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Design principles of the paradoxical feedback between pancreatic alpha and beta cells.

ABSTRACT: Mammalian glucose homeostasis is controlled by the antagonistic hormones insulin and glucagon, secreted by pancreatic beta and alpha cells respectively. These two cell types are adjacently located in the islets of Langerhans and affect each others' secretions in a paradoxical manner: while insulin inhibits glucagon secretion from alpha cells, glucagon seems to stimulate insulin secretion from beta cells. Here we ask what are the design principles of this negative feedback loop. We systematically simulate the dynamics of all possible islet inter-cellular connectivity patterns and analyze different performance criteria. We find that the observed circuit dampens overshoots of blood glucose levels after reversion of glucose drops. This feature is related to the temporal delay in the rise of insulin concentrations in peripheral tissues, compared to the immediate hormone action on the liver. In addition, we find that the circuit facilitates coordinate secretion of both hormones in response to protein meals. Our study highlights the advantages of a paradoxical paracrine feedback loop in maintaining metabolic homeostasis.

SUBMITTER: Garzilli I

PROVIDER: S-EPMC6048053 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Design principles of the paradoxical feedback between pancreatic alpha and beta cells.

Garzilli Immacolata I Itzkovitz Shalev S

Scientific reports 20180716 1

Mammalian glucose homeostasis is controlled by the antagonistic hormones insulin and glucagon, secreted by pancreatic beta and alpha cells respectively. These two cell types are adjacently located in the islets of Langerhans and affect each others' secretions in a paradoxical manner: while insulin inhibits glucagon secretion from alpha cells, glucagon seems to stimulate insulin secretion from beta cells. Here we ask what are the design principles of this negative feedback loop. We systematically ...[more]

PMID: 30013127

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Project description:microRNAs (miRNAs) play an important role in pancreatic development and adult ?-cell physiology. Our hypothesis is based on the assumption that each islet cell type has a specific pattern of miRNA expression. We sought to determine the profile of miRNA expression in ?-and ?-cells, the main components of pancreatic islets, because this analysis may lead to a better understanding of islet gene regulatory pathways. Highly enriched (>98%) subsets of human ?-and ?-cells were obtained by flow cytometric sorting after intracellular staining with c-peptide and glucagon antibody. The method of sorting based on intracellular staining is possible because miRNAs are stable after fixation. MiRNA expression levels were determined by quantitative high throughput PCR-based miRNA array platform screening. Most of the miRNAs were preferentially expressed in ?-cells. From the total of 667 miRNAs screened, the Significant Analysis of Microarray identified 141 miRNAs, of which only 7 were expressed more in ?-cells (?-miRNAs) and 134 were expressed more in ?-cells (?-miRNAs). Bioinformatic analysis identified potential targets of ?-miRNAs analyzing the Beta Cell Gene Atlas, described in the T1Dbase, the web platform, supporting the type 1 diabetes (T1D) community. cMaf, a transcription factor regulating glucagon expression expressed selectively in ?-cells (TF?) is targeted by ?-miRNAs; miR-200c, miR-125b and miR-182. Min6 cells treated with inhibitors of these miRNAs show an increased expression of cMaf RNA. Conversely, over expression of miR-200c, miR-125b or miR-182 in the mouse alpha cell line ?TC6 decreases the level of cMAF mRNA and protein. MiR-200c also inhibits the expression of Zfpm2, a TF? that inhibits the PI3K signaling pathway, at both RNA and protein levels.In conclusion, we identified miRNAs differentially expressed in pancreatic ?- and ?-cells and their potential transcription factor targets that could add new insights into different aspects of islet biology and pathophysiology.

Project description:C-X-C Motif Chemokine Ligand 10 (CXCL10) is a pro-inflammatory chemokine specifically recognized by the ligand receptor CXCR3 which is mostly expressed in T-lymphocytes. Although CXCL10 expression and secretion have been widely associated to pancreatic islets both in non-obese diabetic (NOD) mice and in human type 1 diabetic (T1D) donors, the specific expression pattern among pancreatic endocrine cell subtypes has not been clarified yet. Therefore, the purpose of this study was to shed light on the pancreatic islet expression of CXCL10 in NOD, in C57Bl/6J and in NOD-SCID mice as well as in human T1D pancreata from new-onset T1D patients (DiViD study) compared to non-diabetic multiorgan donors from the INNODIA European Network for Pancreatic Organ Donors with Diabetes (EUnPOD). CXCL10 was expressed in pancreatic islets of normoglycaemic and new-onset diabetic NOD mice but not in C57Bl/6J and NOD-SCID mice. CXCL10 expression was increased in pancreatic islets of new-onset diabetic NOD mice compared to normoglycaemic NOD mice. In NOD mice, CXCL10 colocalized both with insulin and glucagon. Interestingly, CXCL10-glucagon colocalization rate was significantly increased in diabetic vs. normoglycaemic NOD mouse islets, indicating an increased expression of CXCL10 also in alpha-cells. CXCL10 was expressed in pancreatic islets of T1D patients but not in non-diabetic donors. The analysis of the expression pattern of CXCL10 in human T1D pancreata from DiViD study, revealed an increased colocalization rate with glucagon compared to insulin. Of note, CXCL10 was also expressed in alpha-cells residing in insulin-deficient islets (IDI), suggesting that CXCL10 expression in alpha cells is not driven by residual beta-cells and therefore may represent an independent phenomenon. In conclusion, we show that in T1D CXCL10 is expressed by alpha-cells both in NOD mice and in T1D patients, thus pointing to an additional novel role for alpha-cells in T1D pathogenesis and progression.

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Design principles of the paradoxical feedback between pancreatic alpha and beta cells.

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Design principles of the paradoxical feedback between pancreatic alpha and beta cells.

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