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Siegel-Axel, D. ; Gerst, F. ; Panse, M.* ; Wagner, R. ; Machann, J. ; Stefan, N. ; Sipos, B.* ; Fend, F.* ; Thiel, C.* ; Königsrainer, A.* ; Häring, H.-U. ; Ullrich, S.

Interactions of human intrapancreatic pre-adipocytes and differentiated adipocytes and hepatokines with human islet (dys)function in cocultures.

Vortrag: ADA Kongress USA, 09-14 June 2016, New Orleans, USA. (2016)
Aim: Previously we detected with pancreas MRI 6-9 % intrapancreatic fat in subjects with increased risk for type 2 diabetes. The fat content was associated with impaired insulin secretion. Here we examined histologically if pancreatic fat and islets are located closely to each other and if there are interactions between pancreatic fat cells, islets and the hepatokine fetuin-A in vitro. We hypothesize that altered pancreatic fat might represent an additional pathogenetic factor for islet dysfunction. Methods: Pancreatic preadipocytes (PPAC) and islets were isolated from human pancreatic resections. PPAC were characterized and checked for purity by FACS. Differentiation to PPAC were differentiated to adipocytes (PAC) using a special cultivation protocol over 14 d and proved by oil red stainings. PPAC or PAC were cocultured with islets in transwell systems and compared to monocultures. In parts, human 600 μg/ml fetuin-A (Sigma) and palmitate was added. After 24 h, mRNA expression was quantitiated by realtime PCR analysis and protein secretion in supernatants by ELISA or Luminex. Results: Isolation of PPAC and differentiation to PAC was successful in resections obtained from 5 patients. PPAC expressed and secreted proinflammatory cytokines and chemokines in monoculture which was synergistically increased by fetuin-A and palmitate. Cocultivation of PPAC with islets for 24 h resulted in a further accentuation of the proinflammatory response by PPAC. This response was largely reduced after insulin-induced differentiation of PPAC into PAC expressing adiponectin. (Immuno)histochemistry showed that PAC, displaying characteristic oil droplets and adiponectin, infiltrate the exocrine tissue. Islets neighbouring PAC showed normal architecture and hormone distribution. Prediabetic humans with pancreatic adiposis and fatty liver displayed a reduced insulinogenic index. In parallel, fetuin-A diminished glucose- and palmitate-dependent insulin release. Conclusion: These results suggest that PPAC rather than PAC exacerbate fetuin-A/palmitate induced pancreatic inflammation. The crosstalk between the fatty liver releasing hepatokines and the pancreas/islets may promote insulin deficiency and the development of type-2 diabetes in humans.
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Publikationstyp Sonstiges: Vortrag
Konferenztitel ADA Kongress USA
Konferzenzdatum 09-14 June 2016
Konferenzort New Orleans, USA
Institut(e) Institute for Diabetes Research and Metabolic Diseases (IDM)