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Current Diabetes Reports

01.09.2019 | Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)

The Beta Cell in Type 2 Diabetes

Erschienen in: Current Diabetes Reports | Ausgabe 9/2019

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Abstract

Purpose of Review

This review summarizes the alterations in the β-cell observed in type 2 diabetes (T2D), focusing on changes in β-cell identity and mass and changes associated with metabolism and intracellular signaling.

Recent Findings

In the setting of T2D, β-cells undergo changes in gene expression, reverting to a more immature state and in some cases transdifferentiating into other islet cell types. Alleviation of metabolic stress, ER stress, and maladaptive prostaglandin signaling could improve β-cell function and survival.

Summary

The β-cell defects leading to T2D likely differ in different individuals and include variations in β-cell mass, development, β-cell expansion, responses to ER and oxidative stress, insulin production and secretion, and intracellular signaling pathways. The recent recognition that some β-cells undergo dedifferentiation without dying in T2D suggests strategies to revive these cells and rejuvenate their functionality.
Literatur
1.
Ahren B, Pacini G. Insufficient islet compensation to insulin resistance vs. reduced glucose effectiveness in glucose-intolerant mice. Am J Physiol Endocrinol Metab. 2002;283(4):E738–44.PubMedCrossRef
2.
3.
Zhang H, Zhang J, Pope CF, Crawford LA, Vasavada RC, Jagasia SM, et al. Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen. Diabetes. 2010;59(1):143–52.PubMedPubMedCentralCrossRef
4.
Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA. Very slow turnover of beta-cells in aged adult mice. Diabetes. 2005;54(9):2557–67.PubMedCrossRef
5.
6.
Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, et al. PDGF signalling controls age-dependent proliferation in pancreatic beta-cells. Nature. 2011;478(7369):349–55.PubMedPubMedCentralCrossRef
7.
Wong ES, et al. p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev Cell. 2009;17(1):142–9.PubMedCrossRef
8.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10.PubMedCrossRef
9.
Fontes G, et al. Glucolipotoxicity age-dependently impairs beta cell function in rats despite a marked increase in beta cell mass. Diabetologia. 2010;53(11):2369–79.PubMedPubMedCentralCrossRef
10.
Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, et al. Beta-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014;37(6):1751–8.PubMedPubMedCentralCrossRef
11.
Cerf ME. High fat programming of beta cell compensation, exhaustion, death and dysfunction. Pediatr Diabetes. 2015;16(2):71–8.PubMedCrossRef
12.
Sachdeva MM, Claiborn KC, Khoo C, Yang J, Groff DN, Mirmira RG, et al. Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc Natl Acad Sci U S A. 2009;106(45):19090–5.CrossRef
13.
Arunagiri A, Haataja L, Cunningham CN, Shrestha N, Tsai B, Qi L, et al. Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes. Ann N Y Acad Sci. 2018;1418(1):5–19.PubMedPubMedCentralCrossRef
14.
Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. Beta-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36(1):111–7.PubMedCrossRef
15.
Butler AE, Dhawan S, Hoang J, Cory M, Zeng K, Fritsch H, et al. Beta-cell deficit in obese type 2 diabetes, a minor role of beta-cell dedifferentiation and degranulation. J Clin Endocrinol Metab. 2016;101(2):523–32.
16.
Deng S, Vatamaniuk M, Huang X, Doliba N, Lian MM, Frank A, et al. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes. 2004;53(3):624–32.PubMedCrossRef
17.
Jurgens CA, Toukatly MN, Fligner CL, Udayasankar J, Subramanian SL, Zraika S, et al. Beta-cell loss and beta-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol. 2011;178(6):2632–40.
18.
19.
Elsakr JM, Gannon M. Developmental programming of the pancreatic islet by in utero overnutrition. Trends Dev Biol. 2017;10:79–95.PubMedPubMedCentral
20.
Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012;150(6):1223–34.PubMedPubMedCentralCrossRef
21.
•• Nordmann TM, Dror E, Schulze F, Traub S, Berishvili E, Barbieux C, et al. The Role of Inflammation in beta-cell dedifferentiation. Sci Rep. 2017;7(1):6285. Findings from this study reveal that inflammatory cytokines associated with chronic inflammation promote beta cell dedifferentiation in mouse and human islets.
22.
23.
Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, et al. Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Invest. 2013;123(8):3305–16.
24.
Conrad E, Stein R, Hunter CS. Revealing transcription factors during human pancreatic beta cell development. Trends Endocrinol Metab. 2014;25(8):407–14.PubMedPubMedCentralCrossRef
25.
26.
27.
Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 2005;25(12):4969–76.PubMedPubMedCentralCrossRef
28.
Spijker HS, Ravelli RBG, Mommaas-Kienhuis AM, van Apeldoorn AA, Engelse MA, Zaldumbide A, et al. Conversion of mature human beta-cells into glucagon-producing alpha-cells. Diabetes. 2013;62(7):2471–80.PubMedPubMedCentralCrossRef
29.
Cieslar-Pobuda A, et al. Transdifferentiation and reprogramming: overview of the processes, their similarities and differences. Biochim Biophys Acta, Mol Cell Res. 2017;1864(7):1359–69.CrossRef
30.
•• Gutierrez GD, et al. Pancreatic beta cell identity requires continual repression of non-beta cell programs. J Clin Invest. 2017;127(1):244–59. In this study, Nkx2.2, a transcription factor important for beta cell differentiation, was also found to be critical for sustained active maintenance of the beta cell phenotype in adulthood. Studies in mouse and human islets revealed that Nkx2.2 actively represses non-beta cell genes in addtion to activating genes involved in beta cell function. PubMedCrossRef
31.
Moin AS, Dhawan S, Cory M, Butler PC, Rizza RA, Butler AE. Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes. J Clin Endocrinol Metab. 2016;101(10):3628–36.CrossRef
32.
Gao T, McKenna B, Li C, Reichert M, Nguyen J, Singh T, et al. Pdx1 maintains beta cell identity and function by repressing an alpha cell program. Cell Metab. 2014;19(2):259–71.
33.
Collombat P, Hecksher-Sørensen J, Krull J, Berger J, Riedel D, Herrera PL, et al. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. J Clin Invest. 2007;117(4):961–70.
34.
Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. Evidence of beta-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1044–54.
35.
Spijker HS, Song H, Ellenbroek JH, Roefs MM, Engelse MA, Bos E, et al. Loss of beta-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes. 2015;64(8):2928–38.PubMedCrossRef
36.
Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464(7292):1149–54.PubMedPubMedCentralCrossRef
37.
Ye L, Robertson MA, Hesselson D, Stainier DYR, Anderson RM. Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis. Development. 2015;142(8):1407–17.PubMedPubMedCentralCrossRef
38.
Lee SH, et al., Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation. Islets, 2018: p. 1–12.
39.
Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455(7213):627–32.PubMedCrossRefPubMedCentral
40.
Clayton HW, Osipovich AB, Stancill JS, Schneider JD, Vianna PG, Shanks CM, et al. Pancreatic inflammation redirects acinar to beta cell reprogramming. Cell Rep. 2016;17(8):2028–41.
41.
• van der Meulen T, et al. Virgin beta cells persist throughout life at a neogenic niche within pancreatic islets. Cell Metab. 2017;25(4):911–926 e6. This study identified a population of immature beta-like cells within mouse islets that are derived from the transdifferentiation of non-beta cell precursors. These cells are capable of maturing into fully functional, mature beta cells. PubMedCrossRefPubMedCentral
42.
Quintens R, Hendrickx N, Lemaire K, Schuit F. Why expression of some genes is disallowed in beta-cells. Biochem Soc Trans. 2008;36(Pt 3):300–5.PubMedCrossRef
43.
Pullen TJ, Khan AM, Barton G, Butcher SA, Sun G, Rutter GA. Identification of genes selectively disallowed in the pancreatic islet. Islets. 2010;2(2):89–95.PubMedCrossRef
44.
Schuit F, van Lommel L, Granvik M, Goyvaerts L, de Faudeur G, Schraenen A, et al. Beta-cell-specific gene repression: a mechanism to protect against inappropriate or maladjusted insulin secretion? Diabetes. 2012;61(5):969–75.PubMedPubMedCentralCrossRef
45.
Constantin-Teodosiu D. Regulation of muscle pyruvate dehydrogenase complex in insulin resistance: effects of exercise and dichloroacetate. Diabetes Metab J. 2013;37(5):301–14.PubMedPubMedCentralCrossRef
46.
Otonkinski T, et al. Physical exercise-induced hyperglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet. 2007;81(3):467–74.CrossRef
47.
Becker TC, BeltrandelRio H, Noel RJ, Johnson JH, Newgard CB. Overexpression of hexokinase I in isolated islets of Langerhans via recombinant adenovirus. Enhancement of glucose metabolism and insulin secretion at basal but not stimulatory glucose levels. J Biol Chem. 1994;269(33):21234–8.PubMed
48.
Lemaire K, Thorrez L, Schuit F. Disallowed and allowed gene expression: two faces of mature islet Beta cells. Annu Rev Nutr. 2016;36:45–71.PubMedCrossRef
49.
50.
51.
Lu M, Zheng L, Han B, Wang L, Wang P, Liu H, et al. REST regulates DYRK1A transcription in a negative feedback loop. J Biol Chem. 2011;286(12):10755–63.PubMedCrossRefPubMedCentral
52.
Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015;21(4):383–8.PubMedPubMedCentralCrossRef
53.
• Wang P, et al. Combined inhibition of DYRK1A, SMAD, and trithorax pathways synergizes to induce robust replication in adult human beta cells. Cell Metab. 2018;29(3):638–652.e5. This study suggests that simultaneous inhibition of the DYRK1A kinase and TGF-beta signaling enhances beta cell proliferation in mouse and human islets and is the first to use a methodology to determine actual increases in cell number in isolated human islets in response to a proliferative stimulus. PubMed
54.
Dirice E, Walpita D, Vetere A, Meier BC, Kahraman S, Hu J, et al. Inhibition of DYRK1A stimulates human beta-cell proliferation. Diabetes. 2016;65(6):1660–71.PubMedPubMedCentralCrossRef
55.
Brun T, Maechler P. Beta-cell mitochondrial carriers and the diabetogenic stress response. Biochim Biophys Acta. 2016;1863(10):2540–9.PubMedCrossRef
56.
Maechler P. Mitochondrial function and insulin secretion. Mol Cell Endocrinol. 2013;379(1–2):12–8.PubMedCrossRef
57.
Bensellam M, Laybutt DR, Jonas JC. The molecular mechanisms of pancreatic beta-cell glucotoxicity: recent findings and future research directions. Mol Cell Endocrinol. 2012;364(1–2):1–27.PubMedCrossRef
58.
Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev. 2008;29(3):351–66.PubMedCrossRef
59.
Affourtit C, Jastroch M, Brand MD. Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species. Free Radic Biol Med. 2011;50(5):609–16.PubMedPubMedCentralCrossRef
60.
Rovira-Llopis S, Bañuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor VM. Mitochondrial dynamics in type 2 diabetes: pathophysiological implications. Redox Biol. 2017;11:637–45.PubMedPubMedCentralCrossRef
61.
Boland BB, et al. Pancreatic beta-cell rest replenishes insulin secretory capacity and attenuates diabetes in an extreme model of obese type 2 diabetes. Diabetes. 2019;68(1):131–40.PubMedCrossRef
62.
Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339–50 discussion 350-2.PubMedPubMedCentralCrossRef
63.
Casella G, Abbatini F, Calì B, Capoccia D, Leonetti F, Basso N. Ten-year duration of type 2 diabetes as prognostic factor for remission after sleeve gastrectomy. Surg Obes Relat Dis. 2011;7(6):697–702.PubMedCrossRef
64.
65.
Koliaki C, Roden M. Alterations of mitochondrial function and insulin sensitivity in human obesity and diabetes mellitus. Annu Rev Nutr. 2016;36:337–67.PubMedCrossRef
66.
Maechler P, et al. Role of mitochondria in beta-cell function and dysfunction. Adv Exp Med Biol. 2010;654:193–216.PubMedCrossRef
67.
Wang J, Yang X, Zhang J. Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic beta cells. Cell Signal. 2016;28(8):1099–104.PubMedCrossRef
68.
69.
Anello M, Lupi R, Spampinato D, Piro S, Masini M, Boggi U, et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia. 2005;48(2):282–9.PubMedCrossRef
70.
Leloup C, Tourrel-Cuzin C, Magnan C, Karaca M, Castel J, Carneiro L, et al. Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes. 2009;58(3):673–81.PubMedCrossRef
71.
Fu J, Cui Q, Yang B, Hou Y, Wang H, Xu Y, et al. The impairment of glucose-stimulated insulin secretion in pancreatic beta-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response. Food Chem Toxicol. 2017;100:161–7.PubMedCrossRef
72.
Sigfrid LA, Cunningham JM, Beeharry N, Hakan Borg LA, Rosales Hernandez AL, Carlsson C, et al. Antioxidant enzyme activity and mRNA expression in the islets of Langerhans from the BB/S rat model of type 1 diabetes and an insulin-producing cell line. J Mol Med (Berl). 2004;82(5):325–35.
73.
Harmon JS, Bogdani M, Parazzoli SD, Mak SSM, Oseid EA, Berghmans M, et al. Beta-cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice. Endocrinology. 2009;150(11):4855–62.PubMedPubMedCentralCrossRef
74.
Thielen L, Shalev A. Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP. Curr Opin Endocrinol Diabetes Obes. 2018;25(2):75–80.PubMedPubMedCentralCrossRef
75.
Gateva AT, Assyov YS, Velikova T, Kamenov ZA. Higher levels of thioredoxin interacting protein (TXNIP) in patients with prediabetes compared to obese normoglycemic subjects. Diabetes Metab Syndr. 2019;13(1):734–7.PubMedCrossRef
76.
77.
78.
Lee AH, Heidtman K, Hotamisligil GS, Glimcher LH. Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc Natl Acad Sci U S A. 2011;108(21):8885–90.PubMedPubMedCentralCrossRef
79.
Yong J, Itkin-Ansari P, Kaufman RJ. When less is better: ER stress and beta cell proliferation. Dev Cell. 2016;36(1):4–6.PubMedCrossRef
80.
Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005;280(47):39609–15.PubMedCrossRef
81.
Moon JS, Karunakaran U, Elumalai S, Lee IK, Lee HW, Kim YW, et al. Metformin prevents glucotoxicity by alleviating oxidative and ER stress-induced CD36 expression in pancreatic beta cells. J Diabetes Complicat. 2017;31(1):21–30.PubMedCrossRef
82.
Kimple ME, Keller MP, Rabaglia MR, Pasker RL, Neuman JC, Truchan NA, et al. Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes. 2013;62(6):1904–12.PubMedPubMedCentralCrossRef
83.
Carboneau BA, Allan JA, Townsend SE, Kimple ME, Breyer RM, Gannon M. Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human beta-cell survival and proliferation. Mol Metab. 2017;6(6):548–59.PubMedPubMedCentralCrossRef
84.
Kimple ME, Moss JB, Brar HK, Rosa TC, Truchan NA, Pasker RL, et al. Deletion of GalphaZ protein protects against diet-induced glucose intolerance via expansion of beta-cell mass. J Biol Chem. 2012;287(24):20344–55.
85.
Ceddia RP, Lee DK, Maulis MF, Carboneau BA, Threadgill DW, Poffenberger G, et al. The PGE2 EP3 receptor regulates diet-induced adiposity in male mice. Endocrinology. 2016;157(1):220–32.PubMedCrossRef
86.
Chan PC, Hsiao FC, Chang HM, Wabitsch M, Hsieh PS. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. FASEB J. 2016;30(6):2282–97.PubMedCrossRef
Metadaten
Titel
The Beta Cell in Type 2 Diabetes
Publikationsdatum
01.09.2019
Erschienen in
Current Diabetes Reports / Ausgabe 9/2019
Print ISSN: 1534-4827
Elektronische ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-019-1196-4

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