生物活性

• 描述Metformin HCl, a kind of blood glucose-lowing drug, is prevalently used for treating the type 2 diabetes, especially for the obese ones. As the first line medication for type 2 diabetes worldwide, metformin has many unsurpassed advantages, including inexpensiveness, efficacy and safety^[1]. In in vitro, metformin (500 μM) activates AMPK signaling in human and mouse hepatocytes, resulting in decreased activity of acetyl-CoA carboxylase (ACC), induction of fatty acid oxidation, and inhibition of lipogenic enzymes expression^[2]. Low dose of Metformin (2 mM) also effectively promotes glucose uptake by activating the α1- and α2-complexes and increases threonine phosphorylation at site 172 in muscle via AMPK signaling^[3]. Together, Metformin reduces blood glucose levels by suppressing hepatic glucose production and enhancing muscle cell glucose uptake. In in vivo, Metformin (100 mg/ml, orally) significantly reduced SREBP-1, FAS, and S14 mRNA levels in the SD rats livers, which consistent with the results observed in in vitro. In obese mice, Metformin (250 mg/kg) reduces liver lipids through the phosphorylation and activation of AMPK in the liver^[4]. Moreover, the blood glucose is reduced to 40-50% in high-fat fed ob/ob mice^[5], respectively. Though Metformin exhibits potent effect on glucose-lowing, it does not activate insulin secretion. Additionally, Metformin may promotes weight gain or causes lactic acidosis and hypoglycemia. In fact, these side effects were low probability accidents and not affect its popularity in diabetes and other disease. For instance, researches reveal Metformin is also benefits for many other diseases, such as various cancers^[6], atherosclerosis^[7], fibrosis^[8], polycystic ovarian syndrome (PCOS)^[9], non-alcoholic fatty liver disease (NAFLD)^[10], Alzheimer's disease^[11] and so on.
• 作用机制Metformin reduces hyperglycemia in hepatocytes, mainly by inhibiting hepatic glycogen production (hepatic gluconeogenesis) in an AMPK-dependent manner.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human HepG2 cells	-	Function assay	24 h	Increase in glucose consumption in insulin-resistant human HepG2 cells after 24 hrs, EC50=0.27 μM.	21856048
  human HepG2 cells	1 mM	Function assay	24 h	Reduction of glucose consumption in insulin-resistant human HepG2 cells at 1 mM after 24 hrs by glucose oxidase method in presence of 22.2 mM of glucose	23025244
  human HepG2 cells	1 mM	Function assay	24 h	Activation of AMPK in human HepG2 cells assessed as reduction of gluconeogenesis at 1 mM after 24 hrs by enzymatic colorimetric assay	26471090

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• 动物研究
  剂量	Mice: 200 mg/kg - 400 mg/kg[12] (p.o.), 300 mg/kg[13] (p.o.) Dog{28945132}}: 24.77 ± 0.60 mg/kg (i.v.), 19.14 ± 2.78 mg/kg (p.o.)
  给药途径	p.o., i.v.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02435277	Type 2 Diabetes Mellitus	Phase 2	Completed	-	United States, California ... more >> Catalina Research Institute Chino, California, United States, 91710 United States, Florida Palm Beach Research Palm Beach, Florida, United States, 33409 Meridien Research Tampa, Florida, United States, 33606 United States, Georgia River Birch Research Alliance Blue Ridge, Georgia, United States, 3051313 Meridian Research Savannah, Georgia, United States, 31406 United States, Ohio Streling Research Group Cincinnati, Ohio, United States, 45219 United States, South Carolina Medical Research South Charleston, South Carolina, United States, 29407 United States, Tennessee Meharry Medical College Nashville, Tennessee, United States, 37208 Vanderbilt University Medical Center, Diabetes, Endocrinology, and Metabolism Nashville, Tennessee, United States, 37232 Collapse <<
  NCT03056274	Intrahepatic Cholestases ... more >> Pregnancy Complications Collapse <<	Phase 2 Phase 3	Not yet recruiting	September 2019	-
  NCT02115464	Lung Cancer	Phase 2	Recruiting	December 2020	Canada, Alberta ... more >> Cross Cancer Institute Recruiting Edmonton, Alberta, Canada Principal Investigator: Wilson Roa          Canada, Manitoba CancerCare Manitoba Recruiting Winnipeg, Manitoba, Canada, R3E 0V9 Principal Investigator: Naseer Ahmed          Canada, Ontario Juravinski Cancer Centre Recruiting Hamilton, Ontario, Canada Principal Investigator: Theos Tsakiridis          Cancer Centre of Southeastern Ontario at Kingston General Hospital Recruiting Kingston, Ontario, Canada Principal Investigator: Andrew Robinson          Grand River Regional Cancer Centre Active, not recruiting Kitchener, Ontario, Canada Walker Family Cancer Centre - Niagara Health System Recruiting St. Catharines, Ontario, Canada Principal Investigator: Theos Tsakiridis          Canada, Quebec Montreal General Hospital - McGill Recruiting Montreal, Quebec, Canada Principal Investigator: Bassam Abdulkarim Collapse <<

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• 参考文献

• [1] Dos Santos CC, Gopal B, Verma S. Metformin: An Old Dog with a New Trick?. Cell Metab. 2018;28(3):334-336。

  [2] Qin N, Li CB, et al. Synthesis and biological activity of novel tiliroside derivants. Eur J Med Chem. 2011;46(10):5189-95.

  [3] Polianskyte-Prause Z, Tolvanen TA, et al. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. FASEB J. 2019;33(2):2858-2869.

  [4] Takiyama Y, Harumi T, et al. Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1α expression and oxygen metabolism. Diabetes. 2011;60(3):981-92.

  [5] Luo T, Nocon A, et al. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes. 2016;65(8):2295-310.

  [6] Sesen J, Dahan P, et al. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS One. 2015;10(4):e0123721.

  [7] Jenkins AJ, Welsh P, Petrie JR. Metformin, lipids and atherosclerosis prevention. Curr Opin Lipidol. 2018;29(4):346-353.

  [8] Rangarajan S, Bone NB, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24(8):1121-1127.

  [9] D'Amato G, Caringella AM, et al. Mild ovarian stimulation with letrozole plus fixed dose human menopausal gonadotropin prior to IVF/ICSI for infertile non-obese women with polycystic ovarian syndrome being pre-treated with metformin: a pilot study. Reprod Biol Endocrinol. 2018;16(1):89.

  [10] Yan J, Yao B, et al. Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Hepatology. 2018.

  [11] Rotermund C, Machetanz G, Fitzgerald JC. The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front Endocrinol (Lausanne). 2018.

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