Metformin revisited: re‐evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents

Goodarzi, Mark O.; Bryer‐Ash, Michael

doi:10.1111/j.1463-1326.2004.00448.x

Cited by 151 publications

(120 citation statements)

References 121 publications

(191 reference statements)

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“…Glipizide is a sulfonylurea, an insulin secretagogue that alters the bond equilibrium between insulin and b-cells of the pancreas and stimulates endogenous insulin release (Rendell 2004). Metformin is a biguanide that reduces hepatic glucose production by facilitating glucose transporter activity into cells (Goodarzi & Bryer-Ash 2005). A third mechanism of anti-diabetic action is to sensitize the cell to insulin, such as the action of the thiazolidinediones (i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Glipizide and related sulfonylureas stimulate insulin release, in addition to affecting glucose and insulin sensitivity in extrahepatic tissues (Rendell 2004). Metformin inhibits the endogenous production and release of non-carbohydrate-derived glucose (Goodarzi & Bryer-Ash 2005). Rosiglitazone is a thiazolidinedione, which binds to the peroxisome proliferator-activated receptors (PPARs), and functions as an anti-diabetic compound by enhancing the sensitivity of the peripheral tissues to insulin (Pietruck et al 2005).…”

Section: Discussionmentioning

confidence: 99%

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Larval zebrafish as a model for glucose metabolism: expression of phosphoenolpyruvate carboxykinase as a marker for exposure to anti-diabetic compounds

Elo¹,

Villano²,

Govorko³

et al. 2007

Journal of Molecular Endocrinology

141

121

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The zebrafish model system is one of the most widely used animal models for developmental research and it is now becoming an attractive model for drug discovery and toxicological screening. The completion of sequencing the zebrafish genome and the availability of full-length cDNAs and DNA microarrays for expression analysis, in addition to techniques for generating transgenic lines and targeted mutations, have made the zebrafish model even more attractive to researchers. Recent data indicate that the regulation of glucose metabolism in zebrafish, through the production of insulin, is similar to mammalian models, and many of the genes involved in regulating blood glucose levels have been identified in zebrafish. The data presented here show that adult zebrafish respond to anti-diabetic drugs similarly to mammalian models, by reducing blood glucose levels. Furthermore, we show that the expression of phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes a rate-limiting step in gluconeogenesis and is transcriptionally regulated by glucagon and insulin, is regulated in larval zebrafish similarly to that seen in mammalian systems, and changes in PEPCK expression can be obtained through real-time PCR analysis of whole larval RNA. Taken together, these data suggest that larval zebrafish may be an appropriate model for the examination of glucose metabolism, using PEPCK as an indicator of blood glucose levels.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Larval zebrafish as a model for glucose metabolism: expression of phosphoenolpyruvate carboxykinase as a marker for exposure to anti-diabetic compounds

Elo¹,

Villano²,

Govorko³

et al. 2007

Journal of Molecular Endocrinology

141

121

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show abstract

“…However, despite its widespread clinical use the exact mode of action is still not known. A variety of possible mechanisms have been suggested to explain its ability to decrease fasting plasma glucose levels by 25-30% including phosphorylation of insulin receptor and insulin receptor substrate-2, inhibiting key enzymes in the gluconeogenic pathway, activation of pyruvate kinase, inhibition of hepatic glucagon effects and reduction in hepatic uptake of glucogenic substrates (lactate, alanine) (Goodarzi and Bryer-Ash 2005). Interestingly, there is also accumulating data in support of mitochondria being metformin's primary site of action.…”

Section: Introductionmentioning

confidence: 99%

Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Tsuei

Martinus

2012

Cell Stress and Chaperones

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Metformin is in widespread clinical use for the treatment of diabetes mellitus in patients. It has been shown to inhibit mitochondrial bioenergetic functions by inhibiting complex I of the electron transport chain. The expression of mitochondrial-specific molecular stress protein Hsp60 is a key consequence of mitochondrial impairment. Since this protein has important immune-modulatory properties, we have investigated the expression of Hsp60 in human THP-1 monocyte cells exposed to metformin. In this study, we demonstrate significant up-regulation of Hsp60 at both mRNA and protein levels when these cells were exposed to metformin at therapeutic dosage levels. Interestingly, there was also an increase in expression of CD14 mRNA in these cells. This suggested a possible modulation of the differentiation rates of the THP-1 cells during exposure to metformin. As monocyte differentiation marks a critical step in atherosclerosis, these observations suggest that longterm exposure to metformin could have important implications for the diabetic patient.

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“…The discovery of metformin began with the synthesis of galegine-like compounds derived from Gallega officinalis, a plant traditionally employed in Europe as a drug for diabetes treatment for centuries [9]. Metformin acts primarily at the liver by reducing glucose output and secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle.…”

Section: Introductionmentioning

confidence: 99%