Wolf Lab - Research

Diabetes and Metabolic Research

Our research uses genetically modified and diet-induced pig models to investigate the pathophysiology of diabetes, obesity, and metabolic disorders. Due to their physiological similarities to humans, pigs provide valuable translational models for studying disease progression, organ interactions, and the development of novel therapies.
Our work focuses on four complementary research areas.

Pig Models Resembling Diabetes Subtypes

Diabetes is a heterogeneous disease with distinct clinical subtypes and different risks of complications. We have established pig models resembling severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes (SIRD) to investigate disease mechanisms and associated organ damage.

SIDD model: INS-p.C94Y transgenic pigs develop impaired insulin secretion, hyperglycemia, and progressive β-cell loss without obesity (1). They also exhibit cardiac structural and functional alterations. The Munich MIDY Pig Biobank enables systematic multi-organ investigations (2), while multi-omics analyses have identified diabetes-associated molecular changes in the liver, adipose tissue, and lungs (3).
SIRD models: Diet-induced obesity models reproduce key features of insulin resistance and metabolic syndrome. Göttingen Minipigs fed a high-fat diet for 30 weeks develop obesity, hyperinsulinemia, dyslipidemia, adipose tissue inflammation, and early atherosclerotic lesions (4). Interestingly, despite severe obesity, these animals are protected from hepatic steatosis, with transcriptomic analyses identifying 11 potentially protective transcription factors (5). In contrast, Auckland Island Minipigs fed a high-energy, high-fat diet for 30 weeks develop insulin resistance, hepatic steatosis, and atherosclerosis.

Within the DFG-funded Collaborative Research Centre CARDDIAB (CRC 1774), we investigate organ crosstalk, particularly between the liver and heart, using advanced imaging, multi-omics, and metabolic flux analyses (Fig. 1). Additional research addresses the gut–islet axis, microbiome interactions, and subtype-specific responses to incretin-based therapies (6).

 

Fig. 1. Metabolic alterations in translational pig models resembling diabetes subtype SIDD and SIRD.

Effects of Muscle Hypertrophy on Metabolic Health

Skeletal muscle plays a central role in whole-body glucose and energy metabolism. Muscle hypertrophy may therefore provide protection against obesity and diabetes (7, 8).
Within the DFG-funded research group HyperMet (FOR 5795), we investigate how muscle growth influences metabolic exchange between organs. Muscle hypertrophy is induced through Myostatin gene knockout or pharmacological β2-adrenergic stimulation.
We have established arteriovenous (AV) metabolomics combined with stable-isotope tracing to quantify organ-specific metabolite uptake and release. Using [U-¹³C] glucose infusion over 2 hours, we analyse metabolic fluxes across skeletal muscle, adipose tissue, liver, kidney, and brain. Mass spectrometry reveals organ-specific metabolic signatures, including glutamate uptake and lactate release by muscle (Fig. 2).
This approach will also be applied to GHR-knockout pigs, a model of growth hormone insensitivity associated with juvenile hypoglycemia, increased insulin sensitivity, and impaired lipolysis (9). Combining AV metabolomics with isotope tracing will provide new insights into inter-organ metabolic regulation and its alterations in metabolic diseases.

 

Fig. 2. Implementation of arteriovenous metabolomics in combination with stable isotope tracers.

Maternal Diabetes and Offspring Metabolic Health

Maternal diabetes increases the risk of obesity, insulin resistance, and type 2 diabetes in offspring. Even mild maternal hyperglycemia can impair neonatal glucose tolerance (10).
Using our genetically induced maternal diabetes (MIDY) pig model, we investigate how maternal hyperglycemia affects fetal organ development and metabolic programming. The close similarities between human and pig pancreatic development make this model particularly valuable for translational research (11, 12).
By integrating multi-omics, single-cell transcriptomics, quantitative morphology, and functional analyses, we have identified profound alterations in neonatal liver and pancreatic islets (13; Fig. 3).
Liver: Maternal hyperglycemia induces hepatic lipid accumulation and extensive changes in glucose, amino acid, and phospholipid metabolism. These findings suggest increased gluconeogenesis and compensatory metabolic adaptations, while steatosis develops independently of increased de novo lipogenesis (14).
Pancreatic islets: Offspring of diabetic mothers exhibit hyperglycemia, hyperinsulinemia, insulin resistance, and impaired glucose-stimulated insulin secretion. These changes are accompanied by expansion of β- and δ-cell populations and altered islet architecture. Single-cell analyses reveal distinct β-cell populations with impaired glucose sensing, altered calcium homeostasis, and activated cellular stress pathways (15).
Together, these findings demonstrate that maternal diabetes programs offspring metabolism before birth. Ongoing research investigates whether these molecular and cellular alterations persist into later life.

 

Fig. 3. Experimental design of the liver-omics study (A), and Oil red O stains of the liver (B) (from Ref. 14).

Pancreas Development and Islet Transplantation

Understanding pancreatic development and β-cell function is essential for developing regenerative diabetes therapies. However, limited access to human pancreatic tissue and donor islets remains a major challenge.
We develop reporter pig models to investigate pancreatic development, β-cell differentiation, insulin secretion, and transplanted islet function. Beyond our models for endocrine cell tracing, the portfolio also includes genetically engineered models for tracking insulin secretory granules and near-infrared fluorescent reporter systems for non-invasive monitoring of islet grafts (16–19).
These technologies support fundamental research into pancreatic biology and facilitate the development and preclinical evaluation of innovative cell-replacement therapies for diabetes.

Funding

German Research Foundation (DFG; CRC 127; CRC 1774: CARDDIAB; FOR 5795: HyperMet; 458958943) | German Center for Diabetes Research (DZD; 82DZD00801, 82DZD00802, 82DZD08D03, 82DZD00804, 82DZD08E1G, 82DZD08I1G) | European Union (H2020 Marie Skłodowska-Curie grant agreement No. 812660, DohART; H2020 iNanoBIT) | Breakthrough T1D (3-SRA-2022-1155-S-B, 3-SRA-2023-1420-S-B, 3-SRA-2026-1808-S-B).

Selected Publications

1. Renner S, Braun-Reichhart C, Blutke A, Herbach N, Emrich D, Streckel E, Wünsch A, Kessler B, Kurome M, Bähr A, Klymiuk N, Krebs S, Puk O, Nagashima H, Graw J, Blum H, Wanke R, Wolf E. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes. 2013 May;62(5):1505-11. https://doi.org/10.2337/db12-1065
2. Blutke A, Renner S, Flenkenthaler F, Backman M, Haesner S, Kemter E, Ländström E, Braun-Reichhart C, Albl B, Streckel E, Rathkolb B, Prehn C, Palladini A, Grzybek M, Krebs S, Bauersachs S, Bähr A, Brühschwein A, Deeg CA, De Monte E, Dmochewitz M, Eberle C, Emrich D, Fux R, Groth F, Gumbert S, Heitmann A, Hinrichs A, Keßler B, Kurome M, Leipig-Rudolph M, Matiasek K, Öztürk H, Otzdorff C, Reichenbach M, Reichenbach HD, Rieger A, Rieseberg B, Rosati M, Saucedo MN, Schleicher A, Schneider MR, Simmet K, Steinmetz J, Übel N, Zehetmaier P, Jung A, Adamski J, Coskun Ü, Hrabě de Angelis M, Simmet C, Ritzmann M, Meyer-Lindenberg A, Blum H, Arnold GJ, Fröhlich T, Wanke R, Wolf E. The Munich MIDY Pig Biobank - A unique resource for studying organ crosstalk in diabetes. Mol Metab. 2017 Jun 13;6(8):931-940. https://doi.org/10.1016/j.molmet.2017.06.004
3. Shashikadze B, Flenkenthaler F, Kemter E, Franzmeier S, Stöckl JB, Haid M, Riols F, Rothe M, Pichl L, Renner S, Blutke A, Wolf E*, Fröhlich T*. Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus. Dis Model Mech. 2024 Jul 1;17(7):dmm050650. https://doi.org/10.1242/dmm.050650
4. Renner S, Blutke A, Dobenecker B, Dhom G, Müller TD, Finan B, Clemmensen C, Bernau M, Novak I, Rathkolb B, Senf S, Zöls S, Roth M, Götz A, Hofmann SM, Hrabĕ de Angelis M, Wanke R, Kienzle E, Scholz AM, DiMarchi R, Ritzmann M, Tschöp MH, Wolf E. Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs. Mol Metab. 2018 Oct;16:180-190. https://doi.org/10.1016/j.molmet.2018.06.015
5. Gottmann P, Jonas W, Renner S, Philippou-Massier J, Hommel T, Dahlhoff M, Zeigerer A, Wolf E, Vogel H, Schürmann A. Multispecies transcriptome analysis identifies networks protecting against MASLD in Göttingen minipigs. J Lipid Res. 2026 Jun 25:101089. https://doi.org/10.1016/j.jlr.2026.101089
6. Eckstein Y, Kessler B, Hinrichs A, Novak I, von Thaden A, Lorenzen T, Rathkolb B, Scholz A, Blutke A, Koopmans SJ, de Angelis MH, Christoffersen BØ, Wolf E, Renner S. Protocol for in vivo assessment of glucose control and insulin secretion and sensitivity in the pig. STAR Protoc. 2025 Jun 20;6(2):103774. https://doi.org/10.1016/j.xpro.2025.103774
7. Zettler S, Renner S, Kemter E, Hinrichs A, Klymiuk N, Backman M, Riedel EO, Mueller C, Streckel E, Braun-Reichart C, Martins AS, Kurome M, Kessler B, Zakhartchenko V, Flenkenthaler F, Arnold GJ, Froehlich T, Blum H, Blutke A, Wanke R, Wolf E. A decade of experience with genetically tailored pig models for diabetes and metabolic research. Anim Reprod. 2020; Aug 26;17(3):e20200064. https://doi.org/10.1590/1984-3143-AR2020-0064
8. Wackerhage H, Hinrichs A, Wolf E, Hrabe de Angelis M. Turning fat into muscle: can this be an alternative to anti‐obesity drugs such as semaglutide?. The Journal of Physiology. 2024; 602.8 1655-1658. https://doi.org/10.1113/JP286430
9. Hinrichs A, Pafili K, Sancar G, Laane L, Zettler S, Torgeman M, Kessler B, Nono JL, Kunz S, Rathkolb B, Barosa C, Prehn C, Cecil A, Renner S, Kemter E, Kahl S, Szendroedi J, Bidlingmaier M, Jones JG, Hrabe de Angelis M, Roden M, Wolf E. Transient juvenile hypoglycemia in GH insensitive Laron syndrome pigs is associated with insulin hypersensitivity. Mol Metab. 2026 Jan;103:102273. https://doi.org/10.1016/j.molmet.2025.102273
10. Renner S, Martins AS, Streckel E, Braun-Reichhart C, Backman M, Prehn C, Klymiuk N, Bähr A, Blutke A, Landbrecht-Schessl C, Wünsch A, Kessler B, Kurome M, Hinrichs A, Koopmans SJ, Krebs S, Kemter E, Rathkolb B, Nagashima H, Blum H, Ritzmann M, Wanke R, Aigner B, Adamski J, Hrabě de Angelis M, Wolf E. Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring. Dis Model Mech. 2019 Aug 12;12(8):dmm039156. https://doi.org/10.1242/dmm.039156
11. Yang K, Spitzer H, Sterr M, Hrovatin K, de la O S, Zhang X, Setyono ESA, Ud-Dean M, Walzthoeni T, Flisikowski K, Flisikowska T, Schnieke A, Scheibner K, Wells JM, Sneddon JB, Kessler B, Wolf E, Kemter E, Theis FJ, Lickert H. A multimodal cross-species comparison of pancreas development. Nat Commun. 2025 Oct 22;16(1):9355. https://doi.org/10.1038/s41467-025-64774-4
12. Tritschler S, Thomas M, Böttcher A, Ludwig B, Schmid J, Schubert U, Kemter E, Wolf E, Lickert H, Theis FJ. A transcriptional cross species map of pancreatic islet cells. Mol Metab. 2022 Dec;66:101595. https://doi.org/10.1016/j.molmet.2022.101595
13. Shashikadze B, Flenkenthaler F, Stöckl JB, Valla L, Renner S, Kemter E, Wolf E, Fröhlich T. Developmental Effects of (Pre-)Gestational Diabetes on Offspring: Systematic Screening Using Omics Approaches. Genes (Basel). 2021 Dec 15;12(12):1991. https://doi.org/10.3390/genes12121991
14. Shashikadze B, Valla L, Lombardo SD, Prehn C, Haid M, Riols F, Stöckl JB, Elkhateib R, Renner S, Rathkolb B, Menche J, Hrabĕ de Angelis M, Wolf E, Kemter E*, Fröhlich T*. Maternal hyperglycemia induces alterations in hepatic amino acid, glucose and lipid metabolism of neonatal offspring: Multi-omics insights from a diabetic pig model. Mol Metab. 2023;75:101768. https://doi.org/10.1016/j.molmet.2023.101768
15. Valla L, Schwager MF, Cohrs CM, Stoeckl JB, Karampelias C, Shashikadze B, Rathkolb B, Lindner R, Kraetzl M, Renner S, Molina van den Bosch M, Yang K, Sterr M, Boettcher A, Hrabé de Angelis M, Speier S, Fröhlich T, Theis FJ, Lickert H, Wolf E, Kemter E. Pregestational maternal diabetes primes neonatal beta-cell dysfunction with structural remodelling, impaired calcium buffering and altered mTORC2/Gαq/PKCα signalling in a pig model. Diabetologia (accepted).
16. Citro A, Neroni A, Pignatelli C, Campo F, Policardi M, Monieri M, Pellegrini S, Dugnani E, Manenti F, Maffia MC, Valla L, Kemter E, Marzinotto I, Olgasi C, Cucci A, Follenzi A, Lampasona V, Wolf E, Piemonti L. Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes. Nat Commun. 2023 Feb 16;14(1):878. https://doi.org/10.1038/s41467-023-36582-1
17. Kemter E, Müller A, Neukam M, Ivanova A, Klymiuk N, Renner S, Yang K, Broichhagen J, Kurome M, Zakhartchenko V, Kessler B, Knoch KP, Bickle M, Ludwig B, Johnsson K, Lickert H, Kurth T, Wolf E*, Solimena M*. Sequential in vivo labeling of insulin secretory granule pools in INS-SNAP transgenic pigs. PNAS 2021;118(37):e2107665118. https://doi.org/10.1073/pnas.2107665118
18. Kemter E, Citro A, Wolf-van Buerck L, Qiu Y, Böttcher A, Policardi M, Pellegrini S, Valla L, Alunni-Fabbroni M, Kobolák J, Kessler B, Kurome M, Zakhartchenko V, Dinnyes A, Cyran CC, Lickert H, Piemonti L, Seissler J, Wolf E. Transgenic pigs expressing near infrared fluorescent protein-A novel tool for noninvasive imaging of islet xenotransplants. Xenotransplantation 2022;29(1):e12719. https://doi.org/10.1111/xen.12719
19. Zhao S, Todorov MI, Cai R, -Maskari RA, Steinke H, Kemter E, Mai H, Rong Z, Warmer M, Stanic K, Schoppe O, Paetzold JC, Gesierich B, Wong MN, Huber TB, Duering M, Bruns OT, Menze B, Lipfert J, Puelles VG, Wolf E, Bechmann I, Ertürk A. Cellular and Molecular Probing of Intact Human Organs. Cell. 2020 Feb 20;180(4):796-812.e19. https://doi.org/10.1016/j.cell.2020.01.030