Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

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

doi:10.1530/jme-14-0214

Cited by 12 publications

(15 citation statements)

References 65 publications

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“…In the current study, diabetes-like syndromes with contrasting aetiologies were induced in Ins1 Cre/+ /Rosa26-eYFP mice, through administration of STZ, HC or prolonged high fat (45%) feeding. These transgenic mice displayed the classic features related to either beta-cell destruction or insulin resistance (Vasu et al 2015). As expected, the presenting metabolic characteristics and associated pancreatic morphology differed between each mouse model (Vasu et al 2015).…”

Section: Discussionsupporting

confidence: 53%

“…These transgenic mice displayed the classic features related to either beta-cell destruction or insulin resistance (Vasu et al 2015). As expected, the presenting metabolic characteristics and associated pancreatic morphology differed between each mouse model (Vasu et al 2015). Thus, STZ mice exhibited hyperglycaemia-insulin deficiency, whereas HFF and HC induced marked hyperinsulinaemia-insulin resistance.…”

Section: Discussionmentioning

confidence: 58%

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Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes

Tanday

Flatt

Irwin

et al. 2020

Journal of Endocrinology

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Transdifferentiation of beta- to alpha-cells has been implicated in the pathogenesis of diabetes. To investigate the impact of contrasting aetiologies of beta-cell stress, as well as clinically approved incretin therapies on this process, lineage tracing of beta-cells in transgenic Ins1 Cre/+/Rosa26-eYFP mice was investigated. Diabetes-like syndromes were induced by streptozotocin (STZ), high fat feeding (HFF) or hydrocortisone (HC), and effects of treatment with liraglutide or sitagliptin were investigated. Mice developed the characteristic metabolic features associated with beta-cell destruction or development of insulin resistance. Liraglutide was effective in preventing weight gain in HFF mice, with both treatments decreasing energy intake in STZ and HC mice. Treatment intervention also significantly reduced blood glucose levels in STZ and HC mice, as well as increasing either plasma or pancreatic insulin while decreasing circulating or pancreatic glucagon in all models. The recognised changes in pancreatic morphology induced by STZ, HFF or HC were partially, or fully, reversed by liraglutide and sitagliptin, and related to advantageous effects on alpha- and beta-cell growth and survival. More interestingly, induction of diabetes-like phenotype, regardless of pathogenesis, led to increased numbers of beta-cells losing their identity, as well as decreased expression of Pdx1 within beta-cells. Both treatment interventions, and especially liraglutide, countered detrimental islet cell transitioning effects in STZ and HFF mice. Only liraglutide imparted benefits on beta- to alpha-cell transdifferentiation in HC mice. These data demonstrate that beta- to alpha-cell transdifferentiation is a common consequence of beta-cell destruction or insulin resistance and that clinically approved incretin-based drugs effectively limit this.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 58%

Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes

Tanday

Flatt

Irwin

et al. 2020

Journal of Endocrinology

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“…Absorbance was read at 548 nm using microplate reader (Molecular Devices, Sunnyvale, CA, USA). Incubation of cells with cytokine cocktail was used as positive control [49].…”

Section: Nitrite Assaymentioning

confidence: 99%

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

Vasu

Moffett

McClenaghan

et al. 2015

Experimental Cell Research

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“…In addition, it appeared that the lipotoxic effects were mediated by an increased production of ROS. Further studies of Lcells following chemical or cytokine-mediated attack indicate cellular responses similar to those activated in the β-cells, suggesting similarities between the two cell types with regards to antioxidant defence [186].…”

Section: Lipotoxicity and Glp-1mentioning

confidence: 85%

The regulation of function, growth and survival of GLP-1-producing L-cells

2015

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Glucagon-like peptide-1 (GLP-1) is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signalling exerts numerous pleiotropic effects on various tissues, regulating energy absorption and disposal, as well as cell proliferation and survival. In Type 2 Diabetes (T2D) reduced plasma levels of GLP-1 have been observed, and plasma levels of GLP-1, as well as reduced numbers of GLP-1 producing cells, have been correlated to obesity and insulin resistance. Increasing endogenous secretion of GLP-1 by selective targeting of the molecular mechanisms regulating secretion from the L-cell has been the focus of much recent research. An additional and promising strategy for enhancing endogenous secretion may be to increase the L-cell mass in the intestinal epithelium, but the mechanisms that regulate the growth, survival and function of these cells are largely unknown. We recently showed that prolonged exposure to high concentrations of the fatty acid palmitate induced lipotoxic effects, similar to those operative in insulin-producing cells, in an in vitro model of GLP-1-producing cells. The mechanisms inducing this lipototoxicity involved increased production of reactive oxygen species (ROS). In this review, regulation of GLP-1-secreting cells is discussed, with a focus on the mechanisms underlying GLP-1 secretion, long-term regulation of growth, differentiation and survival under normal as well as diabetic conditions of hypernutrition.

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Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Cited by 12 publications

References 65 publications

Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes

Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes

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

The regulation of function, growth and survival of GLP-1-producing L-cells

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