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ncomplete b-cell mass regeneration in PancMet KO mice after Ppx. A: Quantification of b-cell mass in SH-operated (n = 5) and Ppx (n = 7) WT and PancMet KO (n = 5 and n = 10, respectively) mice 28 days after surgery. Results are means 6 SEM. P < 0.05 vs. shamoperated WT or PancMet KO mice and Ppx WT mice. B: Intraperitoneal glucose tolerance test (3 g glucose/kg body wt) in sham-operated (n = 5) and Ppx (n = 7) WT and PancMet KO (n = 5 and n = 10, respectively) mice 25 days after surgery. Results are means 6 SEM. C: Area under the curve (AUC) calculated from the intraperitoneal glucose tolerance test experiments in which sham-operated and Ppx WT and PancMet KO mice 25 days after surgery were examined. Results are means 6 SEM. P < 0.05 vs. sham-operated WT or PancMet KO mice and Ppx WT mice. D: Quantitation of insulin secretion in islets isolated from WT (n = 6) and PancMet KO (n = 4) Ppx mice at 25 days postsurgery and incubated with 2.8 and 22.2 mmol/L glucose for 30 min. Results are means 6 SEM. *P < 0.05 vs. islets at 2.8 mmol/L; #P < 0.05 vs. Ppx WT islets at the same glucose concentration.
Source publication
Hepatocyte growth factor (HGF) is a mitogen required for ß-cell replication during pregnancy. To determine whether HGF/c-Met signaling is required for ß-cell regeneration we characterized mice with pancreatic deletion of the HGF receptor, c-Met, (PancMet KO mice) in two models of reduced ß-cell mass and regeneration: multiple low-dose streptozotoci...
Contexts in source publication
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... activators, we analyzed D-cyclin and cdk-4 levels in PancMet KO and WT mouse islets 7 days post- Ppx. PancMet KO islets post-Ppx displayed a remarkable and significant decrease in cyclins D1 and D2, with no alteration in cdk-4 ( Fig. 2K-N after Ppx. b-Cell mass was increased in WT mice post- Ppx, reaching similar levels to SH-operated mice (Fig. 3A). Importantly, b-cell mass in PancMet KO mice was significantly decreased post-Ppx compared with WT mice and SH-operated mice (Fig. 3A), indicating incomplete b-cell regeneration. Islet number was not different be- tween PancMet KO and WT littermates at 28 days post- Ppx (not shown), suggesting that the early decrease in b-cell ...
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... displayed a remarkable and significant decrease in cyclins D1 and D2, with no alteration in cdk-4 ( Fig. 2K-N after Ppx. b-Cell mass was increased in WT mice post- Ppx, reaching similar levels to SH-operated mice (Fig. 3A). Importantly, b-cell mass in PancMet KO mice was significantly decreased post-Ppx compared with WT mice and SH-operated mice (Fig. 3A), indicating incomplete b-cell regeneration. Islet number was not different be- tween PancMet KO and WT littermates at 28 days post- Ppx (not shown), suggesting that the early decrease in b-cell proliferation was potentially responsible for the incomplete b-cell regeneration in c-Met-deficient mice. Furthermore, PancMet KO mice ...
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... proliferation was potentially responsible for the incomplete b-cell regeneration in c-Met-deficient mice. Furthermore, PancMet KO mice displayed decreased glucose tolerance at 25 days post-Ppx, suggesting that the incomplete b-cell mass and perhaps defective insulin secretion might have an impact on glucose homeostasis in c-Met-deficient mice (Fig. 3B and C). Indeed, glucose- stimulated insulin secretion (GSIS) is decreased in iso- lated islets from PancMet KO mice 25 days post-Ppx compared with WT mice (Fig. 3D). Taken together, these results indicate that HGF/c-Met signaling is required for full b-cell mass recovery and normal GSIS and glucose homeostasis in a model of surgically reduced ...
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... tolerance at 25 days post-Ppx, suggesting that the incomplete b-cell mass and perhaps defective insulin secretion might have an impact on glucose homeostasis in c-Met-deficient mice (Fig. 3B and C). Indeed, glucose- stimulated insulin secretion (GSIS) is decreased in iso- lated islets from PancMet KO mice 25 days post-Ppx compared with WT mice (Fig. 3D). Taken together, these results indicate that HGF/c-Met signaling is required for full b-cell mass recovery and normal GSIS and glucose homeostasis in a model of surgically reduced b-cell mass. Fig. 4G and H). This highlights the therapeutic potential of HGF for increasing b-cell regeneration in ...
Citations
... Macrophages play a pivotal role in this process [34]. Hepatocyte growth factor (HGF), secreted by macrophages [35] and endothelial cells [36], exerts a β-cell replicative and regenerative effect under conditions of increased metabolic demand, such as pregnancy [37] and obesity/insulin resistance [38], and diminished β-cell mass, such as multiple low-dose streptozotocin (STZ) and partial pancreatectomy (PPx) [39]. Other β-cell mitogens secreted by macrophages include transforming growth factor β1 (TGFβ1) and epidermal growth factor (EGF). ...
... Previous studies have demonstrated the vital role of HGF-MET signaling in inducing the proliferation and regeneration of pancreatic β-cells. Indeed, mice with pancreatic deletion of MET (PancMet KO mice) show reduced β-cell proliferation, decreased glucose tolerance and impaired insulin secretion when compared to the wildtype mice (Alvarez-Perez et al., 2014). Defects in HGF-MET signaling has also been associated with the development of gestational diabetes, thereby highlighting its importance in maternal pancreatic β-cell adaptation during pregnancy (Demirci et al., 2012). ...
... In a study, mice undergoing partial pancreatectomy and receiving a daily dose of HGF showed an increased rate of b-cell proliferation, compared to placebo. Conversely, c-Met-knockout mice undergoing partial pancreatectomy showed reduced b-cell mass, glucose intolerance and decreased insulin secretion, when compared to wild type mice, after surgery [124]. By contrast, partial pancreatectomy in adult humans does not seem to cause the same effects. ...
... Pancreatectomy: Several animal studies have suggested increased bcell proliferation after different degrees of pancreatectomy [133]. In this condition HGF seems to be an important factor for b-cell regeneration [124]. ...
Background:
Over the last decades, various approaches have been explored to restore sufficient β-cell mass in diabetic patients. Stem cells are certainly an attractive source of new β-cells, but an alternative option is to induce the endogenous regeneration of these cells.
Scope of review:
Since the exocrine and endocrine pancreatic glands have a common origin and a continuous crosstalk unites the two, we believe that analyzing the mechanisms that induce pancreatic regeneration in different conditions could further advance our knowledge in the field. In this review, we summarize the latest evidence on physiological and pathological conditions associated with the regulation of pancreas regeneration and proliferation, as well as the complex and coordinated signaling cascade mediating cell growth.
Major conclusions:
Unraveling the mechanisms involved in intracellular signaling and regulation of pancreatic cell proliferation and regeneration may inspire future investigations to discover potential strategies to cure diabetes.
... regeneration of pancreatic β-cells. Indeed, mice with pancreatic deletion of MET (PancMet KO mice) show reduced β-cell proliferation, decreased glucose tolerance and impaired insulin secretion when compared to the wild-type mice (Alvarez-Perez et al., 2014). Defects in HGF-MET signaling has also been associated with the development of gestational diabetes, thereby highlighting its importance in maternal pancreatic β-cell adaptation during pregnancy (Demirci et al., 2012). ...
... Among multiple signaling pathways involved, HGF-MET and EGFR (and its ligands) pathways are sufficient to induce hepatocyte proliferation directly [8][9][10][11][12] , and blockade of the MET or EGFR pathway abolishes liver regeneration after partial hepatectomy [13][14][15][16][17] . On the other hand, auxiliary mitogens, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α, are insufficient to initiate hepatocyte proliferation on their own; rather, knockout of IL-6 or TNFR delays liver regeneration after partial hepatectomy 2,18 . ...
The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage-induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.
... Since HGF presents pleiotropic biological activities, ChREBP-mediated HGFAC secretion might be involved in other adaptive responses. Mice lacking pancreatic HGF receptor showed decreased b cells mass and impaired glucose tolerance and insulin secretion (68). In agreement, inhibition of Chrebp in pancreatic b cells leads to decreased glucosestimulated proliferation in rat and human cells. ...
Carbohydrate response element binding protein (ChREBP) is a glucose responsive transcription factor recognized by its critical role in the transcriptional control of glycolysis and de novo lipogenesis. Substantial advances in the field have revealed novel ChREBP functions. Indeed, due to its actions in different tissues, ChREBP modulates the inter-organ communication through secretion of peptides and lipid factors, ensuring metabolic homeostasis. Dysregulation of these orchestrated interactions is associated with development of metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Here, we recapitulate the current knowledge about ChREBP-mediated inter-organ crosstalk through secreted factors and its physiological implications. As the liver is considered a crucial endocrine organ, we will focus in this review on the role of ChREBP-regulated hepatokines. Lastly, we will discuss the involvement of ChREBP in the progression of metabolic pathologies, as well as how the impairment of ChREBP-dependent signaling factors contributes to the onset of such diseases.
... There is increasing evidence suggesting that hepatocyte growth factor (about 83 kDa) and insulin-like growth factors (about 29 kDa) play an important role in the proliferation and survival of pancreatic β-cells both in vitro and in vivo. 48,49 We think that candidate effectors for activating degraded islets are hepatocyte growth factor, insulin-like growth factor, and the transforming growth factor because previous reports have suggested that these cytokines are factors for the activation of pancreas and/or β cells. [50][51][52] In conclusion, we found that certain fractions of the factors secreted by MSCs were able to activate preserved islets. ...
The success of islet transplantation in both basic research and clinical settings has proven that cell therapy has the potential to cure diabetes. Islets intended for transplantation are inevitably subjected to damage from a number of sources, including ischemic injury during removal and delivery of the donor pancreas, enzymatic digestion during islet isolation, and reperfusion injury after transplantation in the recipient. Here, we found that protein factors secreted by porcine adipose-tissue mesenchymal stem cells (AT-MSCs) were capable of activating preserved porcine islets. A conditioned medium was prepared from the supernatant obtained by culturing porcine AT-MSCs for 2 days in serum-free medium. Islets were preserved at 4°C in University of Wisconsin solution during transportation and then incubated at 37°C in RPMI-1620 medium with fractions of various molecular weights prepared from the conditioned medium. After treatment with certain fractions of the AT-MSC secretions, the intracellular ATP levels of the activated islets had increased to over 160% of their initial values after 4 days of incubation. Our novel system may be able to restore the condition of isolated islets after transportation or preservation and may help to improve the long-term outcome of islet transplantation.
Abbreviations: AT-MSC, adipose-tissue mesenchymal stem cell; Cas-3, caspase-3; DAPI, 4,6-diamidino-2-phenylindole; DTZ, dithizone; ES cell, embryonic stem cell; FITC, fluorescein isothiocyanate; IEQ, islet equivalent; INS, insulin; iPS cell, induced pluripotent stem cell; Luc-Tg rat, luciferase-transgenic rat; PCNA, proliferating cell nuclear antigen; PDX1, pancreatic and duodenal homeobox protein-1; UW, University of Wisconsin; ZO1, zona occludens 1.
... HGF, the principal target for HGFAC, has previously been implicated in other aspects of glucose homeostasis. For example, HGF may enhance pancreatic β cell proliferation (45,(69)(70)(71). Increased ChREBP-mediated HGFAC secretion might be a potential mechanism to increase β cell mass in the setting of increased dietary carbohydrate burden. ...
Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
... The presented work aimed to study the changes in some biomarkers in gestational diabetes mellitus (GDM) patients then compared with another groups of normal pregnancy and T2DM group. The age obtained for gestational diabetes mellitus (GDM) group collected was ranged between (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) year and that for group II which include T2DM group II was ranged between year, whereas, the age ranged for group III as a normal pregnant women was (20-37) years. ...
... These changes in the ß-cells cause increased Insulin secretion as a result of increased ß-cell proliferation. [30] Pregnancy causes increased Insulin resistance and so higher Insulin demand. The ß-cell must compensate this by either increasing insulin production or proliferating. ...
... In other words, T2DM may induce imbalances of ECM synthesis and degradation that promote OA progression. [18,19] Functional analysis results of significantly enriched pathways highlighted the key role that cell communication plays in development of both T2DM and OA and are consistent with results of other studies showing that both T2DM onset and development involve complex signaling between pancreatic islet cells and hormones, regulatory factors, and metabolites released from peripheral tissues (e.g., fat, [20] liver, [21][22][23] and skeletal muscle). [24][25][26] Two inhibitory signaling pathways and 4 activation signaling pathways were discovered in further data analysis (Fig. 6). ...
Background:
To explore the effects of type 2 diabetes mellitus (T2DM) on osteoarthritis (OA), 12 bone tissue samples were obtained surgically from the human total knee arthroplasty patients and analyzed by quantitative proteomics.
Methods:
Based on patient clinical histories, patient samples were assigned to diabetes mellitus osteoarthritis (DMOA) and OA groups. A data-independent acquisition method for data collection was used with proteomic data analysis to assess intergroup proteomic differences. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis were used to further find the correlation between T2DM and OA.
Results:
GO functional analysis found 153 differentially expressed proteins between DMOA and OA groups, of which 92 differentially expressed proteins were significantly up-regulated and 61 were significantly down-regulated. Kyoto Encyclopedia of Genes and Genome pathway analysis found 180 pathways, including 9 pathways significantly enriched. Further data analysis revealed that 6 signaling pathways were closely associated with T2DM and OA.
Conclusion:
OA and DMOA onset and progression were closely related to synthesis and metabolism of extracellular matrix components (e.g., fibronectin, decorin, etc.). The effects of T2DM on OA occur though 2 major ways of oxidative stress and low-grade chronic inflammation, involving in 2 inhibited signaling pathways and 4 activated signaling pathways.
