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Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion
Open accessAbstract
Aims/hypothesis Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver. Methods Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining. Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RT-PCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting. Results In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic pre-adipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when co-cultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1β. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase- and Ca 2+-dependent, manner. Conclusions/interpretation These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation.
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“Fetulin-A has been shown to impair β-cell sensing by reducing glucose-stimulated insulin secretion115.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [115]
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Metadata
- Authors
- Gerst, F., Wagner, R., Kaiser, G., Panse, M., Heni, M., Machann, J., Bongers, M. N., Sartorius, T., Sipos, B., Fend, F., Thiel, C., Nadalin, S., Königsrainer, A., Stefan, N., Fritsche, A., Häring, H.-U., Ullrich, S., & Siegel-Axel, D.
- Affiliations
- Universitätsklinikum Tübingen (DE)
- Corresponding author
- Gerst, Felicia
- ORCID
- Venue
- Diabetologia
- Published
- 2017-08-08
- Volume
- 60
- Issue
- 11
- Pages
- 2240-2251
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2744324498
- Cited by
- 151
- References
- 53
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 17 · 2023: 23 · 2022: 24 · 2021: 24 · 2020: 14 · 2019: 8 · 2018: 12 · 2017: 4
- FWCI
- 10.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.) (01GI0925)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- fatty pancreas, hepatic steatosis, metabolic crosstalk, insulin secretion, pancreatic islets, fetuin-A, palmitate, ectopic fat deposition, obesity, type 2 diabetes, insulitis, macrophages, TLR4, interleukin-6, interleukin-8, MCP-1, IL-1β, beta-cell apoptosis, c-Jun N-terminal kinase, glucose-stimulated insulin secretion, pancreatic resection
- MeSH terms
- Insulin Secretion, Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Fatty Liver, Humans, Immunohistochemistry, Inflammation, Insulin, Palmitates, Pancreas, Blotting, Western, Interleukin-6, Interleukin-8, Chemokine CCL2, Insulin-Secreting Cells, Toll-Like Receptor 4, Mice, alpha-2-HS-Glycoprotein
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