Mechanisms of metformin action on glucose transport and metabolism in human adipocytes

Grisouard, Jean; Timper, Katharina; Radimerski, Tanja; Frey, Daniel M.; Peterli, Ralph; Kola, Blerina; Korbonits, Márta; Herrmann, Paul C.; Krähenbühl, Stephan; Zulewski, Henryk; Keller, Ulrich; Müller, Beat; Christ‐Crain, Mirjam

doi:10.1016/j.bcp.2010.08.021

Cited by 60 publications

(46 citation statements)

References 34 publications

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“…However, other studies have shown that metformin had no effect on the insulin-mediated signaling cascaded in human adipocytes of type 2 diabetic and in fish skeletal muscle cells. 9,28,29 In the present study, it was difficult to determine if metformin exerted direct actions on the IRS1/PI3K/Akt-signaling transduction pathway in LYRM1-over-expressing 3T3-L1 adipocytes; further study is required to elucidate if metformin directly affects the IRS1/PI3K/Akt-signaling transduction pathway in LYRM1-over-expressing 3T3-L1 adipocytes. However, it should be noted that the changes in the phosphorylation of IRS1 and Akt associated with metformin pretreatment were accompanied by alterations in the levels of ROS and mitochondrial biogenesis indicators, all of which are affected by LYRM1.…”

Section: Discussionmentioning

confidence: 91%

“…13,14 A recent investigation showed that metformin prevented mitochondrial-driven oxidative stress by reducing ROS production and improving mitochondrial biogenesis through activating the adenosine monophosphate-activated protein kinase (AMPK)-PGC-1/NRFs axis pathway. 3,9,10,15 We propose that mitochondrial dysfunction is the origin of LYRM1-induced insulin resistance in adipocytes. This study was undertaken to elucidate the effects and mechanism of action of metformin on LYRM1-induced insulin resistance in adipocytes.…”

Section: Introductionmentioning

confidence: 99%

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Metformin prevents LYRM1-induced insulin resistance in 3T3-L1 adipocytes via a mitochondrial-dependent mechanism

Qin

Zhang

Dai

et al. 2014

Exp Biol Med (Maywood)

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We previously proposed that LYR motif containing 1 (LYRM1)-induced mitochondrial reactive oxygen species (ROS) production contributes to obesity-related insulin resistance. Metformin inhibits ROS production and promotes mitochondrial biogenesis in specific tissues. We assessed the effects of metformin on insulin resistance in LYRM1-over-expressing 3T3-L1 adipocytes. Metformin enhanced basal and insulin-stimulated glucose uptake and GLUT4 translocation, reduced IRS-1 and Akt phosphorylation and ROS levels, and affected the expression of regulators of mitochondrial biogenesis in LYRM1-over-expressing adipocytes. Metformin may ameliorate LYRM1-induced insulin resistance and mitochondrial dysfunction in part via a direct antioxidant effect and in part by activating the adenosine monophosphate-activated protein kinase (AMPK)-PGC1/NRFs pathway.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Metformin prevents LYRM1-induced insulin resistance in 3T3-L1 adipocytes via a mitochondrial-dependent mechanism

Qin

Zhang

Dai

et al. 2014

Exp Biol Med (Maywood)

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“…Cells were serum starved in 5 mM glucose-DMEM-F12 for 2 h. Cells were then treated with 1 nM GIP for 6 h and in the end with 1 nM insulin for 20 min. Following stimulation, adipocytes were washed with HES buffer, scraped, homogenized, and centrifuged as previously described (24). The supernatant was further centrifuged (18,000 g, 20 min).…”

Section: Methodsmentioning

confidence: 99%

Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes

Timper

Grisouard

Sauter

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1β, and the IL-1 receptor antagonist IL-1Ra, whereas TNFα, IL-8, and monocyte chemotactic protein (MCP)-1 remained unchanged. Cytokine induction involved PKA and the NF-κB pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1β, and TNFα. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-κB activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-κB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes.

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“…And when this occurs, catabolic pathways (as fatty acid oxidation or glucose transport) that generate ATP are induced, whereas ATP-consuming, anabolic processes (namely fatty acid and protein synthesis) are switched off (49). Additionally, AMPK activation has been suggested to indirectly improve hepatic insulin sensitivity (47, 49), to promote GLUT-4 protein expression and glucose uptake in human adipocytes (64) and to regulate adipogenic differentiation via inhibition of peroxisome proliferator-activated receptor gamma (PPAR-γ) (49). In parallel, metformin was also described to inhibit adenylate cyclase (AC) via accumulation of AMP and related nucleotides, thus reducing cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in mouse hepatocytes, culminating in ablation of glucagon-dependent glucose production and output (49).…”

Section: Introductionmentioning

confidence: 99%

Insulin as a Bridge between Type 2 Diabetes and Alzheimer Disease â€“ How Anti-Diabetics Could be a Solution for Dementia

Sebastião¹,

Candeias

Santos

et al. 2014

Front. Endocrinol.

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Type 2 diabetes (T2D) and Alzheimer disease (AD) are two major health issues nowadays. T2D is an ever increasing epidemic, affecting millions of elderly people worldwide, with major repercussions in the patients’ daily life. This is mostly due to its chronic complications that may affect brain and constitutes a risk factor for AD. T2D principal hallmark is insulin resistance which also occurs in AD, rendering both pathologies more than mere unrelated diseases. This hypothesis has been reinforced in the recent years, with a high number of studies highlighting the existence of several common molecular links. As such, it is not surprising that AD has been considered as the “type 3 diabetes” or a “brain-specific T2D,” supporting the idea that a beneficial therapeutic strategy against T2D might be also beneficial against AD. Herewith, we aim to review some of the recent developments on the common features between T2D and AD, namely on insulin signaling and its participation in the regulation of amyloid β (Aβ) plaque and neurofibrillary tangle formation (the two major neuropathological hallmarks of AD). We also critically analyze the promising field that some anti-T2D drugs may protect against dementia and AD, with a special emphasis on the novel incretin/glucagon-like peptide-1 receptor agonists.

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Mechanisms of metformin action on glucose transport and metabolism in human adipocytes

Cited by 60 publications

References 34 publications

Metformin prevents LYRM1-induced insulin resistance in 3T3-L1 adipocytes via a mitochondrial-dependent mechanism

Metformin prevents LYRM1-induced insulin resistance in 3T3-L1 adipocytes via a mitochondrial-dependent mechanism

Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes

Insulin as a Bridge between Type 2 Diabetes and Alzheimer Disease â€“ How Anti-Diabetics Could be a Solution for Dementia

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