Glucose plus metformin compared with glucose alone on β-cell function in mouse pancreatic islets

Hashemitabar, Mahmoud; Bahramzadeh, Somayeh; Saremy, Sadegh; Nejaddehbashi, Fereshteh

doi:10.3892/br.2015.476

Cited by 18 publications

(11 citation statements)

References 28 publications

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“…Using murine islets and human islets Lundquist et al [37] have demonstrated a marked reduction by metformin [20 μM] in nitric oxide synthase-derived nitric oxide, insulin secretory dysfunction and loss in cell viability under conditions of long-term exposure to glibenclamide and HG. Using rodent islets, Hashemitabar and associates have demonstrated beneficial effects of metformin [15 μM] on insulin gene expression, insulin secretion and islet cell viability [38]. Natalichhio and coworkers have shown significant restoration of GLP-1 receptor impairment by metformin [0.5–1.0 mM] in murine islets following exposure to palmitate [39].…”

Section: Discussionmentioning

confidence: 99%

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

et al. 2017

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Emerging evidence suggests that long-term exposure of insulin-secreting pancreatic β-cells to hyperglycemic [HG; glucotoxic] conditions promotes oxidative stress, which, in turn, leads to stress kinase activation, mitochondrial dysfunction, loss of nuclear structure and integrity and cell apoptosis. Original observations from our laboratory have proposed that Rac1 plays a key regulatory role in the generation of oxidative stress and downstream signaling events culminating in the onset of dysfunction of pancreatic β-cells under the duress of metabolic stress. However, precise molecular and cellular mechanisms underlying the metabolic roles of hyperactive Rac1 remain less understood. Using pharmacological and molecular biological approaches, we now report mistargetting of biologically-active Rac1 [GTP-bound conformation] to the nuclear compartment in clonal INS-1 cells, normal rat islets and human islets under HG conditions. Our findings also suggest that such a signaling step is independent of post-translational prenylation of Rac1. Evidence is also presented to highlight novel roles for sustained activation of Rac1 in HG-induced expression of Cluster of Differentiation 36 [CD36], a fatty acid transporter protein, which is implicated in cell apoptosis. Finally, our findings suggest that metformin, a biguanide anti-diabetic drug, at a clinically relevant concentration, prevents β-cell defects [Rac1 activation, nuclear association, CD36 expression, stress kinase and caspase-3 activation, and loss in metabolic viability] under the duress of glucotoxicity. Potential implications of these findings in the context of novel and direct regulation of islet β-cell function by metformin are discussed.

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Section: Discussionmentioning

confidence: 99%

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

et al. 2017

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“… 343 Furthermore, it supports weight loss 344 by reducing food consumption. 345 With respect to its effects on β-cell function, metformin was shown to increase insulin gene expression, 346 possibly by nuclear accumulation of pdx1 and its subsequently improved DNA-binding activity. 347 Interestingly, metformin exerts opposing effects on β-cell proliferation and/or apoptosis; on the one hand, it suppresses β-cell proliferation and enhances apoptosis through an AMPK-dependent and autophagy-mediated mechanism 348 following the metformin-induced activation of c-Jun-N-terminal kinase and caspase-3.…”

Section: Modulating Insulin Secretion As a Means Of Diabetes Therapymentioning

confidence: 99%

Pancreatic regulation of glucose homeostasis

et al. 2016

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In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.

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“…Metformin is a widely used drug of T2DM, and its antidiabetic characteristics should be inhibiting hepatic gluconeogenesis and improving insulin sensitivity in peripheral tissues (Adak, Samadi, Unal, & Sabuncuoglu, ). Based on previous in vivo studies, metformin also can increase glucose oxidation in MIN6 pancreatic β cells, promote insulin release in mouse isolated pancreatic islets (Hashemitabar, Bahramzadeh, Saremy, & Nejaddehbashi, ), and alleviate functional, biochemical, and ultrastructural abnormalities in human islet cells exposed to glucotoxic condition. But so far, the effect and underlying mechanisms of metformin on β cells remain unclear.…”

Section: Introductionmentioning

confidence: 99%

“…. Based on previous in vivo studies, metformin also can increase glucose oxidation in MIN6 pancreatic β cells, promote insulin release in mouse isolated pancreatic islets (Hashemitabar, Bahramzadeh, Saremy, & Nejaddehbashi, 2015), and alleviate functional, biochemical, and ultrastructural abnormalities in human islet cells exposed to glucotoxic condition. But so far, the effect and underlying mechanisms of metformin on β cells remain unclear.…”

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confidence: 99%

Metformin‐induced autophagy and irisin improves INS‐1 cell function and survival in high‐glucose environment via AMPK/SIRT1/PGC‐1α signal pathway

Jia

et al. 2019

Food Science & Nutrition

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In order to explore the protective function of metformin on pancreatic β cells to alleviate insulin resistance and underlying mechanisms, INS‐1 cells were cultured into normal control (N), high glucose (H), high glucose and metformin (H + Met), high glucose and chloroquine (H + CQ), and high glucose and Ex527 (H + Ex527) groups, respectively. Upon 24‐hr cultivation, the proliferation and glucose‐stimulated insulin secretion (GSIS) of INS‐1 cells were determined, and the expression of irisin and other proteins associated with AMPK/SIRT1/PGC‐1α signal pathway, autophagy, and apoptosis was evaluated. Compared with the N group, the cells from the H group revealed lower proliferation, GSIS, and expression of irisin and proteins associated with AMPK/SIRT1/PGC‐1α signal pathway and autophagy, but higher expression of proteins associated with apoptosis; in contrast, metformin could significantly rescue lower cell proliferation, GSIS, and expression of proteins associated with AMPK/SIRT1/PGC‐1α signal pathway and autophagy, as well as irisin, and suppress apoptosis in high‐glucose environment. Meanwhile, autophagy inhibitor CQ and SIRT1 inhibitor Ex527 can block above functions of metformin. Therefore, metformin can promote INS‐1 cell proliferation, enhance GSIS, and suppress apoptosis by activating AMPK/SIRT1/PGC‐1α signal pathway, up‐regulating irisin expression, and inducing autophagy in INS‐1 cells in high‐glucose environment.

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Glucose plus metformin compared with glucose alone on β-cell function in mouse pancreatic islets

Cited by 18 publications

References 28 publications

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

Pancreatic regulation of glucose homeostasis

Metformin‐induced autophagy and irisin improves INS‐1 cell function and survival in high‐glucose environment via AMPK/SIRT1/PGC‐1α signal pathway

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