Top

Open Access 07-11-2024 | Type 2 Diabetes | Extended Article

Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models

Authors: Pascal Gottmann, Thilo Speckmann, Mandy Stadion, Prateek Chawla, Judith Saurenbach, Nikolay Ninov, Heiko Lickert, Annette Schürmann

Published in: Diabetologia

Abstract

Aims/hypothesis

The aim of this work was to understand the role of non-beta cells in pancreatic islets at early stages of type 2 diabetes pathogenesis.

Methods

Specific clustering was employed to single-cell transcriptome data from islet cells of obese mouse strains differing in their diabetes susceptibility (diabetes-resistant B6.V.Lep^ob/ob [OB] and diabetes-susceptible New Zealand Obese [NZO] mice) on a diabetogenic diet.

Results

Refined clustering analysis revealed several heterogeneous subpopulations for alpha cells, delta cells and macrophages, of which 133 mapped to human diabetes genes identified by genome-wide association studies. Importantly, a similar non-beta cell heterogeneity was found in a dataset of human islets from donors at different stages of type 2 diabetes. The predominant alpha cell cluster in NZO mice displayed signs of cellular stress and lower mitochondrial capacity (97 differentially expressed genes [DEGs]), whereas delta cells from these mice exhibited higher expression levels of maturation marker genes (Hhex and Sst) but lower somatostatin secretion than OB mice (184 DEGs). Furthermore, a cluster of macrophages was almost twice as abundant in islets of OB mice, and displayed extensive cell–cell communication with beta cells of OB mice. Treatment of beta cells with IL-15, predicted to be released by macrophages, activated signal transducer and activator of transcription (STAT3), which may mediate anti-apoptotic effects. Similar to mice, humans without diabetes possess a greater number of macrophages than those with prediabetes (39 mmol/mol [5.7%] < HbA_1c < 46 mmol/mol [6.4%]) and diabetes.

Conclusions/interpretation

Our study indicates that the transcriptional heterogeneity of non-beta cells has an impact on intra-islet crosstalk and participates in beta cell (dys)function.

Data availability

scRNA-seq data from the previous study are available in gene expression omnibus under gene accession number GSE159211 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211).

Graphical Abstract

Available only for authorised users

Haakenstad A, Irvine CMS, Knight M et al (2022) Measuring the availability of human resources for health and its relationship to universal health coverage for 204 countries and territories from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 399(10341):2129–2154. https://doi.org/10.1016/S0140-6736(22)00532-3CrossRef

Ahlqvist E, Storm P, Käräjämäki A et al (2018) Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 6(5):361–369. https://doi.org/10.1016/S2213-8587(18)30051-2CrossRefPubMed

Röder PV, Wu B, Liu Y, Han W (2016) Pancreatic regulation of glucose homeostasis. Exp Mol Med 48:e219. https://doi.org/10.1038/emm.2016.6CrossRefPubMedPubMedCentral

Ngara M, Wierup N (2022) Lessons from single-cell RNA sequencing of human islets. Diabetologia 65(8):1241. https://doi.org/10.1007/S00125-022-05699-1CrossRefPubMedPubMedCentral

Wang YJ, Kaestner KH (2019) Single-cell RNA-Seq of the pancreatic islets–a promise not yet fulfilled? Cell Metab 29(3):539–544. https://doi.org/10.1016/J.CMET.2018.11.016CrossRefPubMed

Kluth O, Matzke D, Schulze G, Schwenk RW, Joost HG, Schürmann A (2014) Differential transcriptome analysis of diabetes-resistant and -sensitive mouse islets reveals significant overlap with human diabetes susceptibility genes. Diabetes 63(12):4230–4238. https://doi.org/10.2337/db14-0425CrossRefPubMed

Kluth O, Matzke D, Kamitz A et al (2015) Identification of four mouse diabetes candidate genes altering β-cell proliferation. PLoS Genet 11(9):e1005506. https://doi.org/10.1371/journal.pgen.1005506CrossRefPubMedPubMedCentral

Kluth O, Stadion M, Gottmann P et al (2019) Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans. Cell Rep 26(11):3027-3036.e3. https://doi.org/10.1016/j.celrep.2019.02.056CrossRefPubMed

Gässler A, Quiclet C, Kluth O et al (2020) Overexpression of Gjb4 impairs cell proliferation and insulin secretion in primary islet cells. Mol Metab 41:101042. https://doi.org/10.1016/j.molmet.2020.101042CrossRefPubMedPubMedCentral

10.

Guo J, Fu W (2020) Immune regulation of islet homeostasis and adaptation. J Mol Cell Biol 12(10):764. https://doi.org/10.1093/JMCB/MJAA009CrossRefPubMedPubMedCentral

11.

Carrero JA, McCarthy DP, Ferris ST et al (2017) Resident macrophages of pancreatic islets have a seminal role in the initiation of autoimmune diabetes of NOD mice. Proc Natl Acad Sci U S A 114(48):E10418–E10427. https://doi.org/10.1073/PNAS.1713543114CrossRefPubMedPubMedCentral

12.

Potter KJ, Westwell-Roper CY, Klimek-Abercrombie AM, Warnock GL, Verchere CB (2014) Death and dysfunction of transplanted β-cells: lessons learned from type 2 diabetes? Diabetes 63(1):12–19. https://doi.org/10.2337/DB12-0364CrossRefPubMed

13.

Rohm TV, Meier DT, Olefsky JM, Donath MY (2022) Inflammation in obesity, diabetes, and related disorders. Immunity 55(1):31–55. https://doi.org/10.1016/J.IMMUNI.2021.12.013CrossRefPubMedPubMedCentral

14.

Schonblum A, Ali Naser D, Ovadia S et al (2024) Beneficial islet inflammation in health depends on pericytic TLR/MyD88 signaling. J Clin Invest 134(14):e179335. https://doi.org/10.1172/JCI179335CrossRefPubMedPubMedCentral

15.

Nackiewicz D, Dan M, Speck M et al (2020) Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet insulin-like growth factor-1. iScience 23(1):100775. https://doi.org/10.1016/J.ISCI.2019.100775CrossRefPubMed

16.

Brissova M, Aamodt K, Brahmachary P et al (2014) Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration. Cell Metab 19(3):498–511. https://doi.org/10.1016/J.CMET.2014.02.001CrossRefPubMedPubMedCentral

17.

Xiao X, Gaffar I, Guo P et al (2014) M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A 111(13):E1211–E1220. https://doi.org/10.1073/pnas.1321347111CrossRefPubMedPubMedCentral

18.

Dalmas E, Lehmann FM, Dror E et al (2017) Interleukin-33-activated islet-resident innate lymphoid cells promote insulin secretion through myeloid cell retinoic acid production. Immunity 47(5):928-942.e7. https://doi.org/10.1016/J.IMMUNI.2017.10.015CrossRefPubMed

19.

Riley KG, Pasek RC, Maulis MF et al (2015) Macrophages are essential for CTGF-mediated adult β-cell proliferation after injury. Mol Metab 4(8):584–591. https://doi.org/10.1016/J.MOLMET.2015.05.002CrossRefPubMedPubMedCentral

20.

Ferris ST, Zakharov PN, Wan X et al (2017) The islet-resident macrophage is in an inflammatory state and senses microbial products in blood. J Exp Med 214(8):2369–2385. https://doi.org/10.1084/JEM.20170074CrossRefPubMedPubMedCentral

21.

Chan JY, Lee K, Maxwell EL, Liang C, Laybutt DR (2019) Macrophage alterations in islets of obese mice linked to beta cell disruption in diabetes. Diabetologia 62(6):993–999. https://doi.org/10.1007/S00125-019-4844-YCrossRefPubMed

22.

Ying W, Lee YS, Dong Y et al (2019) Expansion of islet-resident macrophages leads to inflammation affecting β cell proliferation and function in obesity. Cell Metab 29(2):457-474.e5. https://doi.org/10.1016/J.CMET.2018.12.003CrossRefPubMed

23.

Qian B, Yang Y, Tang N et al (2021) M1 macrophage-derived exosomes impair beta cell insulin secretion via miR-212-5p by targeting SIRT2 and inhibiting Akt/GSK-3β/β-catenin pathway in mice. Diabetologia 64(9):2037–2051. https://doi.org/10.1007/S00125-021-05489-1CrossRefPubMed

24.

Gottmann P, Speckmann T, Stadion M et al (2022) Heterogeneous development of β-cell populations in diabetes-resistant and -susceptible mice. Diabetes 71(9):1962–1978. https://doi.org/10.2337/db21-1030CrossRefPubMedPubMedCentral

25.

Sachs S, Bastidas-Ponce A, Tritschler S et al (2020) Targeted pharmacological therapy restores β-cell function for diabetes remission. Nat Metab 2(2):192–209. https://doi.org/10.1038/s42255-020-0171-3CrossRefPubMed

26.

Camunas-Soler J, Dai XQ, Hang Y et al (2020) Patch-Seq links single-cell transcriptomes to human islet dysfunction in diabetes. Cell Metab 31(5):1017-1031.e4. https://doi.org/10.1016/j.cmet.2020.04.005CrossRefPubMedPubMedCentral

27.

Jürgens HS, Schürmann A, Kluge R et al (2006) Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice. Physiol Genomics 25(2):234–241. https://doi.org/10.1152/physiolgenomics.00252.2005CrossRefPubMed

28.

Wolf FA, Angerer P, Theis FJ (2018) SCANPY: large-scale single-cell gene expression data analysis. Genome Biol 19(1):1–5. https://doi.org/10.1186/S13059-017-1382-0/FIGURES/1CrossRef

29.

Wang G, Chiou J, Zeng C et al (2023) Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes. Nat Genet 55(6):984–994. https://doi.org/10.1038/s41588-023-01397-9CrossRefPubMedPubMedCentral

30.

Singh SP, Chawla P, Hnatiuk A et al (2022) A single-cell atlas of de novo β-cell regeneration reveals the contribution of hybrid β/δ-cells to diabetes recovery in zebrafish. Development 149(2):dev199853. https://doi.org/10.1242/dev.199853CrossRefPubMed

31.

Efremova M, Vento-Tormo M, Teichmann SA, Vento-Tormo R (2020) Cell PhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nat Protoc 15(4):1484–1506. https://doi.org/10.1038/s41596-020-0292-xCrossRefPubMed

32.

Browaeys R, Saelens W, Saeys Y (2020) NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods 17(2):159–162. https://doi.org/10.1038/s41592-019-0667-5CrossRefPubMed

33.

Aga H, Hallahan N, Gottmann P et al (2020) Identification of novel potential type 2 diabetes genes mediating β-cell loss and hyperglycemia using positional cloning. Front Genet 11:Article 567191. https://doi.org/10.3389/fgene.2020.567191CrossRefPubMed

34.

Wilhelmi I, Grunwald S, Gimber N et al (2021) The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells. Mol Metab 45:101151. https://doi.org/10.1016/j.molmet.2020.101151CrossRefPubMed

35.

Kluth O, Mirhashemi F, Scherneck S et al (2011) Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure. Diabetologia 54(3):605–616. https://doi.org/10.1007/s00125-010-1973-8CrossRefPubMed

36.

Buniello A, Macarthur JAL, Cerezo M et al (2019) The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res 47(D1):1005–1012. https://doi.org/10.1093/nar/gky1120CrossRef

37.

Suzuki K, Hatzikotoulas K, Southam L et al (2024) Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nat 2024:1–11. https://doi.org/10.1038/s41586-024-07019-6CrossRef

38.

Zhang J, McKenna LB, Bogue CW, Kaestner KH (2014) The diabetes gene Hhex maintains δ-cell differentiation and islet function. Genes Dev 28(8):829. https://doi.org/10.1101/GAD.235499.113CrossRefPubMedPubMedCentral

39.

Moon JS, Won KC (2015) Pancreatic α-cell dysfunction in type 2 diabetes: old kids on the block. Diabetes Metab J 39:1–9. https://doi.org/10.4093/dmj.2015.39.1.1CrossRefPubMedPubMedCentral

40.

Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4(5):E131–E136. https://doi.org/10.1038/ncb0502-e131CrossRefPubMed

41.

Grubelnik V, Zmazek J, Markovič R, Gosak M, Marhl M (2020) Mitochondrial dysfunction in pancreatic alpha and beta cells associated with type 2 diabetes mellitus. Life 10(12):1–16. https://doi.org/10.3390/LIFE10120348CrossRef

42.

Strowski MZ, Parmar RM, Blake AD, Schaeffer JM (2000) Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology 141(1):111–117. https://doi.org/10.1210/ENDO.141.1.7263CrossRefPubMed

43.

Wollam J, Mahata S, Riopel M et al (2017) Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion. Cell Tissue Res 368(3):487–501. https://doi.org/10.1007/S00441-017-2580-5/FIGURES/7CrossRefPubMedPubMedCentral

44.

Grarup N, Andersen G, Krarup NT et al (2008) Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes. Diabetes 57(9):2534–2540. https://doi.org/10.2337/DB08-0436CrossRefPubMedPubMedCentral

45.

Westwell-Roper CY, Chehroudi CA, Denroche HC, Courtade JA, Ehses JA, Verchere CB (2015) IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice. Diabetologia 58(3):575–585. https://doi.org/10.1007/S00125-014-3447-XCrossRefPubMed

46.

Westwell-Roper C, Dai DL, Soukhatcheva G et al (2011) IL-1 blockade attenuates islet amyloid polypeptide-induced proinflammatory cytokine release and pancreatic islet graft dysfunction. J Immunol 187(5):2755–2765. https://doi.org/10.4049/JIMMUNOL.1002854CrossRefPubMed

47.

Larsen CM, Faulenbach M, Vaag A et al (2007) Interleukin-1–receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356(15):1517–1526. https://doi.org/10.1056/NEJMOA065213/SUPPL_FILE/NEJM_LARSEN_1517SA1.PDFCrossRefPubMed

48.

Molawi K, Sieweke MH (2013) Transcriptional control of macrophage identity, self-renewal, and function. Adv Immunol 120:269–300. https://doi.org/10.1016/B978-0-12-417028-5.00010-7CrossRefPubMed

49.

Jones CV, Ricardo SD (2013) Macrophages and CSF-1: implications for development and beyond. Organogenesis 9(4):249. https://doi.org/10.4161/ORG.25676CrossRefPubMedPubMedCentral

50.

Günthner R, Anders HJ (2013) Interferon-regulatory factors determine macrophage phenotype polarization. Mediators Inflamm 2013:731023. https://doi.org/10.1155/2013/731023CrossRefPubMedPubMedCentral

51.

Kiselev VY, Yiu A, Hemberg M (2018) scmap: projection of single-cell RNA-seq data across data sets. Nat Methods 15(5):359–362. https://doi.org/10.1038/nmeth.4644CrossRefPubMed

52.

Boutens L, Stienstra R (2016) Adipose tissue macrophages: going off track during obesity. Diabetologia 59(5):879–894. https://doi.org/10.1007/S00125-016-3904-9CrossRefPubMedPubMedCentral

53.

Wang G, Yu Y, Sun C et al (2016) STAT3 selectively interacts with Smad3 to antagonize TGF-β signaling. Oncogene 35(33):4388. https://doi.org/10.1038/ONC.2015.446CrossRefPubMed

54.

Zarrouki B, Benterki I, Fontés G et al (2014) Epidermal growth factor receptor signaling promotes pancreatic β-cell proliferation in response to nutrient excess in rats through mTOR and FOXM1. Diabetes 63(3):982–993. https://doi.org/10.2337/DB13-0425/-/DC1CrossRefPubMedPubMedCentral

55.

Saksida T, Stosic-Grujicic S, Timotijevic G, Sandler S, Stojanovic I (2012) Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid-induced apoptosis. Immunol Cell Biol 90(7):688–698. https://doi.org/10.1038/ICB.2011.89CrossRefPubMed

56.

Eguchi K, Nagai R (2017) Islet inflammation in type 2 diabetes and physiology. J Clin Invest 127(1):14–23. https://doi.org/10.1172/JCI88877CrossRefPubMedPubMedCentral

57.

Tang W, Lu Y, Tian QY et al (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332(6028):478–484. https://doi.org/10.1126/SCIENCE.1199214CrossRefPubMedPubMedCentral

58.

Perrot V, Vázquez-Prado J, Silvio Gutkind J (2002) Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. J Biol Chem 277(45):43115–43120. https://doi.org/10.1074/JBC.M206005200CrossRefPubMed

59.

Gai JW, Wahafu W, Song L et al (2018) Expression of CD74 in bladder cancer and its suppression in association with cancer proliferation, invasion and angiogenesis in HT-1376 cells. Oncol Lett 15(5):7631–7638. https://doi.org/10.3892/OL.2018.8309CrossRefPubMedPubMedCentral

60.

Dai XQ, Camunas-Soler J, Briant LJB et al (2022) Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state. Cell Metab 34(2):256-268.e5. https://doi.org/10.1016/J.CMET.2021.12.021CrossRefPubMedPubMedCentral

61.

Weng Q, Zhao M, Zheng J et al (2020) STAT3 dictates β-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia. Cell Death Differ 27(1):130. https://doi.org/10.1038/S41418-019-0344-3CrossRefPubMed

62.

Rowe GC, Raghuram S, Jang C et al (2014) PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res 115(5):504–517. https://doi.org/10.1161/CIRCRESAHA.115.303829CrossRefPubMedPubMedCentral

63.

Yu HC, Huang HB, Tseng HYH, Lu MC (2022) Brain-derived neurotrophic factor suppressed proinflammatory cytokines secretion and enhanced microRNA(miR)-3168 expression in macrophages. Int J Mol Sci 23(1):570. https://doi.org/10.3390/IJMS23010570CrossRefPubMedPubMedCentral

64.

Nan J, Lee JS, Moon JH et al (2022) SENP2 regulates mitochondrial function and insulin secretion in pancreatic β cells. Exp Mol Med 54(1):72–80. https://doi.org/10.1038/S12276-021-00723-7CrossRefPubMedPubMedCentral

65.

Dunning BE, Foley JE, Ahrén B (2005) Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 48(9):1700–1713. https://doi.org/10.1007/S00125-005-1878-0/FIGURES/7CrossRefPubMed

66.

Zhang B, Yang L, Yu L et al (2012) Acetylcholinesterase is associated with apoptosis in β cells and contributes to insulin-dependent diabetes mellitus pathogenesis. Acta Biochim Biophys Sin (Shanghai) 44(3):207–216. https://doi.org/10.1093/ABBS/GMR121CrossRefPubMed

Title: Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models
Authors: Pascal Gottmann
Thilo Speckmann
Mandy Stadion
Prateek Chawla
Judith Saurenbach
Nikolay Ninov
Heiko Lickert
Annette Schürmann
Publication date: 07-11-2024
Publisher: Springer Berlin Heidelberg
Keyword: Type 2 Diabetes
Published in: Diabetologia
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-024-06301-6

Keynote series | Spotlight on menopause

Menopause
Video Series

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the broader systemic effects of menopause, so you can help patients in your clinics through the transition.

Launching: Thursday 12th December 2024

Prof. Martha Hickey

Dr. Claudia Barth

Dr. Samar El Khoudary

Developed by: Springer Medicine

Keynote webinar | Spotlight on adolescent vaping

Live
Webinar | 29-01-2025 | 18:00 (CET)

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?

Watch it live: Wednesday 29th January, 18:00-19:30 CET

Prof. Ann McNeill

Dr. Debbie Robson

Benji Horwell

Developed by: Springer Medicine

Join the webinar

Keynote webinar | Spotlight on modern management of frailty

Frailty in Geriatric Patients
On-demand webinar

Frailty has a significant impact on health and wellbeing, especially in older adults. Our experts explain the factors that contribute to the development of frailty and how you can manage the condition and reduce the risk of disability, dependency, and mortality in your patients.

Prof. Alfonso Cruz-Jentoft

Prof. Barbara C. van Munster

Prof. Mirko Petrovic

Developed by: Springer Medicine

Watch now

A quick guide to ECGs

Electrocardiography
Training Course

Improve your ECG interpretation skills with this comprehensive, rapid, interactive course. Expert advice provides detailed feedback as you work through 50 ECGs covering the most common cardiac presentations to ensure your practice stays up to date.

PD Dr. Carsten W. Israel

Developed by: Springer Medizin

Start the cases

At a glance: The STEP trials

Obesity
Clinical Trial Summary

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote series | Spotlight on menopause

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Data availability

Graphical Abstract

Please log in to get access to this content

Keynote series | Spotlight on menopause

Keynote webinar | Spotlight on adolescent vaping

Keynote webinar | Spotlight on modern management of frailty

A quick guide to ECGs

At a glance: The STEP trials