New therapeutic perspectives

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1- Gestational diabetes

The risk of gestational diabetes (GD) is increasing in obese women and is associated with adverse pregnancy outcomes [143]. Recently, data accumulated from case control studies [144] or the Metformin in Gestational Diabetes Trial [145] suggested that women treated with metformin had less weight gain and improved neonatal outcomes compared with those treated with insulin. Although no significant adverse events were observed when metformin was administered during pregnancy, its use in overweight women with GD has to be confirmed by additional studies and new guidelines.

2- Diabetes prevention

The Diabetes Prevention Program (DPP) was a clinical trial comparing the efficacy of lifestyle modifications and metformin on glucose homeostasis in 3234 pre-diabetic patients. In this study, metformin was efficient to significantly reduce (-31%) the development of T2D [146]. Even if reduction of body weight through physical activity and hypocaloric diet is unanimously recognized as a cornerstone for a global prevention of T2D, the use of metformin in pre-diabetic population looks promising but have to be evaluated in additional studies. 

3- Regulation of circadian clock

Mammalian behavior, including spontaneous locomotion, sleeping, eating, and drinking are influenced by a circadian system, composed of a central clock in the brain and subsidiary oscillators existing in peripheral tissues. Circadian rhythms are regulated by alternating actions of activators and repressors of transcription, in particular CLOCK (circadian locomotor output cycles kaput), BMAL1 (brain and muscle ARNT-like protein 1), PER (Period) and CRY (Cryptochrome) [147]. Um et al. [148] have recently proposed a molecular mechanism by which metformin causes a dramatic shift in the circadian phase of peripheral tissues. It was indeed shown that metformin-induced AMPK activation promotes  phosphorylation of Ser 386 on casein kinase 1 (CK1), one of the key circadian regulators, thereby enhances the CK1-mediated phosphorylation of PER2, leading to its the degradation and ultimately to the shortening of the period length. Accordingly, PER2 accumulates to higher levels in organs of mice lacking the catalytic subunit a2 of AMPK [148]. Recent evidence indicates that dysregulation of circadian functions could underlie, at least partly, the development of obesity and insulin resistance. Caton et al. recently examined the effect of metformin on the dysregulation of clock genes in adipose tissue of obese db/db mice and in mice fed a high-fat diet [40]. Interestingly, metformin markedly enhanced expression of the core clock components CLOCK, BMAL1 and PER2 through induction of AMPK-NAMPT-SIRT1 signaling and was associated with reduction of hyperglycemia and hyperinsulinemia in db/db mice. Taken together, the apparent beneficial association between targeted modulation of the circadian system and whole-body metabolic state suggests that chronotherapy could be a promising approach for the treatment of obesity and T2D.

4- Metformin and pharmacogenetics

Metformin is a hydrophilic base which exists at physiological pH as an organic cation (pKa 12.4). Consequently, its passive diffusion through cell membranes is very limited. Indeed, it has been shown that metformin only negligibly permeate the plasma membrane by passive diffusion [29] and cationic transporters such OCT1/2 are, to date, the main transporters identified to be involved in the intracellular internalization of the drug [15, 149]. It is worth noting that most of the experiments using metformin were performed in immortalized cell lines treated with drug concentrations far above those reported to accumulate in tissues after oral administration of metformin [149]. It may be related to the low levels of cationic transporters at the surface of these cell lines. Interestingly, uptake of metformin into immortalized cell lines is very low and can be greatly enhanced by ectopic expression of organic ion transporter cDNAs [150, 151]. Thus, the key determinant for metformin’s action appears to be a balance between concentration and time of exposure which can in fact reflects the tissue/cell-specific abundance of organic transporters

Understanding the link between genetic variation and response to drugs will be essential to move towards personalized medicine. Metformin requires the organic cation transporters (OCTs) to be transported into the liver and the gut (OCT1) and the kidney (OCT1 and OCT2) [152]. In contrast, the multidrug and toxin extrusion 1 protein (MATE1) facilitates metformin excretion into bile and urine [152]. OCT1 and OCT2 are encoded by the SLC22A1 and SLC22A2 genes, respectively, and MATE1 by the SLC47A1 gene. In OCT1-/- mice, hepatic metformin concentration in the liver and in the gut is lower than in control mice suggesting that OCT1 is essential for the uptake of the drug in these tissues [15]. Recently, Shu et al. showed that SLC22A1 variants reducing OCT1 function increased the area under the curve of glucose during OGTT after metformin treatment in healthy volunteers compared to subjects with wild type alleles [15]. In contrast, the loss-of-function variants R61C and 420del have no consequence on HbA1c level achieved during metformin treatment in T2D patients [153]. Urinary excretion of metformin is preserved in OCT1-/- mice indicating that renal excretion of metformin is dependent of OCT2. This last point has been challenged by Tzvetkov et al. which demonstrate a significant OCT1 expression in human kidney and a reduction of metformin renal clearance depending on OCT1 polymorphisms (Arg61Cys, Gly401Ser, 420del or Gly465Arg) [154]. OCT2 polymorphisms are also known to modify metformin renal clearance. Indeed, 14 genetic variants of SLC22A2 gene were identified of which the 808G>T polymorphism was associated with a reduced metformin tubular clearance and prevented the tubular secretion of metformin by cimetidine [155]. Other important OCT2 variants for the renal elimination of metformin have been described in healthy volunteers (see for review [156]). Nevertheless, the clinical relevance of such variants in T2D patients remains to be determined in a large scale studies. In addition, other candidate genes may be involved in the therapeutic response to metformin in diabetic population. Thus, in a genome-wide association study investigating glycemic response to metformin, Zhou et al. have found a locus associated with treatment success and containing the ataxia telangiectasia mutated gene (ATM), a gene involved in DNA repair and cell cycle control [157]. Interestingly, it was found that inhibition of ATM markedly reduced AMPK activation by metformin indicating that ATM acts upstream of AMPK and is probably required for mediating metformin effect [157].