Findings from the past 10 years have placed the glucagon-secreting pancreatic α-cell centre stage in the development of diabetes mellitus, a disease affecting almost one in every ten adults worldwide. Glucagon secretion is reduced in patients with type 1 diabetes mellitus, increasing the risk of insulin-induced hypoglycaemia, but is enhanced in type 2 diabetes mellitus, exacerbating the effects of diminished insulin release and action on blood levels of glucose. A better understanding of the mechanisms underlying these changes is therefore an important goal. RNA sequencing reveals that, despite their opposing roles in the control of blood levels of glucose, α-cells and β-cells have remarkably similar patterns of gene expression. This similarity might explain the fairly facile interconversion between these cells and the ability of the α-cell compartment to serve as a source of new β-cells in models of extreme β-cell loss that mimic type 1 diabetes mellitus. Emerging data suggest that GABA might facilitate this interconversion, whereas the amino acid glutamine serves as a liver-derived factor to promote α-cell replication and maintenance of α-cell mass. Here, we survey these developments and their therapeutic implications for patients with diabetes mellitus.
The mechanisms involved in the control of glucagon secretion in pancreatic α-cells have now been identified.
The pancreatic α-cell has a role in the development of diabetes mellitus.
Physiological and pharmacological activators and inhibitors of glucagon secretion might provide therapeutic targets.
Single α-cell gene expression profiling in health and disease has resulted in new insights about the function of α-cells.
Advances in understanding α-cell to β-cell reprogramming could lead to new therapeutic strategies for diabetes mellitus.
The history of glucagon begins in 1921 when Frederick Banting and Charles Best tested pancreatic extracts in depancreatized dogs and detected transient hyperglycaemia that preceded insulin-induced hypoglycaemia1. Murlin et al.2 suggested 2 years later that the early hyperglycaemia was due to a contaminant in the pancreatic extract that had glucose agonist properties. In 1948, Sutherland and de Duve3 established that the α-cells of the endocrine pancreas are the source of glucagon. Glucagon is a regulator of glucose homeostasis in animals and humans. This hormone stimulates glycogenolysis and gluconeogenesis by the liver and is the key counter-regulatory hormone responsible for opposing the glucose-lowering effects of insulin. The physiology and pharmacology of glucagon in health and disease have been covered in recent reviews4,5.
Here, we summarize the role of the glucagon-secreting pancreatic α-cell in the development and progression of diabetes mellitus. We review advances in our understanding of the α-cell gene expression profile and signalling mechanisms and discuss how the α-cell might become a more prominent target for the treatment of diabetes mellitus by promoting the reprogramming of these cells into insulin-secreting β-like-cells.
The islet of Langerhans
The pancreatic α-cell was discovered in 1907 (ref.6) and is one of four major types of endocrine cells in the islets of Langerhans: glucagon-secreting α-cells, insulin-producing β-cells, somatostatin-releasing δ-cells and pancreatic polypeptide (PP)-secreting cells. Rare ghrelin-producing ε-cells also exist in the islet. It is now clear that the human islet cytoarchitecture is similar to that of rodents7. The islets are made up of subunits with a central core of β-cells and a mantle of non-β-cells, including α-cells7. Moreover, good evidence indicates that the portal blood flow relationships are similar in humans and rodents7. The anatomical similarities are important for understanding paracrine regulation of hormone secretion and for extrapolating decades of rodent islet research to humans. In particular, the key observation of β-cells being upstream from α-cells was shown in a study in which insulin antibody was infused into perfused rat pancreases8 (see later section). This finding was followed by subsequent studies demonstrating that the same mechanism was present in the pancreases of dogs, rats, non-human primates and humans9. Thus, good evidence suggests that local insulin secretion has a key role in the suppression of glucagon secretion by hyperglycaemia in representative mammalian species. As discussed below, the remaining puzzle is whether insulin’s suppressive effects are exerted via somatostatin secretion from δ-cells or by direct effects of insulin on α-cells or, as may well be the case, by both. Using large-scale single-islet cell quantification, the ratio of α-cells to β-cells was shown to be higher in human than in mouse islets, whereas the number of δ-cells and PP-secreting cells is similar in these species (Fig. 1). However, during the characterization of pancreatic islet preparations for clinical trials, it was found that the number of β-cells is three times higher than the number of non-β-islet cells, including α-cells10. Interestingly, α-cells might have distinct roles in humans and rodents in responses to parasympathetic innervation of the islet, serving in the former (only) as a source of acetylcholine that then ‘primes’ β-cells11.
Despite a key role for insulin in suppression of glucagon secretion, the reason for the differences in the ratio of human α-cells to β-cells versus that seen in the rodent is unknown. In this context, it is also important to further investigate potential differences in the α-cell-to-β-cell ratio observed between human islet isolation centres.
α-Cell function and mass in T2DM
Type 2 diabetes mellitus (T2DM) is often thought of as a bi-hormonal disease characterized by hypoinsulinaemia and hyperglucagonaemia with elevated blood levels of glucose. The hypoinsulinaemia results from insufficient insulin secretion and is associated with a 25–50% decrease in β-cell mass12,13,14,15,16,17,18. In contrast to the effects on levels of insulin, patients with T2DM often show persistent fasting hyperglucagonaemia and lack of suppression of glucagon levels in the postprandial state19. This hyperglucagonaemia aggravates the hyperglycaemia induced by the hypoinsulinaemia, as the hyperglucagonaemia enhances hepatic glucose production20. These data suggest a causal role for glucagon in the pathophysiology of T2DM and support the development of pharmacological agents that inhibit glucagon secretion (or action) to alleviate hyperglycaemia in patients with T2DM. The status of these agents has been reviewed elsewhere4,5. Briefly, studies in humans using small-molecule inhibitors or blocking antibodies towards the glucagon receptor have uncovered strong effects on lowering blood levels of glucose but also on-target adverse effects. The essential question for drug development is whether these features can be separated sufficiently to provide a wide enough therapeutic window to allow for safe long-term use.
In particular, blockade of glucagon receptors is associated with α-cell hyperplasia, abnormal lipid metabolism, hepatic steatosis and elevated plasma levels of liver enzymes, making inhibition of α-cell hypersecretion an appealing strategy for treatment of T2DM4,5. The mechanism for the link between inhibition of glucagon receptors in the liver and induction of α-cell hyperplasia is discussed in a subsequent section. This effect is a safety concern as α-cell hyperplasia increases the risk of developing glucagonoma21. Glucagon is known to have potent hypolipaemic effects22,23, including causing a decrease in triglyceride and VLDL release by the liver24,25, a reduction in plasma levels of cholesterol23,25 and stimulation of free fatty acid β-oxidation in the liver26. The decrease in triglyceride and VLDL release is secondary to reduced VLDL apoprotein production22. Glucagon also reduces levels of LDL27. Therefore, it is not surprising that glucagon receptor inhibition is associated with increases in circulating levels of triglycerides and LDL cholesterol in preclinical models and humans28. The increase in levels of LDL cholesterol is also attributed to overexpression of genes with protein products involved in cholesterol synthesis29 and re-absorption30. LDL cholesterol adversely influences the risk of cardiovascular disease and increases levels of LDL cholesterol in the setting of T2DM (the target population of patients for therapies that block glucagon receptors), which is a cause for concern as this effect could potentiate the already elevated risk of cardiovascular disease in these patients. The increased risk of developing hepatic steatosis following glucagon receptor inhibition could be due to reduced free fatty acid β-oxidation in the liver31. The reason for the increase in plasma levels of liver enzymes is unknown. It is important to emphasize that although drugs that antagonize glucagon might be of great benefit for the treatment of T2DM, sufficient levels of basal insulin are required for their maximal therapeutic effects32,33.
Whether α-cell mass is unchanged34,35 or increased15,17,36,37 in patients with T2DM is not clear. Importantly, even in the setting of unchanged α-cell number, the ratio of α-cells to β-cells is higher in patients with T2DM owing to the reduced β-cell mass compared with people who do not have T2DM34. Evidence from the past few years obtained in mouse and non-human primate models of diabetes mellitus and in humans with T2DM suggests that β-cells dedifferentiate and adopt α-cell characteristics38,39,40. This finding is substantiated by the detection of insulin and glucagon bi-hormonal cells in islets from patients with T2DM41. However, it remains to be established whether the dedifferentiated β-cells make a notable contribution to decreased insulin secretion and whether they transdifferentiate into α-cells and secrete glucagon.
In patients with type 1 diabetes mellitus (T1DM), where most (although often not all)42,43 β-cells are lost, α-cells make up three-quarters of the total cell number in islets44; however, the absolute mass and therefore the ratio of α-cells to δ-cells to PP cells does not seem to be altered37. Interestingly, α-cells might be an important source of glucagon-like peptide 1 (GLP1), and other peptides45,46, capable of stimulating insulin secretion to lessen the symptoms of T2DM.
Glucagon secretion is regulated by glucose
Appropriate stimulation of glucagon release from α-cells is particularly important to minimize the impact of acute insulin-induced hypoglycaemia. This form of hypoglycaemia is a major complication of T1DM, and it is estimated to be responsible for up to 4% of all deaths in patients with this disease47. Whereas glucagon release is normally regulated reciprocally to that of insulin, being stimulated as blood concentrations of glucose fall, the response to low blood levels of glucose is progressively diminished in T1DM48,49. Given the preserved α-cell mass, the insufficient glucagon secretion could be due to ‘hypoglycaemia blindness’ in the T1DM α-cell population. The mechanism underlying the inability of the α-cells in patients with T1DM to sense or respond to low blood levels of glucose is unknown.
Although the molecular mechanisms involved in the regulation of insulin secretion are increasingly well understood50, our knowledge of those that mediate the inhibition of glucagon release remains fragmentary. Glucose suppresses glucagon secretion by direct signalling mechanisms involving its uptake and metabolism51 but also indirectly through controlling the release of paracrine factors derived from β-cells (or other islet cells) (Fig. 2) and via glucose-sensing neurons in the brain52. These mechanisms are discussed in subsequent sections and outlined in Supplementary Table 1.
Direct effects of glucose on α-cells
α-Cells display spontaneous oscillations in cytosolic levels of Ca2+ at low (<3 mM) concentrations of glucose, and increases in the glucose concentration lead to both a decrease in electrical activity53 and a fall in cytosolic concentrations and oscillations of Ca2+ (refs54,55,56). Although these changes in Ca2+ are the opposite of those observed in β-cells21, evidence suggests that the initial metabolic sensing of glucose by the α-cells might be similar to that of β-cells57 (Supplementary Table 1). In particular, glucokinase (encoded by GCK in humans and Gck in rodents) is expressed in both cell types58, a feature expected to allow α-cells to respond metabolically to changes in blood concentrations of glucose in the physiological (3–11 mM) and immediate subphysiological (2–3 mM) range. Correspondingly, knockout of Gck in α-cells leads to hyperglucagonaemia and progressive development of hyperglycaemia59. Interestingly, the glucose transporter GLUT2 (encoded by SLC2A2 or Slc2a2 in humans and rodents, respectively), which has an affinity for glucose in the physiological range, is largely absent from α-cells, whereas the higher-affinity glucose transporter GLUT1 (encoded by SLC2A1 or Slc2a1 in humans and rodents, respectively) is present in both mouse60,61 and human62 α-cells. Glucose 6-phosphatase catalytic subunit 2, which might dephosphorylate glucose to establish a futile cycle in β-cells, is also present in human63, although not mouse61, α-cells. The nutrient-sensitive protein kinases AMP-activated protein kinase (AMPK)64 and PAS domain-containing serine/threonine-protein kinase (PASK)65 are also implicated in α-cell glucose sensing. Thus, metabolic sensing of glucose by the α-cell is likely to be similar to that of β-cells but acts through different glucose transporters. The differential expression of GLUT1 and GLUT2 in α-cells versus β-cells might affect the detection glucose range for the sugar and, conceivably, downstream cellular responses.
Mitochondrial metabolism of glucose is central to the stimulation of insulin release from β-cells66,67 and is abnormal in patients with T2DM68. Both α-cells and β-cells express fairly low levels of lactate dehydrogenase (LDHA)69,70 and the monocarboxylate transporter MCT1 (encoded by Slc16a1)71, which are both ‘disallowed’ islet genes (that is, genes for which the expression is suppressed compared with the majority of cells in the body)72,73. Thus, oxidative metabolism of glycolytically derived NADH and pyruvate might be critical for suppressing glucagon secretion. Nonetheless, a study of fluorescence-activated cell sorting (FACS)-purified cells61 revealed that Ldha (sixfold) and Slc16a1 (threefold to fourfold) mRNA levels are significantly higher in mouse α-cells than β-cells61, suggestive of at least partially distinct signalling mechanisms for glucose in the two cell types. As discussed in a subsequent section, RNA sequencing of single human α-cells did not reveal changes in the expression of genes associated with glucose metabolism or related pathways in T2DM; however, the limited sensitivity of this approach might preclude the detection of changes in the expression of disallowed genes.
Paracrine control of glucagon secretion
In addition to glucose, numerous paracrine, hormonal and nervous signals fine-tune glucagon secretion under different physiological conditions74. Possible roles for key paracrine signalling are presented in Fig. 2 and discussed in this section.
Several studies have provided evidence that insulin suppresses glucagon secretion75,76,77. This effect could be mediated directly via insulin receptors on the α-cells or indirectly via increased somatostatin secretion from neighbouring δ-cells78 (Fig. 2). The suppression of glucagon secretion by insulin is, at least in part, mediated by a reduction of intracellular cAMP levels and weakened protein kinase A (PKA) signalling79. α-Cells express somatostatin receptors, and their activation suppresses glucagon secretion78. In T2DM, altered α-cell function could result from a combination of reduced insulin secretion and impaired insulin action80,81,82.
Zn2+ has an important role in the storage of insulin in β-cell secretory granules. In 2003, Ishihara and colleagues83 provided evidence that, in the perfused rat pancreas, glucose-stimulated release of Zn2+ from β-cells contributed to the inhibition of glucagon secretion. However, a similar role for Zn2+ in the control of glucagon secretion from mouse islets has not been found51. Moreover, glucagon secretion was normal when measured in islets from mice with inactivation of the secretory granule Zn2+ transporter ZnT8 (Slc30a8)84 under conditions where release of Zn2+ from the β-cell is essentially eliminated85. Interestingly, presumed loss-of-function variants in the SLC30A8 gene are associated with reduced risk of T2DM86, and inactivation87 or overexpression88 of Slc30a8 selectively in the α-cell enhances or reduces hypoglycaemia-induced glucagon release, respectively, suggesting a possible contribution to altered T2DM risk. Of note, we have also reported that selective deletion of the T2DM-associated gene Tcf7l2, which encodes transcription factor 7-like-2 and is involved in WNT signalling, from the α-cell in mice89 impairs the normal regulation of glucagon secretion by glucose, possibly by increasing Slc30a8 expression (as observed after Tcf7l2 silencing in islets)90. Thus, the actions of the T2DM-associated variants present at the risk loci described here, and some of the ~400 other T2DM risk loci in humans91, might also, at least in part, be mediated via altered release of glucagon. This possibility is an exciting current area of research.
GABA92,93 is stored in specialized vesicles in the β-cells, and GABA release contributes to the inhibition of glucagon secretion in rodents and humans. As mentioned in a subsequent section, GABA might have a role in the reprogramming of α-cells into β-like-cells. This effect of GABA holds promise for replenishing the pool of functional β-cells in diabetes mellitus.
In addition to insulin, GABA and Zn2+ ions, glucagon secretion is regulated by adrenaline, acting via β-adrenergic receptors, as well as by the parasympathetic tone and GABAergic neurons. The activity of the parasympathetic and GABAergic neurons is controlled by glucose in the brain (Fig. 2).
Activators and inhibitors
Figure 3 lists physiological and pharmacological activators and inhibitors of glucagon secretion. For example, catecholamines stimulate glucagon secretion via the activation of adrenergic receptors on both rodent and human α-cells94. Sulfonylureas have been reported to both stimulate and inhibit glucagon release depending on the experimental conditions. The intestinal-derived glucose-dependent insulinotropic polypeptide (GIP) stimulates glucagon secretion and contributes to hyperglycaemia in T2DM95. Accordingly, an antagonist of the GIP receptor dampens hyperglycaemia in T2DM95. Another intestinally derived peptide, GLP1, inhibits glucagon secretion via paracrine mechanisms involving stimulation of somatostatin and potentially insulin secretion96. Inhibitors of dipeptidyl peptidase 4 (DDP4), which degrades and inactivates GLP1, also inhibit glucagon secretion4,5. GLP1 receptor agonists and DPP4 inhibitors are widely used anti-diabetic drugs4,5. Of note, inhibition of the sodium–glucose cotransporter 2 (SGLT2) with dapagliflozin, a treatment now widely used in T2DM to promote glucose loss through the kidney, also triggers glucagon secretion from α-cells97. The potential long-term implications of this unexpected effect of dapagliflozin on the α-cell remain to be determined. Other activators of α-cells and glucagon secretion not mentioned elsewhere in this Review include gastrin-releasing peptide (GRP), acetylcholine from parasympathetic nerves and ghrelin. In addition, leptin, secretin and serotonin inhibit glucagon secretion. The relative contributions of these regulators of human α-cell glucagon secretion in physiology and pathophysiology remain to be determined.
Single α-cell gene expression profiling
A better understanding of the mechanisms involved in the control of glucagon secretion, and its dysregulation in T2DM, has been facilitated by our growing understanding of the molecular identity of the α-cell. In particular, advances in the past 5 years in single-cell RNA sequencing technologies have provided unprecedented insights into the gene expression profiles of human and mouse α-cells63,98,99,100,101,102. Figure 4a exemplifies the workflow for large-scale single human islet cell RNA sequencing. Human α-cells and β-cells express at least 17,000–18,000 genes (Fig. 4b). More genes are likely to be detected once more sensitive RNA sequencing methods become available. The scatterplot of all expressed genes reveals that the transcriptomes of human α-cells and β-cells are strikingly similar. In fact, using a stringent report, we found that only 97 genes (0.47%; n = 20,757 for combined gene sets) are enriched or unique to either cell type (Fig. 4c). The top ten enriched or unique α-cell and β-cell genes103,104 are shown in Fig. 4d. A brief description of each gene and its role in α-cell and β-cell function is provided in Supplementary Table 2. Thus, the phenotypes of α-cells and β-cells are determined by a fairly small number of genes, supporting the observation that the cells of the endocrine pancreas are highly plastic in nature105,106. Similar overlap exists between mouse α-cell and β-cell transcriptomes61,107,108. Correspondingly, an analysis of the expression of islet disallowed genes has revealed broad overlap between these two cell types in mouse islets72. This observation is an important aspect when considering approaches for reprogramming α-cells into β-like-cells as a novel treatment approach for patients with diabetes mellitus.
The liver–α-cell loop
As discussed in the next section, α-cells might provide a source of new β-cells to replace those that are lost or become dysfunctional in T1DM and T2DM. However, to avoid a depletion of the α-cell pool itself, insights are required as to how the proliferation of these cells might be controlled. Amino acids constitute an integral part of a liver–α-cell axis by promoting glucagon secretion and serving as substrates in the process of gluconeogenesis to produce glucose in the liver109. Disruption of the liver–α-cell axis by genetic (using glucagon receptor-deficient or glucagon-deficient mice or liver-specific deletion of Gcgr or the G protein Gs in mice) or pharmacological inhibition of glucagon action using antibodies to glucagon or the glucagon receptor, as well as knockdown of the glucagon receptor using an antisense oligonucleotide approach, has invariably been linked to increased α-cell mass (Fig. 5a). This finding is supported by the observation that rare inactivating mutations in GCGR in humans are associated with glucagonoma21. Amino acids, and in particular glutamine, are critical for promoting α-cell expansion following disruption of the glucagon signalling pathway110,111,112,113. In mouse α-cells, the amino acid transporter SLC38A5 and the amino acid sensor mTOR have important roles in regulating α-cell expansion following inhibition of glucagon action111,112,113 (Fig. 5b). mTOR is also important for α-cell expansion during development in mice114, and the increase in α-cell mass observed after α-cell-selective deletion of AMPK might be explained by a resulting activation of mTORC1, which is involved in the regulation of cell size115. Little is known about the pathways regulating human α-cell proliferation. Human α-cells express several amino acid transporters, but their contribution to α-cell hyperplasia following disruption of hepatic glucagon signalling is a topic for future research113 (Fig. 5b).
α-Cell to β-cell reprogramming
Cell reprogramming strategies for the generation of insulin-producing β-like-cells for the treatment of diabetes mellitus have been investigated and hold promise for the treatment of T1DM and possibly T2DM. The results are encouraging, and restoration of normal glucose levels has been achieved in diabetic animal models116. Several reasons could explain why α-cells might be a good source for new β-cells. First, α-cells and β-cells have the same developmental origin, and these cell types mostly express similar genes104. Second, α-cell to β-cell reprogramming has been accomplished by repression or expression of key transcription factors39,117,118,119 (Fig. 6a), after extreme β-cell loss120 or following treatment of α-cells with circulating factors and pharmacological agents, including GABA and artemisinins121,122,123 (Fig. 6b). The latter studies have also demonstrated that glucagon secretion and detection via an autocrine loop help maintain the α-cell phenotype. Thus, GABA-induced inhibition of glucagon secretion contributes to the instability of the α-cell phenotype and facilitates reprogramming into β-cells. Particularly encouraging are transcriptional data indicating that the phenotypes of human α-cells and β-cells are very similar, which might facilitate reprogramming101. It is important to note, however, that the findings using the artemisinin artemether have been questioned124, although it is unclear whether the conditions used in the latter study (notably the culture period) fully mimic those used in the former study122. The physiological role of GABA for α-cell to β-cell reprogramming remains to be established.
An additional reason why α-cells could be a good source of β-cells is that α-cell mass is maintained in the diabetic state34,35 (see previous sections). Thus, the rate of reprogramming of α-cells into β-like-cells is unlikely to be limited by the availability of α-cells, whereas the pool of α-cells will be depleted and affect blood levels of glucose. This view is supported by an α-cell ablation study in mice demonstrating that only 2% of the α-cell mass is required for normal α-cell function, glucagon signalling and maintenance of blood levels of glucose125. Furthermore, the mechanisms that regulate DNA methylation and chromatin modifications are similar in human α-cells and β-cells, which facilitates α-cell to β-cell reprogramming126,127,128,129,130,131,132. In addition, human α-cells proliferate at a higher rate than other islet cell types and can be induced to proliferate following disruption of the hepatic glucagon signalling pathway133,134,135,136. α-Cell proliferation could help maintain the α-cell mass in a setting of accelerated reprogramming to β-like-cells. However, this maintenance might not be necessary as enhanced glucagon signalling contributes to the diabetic state and a partial reduction in α-cell mass could be beneficial for maintaining optimal glycaemic control. Finally, the remaining α-cells might secrete factors (for example, GLP1) that could accelerate the maturation and increase the function of the newly formed β-like-cells137,138.
These data support the view that further research is needed to understand the detailed molecular mechanisms that govern α-cell and β-cell fates and how to safely promote α-cell to β-cell reprogramming. In patients with T1DM, efforts towards β-cell replacement might need to be combined with immune suppression; however, α-cell to β-cell reprogramming studies in autoimmune non-obese diabetic mice did not require immune suppression to achieve long-term normalization of blood levels of glucose116.
Gene expression in T2DM α-cells
RNA sequencing studies of single human islet cells have revealed that <0.5% of all detected genes are affected in T2DM63,101. Stringent inclusion criteria were applied in the studies to minimize the contribution of, for instance, donor–donor variability, differences in medication and glucose control to the observed changes in gene expression. Of the differentially regulated genes, only a few have an assigned role in islet cell development, growth or function. None of the detected genes are involved in nutrient sensing or intermediary metabolism. Interestingly, 40% of the affected genes have been implicated in cell growth in other cell types, whereas 28% have no known function101. This finding is of interest as reduced β-cell mass in patients with T2DM contributes to onset and progression of the disease (see previously). Figure 7 shows the directionality of change of the affected genes in α-cells from patients with T2DM. Future studies of the affected genes might provide exciting insights into the disease aetiology and unravel druggable pathways for correction of defects in glucagon secretion and maintenance of cell number and phenotype in patients with T2DM.
A novel perspective
Work published in the late 1980s and early 1990s139,140, as well as more recent studies using RNA sequencing and other omics approaches at the single-cell level, have demonstrated substantial heterogeneity in the β-cell population from mice102 and humans63 (reviewed in ref.141). Importantly, β-cells in the intact mouse islet display functional heterogeneity, with a hierarchy existing in which subsets of interconnected cells behave as ‘hubs’ and ‘followers’. The former are able to serve as pacemakers to control overall islet Ca2+ dynamics and insulin secretion142,143. Whether similar α-cell–α-cell connectivity exists and controls overall glucagon secretion remains unclear56 (Fig. 8). Nonetheless, indirect evidence in support of this view includes the remarkably penetrant phenotypes of genetic modifications affecting only a minority (~14%) of α-cells in the mouse87. β-Cell connectivity is altered in human obesity142, in in vitro models of T2DM143 and after disruption of several genes associated with T2DM144,145,146. Whether similar changes might affect the α-cell population is an intriguing proposal (Fig. 8). Of note, α-cell heterogeneity and specialization should be borne in mind when considering therapies that could deplete the α-cell pool to generate new β-cells.
In this article, we have presented an overview of nutrient and stimulus sensing by the α-cell and compared the properties of the α-cell to those of the β-cell. We also described changes that occur in each cell type in T2DM and highlighted critical differences between them in this disease setting. Finally, we discussed the potential for α-cells to serve as a source of new β-like-cells.
Soon, 100 years will have passed since we learned that glucagon has an important role in the maintenance of glucose homeostasis by opposing the glucose-lowering effects of insulin. Although long thought of as culprits, the dysfunction of which contributes to the pathology of both T1DM and T2DM, it now appears that α-cells might also be saviours, able to provide a new source of β-cells. This theory is supported by exciting studies using pharmacological tools to promote the reprogramming of α-cells into insulin-secreting β-cells in a preclinical model of T1DM, resulting in normalization of the blood levels of glucose116. A demonstration of this provocative concept in clinical practice might ultimately herald a new era in diabetes mellitus research and treatment.
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The authors thank Y. Xin and J. Kim for help with preparation of the manuscript and figures. G.A.R. was supported by MRC Programmes (MR/J0003042/1, MR/N00275X/1 and MR/L020149/1 (DIVA)), Wellcome Trust Senior Investigator Award (WT098424AIA), Diabetes UK (BDA11/0004210 and BDA/15/0005275) and Biotechnology and Biological Sciences Research Council (BB/J015873/1) project grants.