The AMP-activated protein kinase (AMPK) is a pivotal serine/threonine kinase participating in the regulation of glucose, lipid as well as protein metabolism and maintenance of energy homeostasis. Recent studies demonstrated that AMPK can also inhibit nuclear factor-κB, suppress the expression of inflammatory genes and attenuate inflammatory injury through phosphorylating its downstream targets including SIRT1, PGC-lα, p53 and FoxO3a. In addition, the widely used antidiabetic metformin also exerts its anti-inflammatory effects through activating AMPK. Therefore, AMPK is emerging as a promising novel target for the development of anti-inflammatory drugs. This review summarized the anti-inflammatory effects of AMPK and the underling molecular mechanisms.
AMP-Activated Protein Kinases ; metabolism ; Homeostasis ; Inflammation ; enzymology ; Metformin ; pharmacology ; NF-kappa B ; antagonists & inhibitors ; Phosphorylation

To investigate the effect and mechanism of metformin on intestinal epithelial barrier injury in ulcerative colitis. A cell model of colitis was established by co-culture of human colon cancer cell line Caco-2 and human monocyte cell line THP-1. The colitis model cells were treated with metformin at concentration of for Flow cytometry was used to detect Caco-2 cell apoptosis, and Western blotting was used to detect the protein expression of tight junction proteins and endoplasmic reticulum stress-related proteins. After metformin treatment, the apoptosis rate of Caco-2 cells was decreased from (14.22±2.34)% to 0.61)% (=3.119, <0.05), and the expression levels of tight junction protein-1 and claudin-1 increased (=5.172 and 3.546, both <0.05). In addition, the expression levels of endoplasmic reticulum-related proteins glucose regulated protein (GRP) 78, C/EBP homologous protein (CHOP) and caspase-12, as well as the phosphorylation level of PRKR-like endoplasmic reticulum kinase (PERK) and eukaryotic translation initiation factor 2α (eIF2α) decreased (all <0.05). Metformin may alleviate the intestinal epithelial barrier damage in colitis by reducing intestinal epithelial cell apoptosis and increasing the expression of tight junction proteins, which may be associated with the inhibition of endoplasmic reticulum stress-induced apoptotic pathway.
Apoptosis ; Caco-2 Cells ; Colitis, Ulcerative ; Endoplasmic Reticulum Stress ; Humans ; Metformin/pharmacology*

As an important enzyme for gluconeogenesis, mitochondrial phosphoenolpyruvate carboxykinase (PCK2) has further complex functions beyond regulation of glucose metabolism. Here, we report that conditional knockout of Pck2 in osteoblasts results in a pathological phenotype manifested as craniofacial malformation, long bone loss, and marrow adipocyte accumulation. Ablation of Pck2 alters the metabolic pathways of developing bone, particularly fatty acid metabolism. However, metformin treatment can mitigate skeletal dysplasia of embryonic and postnatal heterozygous knockout mice, at least partly via the AMPK signaling pathway. Collectively, these data illustrate that PCK2 is pivotal for bone development and metabolic homeostasis, and suggest that regulation of metformin-mediated signaling could provide a novel and practical strategy for treating metabolic skeletal dysfunction.
Mice ; Animals ; Metformin/pharmacology* ; Phosphoenolpyruvate Carboxykinase (ATP)/metabolism* ; Gluconeogenesis/genetics* ; Mice, Knockout

OBJECTIVE: To investigate the effect of metformin on the proliferation, apoptosis and energy metabolism of acute myeloid leukemia (AML) K562 cells and the possible mechanism. METHODS: Different doses (0, 5, 10, 20 and 30 mmol/L) of metformin was added into the K562 cells, which were cultivated for 24 h, 48 h and 72 h. The inverted optical microscope was used to observe the cell growth, CCK 8 was used to detect the cell vitality. The appropriate metformin doses (0, 10, 20 and 30 mmol/L) and the best time (48 h) were selected for subsequent experiments. The flow cytometer with Annexin V-FITC /PI doulde staining was used to detect apoptosis; the glucose detection kit and lactate detection kit were used to detect glucose consumption and lactate production; fluorescence quantitative PCR was used to detect glycolysis-related gene expression, and Western blot was used to detect protein expression. RESULTS: Metformin inhibited the proliferation of K562 cells in a dose-dependent manner (r=0.92), and the relative survival in the 30 mmol/L group was as low as 19.84% at 72 h. When treated with metformin for 48 h, the apoptosis rates of 0, 10, 20 and 30 mmol/L groups were 5.14%, 12.19%, 26.29% and 35.5%, respectively. Compared with the control group, the glucose consumption and lactate secretion of K562 cells treated with metformin were significantly reduced (P<0.05), and showed a dose-dependent effect(r=0.94,r=0.93,respectively). Metformin inhibited the expression of GLUT1, LDHA, ALDOA, PDK1, and PGK1 genes of K562 cells (P<0.05) showing a dose-dependent manner(r=0.83，r=0.80，r=0.72，r=0.76，r=0.73,respectively). Metformin inhibited the expression of P-Akt, P-S6, GLUT1, LDHA proteins of K562 cells(P<0.05), showing a dose-dependent relationship(r=0.80，r=0.92，r=0.83，r=0.92,respectively). CONCLUSION Metformin can inhibit the growth and proliferation of K562 cells and promote the apoptosis of K562 cells by inhibiting glycolysis energy metabolism. PI3K/Akt/mTOR signaling pathway may be one of the molecular mechanisms of metformin on k562 cells.
Apoptosis ; Cell Proliferation ; Glycolysis ; Humans ; K562 Cells ; Metformin ; pharmacology ; Phosphatidylinositol 3-Kinases

AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of cellular energy homeostasis. Recent studies demonstrated that AMPK also plays an important role in the modulation of inflammation, an energy-intensive molecular response. The commonly used AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and A-769662. In addition, the biological activities of metformin and adiponectin are closely related to activation of AMPK. Numerous studies have shown that these AMPK activators play an effectively protective role in animal models of acute lung injury, asthma, colitis, hepatitis, atherosclerosis and other inflammatory diseases. Therefore, AMPK activators may have promising potential for the prevention and treatment of inflammation related diseases.
AMP-Activated Protein Kinases ; physiology ; Adiponectin ; pharmacology ; Aminoimidazole Carboxamide ; pharmacology ; Animals ; Enzyme Activation ; Inflammation ; enzymology ; Metformin ; pharmacology ; Pyrones ; pharmacology ; Thiophenes ; pharmacology

OBJECTIVETo investigate the therapeutical effects of visfatin and metformin on insulin resistance and reproductive endocrine disorder in rats with polycystic ovary syndrome (PCOS).

METHODSForty female Wistar rats were divided into 4 equal groups, and in groups A, B and C, the rats were injected subcutaneously with dehydroepiandrosterone (DHEA) for PCOS modeling, with group D as the blank control injected with soybean oil. Vaginal smears and serological testing were taken to assess the modeling. After the modeling, the rats in group A received 10 µg reorganized visfatin injection and those in group B were treated with metformin (14 mg/100 g) on a daily basis for 15 days. Serum levels of T, LH, FSH, FINS and blood glucose levels during OGTT were measured before and after the treatments, and HOMA-IR and LH to FSH ratio were calculated. The ovaries were then dissected for pathological examination.

RESULTSIn groups A and B, FINS, FPG, T, HOMA-IR and blood glucose levels during OGTT were significantly decreased after the treatments (P<0.05), which resulted in recovery of regular menses in 8 (80%) rats in group A and 7 (77.8%) rats in group B with the development of normal follicles. Visfatin and metformin produced equivalent therapeutic effects in improving the insulin resistance and hyperandrogenism in PCOS rats.

CONCLUSIONVisfatin and metformin have equivalent therapeutic effects in improving insulin resistance and hyperandrogenism and in promoting the recovery of regular menses and development of normal follicles in PCOS rats.

Animals ; Female ; Humans ; Insulin Resistance ; Metformin ; pharmacology ; Nicotinamide Phosphoribosyltransferase ; pharmacology ; Polycystic Ovary Syndrome ; complications ; drug therapy ; Rats ; Rats, Wistar

OBJECTIVE: To determine the effect of metformin and adiponectin on the proliferation of EC cells and the relationship between metformin and adiponectin. METHODS: The proliferation impact of different concentrations of metformin and adiponectin on two types of EC cells ishikawa (IK) and HEC-1B was confirmed by CCK-8 method. qRT-PCR and Western blot were used to detect the effect of different concentrations of metformin on the changes of adiponectin receptors (AdipoR1 and AdipoR2) of the EC cells both in mRNA and protein level and the role of compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, on the above effects. RESULTS: (1) Both metformin and adiponectin could significantly promote the proliferation of endometrial cancer (EC) cells in a time and concentration dependent manner (P<0.05).(2)Metformin and adiponectin had synergy anti-proliferative effect on EC cells and the combination index (CI) value of IK cells was 0.906 34 and of HEC-1B cells was 0.827 65. (3)qRT-PCR was used to detect the mRNA levels of AdipoR1 and AdipoR2 after 5 mmol/L and 10 mmol/L metformin, respectively, stimulating IK and HEC-1B cells for 48 hours and the mRNA expressions of AdipoR1 and AdipoR2 were significantly increased when compared with the control group (0 mmol/L)(IK: AdipoR1 of 5 mmol/L and 10 mmol/L group: P<0.001,AdipoR2 of 5 mmol/L group: P<0.001; HEC-1B: AdipoR1 of 5 mmol/L group: P<0.001, 10 mmol/L group: P=0.023, AdipoR2 of 5 mmol/L group: P<0.001, 10 mmol/L group: P=0.024). When combined with compound C, the RNA levels of AdipoR1 and AdipoR2 were not different compared with the control group (0 mmol/L, P>0.05). (4) Western blot was used to detect the protein levels of AdipoR1 and AdipoR2 after 5 mmol/L and 10 mmol/L metformin, stimulating IK and HEC-1B cells for 48 hours and the protein level was significantly increased when compared with the control group (0 mmol/L)(IK: AdipoR1 of 5 mmol/L group: P=0.04, 10 mmol/L group: P=0.033, AdipoR2 of 5 mmol/L group: P=0.044, 10 mmol/L group: P=0.046; HEC-1B: AdipoR1 of 5 mmol/L group: P=0.04, 10 mmol/L group: P=0.049, AdipoR2 of 5 mmol/L group: P=0.043, 10 mmol/L group: P=0.035). When combined with compound C,the protein levels of AdipoR1 and AdipoR2 were not different compared with the control group (0 mmol/L, P>0.05). CONCLUSION We find that metformin and adiponectin have synergy anti-proliferative effect on EC cells. Besides, metformin can increase adiponectin receptors expressions of EC cells both in mRNA and protein levels and this effect is accomplished by the activation of AMPK signaling pathway.
Adiponectin/physiology* ; Cell Proliferation/drug effects* ; Endometrial Neoplasms/pathology* ; Female ; Humans ; Hypoglycemic Agents/pharmacology* ; Metformin/pharmacology* ; Receptors, Adiponectin ; Signal Transduction

Animals ; Insulin Resistance ; Liver Diseases, Alcoholic ; drug therapy ; metabolism ; prevention & control ; Male ; Metformin ; pharmacology ; Rats ; Rats, Wistar

OBJECTIVE: To detect the effects of metformin on the depressive-like behaviors in rats. METHODS: Forty male SD rats were randomly divided into four groups: control group (CON group), metformin group (MET group), model group (CUMS group), model + metformin group (CUMS + MET group), 10 rats in each group. Chronic unpredictable mild stress (CUMS) method was used to establish rat depression model in three weeks. After the model was established successfully, two metformin groups were intraperitoneally injected with metformin (100 mg/kg), while the control group and the model group were injected with the same amount of saline once a day for two weeks. After that, the changes of weight gain, sucrose water preference experiment, forced swimming test, tail suspension immobility test and open field test were detected. The morphological changes of hippocampus were observed by Nissl staining. RESULTS: Compared with the control group, the weight gain of rats in CUMS group was significantly slowed down (P＜0.05), the sucrose preference rate and the spontaneous activity were significantly reduced (P＜0.05), and the immobility time in forced swimming and tail suspension immobility test was significantly prolonged (P＜0.05), and the morphological structure of hippocampus was changed, which confirmed the success of CUMS depression model. Compared with CUMS group, metformin treatment had no significant effect on body weight of rats, but it could significantly improve sucrose water intake, immobility time and spontaneous activity of CUMS depression model rats (P＜0.05), and improve the abnormal morphological changes of hippocampus in CUMS rats. CONCLUSION Metformin has a therapeutic benefit against CUMS-induced depression, which provides a new treatment for patients with diabetes mellitus complicated with depression.
Animals ; Depression ; drug therapy ; Hippocampus ; anatomy & histology ; drug effects ; Male ; Metformin ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Stress, Psychological

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
Humans ; Metformin/pharmacokinetics* ; Diabetes Mellitus, Type 2/metabolism* ; Hypoglycemic Agents/pharmacology* ; AMP-Activated Protein Kinases/metabolism* ; Aging