Molecular mechanisms of lipoapoptosis and metformin protection in GLP-1 secreting cells

Kappe, Camilla; Holst, Jens J.; Zhang, Qimin; Sjöholm, Åke

doi:10.1016/j.bbrc.2012.09.010

Cited by 16 publications

(19 citation statements)

References 191 publications

(225 reference statements)

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“…15,28). High levels of FFAs induce insulin resistance and are toxic to many cell types, and we have, using the fatty acid palmitate to simulate hyperlipidemia, previously shown lipotoxicity in GLP-1-secreting cells in vitro (13)(14). Palmitate was used to evaluate the effect of high concentrations of FFAs relevant to T2D, as it is the most abundant saturated FFA bound to human serum albumin (27) and is the most studied FFA in other endocrine cell types.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that palmitate-induced ROS production mediates the increased caspase-3 activity and lipotoxicity observed in response to simulated hyperlipidemia in vitro (13). In addition, exendin-4 has previously been reported to reduce ROS production in other cell systems (29).…”

Section: Exendin-4 and Insulin Reduce Palmitate-induced Ros Productiomentioning

confidence: 96%

“…The assay is based on 5-(and-6)-carboxy-2=,7=-dichlorodihydrofluorescein diacetate (carboxy-H 2DCFDA), a reliable fluorogenic marker for ROS in live cells. Cellular levels of ROS were measured following exposure to 0.125 mM palmitate in the presence/ absence of exendin-4 (13). Each experiment was performed in duplicates and repeated at least three times to assess consistency of results.…”

Section: Analysis Of Ros Levelsmentioning

confidence: 99%

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Evidence for paracrine/autocrine regulation of GLP-1-producing cells

Kappe

Zhang

Holst³

et al. 2013

American Journal of Physiology-Cell Physiology

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Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9-39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP-1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion.

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Section: Discussionmentioning

confidence: 99%

Section: Exendin-4 and Insulin Reduce Palmitate-induced Ros Productiomentioning

confidence: 96%

Section: Analysis Of Ros Levelsmentioning

confidence: 99%

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Evidence for paracrine/autocrine regulation of GLP-1-producing cells

Kappe

Zhang

Holst³

et al. 2013

American Journal of Physiology-Cell Physiology

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“…Few studies have been designed to investigate effects of this on L-cells and whether lipotoxicity occurs also in these cells. In a series of recent studies, cells of the GLUTag cell line were exposed to simulated hyperlipidaemia using the saturated fatty acid palmitate, the most abundant saturated fatty acid in serum [121,184,185]. This resulted in increased DNA fragmentation and caspase-3 activity in conjunction with reduced viability of GLP-1-producing cells [121,184,185].…”

Section: Lipotoxicity and Glp-1mentioning

confidence: 99%

“…In a series of recent studies, cells of the GLUTag cell line were exposed to simulated hyperlipidaemia using the saturated fatty acid palmitate, the most abundant saturated fatty acid in serum [121,184,185]. This resulted in increased DNA fragmentation and caspase-3 activity in conjunction with reduced viability of GLP-1-producing cells [121,184,185]. In resemblance with the β-cells, and in accordance with what has previously been found, there was a positive secretory response to acute exposure to the fatty acid, whereas impaired function was observed following long-term exposure.…”

Section: Lipotoxicity and Glp-1mentioning

confidence: 99%

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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Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA

Khat

Husain

2018

Curr Diab Rep

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SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system. This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.

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Molecular mechanisms of lipoapoptosis and metformin protection in GLP-1 secreting cells

Cited by 16 publications

References 191 publications

Evidence for paracrine/autocrine regulation of GLP-1-producing cells

Evidence for paracrine/autocrine regulation of GLP-1-producing cells

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

Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA

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