Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

Abstract

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 preadipocytes 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 cocultured 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.

Hypertension, but not body mass index, is predictive of increased pancreatic lipid content and islet dysfunction

“…Mouse islets cultured in media with elevated fatty acid levels resulted in increased intracellular triglyceride storage, as evidenced by Oil Red O (ORO)‐positive staining, coincident with morphological changes in the islets and reduced glucose‐stimulated insulin secretion (GSIS) performance . Moreover, a study of isolated human islets cocultured with pancreatic adipocytes showed that adipocyte‐secreted cytokines (interleukins 6 and 8 and MCP‐1) impair GSIS through inflammation of the islet milieu …”

Impact of Fetuin-A (AHSG) on Tumor Progression and Type 2 Diabetes

“…Recent studies have indicated a robust cross-talk between fatty pancreas and fatty liver affecting the local inflammation and insulin secretion by the islets cells. In these studies, differentiated adipocytes were detected in the vicinity of pancreatic islet cells [19,79]. Expression levels of cytokines such as IL6 and CXCL8 were elevated by fetuin-A and free fatty acids such as palmitate in a TLR4-dependent manner [19,79,89].…”

“…In these studies, differentiated adipocytes were detected in the vicinity of pancreatic islet cells [19,79]. Expression levels of cytokines such as IL6 and CXCL8 were elevated by fetuin-A and free fatty acids such as palmitate in a TLR4-dependent manner [19,79,89]. Interestingly, it has been demonstrated that free fatty acids such as palmitate do not bind directly to TLR4 but rather via fetuin-A [78].…”

“…In other words, palmitate interacts with fetuin-A, which then links the FFA to TLR4, to induce pro-apoptotic signals in islet cells, as shown in Figure 4. Fetuin-A also impaired glucose-induced insulin secretion in a c-Jun N-terminal kinase (JNK)- and Ca 2+ -dependent manner [19,89]. Interestingly, JNK and other pro-inflammatory cytokines such as TNFα can mediate serine phosphorylation of the IRS proteins associated with the insulin receptor, resulting in its inhibition [90].…”

“…This relationship between insulin and fetuin-A is important for the control of glucose homeostasis. In addition to its regulation of insulin signaling at the receptor level, fetuin-A also modulated FFA-mediated inflammation of the β-cells in the pancreas [19], thereby contributing to insulin resistance at this level also. We will discuss these two pathways by which fetuin-A mediates insulin resistance, thereby contributing to the sequelae of type 2 diabetes and pre-diabetes.…”