Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent now recommended as the first-line oral therapy for T2D (Type 2 diabetes). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The demonstration that respiratory chain complex I, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin has been reported to restore ovarian function in PCOS (polycystic ovary syndrome), reduce fatty liver, and to lower microvascular and macrovascular complications associated with T2D. Its use has also recently been suggested as an adjuvant treatment for cancer or gestational diabetes and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.

https://www.hal.inserm.fr/inserm-00658070/document

Cellular and molecular mechanisms of metformin: an overview

Sugar efflux transporters are essential for the maintenance of animal blood glucose levels, plant nectar production, and plant seed and pollen development. Despite broad biological importance, the identity of sugar efflux transporters has remained elusive. Using optical glucose sensors, we identified a new class of sugar transporters, named SWEETs, and show that at least six out of seventeen Arabidopsis, two out of over twenty rice and two out of seven homologues in Caenorhabditis elegans, and the single copy human protein, mediate glucose transport. Arabidopsis SWEET8 is essential for pollen viability, and the rice homologues SWEET11 and SWEET14 are specifically exploited by bacterial pathogens for virulence by means of direct binding of a bacterial effector to the SWEET promoter. Bacterial symbionts and fungal and bacterial pathogens induce the expression of different SWEET genes, indicating that the sugar efflux function of SWEET transporters is probably targeted by pathogens and symbionts for nutritional gain. The metazoan homologues may be involved in sugar efflux from intestinal, liver, epididymis and mammary cells.

/pdf/sugar-transporters-for-intercellular-exchange-and-nutrition-54v09mfrcb.pdf

Sugar transporters for intercellular exchange and nutrition of pathogens

Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signalling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us to develop novel treatments. The centre of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer.

Metformin—mode of action and clinical implications for diabetes and cancer

Osmotic regulation in crustaceans

Metformin and thiazolidinediones (TZDs) are believed to exert their antidiabetic effects via different mechanisms. As evidence suggests that both impair cell respiration in vitro, this study compared their effects on mitochondrial functions. The activity of complex I of the respiratory chain, which is known to be affected by metformin, was measured in tissue homogenates that contained disrupted mitochondria. In homogenates of skeletal muscle, metformin and TZDs reduced the activity of complex I (30 mmol/l metformin, -15 +/- 2%; 100 micromol/l rosiglitazone, -54 +/- 7; and 100 micromol/l pioglitazone, -12 +/- 4; P < 0.05 each). Inhibition of complex I was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate + malate as substrates for complex I (30 mmol/l metformin, -77 +/- 1%; 100 micromol/l rosiglitazone, -24 +/- 4; and 100 micromol/l pioglitazone, -18 +/- 5; P < 0.05 each), whereas respiration with succinate feeding into complex II was unaffected. In line with inhibition of complex I, 24-h exposure of isolated rat soleus muscle to metformin or TZDs reduced cell respiration and increased anaerobic glycolysis (glucose oxidation: 270 micromol/l metformin, -30 +/- 9%; 9 micromol/l rosiglitazone, -25 +/- 8; and 9 micromol/l pioglitazone, -45 +/- 3; lactate release: 270 micromol/l metformin, +84 +/- 12; 9 micromol/l rosiglitazone, +38 +/- 6; and 9 micromol/l pioglitazone, +64 +/- 11; P < 0.05 each). As both metformin and TZDs inhibit complex I activity and cell respiration in vitro, similar mitochondrial actions could contribute to their antidiabetic effects.

https://diabetes.diabetesjournals.org/content/diabetes/53/4/1052.full.pdf

Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions?

https://nctc.fws.gov/resources/course-resources/pesticides/Aquatic%20Effects/AtznGoldfish.pdf

Effects of atrazine on sex steroid dynamics, plasma vitellogenin concentration and gonad development in adult goldfish (Carassius auratus)

After intraperitoneal injection of microcystin-LR (MC-LR) (125 μg kg−1 body wt.), the concentration of MC-LR in the liver of juvenile goldfish Carassius auratus (30 g body wt.) was assayed by a modified protein phosphatase inhibition method. A temporary accumulation occurred from 3 to 48 h post-injection, followed by a significant decrease between 48 and 96 h. Under our experimental conditions, contamination by MC-LR did not change ionic homeostasis, as attested by blood osmolality values and gill Na+/K+ ATPase activity. Light microscopy observations revealed lesions and cellular necrosis progression, which was concomitant with an increase in enzyme activity of plasma aspartate aminotransferase (AspAT), alanine aminotransferase (AlaAT) and l-lactate dehydrogenase (LDH) and with a decrease of hepatic glutathione-S-transferase (GST) activity. Structural alterations and enzymatic activity modifications became significant within 24 h post-injection. Recovery of hepatocytes on day 21 after MC-LR injection was evident, together with a decrease in the MC-LR equivalent content of the liver.

Pierre Devos

Papers

Effects of atrazine on sex steroid dynamics, plasma vitellogenin concentration and gonad development in adult goldfish (Carassius auratus)

Hepatic accumulation and effects of microcystin-LR on juvenile goldfish Carassius auratus L.

Differential protein expression profiles in anterior gills of Eriocheir sinensis during acclimation to cadmium.

Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function.

Effect of microcystin-LR on protein phosphatase activity in fed and fasted juvenile goldfish Carassius auratus L.