β-Cell Maturation and Identity in Health and Disease

Salinno, Ciro; Cota, Perla; Bastidas-Ponce, Aimée; Tarquis-Medina, Marta; Lickert, Heiko; Bakhti, Mostafa

doi:10.3390/ijms20215417

Cited by 70 publications

(62 citation statements)

References 166 publications

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“…Multiple causes have been suggested to explain the lower functional β-cell mass present in the pancreas of type 2 diabetics (T2D) [ 1 ], which include increased susceptibility to apoptosis of β-cells caused by exposure to chronic glucolipotoxicity [ 2 ], excessive endoplasmic reticulum (ER) stress [ 3 , 4 ], oxidative stress [ [5] , [6] , [7] ] and accumulation of DNA damage in the form of double-strand DNA breaks [ 8 ]. Recently, an alternative pathway has been invoked that involves β-cell de-differentiation or even complete loss of β-cell identity to explain reduced functional β-cell mass in T2D [ [9] , [10] , [11] ]. However, the evidence supporting the existence of the de-differentiated cellular state in human islet cells of diabetics is limited, and the precise nature, level of plasticity and functional outcome of this altered cellular state are unclear [ [12] , [13] , [14] ].…”

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

Avrahami

Wang

Schug

et al. 2020

Molecular Metabolism

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Objective Dedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown. Methods We employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. We also compared islets from non-diabetic and T2D individuals. Results Both α- and β-cells mature in part by repressing non-endocrine genes; however, α-cells retain hallmarks of an immature state, while β-cells attain a full β-cell specific gene expression program. In islets from T2D donors, both α- and β-cells have a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes and increasing expression of exocytosis, inflammation and stress response signalling pathways. These changes are consistent with the increased proportion of β-cells displaying suboptimal function observed in T2D islets. Conclusions These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.

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Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

Avrahami

Wang

Schug

et al. 2020

Molecular Metabolism

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“…e FoxO1 and Pdx1-Glut2insulin pathway plays an important role in glucosestimulated insulin secretion (GSIS) [19]. Wnt5a increased the expression of the maturation marker Glut2 after coculture with mouse islets and Min6 cells [20]. Previous studies of Wnt5a and diabetes focused on islet development, insulin resistance, inflammation, and studies relating the Wnt5a antagonist protein Sfrp5 to islet function.…”

Section: Introductionmentioning

confidence: 99%

“…Our study aimed at defining the specific mechanism by which ISCs promote insulin secretion in Min6 cells via the Wnt5a protein. (8,20, and 28 weeks old) and sex-matched male db/m mice were purchased from the Model Animal Research Centre of Nanjing University (Nanjing, China). All animal procedures were approved by our Institution's Ethics Committee and carried out under a licence.…”

Section: Introductionmentioning

confidence: 99%

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

Jones

Geng

et al. 2020

International Journal of Endocrinology

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Background. Type 2 diabetes mellitus is a serious public health problem worldwide. Accumulating evidence has shown that β-cell dysfunction is an important mechanism underlying diabetes mellitus. e changes in the physiological state of islet stellate cells (ISCs) and the effects of these cells on β cell function play an important role in the development of diabetes. is study aimed at elucidating the mechanism by which ISCs regulate insulin secretion from Min6 cells via the Wnt5a protein. Methods. Glucosestimulated insulin secretion (GSIS) from Min6 cells was examined by estimating the insulin levels in response to high glucose challenge after culture with ISC supernatant or exogenous Wnt5a. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used to observe changes in the β-catenin, receptor tyrosine kinase-like orphan receptor 2 (Ror2), Ca (2+)/calmodulin (CaM)-dependent protein kinase II (CamKII), forkhead box O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX1), glucose transporter 2 (Glut2), insulin, and Cask mRNA and protein levels in the Wnt and insulin secretory pathways. Flow cytometry was used to confirm the intracellular Ca 2+ concentration in Min6 cells. Results. We observed a significant increase in insulin secretion from Min6 cells cocultured in vitro with supernatant from db/m mouse ISCs compared to that from Min6 cells cocultured with supernatant from db/db mouse ISCs; e intracellular Ca 2+ concentration in Min6 cells increased in cultured in vitro with supernatant from db/m mouse ISCs and exogenous Wnt5a compared to that from control Min6 cells. Culture of Min6 cells with exogenous Wnt5a caused a significant increase in pCamKII, pFoxO1, PDX-1, and Glut2 levels compared to those in Min6 cells cultured alone; this treatment further decreased Ror2 and Cask expression but did not affect β-catenin expression. Conclusion. ISCs regulate insulin secretion from Min6 cells through the Wnt5a protein-induced Wntcalcium and FoxO1-PDX1-GLUT2-insulin signalling cascades.

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“…In mouse, embryonic beta-cells are described as immature, highly proliferative, and unipotent, albeit still plastic 47 . After birth, beta-cells are abundant, organized in clusters, and follow a biphasic pattern of maturation 47 .…”

Section: Discussionmentioning

confidence: 99%

Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice

Deng

Yang

et al. 2020

Cell Transplant

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In vivo beta-cell neogenesis may be one way to treat diabetes. We aimed to investigate the effect of glucagon-like peptide-1 (GLP-1) on beta-cell neogenesis in type 2 diabetes mellitus (T2DM). Male C57BL/6J mice, 6 wk old, were randomly divided into three groups: Control, T2DM, and T2DM + Lira. T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin (40 mg/kg/d for 3 d). At 8 wk after streptozotocin injection, T2DM + Lira group was injected intraperitoneally with GLP-1 analog liraglutide (0.8 mg/kg/d) for 4 wk. Apparently for the first time, we report the appearance of a primitive bud connected to pancreas in all adult mice from each group. The primitive bud was characterized by scattered single monohormonal cells expressing insulin, GLP-1, somatostatin, or pancreatic polypeptide, and four-hormonal cells, but no acinar cells and ductal epithelial cells. Monohormonal cells in it were small, newborn, immature cells that rapidly proliferated and expressed cell markers indicative of immaturity. In parallel, Ngn3+ endocrine progenitors and Nestin+ cells existed in the primitive bud. Liraglutide facilitated neogenesis and rapid growth of acinar cells, pancreatic ducts, and blood vessels in the primitive bud. Meanwhile, scattered hormonal cells aggregated into cell clusters and grew into larger islets; polyhormonal cells differentiated into monohormonal cells. Extensive growth of exocrine and endocrine glands resulted in the neogenesis of immature pancreatic lobes in adult mice of T2DM + Lira group. Contrary to predominant acinar cells in mature pancreatic lobes, there were still a substantial number of mesenchymal cells around acinar cells in immature pancreatic lobes, which resulted in the loose appearance. Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud, which liraglutide facilitates in adult T2DM mice. To our knowledge, this is the first time such a phenomenon has been reported.

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β-Cell Maturation and Identity in Health and Disease

Cited by 70 publications

References 166 publications

Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice

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