back to bilaterian ancestors and illustrating how invertebrate systems prefigure vertebrate glucagon pathways for energy mobilization. This homology highlights the ancient origins of alpha cell-like functions in non-mammalian species, bridging invertebrate neurosecretion to vertebrate endocrine control.

References

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