Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeting pancreatic β cells for diabetes treatment

Abstract

Insulin is a life-saving drug for patients with type 1 diabetes; however, even today, no pharmacotherapy can prevent the loss or dysfunction of pancreatic insulin-producing β cells to stop or reverse disease progression. Thus, pancreatic β cells have been a main focus for cell-replacement and regenerative therapies as a curative treatment for diabetes. In this Review, we highlight recent advances toward the development of diabetes therapies that target β cells to enhance proliferation, redifferentiation and protection from cell death and/or enable selective killing of senescent β cells. We describe currently available therapies and their mode of action, as well as insufficiencies of glucagon-like peptide 1 (GLP-1) and insulin therapies. We discuss and summarize data collected over the last decades that support the notion that pharmacological targeting of β cell insulin signalling might protect and/or regenerate β cells as an improved treatment of patients with diabetes.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Comparative islet architecture overview of mice versus human under healthy and diabetic states.
Fig. 2: Effects of alterations in β cell insulin signalling pathway components on β cell function.
Fig. 3: Targeting inceptor to improve β cell insulin signalling as a potential diabetes therapy.
Fig. 4: Targeting β cells to lower hyperglycaemia.

References

  1. Banting, F. G. & Best, C. H. The internal secretion of the pancreas. Transl. Res. VII, 251–266 (1992).

  2. Banting, F. G. The history of insulin. Edinb. Med. J. 36, 1–18 (1929).

    PubMed Central  Google Scholar 

  3. Ashcroft, F. M. & Rorsman, P. Diabetes mellitus and the β cell: the last ten years. Cell 148, 1160–1171 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vecchio, I., Tornali, C., Bragazzi, N. L. & Martini, M. The discovery of insulin: an important milestone in the history of medicine. Front. Endocrinol. 9, 613 (2018).

    Article  Google Scholar 

  5. Florez, J. C. Newly identified loci highlight β cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51, 1100–1110 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. McCarthy, M. I. Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 363, 2339–2350 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Voight, B. F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nolan, C. J. & Prentki, M. Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: time for a conceptual framework shift. Diab. Vasc. Dis. Res. 16, 118–127 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Kulkarni, R. N. et al. Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96, 329–339 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Withers, D. J. et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Ueki, K. et al. Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes. Nat. Genet. 38, 583–588 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Kulkarni, R. N. Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. Biochem. Soc. Trans. 30, 317–322 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Leibiger, I. B., Leibiger, B. & Berggren, P.-O. Insulin signaling in the pancreatic β-cell. Annu. Rev. Nutr. 28, 233–251 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Brissova, M. et al. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J. Histochem. Cytochem. 53, 1087–1097 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Cabrera, O. et al. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl Acad. Sci. USA 103, 2334–2339 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dolenšek, J., Rupnik, M. S. & Stožer, A. Structural similarities and differences between the human and the mouse pancreas. Islets 7, e1024405 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gan, W. J. et al. Cell polarity defines three distinct domains in pancreatic β-cells. J. Cell Sci. 130, 143–151 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bosco, D. et al. Unique arrangement of α- and β-cells in human islets of Langerhans. Diabetes 59, 1202–1210 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stožer, A. et al. Functional connectivity in islets of Langerhans from mouse pancreas tissue slices. PLoS Comput. Biol. 9, e1002923 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tritschler, S., Theis, F. J., Lickert, H. & Böttcher, A. Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. Mol. Metab. 6, 974–990 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carrano, A. C., Mulas, F., Zeng, C. & Sander, M. Interrogating islets in health and disease with single-cell technologies. Mol. Metab. 6, 991–1001 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nasteska, D. & Hodson, D. J. The role of β cell heterogeneity in islet function and insulin release. J. Mol. Endocrinol. 61, R43–R60 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bader, E. et al. Identification of proliferative and mature β-cells in the islets of Langerhans. Nature 535, 430–434 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Roscioni, S. S., Migliorini, A., Gegg, M. & Lickert, H. Impact of islet architecture on β-cell heterogeneity, plasticity and function. Nat. Rev. Endocrinol. 12, 695–709 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Bilekova, S., Sachs, S. & Lickert, H. Pharmacological targeting of endoplasmic reticulum stress in pancreatic β cells. Trends Pharmacol. Sci. 42, 85–95 (2021).

    Article  CAS  PubMed  Google Scholar 

  26. Iversen, J. & Miles, D. W. Evidence for a feedback inhibition of insulin on insulin secretion in the isolated, perfused canine pancreas. Diabetes 20, 1–9 (1971).

    Article  CAS  PubMed  Google Scholar 

  27. Rappaport, A. M. et al. Effects on insulin output and on pancreatic blood flow of exogenous insulin infusion into an in situ isolated portion of the pancreas. Endocrinology 91, 168–176 (1972).

    Article  CAS  PubMed  Google Scholar 

  28. Okada, T. et al. Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance. Proc. Natl Acad. Sci. USA 104, 8977–8982 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Otani, K. et al. Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice. Am. J. Physiol. Endocrinol. Metab. 286, E41–E49 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Kulkarni, R. N. et al. β-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass. Nat. Genet. 31, 111–115 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. George, M. et al. β cell expression of IGF-I leads to recovery from type 1 diabetes. J. Clin. Invest. 109, 1153–1163 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Johnson, J. D. A practical guide to genetic engineering of pancreatic β-cells in vivo: getting a grip on RIP and MIP. Islets 6, e944439 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mehran, A. E. et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16, 723–737 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Wicksteed, B. et al. Conditional gene targeting in mouse pancreatic β-cells: analysis of ectopic Cre transgene expression in the brain. Diabetes 59, 3090–3098 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Trinder, M., Zhou, L., Oakie, A., Riopel, M. & Wang, R. β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response. Oncotarget 7, 44927–44940 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Skovsø, S. et al. β-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nat. Commun. 13, 735 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Brouwers, B. et al. Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression. Cell Metab. 20, 979–990 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thorens, B. et al. Ins1Cre knock-in mice for β cell-specific gene recombination. Diabetologia 58, 558–565 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Hashimoto, N. et al. Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nat. Genet. 38, 589–593 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Bernal-Mizrachi, E. et al. Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells. J. Clin. Invest. 114, 928–936 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nakae, J. et al. Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat. Genet. 32, 245–253 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Rachdi, L. et al. Disruption of Tsc2 in pancreatic cells induces cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc. Natl Acad. Sci. USA 105, 9250–9255 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rothenberg, P. L., Willison, L. D., Simon, J. & Wolf, B. A. Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting β-cells. Diabetes 44, 802–809 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Velloso, L. A., Carneiro, E. M., Crepaldi, S. C., Boschero, A. C. & Saad, M. J. Glucose- and insulin-induced phosphorylation of the insulin receptor and its primary substrates IRS-1 and IRS-2 in rat pancreatic islets. FEBS Lett. 377, 353–357 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Rachdaoui, N. Insulin: the friend and the foe in the development of type 2 diabetes mellitus. Int. J. Mol. Sci. 21, 1770 (2020).

  47. Leibiger, B. et al. Short-term regulation of insulin gene transcription by glucose. Proc. Natl Acad. Sci. USA 95, 9307–9312 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Leibiger, B., Wahlander, K., Berggren, P. O. & Leibiger, I. B. Glucose-stimulated insulin biosynthesis depends on insulin-stimulated insulin gene transcription. J. Biol. Chem. 275, 30153–30156 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Leibiger, B. et al. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic β cells. Mol. Cell 7, 559–570 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Leibiger, B., Moede, T., Uhles, S., Berggren, P. O. & Leibiger, I. B. Short-term regulation of insulin gene transcription. Biochem. Soc. Trans. 30, 312–317 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Xu, G. G. & Rothenberg, P. L. Insulin receptor signaling in the beta-cell influences insulin gene expression and insulin content: evidence for autocrine β-cell regulation. Diabetes 47, 1243–1252 (1998).

    CAS  PubMed  Google Scholar 

  52. Johnson, J. D. et al. Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome. Proc. Natl Acad. Sci. USA 103, 19575–19580 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Movassat, J., Saulnier, C. & Portha, B. Insulin administration enhances growth of the β-cell mass in streptozotocin-treated newborn rats. Diabetes 46, 1445–1452 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Beith, J. L., Alejandro, E. U. & Johnson, J. D. Insulin stimulates primary β-cell proliferation via Raf-1 kinase. Endocrinology 149, 2251–2260 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Frerichs, H., Reich, U. & Creutzfeldt, W. Insulin secretion in vitro. I. Inhibition of glucose-induced insulin release by insulin. Klin. Wochenschr. 43, 136–140 (1965).

  56. Ammon, H. P., Reiber, C. & Verspohl, E. J. Indirect evidence for short-loop negative feedback of insulin secretion in the rat. J. Endocrinol. 128, 27–34 (1991).

    Article  CAS  PubMed  Google Scholar 

  57. Jimenez-Feltstrom, J., Lundquist, I., Obermuller, S. & Salehi, A. Insulin feedback actions: complex effects involving isoforms of islet nitric oxide synthase. Regul. Pept. 122, 109–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Carpentier, J. L., Fehlmann, M., Van Obberghen, E., Gorden, P. & Orci, L. Insulin receptor internalization and recycling: mechanism and significance. Biochimie 67, 1143–1145 (1985).

    Article  CAS  PubMed  Google Scholar 

  59. Zick, Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci. STKE 2005, e4 (2005).

    Article  Google Scholar 

  60. Guillen, C., Bartolomé, A., Nevado, C. & Benito, M. Biphasic effect of insulin on β cell apoptosis depending on glucose deprivation. FEBS Lett. 582, 3855–3860 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Bucris, E. et al. Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells. J. Endocrinol. 230, 291–307 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Rachdaoui, N., Polo-Parada, L. & Ismail-Beigi, F. Prolonged exposure to insulin inactivates Akt and Erk1/2 and increases pancreatic islet and INS1E β-cell apoptosis. J. Endocr. Soc. 3, 69–90 (2019).

    Article  CAS  PubMed  Google Scholar 

  63. Marchetti, P. et al. Insulin inhibits its own secretion from isolated, perifused human pancreatic islets. Acta Diabetol. 32, 75–77 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Song, S. H. et al. Direct measurement of pulsatile insulin secretion from the portal vein in human subjects. J. Clin. Endocrinol. Metab. 85, 4491–4499 (2000).

    CAS  PubMed  Google Scholar 

  65. Wang, M., Li, J., Lim, G. E. & Johnson, J. D. Is dynamic autocrine insulin signaling possible? A mathematical model predicts picomolar concentrations of extracellular monomeric insulin within human pancreatic islets. PLoS ONE 8, e64860 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ansarullah et al. Inceptor counteracts insulin signalling in β-cells to control glycaemia. Nature 590, 326–331 (2021).

    Article  CAS  PubMed  Google Scholar 

  67. Finegood, D. T., Scaglia, L. & Bonner-Weir, S. Dynamics of β-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44, 249–256 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Weir, G. C. & Bonner‐Weir, S. Islet β cell mass in diabetes and how it relates to function, birth, and death. Ann. N. Y. Acad. Sci. 1281, 92–105 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Meier, J. J. et al. β-cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes 57, 1584–1594 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Kassem, S. A., Ariel, I., Thornton, P. S., Scheimberg, I. & Glaser, B. β-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49, 1325–1333 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Gregg, B. E. et al. Formation of a human β-cell population within pancreatic islets is set early in life. J. Clin. Endocrinol. Metab. 97, 3197–3206 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Perl, S. et al. Significant human β-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. J. Clin. Endocrinol. Metab. 95, E234–E239 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cnop, M. et al. The long lifespan and low turnover of human islet β cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 53, 321–330 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. In’t Veld, P. et al. β-cell replication is increased in donor organs from young patients after prolonged life support. Diabetes 59, 1702–1708 (2010).

    Article  PubMed  Google Scholar 

  75. Ritzel, R. A., Butler, A. E., Rizza, R. A., Veldhuis, J. D. & Butler, P. C. Relationship between β-cell mass and fasting blood glucose concentration in humans. Diabetes Care 29, 717–718 (2006).

    Article  PubMed  Google Scholar 

  76. Wang, Y. J. et al. Single-cell mass cytometry analysis of the human endocrine pancreas. Cell Metab. 24, 616–626 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kulkarni, R. N., Mizrachi, E.-B., Ocana, A. G. & Stewart, A. F. Human β-cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes 61, 2205–2213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bernal-Mizrachi, E. et al. Human β-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes 63, 819–831 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Stewart, A. F. et al. Human β-cell proliferation and intracellular signaling: part 3. Diabetes 64, 1872–1885 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Alonso, L. C. et al. Glucose infusion in mice: a new model to induce β-cell replication. Diabetes 56, 1792–1801 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Levitt, H. E. et al. Glucose stimulates human β cell replication in vivo in islets transplanted into NOD-severe combined immunodeficiency (SCID) mice. Diabetologia 54, 572–582 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Kondegowda, N. G. et al. Osteoprotegerin and denosumab stimulate human β cell proliferation through inhibition of the receptor activator of NF-κB ligand pathway. Cell Metab. 22, 77–85 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Robitaille, K. et al. High-throughput functional genomics identifies regulators of primary human β cell proliferation. J. Biol. Chem. 291, 4614–4625 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dirice, E. et al. Inhibition of DYRK1A stimulates human β-cell proliferation. Diabetes 65, 1660–1671 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang, P. et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic β cell replication. Nat. Med. 21, 383–388 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shen, W. et al. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nat. Commun. 6, 8372 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Shcheglova, E., Blaszczyk, K. & Borowiak, M. Mitogen synergy: an emerging route to boosting human β cell proliferation. Front. Cell Dev. Biol. 9, 734597 (2021).

    Article  PubMed  Google Scholar 

  88. Wang, P. et al. Human β cell regenerative drug therapy for diabetes: past achievements and future challenges. Front. Endocrinol. 12, 671946 (2021).

  89. Robertson, R. P. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet β cells in diabetes. J. Biol. Chem. 279, 42351–42354 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Tanaka, Y., Gleason, C. E., Tran, P. O., Harmon, J. S. & Robertson, R. P. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc. Natl Acad. Sci. USA 96, 10857–10862 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kaneto, H. et al. Beneficial effects of antioxidants in diabetes: possible protection of pancreatic β-cells against glucose toxicity. Diabetes 48, 2398–2406 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Leibowitz, G. et al. Glucose regulation of β-cell stress in type 2 diabetes. Diabetes Obes. Metab. 12, 66–75 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Kim, J.-W. & Yoon, K.-H. Glucolipotoxicity in pancreatic β-cells. Diabetes Metab. J. 35, 444–450 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Poitout, V. & Robertson, R. P. Glucolipotoxicity: fuel excess and β-cell dysfunction. Endocr. Rev. 29, 351–366 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Prentki, M. & Nolan, C. J. Islet β cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. van Raalte, D. H. & Diamant, M. Glucolipotoxicity and β cells in type 2 diabetes mellitus: target for durable therapy? Diabetes Res. Clin. Pract. 93, S37–S46 (2011).

    Article  PubMed  Google Scholar 

  97. Eizirik, D. L., Cardozo, A. K. & Cnop, M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 29, 42–61 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Oslowski, C. M. & Urano, F. A switch from life to death in endoplasmic reticulum stressed β-cells. Diabetes Obes. Metab. 12, 58–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Eguchi, N., Vaziri, N. D., Dafoe, D. C. & Ichii, H. The role of oxidative stress in pancreatic β cell dysfunction in diabetes. Int. J. Mol. Sci. 22, 1509 (2021).

  100. Robertson, R. P., Harmon, J., Tran, P. O., Tanaka, Y. & Takahashi, H. Glucose toxicity in β-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52, 581–587 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Hansen, J. B. et al. Glucolipotoxic conditions induce β-cell iron import, cytosolic ROS formation and apoptosis. J. Mol. Endocrinol. 61, 69–77 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Del Guerra, S. et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54, 727–735 (2005).

    Article  PubMed  Google Scholar 

  103. Maedler, K. et al. Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 127, 1589 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Ehses, J. A., Böni-Schnetzler, M., Faulenbach, M. & Donath, M. Y. Macrophages, cytokines and β-cell death in type 2 diabetes. Biochem. Soc. Trans. 36, 340–342 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Welsh, N. et al. Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes 54, 3238–3244 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Wali, J. A. et al. Activation of the NLRP3 inflammasome complex is not required for stress-induced death of pancreatic islets. PLoS ONE 9, e113128 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Inoue, H. et al. Signaling between pancreatic β cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation. J. Biol. Chem. 293, 5934–5946 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wajchenberg, B. L. β-cell failure in diabetes and preservation by clinical treatment. Endocr. Rev. 28, 187–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. DeFronzo, R. A. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. Int. J. Clin. Pract. Suppl. https://doi.org/10.1111/j.1368-504x.2004.00389.x 9–21 (2004).

  110. Lytrivi, M., Castell, A.-L., Poitout, V. & Cnop, M. Recent insights into mechanisms of β-cell lipo- and glucolipotoxicity in type 2 diabetes. J. Mol. Biol. 432, 1514–1534 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Prentki, M., Peyot, M.-L., Masiello, P. & Madiraju, S. R. M. Nutrient-induced metabolic stress, adaptation, detoxification, and toxicity in the pancreatic β-cell. Diabetes 69, 279–290 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Weir, G. C. Glucolipotoxicity, β-cells, and diabetes: the emperor has no clothes. Diabetes 69, 273–278 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Forouhi, N. G. et al. Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case–cohort study. Lancet Diabetes Endocrinol. 2, 810–818 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cnop, M. et al. RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes 63, 1978–1993 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Mir, S. U. R. et al. Inhibition of autophagic turnover in β-cells by fatty acids and glucose leads to apoptotic cell death. J. Biol. Chem. 290, 6071–6085 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Trudeau, K. M. et al. Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity. J. Cell Biol. 214, 25–34 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Las, G., Serada, S. B., Wikstrom, J. D., Twig, G. & Shirihai, O. S. Fatty acids suppress autophagic turnover in β-cells. J. Biol. Chem. 286, 42534–42544 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen, Y.-Y. et al. Palmitate induces autophagy in pancreatic β-cells via endoplasmic reticulum stress and its downstream JNK pathway. Int. J. Mol. Med. 32, 1401–1406 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Bugliani, M. et al. Modulation of autophagy influences the function and survival of human pancreatic β cells under endoplasmic reticulum stress conditions and in type 2 diabetes. Front. Endocrinol. 10, 52 (2019).

    Article  CAS  Google Scholar 

  120. Hong, S.-W. et al. Clusterin protects lipotoxicity-induced apoptosis via upregulation of autophagy in insulin-secreting cells. Endocrinol. Metab. 35, 943–953 (2020).

    Article  CAS  Google Scholar 

  121. Thompson, P. J. et al. Targeted elimination of senescent β cells prevents type 1 diabetes. Cell Metab. 29, 1045–1060 (2019).

    Article  CAS  PubMed  Google Scholar 

  122. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Prata, L. G. P. L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin. Immunol. 40, 101275 (2018).

    Article  CAS  PubMed  Google Scholar 

  126. Midha, A. et al. Unique human and mouse β-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors. Diabetes 70, 1098–1116 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Niedernhofer, L. J. et al. Nuclear genomic instability and aging. Annu. Rev. Biochem. 87, 295–322 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Ardestani, A. et al. MST1 is a key regulator of β cell apoptosis and dysfunction in diabetes. Nat. Med. 20, 385–397 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Thompson, P. J., Shah, A., Apostolopolou, H. & Bhushan, A. BET proteins are required for transcriptional activation of the senescent islet cell secretome in type 1 diabetes. Int. J. Mol. Sci. 20, 4776 (2019).

  130. Aguayo-Mazzucato, C. et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30, 129–142 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150, 1223–1234 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang, Z., York, N. W., Nichols, C. G. & Remedi, M. S. Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 19, 872–882 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Marselli, L. et al. Are we overestimating the loss of β cells in type 2 diabetes? Diabetologia 57, 362–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Cinti, F. et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 1044–1054 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Sachs, S. et al. Targeted pharmacological therapy restores β-cell function for diabetes remission. Nat. Metab. 2, 192–209 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Camunas-Soler, J. et al. Patch-seq links single-cell transcriptomes to human islet dysfunction in diabetes. Cell Metab. 31, 1017–1031 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kluth, O. et al. Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced β cell failure. Diabetologia 54, 605–616 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Sheng, C. et al. Reversibility of β-cell-specific transcript factors expression by long-term caloric restriction in db/db mouse. J. Diabetes Res. 2016, 6035046 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Casteels, T. et al. An inhibitor-mediated β-cell dedifferentiation model reveals distinct roles for FoxO1 in glucagon repression and insulin maturation. Mol. Metab. 54, 101329 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Oppenländer, L. et al. Vertical sleeve gastrectomy triggers fast β-cell recovery upon overt diabetes. Mol. Metab. 54, 101330 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Butler, A. E. et al. β-cell deficit in obese type 2 diabetes, a minor role of β-cell dedifferentiation and degranulation. J. Clin. Endocrinol. Metab. 101, 523–532 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Amo-Shiinoki, K. et al. Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes. JCI Insight 6, e143791 (2021).

  143. Abd El Aziz, M. S., Kahle, M., Meier, J. J. & Nauck, M. A. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes Obes. Metab. 19, 216–227 (2017).

    Article  CAS  PubMed  Google Scholar 

  144. Chaplin, S. Rybelsus: an oral formulation of the GLP‐1 agonist semaglutide. Prescriber 31, 32–33 (2020).

    Google Scholar 

  145. Danielsen, M. K., Bohsen, D. M., Svarrer, V. B., Rendbæk, A. S. & Root, M. J. Rybelsus® was more effective in achieving clinically relevant blood sugar and weight reductions in people with type 2 diabetes vs all active comparators. Ann Søndermølle Rendbæk 45, 2253 (2020).

  146. Griffith, D. A. et al. A small-molecule oral agonist of the human glucagon-like peptide-1 receptor. J. Med. Chem. 65, 8208–8226 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Cornu, M. et al. Glucagon-like peptide-1 increases β-cell glucose competence and proliferation by translational induction of insulin-like growth factor-1 receptor expression. J. Biol. Chem. 285, 10538–10545 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Szczerbinska, I. et al. Large-scale functional genomics screen to identify modulators of human β-cell insulin secretion. Biomedicines 10, 103 (2022).

  149. Yang, Y. et al. Rheb1 promotes glucose-stimulated insulin secretion in human and mouse β-cells by upregulating GLUT expression. Metabolism 123, 154863 (2021).

    Article  CAS  PubMed  Google Scholar 

  150. Daziano, G. et al. Sortilin-derived peptides promote pancreatic β-cell survival through CREB signaling pathway. Pharmacol. Res. 167, 105539 (2021).

    Article  CAS  PubMed  Google Scholar 

  151. Ardestani, A. et al. Neratinib protects pancreatic β cells in diabetes. Nat. Commun. 10, 5015 (2019).

  152. Home, P. D. The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes. Metab. 14, 780–788 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Owens, D. R. & Bolli, G. B. The continuing quest for better subcutaneously administered prandial insulins: a review of recent developments and potential clinical implications. Diabetes Obes. Metab. 22, 743–754 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Marso, S. P. et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N. Engl. J. Med. 377, 723–732 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Najjar, S. M. & Perdomo, G. Hepatic insulin clearance: mechanism and physiology. Physiology 34, 198–215 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Caparrotta, T. M. & Evans, M. PEGylated insulin Lispro, (LY2605541)—a new basal insulin analogue. Diabetes Obes. Metab. 16, 388–395 (2013).

    Article  PubMed  Google Scholar 

  157. Geho, W. B., Geho, H. C., Lau, J. R. & Gana, T. J. Hepatic-directed vesicle insulin: a review of formulation development and preclinical evaluation. J. Diabetes Sci. Technol. 3, 1451–1459 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Zeng, Y., Wang, J., Gu, Z. & Gu, Z. Engineering glucose-responsive insulin. Med. Drug Discov. 3, 100010 (2019).

    Article  Google Scholar 

  159. Wang, J. et al. Glucose-responsive insulin and delivery systems: innovation and translation. Adv Mater. 32, 1–35 (2020).

    Google Scholar 

  160. Zhou, X. et al. Oral delivery of insulin with intelligent glucose-responsive switch for blood glucose regulation. J. Nanobiotechnology 18, 96 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. The Diabetes Control and Complications Trial Research Group, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–986 (1993).

  162. Cully, M. Findings from DCCT — glycaemic control prevents diabetes complications. Nat. Milestones, Diabetes https://go.nature.com/3wqnYKI (2021).

  163. Inzucchi, S. E. et al. Management of hyperglycemia in type 2 diabetes: A patient- centered approach. Diabetes Care 35, 1364–1379 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Weng, J. et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet 371, 1753–1760 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Li, Y. et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic. Diabetes Care 27, 2597–2602 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Xu, W., Li, Y.-B., Deng, W.-P., Hao, Y.-T. & Weng, J.-P. Remission of hyperglycemia following intensive insulin therapy in newly diagnosed type 2 diabetic patients: a long-term follow-up study. Chin. Med. J. (Engl) 122, 2554–2559 (2009).

    CAS  Google Scholar 

  167. Hanefeld, M., Fleischmann, H., Landgraf, W. & Pistrosch, F. EARLY study: early basal insulin therapy under real-life conditions in type 2 diabetics. Diabetes Stoffw. Herz. 21, 91–97 (2012).

    Google Scholar 

  168. Kramer, C. K., Zinman, P. B. & Retnakaran, R. Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis. Lancet, Diabetes Endocrinol. 1, 28–34 (2013).

    Article  CAS  Google Scholar 

  169. Adeva-Andany, M. M., Martínez-Rodríguez, J., González-Lucán, M., Fernández-Fernández, C. & Castro-Quintela, E. Insulin resistance is a cardiovascular risk factor in humans. Diabetes Metab. Syndr. 13, 1449–1455 (2019).

    Article  PubMed  Google Scholar 

  170. Herman, M. E., O’Keefe, J. H., Bell, D. S. H. & Schwartz, S. S. Insulin therapy increases cardiovascular risk in type 2 diabetes. Prog. Cardiovasc. Dis. 60, 422–434 (2017).

    Article  PubMed  Google Scholar 

  171. Holden, S. E. et al. Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: dose association with all-cause mortality, cardiovascular events and cancer. Diabetes Obes. Metab. 17, 350–362 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Gamble, J.-M. et al. Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study. Lancet Diabetes Endocrinol. 5, 43–52 (2017).

    Article  CAS  PubMed  Google Scholar 

  173. Yki-Jaarvinen, H. et al. Comparison of insulin regimens in patients with non-insulin dependent diabetes mellitus. Endocrinologist 3, 159 (1993).

    Article  Google Scholar 

  174. Holman, R. R. et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N. Engl. J. Med. 361, 1736–1747 (2009).

    Article  CAS  PubMed  Google Scholar 

  175. Bonds, D. E. et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 340, b4909 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Skyler, J. S. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 32, e92–e93 (2009).

    Article  Google Scholar 

  177. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

C.J., A., S.B. and H.L. conceived the concepts described in this review. C.J., A., S.B. and H.L. wrote the manuscript. Figures were prepared by C.J., A. and S.B.

Corresponding author

Correspondence to Heiko Lickert.

Ethics declarations

Competing interests

The authors declare no competing interest. C.J. works as a fulltime employee at Genentech Inc., CA 94080, USA, and A. works as a fulltime employee at The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Peer review

Peer review information

Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jain, C., Ansarullah, Bilekova, S. et al. Targeting pancreatic β cells for diabetes treatment. Nat Metab 4, 1097–1108 (2022). https://doi.org/10.1038/s42255-022-00618-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-022-00618-5

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing