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.
Nature Metabolism volume 4, pages 1097–1108 (2022 )Cite this article
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
Get full journal access for 1 year
All prices are NET prices. VAT will be added later in the checkout. Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Banting, F. G. & Best, C. H. The internal secretion of the pancreas. Transl. Res. VII, 251–266 (1992).
Banting, F. G. The history of insulin. Edinb. Med. J. 36, 1–18 (1929).
Ashcroft, F. M. & Rorsman, P. Diabetes mellitus and the β cell: the last ten years. Cell 148, 1160–1171 (2012).
CAS PubMed PubMed Central Article Google Scholar
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).
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).
CAS PubMed Article Google Scholar
McCarthy, M. I. Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 363, 2339–2350 (2010).
CAS PubMed Article Google Scholar
Voight, B. F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Withers, D. J. et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904 (1998).
CAS PubMed Article Google Scholar
Ueki, K. et al. Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes. Nat. Genet. 38, 583–588 (2006).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Leibiger, I. B., Leibiger, B. & Berggren, P.-O. Insulin signaling in the pancreatic β-cell. Annu. Rev. Nutr. 28, 233–251 (2008).
CAS PubMed Article Google Scholar
Brissova, M. et al. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J. Histochem. Cytochem. 53, 1087–1097 (2005).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Dolenšek, J., Rupnik, M. S. & Stožer, A. Structural similarities and differences between the human and the mouse pancreas. Islets 7, e1024405 (2015).
PubMed PubMed Central Article Google Scholar
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
Bosco, D. et al. Unique arrangement of α- and β-cells in human islets of Langerhans. Diabetes 59, 1202–1210 (2010).
CAS PubMed PubMed Central Article Google Scholar
Stožer, A. et al. Functional connectivity in islets of Langerhans from mouse pancreas tissue slices. PLoS Comput. Biol. 9, e1002923 (2013).
PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Nasteska, D. & Hodson, D. J. The role of β cell heterogeneity in islet function and insulin release. J. Mol. Endocrinol. 61, R43–R60 (2018).
CAS PubMed PubMed Central Article Google Scholar
Bader, E. et al. Identification of proliferative and mature β-cells in the islets of Langerhans. Nature 535, 430–434 (2016).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Bilekova, S., Sachs, S. & Lickert, H. Pharmacological targeting of endoplasmic reticulum stress in pancreatic β cells. Trends Pharmacol. Sci. 42, 85–95 (2021).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
George, M. et al. β cell expression of IGF-I leads to recovery from type 1 diabetes. J. Clin. Invest. 109, 1153–1163 (2002).
CAS PubMed PubMed Central Article Google Scholar
Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).
CAS PubMed PubMed Central Article Google Scholar
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).
PubMed PubMed Central Article Google Scholar
Mehran, A. E. et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16, 723–737 (2012).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
PubMed PubMed Central Article Google Scholar
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).
PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Thorens, B. et al. Ins1Cre knock-in mice for β cell-specific gene recombination. Diabetologia 58, 558–565 (2015).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Rachdaoui, N. Insulin: the friend and the foe in the development of type 2 diabetes mellitus. Int. J. Mol. Sci. 21, 1770 (2020).
Leibiger, B. et al. Short-term regulation of insulin gene transcription by glucose. Proc. Natl Acad. Sci. USA 95, 9307–9312 (1998).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
Beith, J. L., Alejandro, E. U. & Johnson, J. D. Insulin stimulates primary β-cell proliferation via Raf-1 kinase. Endocrinology 149, 2251–2260 (2008).
CAS PubMed PubMed Central Article Google Scholar
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).
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Zick, Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci. STKE 2005, e4 (2005).
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).
CAS PubMed Article Google Scholar
Bucris, E. et al. Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells. J. Endocrinol. 230, 291–307 (2016).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Marchetti, P. et al. Insulin inhibits its own secretion from isolated, perifused human pancreatic islets. Acta Diabetol. 32, 75–77 (1995).
CAS PubMed Article Google Scholar
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).
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).
CAS PubMed PubMed Central Article Google Scholar
Ansarullah et al. Inceptor counteracts insulin signalling in β-cells to control glycaemia. Nature 590, 326–331 (2021).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
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).
Wang, Y. J. et al. Single-cell mass cytometry analysis of the human endocrine pancreas. Cell Metab. 24, 616–626 (2016).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Stewart, A. F. et al. Human β-cell proliferation and intracellular signaling: part 3. Diabetes 64, 1872–1885 (2015).
CAS PubMed PubMed Central Article Google Scholar
Alonso, L. C. et al. Glucose infusion in mice: a new model to induce β-cell replication. Diabetes 56, 1792–1801 (2007).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Robitaille, K. et al. High-throughput functional genomics identifies regulators of primary human β cell proliferation. J. Biol. Chem. 291, 4614–4625 (2016).
CAS PubMed PubMed Central Article Google Scholar
Dirice, E. et al. Inhibition of DYRK1A stimulates human β-cell proliferation. Diabetes 65, 1660–1671 (2016).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Shen, W. et al. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nat. Commun. 6, 8372 (2015).
CAS PubMed Article Google Scholar
Shcheglova, E., Blaszczyk, K. & Borowiak, M. Mitogen synergy: an emerging route to boosting human β cell proliferation. Front. Cell Dev. Biol. 9, 734597 (2021).
Wang, P. et al. Human β cell regenerative drug therapy for diabetes: past achievements and future challenges. Front. Endocrinol. 12, 671946 (2021).
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Kaneto, H. et al. Beneficial effects of antioxidants in diabetes: possible protection of pancreatic β-cells against glucose toxicity. Diabetes 48, 2398–2406 (1999).
CAS PubMed Article Google Scholar
Leibowitz, G. et al. Glucose regulation of β-cell stress in type 2 diabetes. Diabetes Obes. Metab. 12, 66–75 (2010).
CAS PubMed Article Google Scholar
Kim, J.-W. & Yoon, K.-H. Glucolipotoxicity in pancreatic β-cells. Diabetes Metab. J. 35, 444–450 (2011).
PubMed PubMed Central Article Google Scholar
Poitout, V. & Robertson, R. P. Glucolipotoxicity: fuel excess and β-cell dysfunction. Endocr. Rev. 29, 351–366 (2008).
CAS PubMed Article Google Scholar
Prentki, M. & Nolan, C. J. Islet β cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006).
CAS PubMed PubMed Central Article Google Scholar
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).
Eizirik, D. L., Cardozo, A. K. & Cnop, M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 29, 42–61 (2008).
CAS PubMed Article Google Scholar
Oslowski, C. M. & Urano, F. A switch from life to death in endoplasmic reticulum stressed β-cells. Diabetes Obes. Metab. 12, 58–65 (2010).
CAS PubMed PubMed Central Article Google Scholar
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).
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).
CAS PubMed Article Google Scholar
Hansen, J. B. et al. Glucolipotoxic conditions induce β-cell iron import, cytosolic ROS formation and apoptosis. J. Mol. Endocrinol. 61, 69–77 (2018).
CAS PubMed Article Google Scholar
Del Guerra, S. et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54, 727–735 (2005).
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).
PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Wajchenberg, B. L. β-cell failure in diabetes and preservation by clinical treatment. Endocr. Rev. 28, 187–218 (2007).
CAS PubMed Article Google Scholar
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).
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Weir, G. C. Glucolipotoxicity, β-cells, and diabetes: the emperor has no clothes. Diabetes 69, 273–278 (2020).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Trudeau, K. M. et al. Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity. J. Cell Biol. 214, 25–34 (2016).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
Hong, S.-W. et al. Clusterin protects lipotoxicity-induced apoptosis via upregulation of autophagy in insulin-secreting cells. Endocrinol. Metab. 35, 943–953 (2020).
Thompson, P. J. et al. Targeted elimination of senescent β cells prevents type 1 diabetes. Cell Metab. 29, 1045–1060 (2019).
CAS PubMed Article Google Scholar
Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).
CAS PubMed Article Google Scholar
He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017).
CAS PubMed PubMed Central Article Google Scholar
Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 (2017).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Niedernhofer, L. J. et al. Nuclear genomic instability and aging. Annu. Rev. Biochem. 87, 295–322 (2018).
CAS PubMed Article Google Scholar
Ardestani, A. et al. MST1 is a key regulator of β cell apoptosis and dysfunction in diabetes. Nat. Med. 20, 385–397 (2014).
CAS PubMed PubMed Central Article Google Scholar
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).
Aguayo-Mazzucato, C. et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30, 129–142 (2019).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Marselli, L. et al. Are we overestimating the loss of β cells in type 2 diabetes? Diabetologia 57, 362–365 (2014).
CAS PubMed Article Google Scholar
Cinti, F. et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 1044–1054 (2016).
CAS PubMed Article Google Scholar
Sachs, S. et al. Targeted pharmacological therapy restores β-cell function for diabetes remission. Nat. Metab. 2, 192–209 (2020).
CAS PubMed Article Google Scholar
Camunas-Soler, J. et al. Patch-seq links single-cell transcriptomes to human islet dysfunction in diabetes. Cell Metab. 31, 1017–1031 (2020).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Oppenländer, L. et al. Vertical sleeve gastrectomy triggers fast β-cell recovery upon overt diabetes. Mol. Metab. 54, 101330 (2021).
PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
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).
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).
CAS PubMed Article Google Scholar
Chaplin, S. Rybelsus: an oral formulation of the GLP‐1 agonist semaglutide. Prescriber 31, 32–33 (2020).
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).
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).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Szczerbinska, I. et al. Large-scale functional genomics screen to identify modulators of human β-cell insulin secretion. Biomedicines 10, 103 (2022).
Yang, Y. et al. Rheb1 promotes glucose-stimulated insulin secretion in human and mouse β-cells by upregulating GLUT expression. Metabolism 123, 154863 (2021).
CAS PubMed Article Google Scholar
Daziano, G. et al. Sortilin-derived peptides promote pancreatic β-cell survival through CREB signaling pathway. Pharmacol. Res. 167, 105539 (2021).
CAS PubMed Article Google Scholar
Ardestani, A. et al. Neratinib protects pancreatic β cells in diabetes. Nat. Commun. 10, 5015 (2019).
Home, P. D. The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes. Metab. 14, 780–788 (2012).
CAS PubMed Article Google Scholar
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).
CAS PubMed PubMed Central Article Google Scholar
Marso, S. P. et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N. Engl. J. Med. 377, 723–732 (2017).
CAS PubMed PubMed Central Article Google Scholar
Najjar, S. M. & Perdomo, G. Hepatic insulin clearance: mechanism and physiology. Physiology 34, 198–215 (2019).
CAS PubMed PubMed Central Article Google Scholar
Caparrotta, T. M. & Evans, M. PEGylated insulin Lispro, (LY2605541)—a new basal insulin analogue. Diabetes Obes. Metab. 16, 388–395 (2013).
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).
PubMed PubMed Central Article Google Scholar
Zeng, Y., Wang, J., Gu, Z. & Gu, Z. Engineering glucose-responsive insulin. Med. Drug Discov. 3, 100010 (2019).
Wang, J. et al. Glucose-responsive insulin and delivery systems: innovation and translation. Adv Mater. 32, 1–35 (2020).
Zhou, X. et al. Oral delivery of insulin with intelligent glucose-responsive switch for blood glucose regulation. J. Nanobiotechnology 18, 96 (2020).
CAS PubMed PubMed Central Article Google Scholar
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).
Cully, M. Findings from DCCT — glycaemic control prevents diabetes complications. Nat. Milestones, Diabetes https://go.nature.com/3wqnYKI (2021).
Inzucchi, S. E. et al. Management of hyperglycemia in type 2 diabetes: A patient- centered approach. Diabetes Care 35, 1364–1379 (2012).
CAS PubMed PubMed Central Article Google Scholar
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).
CAS PubMed Article Google Scholar
Li, Y. et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic. Diabetes Care 27, 2597–2602 (2004).
CAS PubMed Article Google Scholar
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).
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).
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).
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).
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).
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).
CAS PubMed Article Google Scholar
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).
CAS PubMed Article Google Scholar
Yki-Jaarvinen, H. et al. Comparison of insulin regimens in patients with non-insulin dependent diabetes mellitus. Endocrinologist 3, 159 (1993).
Holman, R. R. et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N. Engl. J. Med. 361, 1736–1747 (2009).
CAS PubMed Article Google Scholar
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).
PubMed PubMed Central Article Google Scholar
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).
Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).
CAS PubMed Article Google Scholar
Present address: Immunology Discovery, Genentech Inc., South San Francisco, CA, USA
Present address: The Jackson Laboratory, Bar Harbor, ME, USA
These authors contributed equally: Chirag Jain, Ansarullah.
Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
Chirag Jain, Ansarullah, Sara Bilekova & Heiko Lickert
German Center for Diabetes Research (DZD), Neuherberg, Germany
Chirag Jain, Ansarullah, Sara Bilekova & Heiko Lickert
Chair of β-Cell Biology, Technische Universität München, School of Medicine, Klinikum Rechts der Isar, München, Germany
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
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.
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.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
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
DOI: https://doi.org/10.1038/s42255-022-00618-5
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
Nature Metabolism (Nat Metab) ISSN 2522-5812 (online)
Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.