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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Best, C. H. in Glucagon: Molecular Physiology, Clinical and Therapeutic Implications Ch. 1 (eds Lefebvre, P. J. & Unger, R. H.) 1–6 (Pergamon Press, Oxford, 1972).
Murlin, J. R., Clough, H. D., Gibbs, C. B. F. & Stokes, A. M. Aqueous extracts of the pancreas. 1 Influence on the carbohydrate metabolism of depancreatized animals. J. Biol. Chem. 56, 253–296 (1923).
Sutherland, E. W. & De Duve, C. Origin and distribution of the hyperglycemic-glycogenolytic factor of the pancreas. J. Biol. Chem. 175, 663–674 (1948).
Muller, T. D., Finan, B., Clemmensen, C., DiMarchi, R. D. & Tschop, M. H. The new biology and pharmacology of glucagon. Physiol. Rev. 97, 721–766 (2017).
Sandoval, D. A. & D’Alessio, D. A. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol. Rev. 95, 513–548 (2015).
Lane, M. A. The cytological characters of the areas of langerhans. Am. J. Anat. 7, 409–422 (1907).
Bonner-Weir, S., Sullivan, B. A. & Weir, G. C. Human islet morphology revisited: human and rodent islets are not so different after all. J. Histochem. Cytochem. 63, 604–612 (2015).
Maruyama, H., Hisatomi, A., Orci, L., Grodsky, G. M. & Unger, R. H. Insulin within islets is a physiologic glucagon release inhibitor. J. Clin. Invest. 74, 2296–2299 (1984).
Stagner, J. I. & Samols, E. The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41, 93–97 (1992).
Pisania, A. et al. Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab. Invest. 90, 1661–1675 (2010).
Rodriguez-Diaz, R. et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat. Med. 17, 888–892 (2011).
Cerasi, E. Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible? Diabetologia 38, 992–997 (1995).
Kahn, S. E., Zraika, S., Utzschneider, K. M. & Hull, R. L. The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia 52, 1003–1012 (2009).
Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).
Clark, A. et al. Islet amyloid, increased A-cells, reduced B cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 9, 151–159 (1988).
Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. & Henquin, J. C. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes. Metab. 10, 32–42 (2008).
Sakuraba, H. et al. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia 45, 85–96 (2002).
Marselli, L. et al. Are we overestimating the loss of beta cells in type 2 diabetes? Diabetologia 57, 362–365 (2014).
Muller, W. A., Faloona, G. R., Aguilar-Parada, E. & Unger, R. H. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N. Engl. J. Med. 283, 109–115 (1970).
Myers, S. R. et al. Effects of small changes in glucagon on glucose production during a euglycemic, hyperinsulinemic clamp. Metabolism 40, 66–71 (1991).
Yu, R. Pancreatic alpha-cell hyperplasia: facts and myths. J. Clin. Endocrinol. Metab. 99, 748–756 (2014).
Eaton, R. P. Hypolipemic action of glucagon in experimental endogenous lipemia in the rat. J. Lipid Res. 14, 312–318 (1973).
Guettet, C. et al. Effect of chronic glucagon administration on lipoprotein composition in normally fed, fasted and cholesterol-fed rats. Lipids 26, 451–458 (1991).
Bobe, G., Ametaj, B. N., Young, J. W. & Beitz, D. C. Potential treatment of fatty liver with 14-day subcutaneous injections of glucagon. J. Dairy Sci. 86, 3138–3147 (2003).
Guettet, C., Mathe, D., Navarro, N. & Lecuyer, B. Effects of chronic glucagon administration on rat lipoprotein composition. Biochim. Biophys. Acta 1005, 233–238 (1989).
Prip-Buus, C., Pegorier, J. P., Duee, P. H., Kohl, C. & Girard, J. Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit. Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes. Biochem. J. 269, 409–415 (1990).
Brown, N. F., Salter, A. M., Fears, R. & Brindley, D. N. Glucagon, cyclic AMP and adrenaline stimulate the degradation of low-density lipoprotein by cultured rat hepatocytes. Biochem. J. 262, 425–429 (1989).
Nunez, D. J. & D’Alessio, D. Glucagon receptor as a drug target: a witches’ brew of eye of newt (peptides) and toe of frog (receptors). Diabetes Obes. Metab. 20, 233–237 (2018).
Han, S. et al. Effects of small interfering RNA-mediated hepatic glucagon receptor inhibition on lipid metabolism in db/db mice. J. Lipid Res. 54, 2615–2622 (2013).
Guan, H. P. et al. Glucagon receptor antagonism induces increased cholesterol absorption. J. Lipid Res. 56, 2183–2195 (2015).
Bechmann, L. P. et al. The interaction of hepatic lipid and glucose metabolism in liver diseases. J. Hepatol. 56, 952–964 (2012).
Damond, N. et al. Blockade of glucagon signaling prevents or reverses diabetes onset only if residual beta-cells persist. eLife 5, 10 (2016).
Holst, J. J. et al. Insulin and glucagon: partners for life. Endocrinology 158, 696–701 (2017).
Henquin, J. C. & Rahier, J. Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia 54, 1720–1725 (2011).
Stefan, Y. et al. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 8, 694–700 (1982).
Nano, R. et al. Human islet distribution programme for basic research: activity over the last 5 years. Diabetologia 58, 1138–1140 (2015).
Rahier, J., Goebbels, R. M. & Henquin, J. C. Cellular composition of the human diabetic pancreas. Diabetologia 24, 366–371 (1983).
Cinti, F. et al. Evidence of beta-cell dedifferentiation in human type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 1044–1054 (2016).
Gao, T. et al. Pdx1 maintains beta cell identity and function by repressing an alpha cell program. Cell Metab. 19, 259–271 (2014).
Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150, 1223–1234 (2012).
Mezza, T. et al. Beta-cell glucose sensitivity is linked to insulin/glucagon bihormonal cells in nondiabetic humans. J. Clin. Endocrinol. Metab. 101, 470–475 (2016).
Keenan, H. A. et al. Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59, 2846–2853 (2010).
Oram, R. A. et al. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia 57, 187–191 (2014).
Orci, L. et al. Hypertrophy and hyperplasia of somatostatin-containing D-cells in diabetes. Proc. Natl Acad. Sci. USA 73, 1338–1342 (1976).
Marchetti, P. et al. A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia 55, 3262–3272 (2012).
Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).
Cryer, P. E. Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes*. Diabetologia 45, 937–948 (2002).
Gerich, J. E., Langlois, M., Noacco, C., Karam, J. H. & Forsham, P. H. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science 182, 171–173 (1973).
Bolli, G. et al. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32, 134–141 (1983).
Rutter, G. A., Pullen, T. J., Hodson, D. J. & Martinez-Sanchez, A. Pancreatic beta cell identity, glucose sensing and the control of insulin secretion. Biochem. J. 466, 202–218 (2015).
Ravier, M. A. & Rutter, G. A. Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic alpha-cells. Diabetes 54, 1789–1797 (2005).
Lamy, C. M. et al. Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Cell Metab. 19, 527–538 (2014).
Rorsman, P. & Hellman, B. Voltage-activated currents in guinea pig pancreatic alpha 2 cells. Evidence for Ca2+-dependent action potentials. J. Gen. Physiol. 91, 223–242 (1988).
Berts, A., Gylfe, E. & Hellman, B. Ca2+ oscillations in pancreatic islet cells secreting glucagon and somatostatin. Biochem. Biophys. Res. Commun. 208, 644–649 (1995).
Berts, A., Ball, A., Gylfe, E. & Hellman, B. Suppression of Ca2+ oscillations in glucagon-producing alpha 2-cells by insulin/glucose and amino acids. Biochim. Biophys. Acta 1310, 212–216 (1996).
Nadal, A., Quesada, I. & Soria, B. Homologous and heterologous asynchronicity between identified alpha-, beta- and delta-cells within intact islets of Langerhans in the mouse. J. Physiol. 517, 85–93 (1999).
Grapengiesser, E., Gylfe, E. & Hellman, B. Glucose effects on cytoplasmic Ca2+ of individual pancreatic beta- cells recorded by two procedures for dual-wavelength fluorometry. Exp. Clin. Endocrinol. 93, 321–327 (1989).
Heimberg, H. et al. The glucose sensor protein glucokinase is expressed in glucagon-producing alpha-cells. Proc. Natl Acad. Sci. USA 93, 7036–7041 (1996).
Basco, D. et al. Alpha-cell glucokinase suppresses glucose-regulated glucagon secretion. Nat. Commun. 9, 546–03034 (2018).
Heimberg, H., De Vos, A., Pipeleers, D., Thorens, B. & Schuit, F. Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization. J. Biol. Chem. 270, 8971–8975 (1995).
Benner, C. et al. The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15, 620–615 (2014).
Blodgett, D. M. et al. Novel observations from next-generation RNA sequencing of highly purified human adult and fetal islet cell subsets. Diabetes 64, 3172–3181 (2015).
Segerstolpe, A. et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 24, 593–607 (2016).
Sun, G. et al. LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia. Mol. Metab. 4, 277–286 (2015).
Semplici, F. et al. Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production. Diabetologia 59, 1938–1947 (2016).
Hutton, J. C. et al. Similarities in the stimulus-secretion coupling mechanisms of glucose- and 2-keto acid-induced insulin release. Endocrinology 106, 203–219 (1980).
Maechler, P. & Wollheim, C. B. Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell. J. Physiol. 529, 49–56 (2000).
Del Guerra, S. et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54, 727–735 (2005).
Sekine, N. et al. Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogease in pancreatic β-cell. Potential role in nutrient sensing. J. Biol. Chem. 269, 4895–4902 (1994).
Jijakli, H. et al. Relevance of lactate dehydrogenase activity to the control of oxidative glycolysis in pancreatic islet B cells. Arch. Biochem. Biophys. 327, 260–264 (1996).
Zhao, C., Wilson, C. M., Schuit, F., Halestrap, A. P. & Rutter, G. A. Expression and distribution of lactate/monocarboxylate transporter (MCT) isoforms in pancreatic islets and the exocrine pancreas. Diabetes 50, 361–366 (2001).
Pullen, T. J., Huising, M. O. & Rutter, G. A. Analysis of purified pancreatic islet beta and alpha cell transcriptomes reveals 11β-hydroxysteroid dehydrogenase (Hsd11b1) as a novel disallowed gene. Front. Genet. 8, 41 (2017).
Lemaire, K., Thorrez, L. & Schuit, F. Disallowed and allowed gene expression: two faces of mature islet beta cells. Annu. Rev. Nutr. 36, 45–71 (2016).
Gromada, J., Franklin, I. & Wollheim, C. B. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr. Rev. 28, 84–116 (2007).
Taborsky, G. J. et al. Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia. Diabetes Nutr. Metab. 15, 318–322 (2002).
Maruyama, H., Tominaga, M., Bolli, G., Orci, L. & Unger, R. H. The alpha cell response to glucose change during perfusion of anti-insulin serum in pancreas isolated from normal rats. Diabetologia 28, 836–840 (1985).
Kawamori, D. et al. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metab. 9, 350–361 (2009).
Briant, L. J. B. et al. Delta-cells and beta-cells are electrically coupled and regulate alpha-cell activity via somatostatin. J. Physiol. 596, 197–215 (2018).
Elliott, A. D., Ustione, A. & Piston, D. W. Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic alpha-cell by lowering cAMP. Am. J. Physiol. Endocrinol. Metab. 308, E130–E143 (2015).
Lee, Y. et al. Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells. Proc. Natl Acad. Sci. USA 111, 13217–13222 (2014).
Faerch, K. et al. Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation. Diabetes 65, 3473–3481 (2016).
Sharma, A. et al. Impaired insulin action is associated with increased glucagon concentrations in nondiabetic humans. J. Clin. Endocrinol. Metab. 103, 314–319 (2018).
Ishihara, H., Maechler, P., Gjinovci, A., Herrera, P. L. & Wollheim, C. B. Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. Nat. Cell Biol. 5, 330–335 (2003).
Nicolson, T. J. et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58, 2070–2083 (2009).
Li, D. et al. Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR). Proc. Natl Acad. Sci. USA 108, 21063–21068 (2011).
Sladek, R. et al. A genome-wide assocation study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).
Solomou, A. et al. The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic α cells for hypoglycemia-induced glucagon secretion. J. Biol. Chem. 290, 21432–21442 (2015).
Solomou, A. et al. Over-expression of Slc30a8/ZnT8 selectively in the mouse alpha cell impairs glucagon release and responses to hypoglycemia. Nutr. Metab. 13, 46–0104 (2016).
da Silva Xavier, G. et al. Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice. Diabetologia 60, 1043–1050 (2017).
da Silva Xavier, G. et al. TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes 58, 894–905 (2009).
Fuchsberger, C. et al. The genetic architecture of type 2 diabetes. Nature 536, 41–47 (2016).
Rorsman, P. et al. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature 341, 233–236 (1989).
Bailey, S. J., Ravier, M. A. & Rutter, G. A. Glucose-dependent regulation of γ-aminobutyric acid (GABA A) receptor expression in mouse pancreatic islet alpha-cells. Diabetes 56, 320–327 (2007).
Taborsky, G. J. Jr, Ahren, B. & Havel, P. J. Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired alpha-cell responses in type 1 diabetes. Diabetes 47, 995–1005 (1998).
Gasbjerg, L. S. et al. Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents. Peptides 100, 173–181 (2018).
Orgaard, A. & Holst, J. J. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice. Diabetologia 60, 1731–1739 (2017).
Madaan, T., Akhtar, M. & Najmi, A. K. Sodium glucose cotransporter 2 (SGLT2) inhibitors: current status and future perspective. Eur. J. Pharm. Sci. 93, 244–252 (2016).
Baron, M. et al. A single-cell transcriptomic map of the human and mouse pancreas reveals inter- and intra-cell population structure. Cell Syst. 3, 346–360 (2016).
Muraro, M. J. et al. A single-cell transcriptome atlas of the human pancreas. Cell Syst. 3, 385–394 (2016).
Li, J. et al. Single-cell transcriptomes reveal characteristic features of human pancreatic islet cell types. EMBO Rep. 17, 178–187 (2016).
Xin, Y. et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab. 24, 608–615 (2016).
Xin, Y. et al. Use of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells. Proc. Natl Acad. Sci. USA 113, 3293–3298 (2016).
Dominguez, G. G. et al. Gene signature of proliferating human pancreatic alpha-cells. Endocrinology 159, 3177–3186 (2018).
Xin, Y. et al. Pseudotime ordering of single human beta-cells reveals states of insulin production and unfolded protein response. Diabetes 67, 1783–1794 (2018).
Tritschler, S., Theis, F. J., Lickert, H. & Bottcher, A. Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. Mol. Metab. 6, 974–990 (2017).
Ziv, O., Glaser, B. & Dor, Y. The plastic pancreas. Dev. Cell 26, 3–7 (2013).
Adriaenssens, A. E. et al. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets. Diabetologia 59, 2156–2165 (2016).
DiGruccio, M. R. et al. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Mol. Metab. 5, 449–458 (2016).
Holst, J. J., Wewer Albrechtsen, N. J., Pedersen, J. & Knop, F. K. Glucagon and amino acids are linked in a mutual feedback cycle: the liver-alpha-cell axis. Diabetes 66, 235–240 (2017).
Longuet, C. et al. Liver-specific disruption of the murine glucagon receptor produces alpha-cell hyperplasia: evidence for a circulating alpha-cell growth factor. Diabetes 62, 1196–1205 (2013).
Solloway, M. J. et al. Glucagon couples hepatic amino acid catabolism to mTOR-dependent regulation of alpha-cell mass. Cell Rep. 12, 495–510 (2015).
Dean, E. D. et al. Interrupted glucagon signaling reveals hepatic alpha cell axis and role for L-glutamine in alpha cell proliferation. Cell Metab. 25, 1362–1373 (2017).
Kim, J. et al. Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic alpha cell hyperplasia in mice. Cell Metab. 25, 1348–1361 (2017).
Bozadjieva, N. et al. Loss of mTORC1 signaling alters pancreatic alpha cell mass and impairs glucagon secretion. J. Clin. Invest. 127, 4379–4393 (2017).
Sayers, S. R. et al. Proglucagon promoter cre-mediated AMPK deletion in mice increases circulating GLP-1 levels and oral glucose tolerance. PLOS ONE 11, e0149549 (2016).
Xiao, X. et al. Endogenous reprogramming of alpha cells into beta cells, induced by viral gene therapy, reverses autoimmune diabetes. Cell Stem Cell 22, 78–90 (2018).
Chakravarthy, H. et al. Converting adult pancreatic islet alpha cells into beta cells by targeting both Dnmt1 and Arx. Cell Metab. 25, 622–634 (2017).
Wilcox, C. L., Terry, N. A., Walp, E. R., Lee, R. A. & May, C. L. Pancreatic alpha-cell specific deletion of mouse Arx leads to alpha-cell identity loss. PLOS ONE 8, e66214 (2013).
Courtney, M. et al. The inactivation of Arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells. PLOS Genet. 9, e1003934 (2013).
Thorel, F. et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149–1154 (2010).
Lu, J. et al. IGFBP1 increases beta-cell regeneration by promoting alpha- to beta-cell transdifferentiation. EMBO J. 35, 2026–2044 (2016).
Ben-Othman, N. et al. Long-term GABA administration induces alpha cell-mediated beta-like cell neogenesis. Cell 168, 73–85 (2017).
Brown, M. L., Andrzejewski, D., Burnside, A. & Schneyer, A. L. Activin enhances alpha- to beta-cell transdifferentiation as a source for beta-cells in male FSTL3 knockout mice. Endocrinology 157, 1043–1054 (2016).
van der Meulen, T. et al. Artemether does not turn alpha cells into beta cells. Cell Metab. 27, 218–225 (2018).
Thorel, F. et al. Normal glucagon signaling and beta-cell function after near-total alpha-cell ablation in adult mice. Diabetes 60, 2872–2882 (2011).
Ackermann, A. M., Wang, Z., Schug, J., Naji, A. & Kaestner, K. H. Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes. Mol. Metab. 5, 233–244 (2016).
Bramswig, N. C. et al. Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming. J. Clin. Invest. 123, 1275–1284 (2013).
Papizan, J. B. et al. Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming. Genes Dev. 25, 2291–2305 (2011).
Avrahami, D. et al. Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved beta cell function. Cell Metab. 22, 619–632 (2015).
Dhawan, S. et al. DNA methylation directs functional maturation of pancreatic beta cells. J. Clin. Invest. 125, 2851–2860 (2015).
Arda, H. E. et al. Age-dependent pancreatic gene regulation reveals mechanisms governing human beta cell function. Cell Metab. 23, 909–920 (2016).
Moran, I. et al. Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab. 16, 435–448 (2012).
Wang, Y. J. et al. Single-cell mass cytometry analysis of the human endocrine pancreas. Cell Metab. 24, 616–626 (2016).
Sipos, B. et al. Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. J. Clin. Endocrinol. Metab. 100, E783–E788 (2015).
Larger, E. et al. Pancreatic alpha-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation. Endocrinol. Diabetes Metab. Case Rep. 2016, 16-0081 (2016).
Challis, B. G. et al. Heterogeneity of glucagonomas due to differential processing of proglucagon-derived peptides. Endocrinol. Diabetes Metab. Case Rep. 2015, 150105 (2015).
Chambers, A. P. et al. The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab. 25, 927–934 (2017).
Traub, S. et al. Pancreatic alpha cell-derived glucagon-related peptides are required for beta cell adaptation and glucose homeostasis. Cell Rep. 18, 3192–3203 (2017).
Saloman, D. & Meda, P. Heterogeneity and contact-dependent regulation of hormone secretion by individual B cells. Exp. Cell Res. 162, 507–520 (1986).
Pipeleers, D. G. Heterogeneity in pancreatic β-cell population. Diabetes 41, 777–781 (1992).
Gutierrez, G. D., Gromada, J. & Sussel, L. Heterogeneity of the pancreatic beta cell. Front. Genet. 8, 22 (2017).
Hodson, D. J. et al. Lipotoxicity disrupts incretin-regulated human beta cell connectivity. J. Clin. Invest. 123, 4182–4194 (2013).
Johnston, N. R. et al. Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab. 24, 389–401 (2016).
Mitchell, R. K. et al. Selective disruption of Tcf7l2 in the pancreatic beta cell impairs secretory function and lowers beta cell mass. Hum. Mol. Genet. 24, 1390–1399 (2014).
Hodson, D. J. et al. ADCY5 couples glucose to insulin secretion in human islets. Diabetes 63, 3009–3021 (2014).
Mitchell, R. K. et al. The transcription factor Pax6 is required for pancreatic beta cell identity, glucose-regulated ATP synthesis, and Ca2+ dynamics in adult mice. J. Biol. Chem. 292, 8892–8906 (2017).
Rutter, G. A. GABA signaling: a route to new pancreatic beta cells. Cell Res. 27, 309–310 (2017).
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.