Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells

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

doi:10.1007/s00535-012-0637-5

Cited by 44 publications

(50 citation statements)

References 28 publications

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“…The mechanisms of action explaining why metformin may promote GLP-1 secretion from L cells are rather complex 84 . A recent study demonstrated that metformin protects against lipoapoptosis (possibly by blocking JNK2 activation), and enhances GLP-1 secretion from GLP-1-producing cells in vitro 85 . These direct effects of the drug might explain the elevated plasma GLP-1 levels seen in diabetic patients on chronic metformin therapy 81 .…”

Section: Potential Synergistic Activitymentioning

confidence: 99%

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Scheen

2013

Expert Opinion on Drug Metabolism & Toxicology

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SUMMARYIntroduction : The first-choice drug therapy in the management of type 2 diabetes is metformin. However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidylpeptidase-4 (DPP-4) inhibitors, commonly referred to as gliptins, offer new options for combined therapy with metformin. Linagliptin is the most recent launched gliptin, with a unique pharmacokinetic profile characterized by negligible renal excretion, and is now also available as a fixed-dose combination (FDC) with metformin.Area covered: An extensive literature search was performed to analyze the potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between linagliptin and metformin. Linaglipin and metformin may be administered together, either separately or as FDC supported by bioequivalence studies. Linagliptin and metformin are not prone to PK drug-drug interactions. Their co-administration improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metforminrelated gastrointestinal side effects.Expert Opinion : The combination linaglitpin plus metformin, if not contraindicated (renal failure), may be used as first-line or second-line therapy in the management of type 2 diabetes.

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Section: Potential Synergistic Activitymentioning

confidence: 99%

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Scheen

2013

Expert Opinion on Drug Metabolism & Toxicology

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“…Protein samples from cells were prepared for Western blot analysis using a modified RIPA buffer, and Western blot was performed as described previously [26]. Immunoblot analyses were performed using antibodies that recognize phosphorylated ERK 1/2, total ERK 1/2, phosphorylated p38 MAPK, total p38 MAPK, phosphorylated JNK, total JNK, phosphorylated eNOS and total eNOS (Cell Signaling Technology, Danvers, Mass., USA), pS239-VASP (16C2 [27]) and VASP (AB19728 [28]).…”

Section: Methodsmentioning

confidence: 99%

Glucagon-Like Peptide-1 Receptor Activation Does Not Affect Re-Endothelialization but Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Nondiabetic Model of Arterial Injury

Eriksson

Saxelin²,

Röhl³

et al. 2015

J Vasc Res

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Diabetic patients have an increased risk of restenosis and late stent thrombosis after angioplasty, i.e. complications that are related to a defective re-endothelialization. Exendin-4, a stable glucagon-like peptide (GLP)-1 receptor agonist, has been suggested to influence the formation of intimal hyperplasia and to increase endothelial cell proliferation in vitro. Thus, the aim of this study was to investigate the mechanisms by which treatment with exendin-4 could influence re-endothelialization and intimal hyperplasia after vascular injury. Methods: Sprague-Dawley rats were subjected to balloon injury of the left common carotid artery and treated for 4 weeks with exendin-4 or vehicle. Intimal hyperplasia and vessel wall elasticity were monitored noninvasively by high-frequency ultrasound, and re-endothelialization was evaluated upon sacrifice using Evans blue dye. Results and Conclusion: Exendin-4 selectively reduced the proliferation of smooth muscle cells (SMCs) and intimal hyperplasia in vivo without affecting the re-endothelialization process, but treatment with exendin-4 improved arterial wall elasticity. Our data also show that exendin-4 significantly decreased the proliferation and increased the apoptosis of SMCs in vitro, effects that appear to be mediated through cAMP signaling and endothelial nitric oxide synthase following GLP-1 receptor activation. Together, these effects of exendin-4 are highly desirable and may lead to an improved outcome for patients undergoing vascular interventions.

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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: 97%

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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Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells

Cited by 44 publications

References 28 publications

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Glucagon-Like Peptide-1 Receptor Activation Does Not Affect Re-Endothelialization but Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Nondiabetic Model of Arterial Injury

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

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