Differential molecular and cellular responses of GLP-1 secreting L-cells and pancreatic alpha cells to glucotoxicity and lipotoxicity

Vasu, Srividya; Moffett, R. Charlotte; McClenaghan, Neville H.; Flatt, Peter R.

doi:10.1016/j.yexcr.2015.05.022

Cited by 34 publications

(22 citation statements)

References 56 publications

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“…Similarly, Filipello et al [47] reported decreased insulin-dependent GLP-1 secretion from L-cell-derived GLUTag cells, and increased glucagon release, upon fatty acid treatment. Similar findings on GLP-1 secretion were reported by others [48,49], whist long chain saturated (palmitate) but not unsaturated (oleate) fatty acids lead to L-cell apoptosis [50]. On the other hand, activation of free fatty acid receptors with FFAR1/GPR40 agonist TAK-875 [51] or with short-chain fatty acids (FFAR2/GPR43) [52] acutely increased GLP-1 secretion from L-cells, indicating a balance between shorter term, and more chronic "lipotoxic" effects, is likely to govern overall GLP-1 production, with the latter predominating after Tcf7l2 deletion in adipocytes.…”

Section: Discussionsupporting

confidence: 92%

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Nguyen-Tu

Martínez-Sánchez

Leclerc

et al. 2020

Preprint

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Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/beta-catenin signalling pathway and its expression is critical for adipocyte development. The precise role of TCF7L2 in glucose and lipid metabolism in adult adipocytes remains to be defined. Here, we aim to investigate how changes in TCF7L2 expression in mature adipocytes affect glucose homeostasis. Tcf7l2 was selectively ablated from mature adipocytes in C57BL/6J mice using an adiponectin promoter-driven Cre recombinase to recombine alleles floxed at exon 1 of the Tcf7l2 gene. Mice lacking Tcf7l2 in mature adipocytes displayed normal body weight. Male mice exhibited normal glucose homeostasis at eight weeks of age. Male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance (AUC increased 1.14 ± 0.04 -fold, p=0.03), as assessed by intraperitoneal glucose tolerance test, and changes in fat mass at 16 weeks (increased by 1.4 ± 0.09-fold, p=0.007). Homozygote knockout mice exhibited impaired oral glucose tolerance at 16 weeks of age (AUC increased 2.15 ± 0.15-fold, p=0.0001). Islets of Langerhans exhibited impaired glucose-stimulated insulin secretion in vitro (decreased 0.54 ± 0.13-fold aTCF7L2KO vs control, p=0.02), but no changes in in vivo glucosestimulated insulin secretion. Female mice in which one or two alleles of the Tcf7l2 gene was knocked out in adipocytes displayed no changes in glucose tolerance, insulin sensitivity or insulin secretion.Plasma levels of glucagon-like peptide-1 and gastric inhibitory polypeptide were lowered in knockout mice (decreased 0.57 ± 0.03-fold and 0.41 ± 0.12-fold, p=0.04 and p=0.002, respectively), whilst plasma free fatty acids and Fatty Acid Binding Protein 4 circulating levels were increased by 1.27 ± 0.07 and 1.78 ± 0.32-fold, respectively (p=0.05 and p=0.03). Mice with biallelic Tcf7l2 deletion exposed to high fat diet for 9 weeks exhibited impaired glucose tolerance (p=0.003 at 15 min after glucose injection) which was associated with reduced in vivo glucose-stimulated insulin secretion (decreased 0.51 ± 0.03-fold, p=0.02). Thus, our data indicate that loss of Tcf7l2 gene expression in adipocytes leads to impairments on metabolic responses which are dependent on gender, age and nutritional status. Our findings further illuminate the role of TCF7L2 in the maintenance of glucose homeostasis.

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Section: Discussionsupporting

confidence: 92%

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Nguyen-Tu

Martínez-Sánchez

Leclerc

et al. 2020

Preprint

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“…b cell-specific apoptosis is most likely the result of the activation by exosomes of cell death pathways operating only in insulinsecreting cells. Human and rodent a cells have been reported to be resistant to metabolic and immune stresses that induce b cell death (Marroqui et al, 2015;Takeda et al, 2012;Vasu et al, 2015). In agreement with this hypothesis, Ccl2, Ccl7, and Cxcl10 were solely increased in b cells and not in a cells upon exosome treatment.…”

Section: Discussionmentioning

confidence: 78%

Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic β Cell Death and May Contribute to Type 1 Diabetes Development

et al. 2019

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Graphical Abstract Highlights d T lymphocytes release exosomes containing specific microRNAs d T lymphocyte exosomes can transfer microRNAs to rodent and human pancreatic b cells d The transferred microRNAs trigger chemokine expression and apoptosis of b cells d Blockade of microRNAs transferred in b cells decreases diabetes incidence in NOD mice In Brief Guay et al. show that T cells release exosomes containing specific microRNAs that trigger chemokine expression and apoptosis in recipient pancreatic b cells in type 1 diabetes. Inactivation of miR-142-3p/-5p and miR-155 in b cells results in higher insulin levels, lower insulitis scores, and reduced inflammation and protects NOD mice from diabetes development.

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“…Although it has been widely observed that nutrients and hormones are necessary and sufficient to regulate GLP-1 secretion, whether and through what mechanism chronic exposure to these factors affects L-cell function remains unclear. Existing data are lacking and also somewhat controversial (8,27,45,52). Furthermore, whether glucotoxicity affects the responsiveness of L-cells to acute glucose stimuli remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus

Urbano

Filippello

Pino

et al. 2016

American Journal of Physiology-Cell Physiology

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Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose-stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1-secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP(+)) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion.

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Differential molecular and cellular responses of GLP-1 secreting L-cells and pancreatic alpha cells to glucotoxicity and lipotoxicity

Cited by 34 publications

References 56 publications

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic β Cell Death and May Contribute to Type 1 Diabetes Development

Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus

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