Abstract
BackgroundThe novel small molecule R118 and the biguanide metformin, a first-line therapy for type 2 diabetes (T2D), both activate the critical cellular energy sensor 5′-AMP-activated protein kinase (AMPK) via modulation of mitochondrial complex I activity. Activation of AMPK results in both acute responses and chronic adaptations, which serve to restore energy homeostasis. Metformin is thought to elicit its beneficial effects on maintenance of glucose homeostasis primarily though impacting glucose and fat metabolism in the liver. Given the commonalities in their mechanisms of action and that R118 also improves glucose homeostasis in a murine model of T2D, the effects of both R118 and metformin on metabolic pathways in vivo were compared in order to determine whether R118 elicits its beneficial effects through similar mechanisms.ResultsGlobal metabolite profiling of tissues and plasma from mice with diet-induced obesity chronically treated with either R118 or metformin revealed tissue-selective effects of each compound. Whereas metformin treatment resulted in stronger reductions in glucose and lipid metabolites in the liver compared to R118, upregulation of skeletal muscle glycolysis and lipolysis was apparent only in skeletal muscle from R118-treated animals. Both compounds increased β-hydroxybutyrate levels, but this effect was lost after compound washout. Metformin, but not R118, increased plasma levels of metabolites involved in purine metabolism.ConclusionsR118 treatment but not metformin resulted in increased glycolysis and lipolysis in skeletal muscle. In contrast, metformin had a greater impact than R118 on glucose and fat metabolism in liver tissue.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-674) contains supplementary material, which is available to authorized users.
Highlights
The novel small molecule R118 and the biguanide metformin, a first-line therapy for type 2 diabetes (T2D), both activate the critical cellular energy sensor 5′-AMP-activated protein kinase (AMPK) via modulation of mitochondrial complex I activity
Mice were treated with either High fat diet (HFD) (n = 12), HFD formulated with 200 mg/kg R118 (n = 12), or HFD formulated with 5 g/kg metformin (n = 12)
R118 has a stronger chronic effect on skeletal muscle metabolism compared to liver and adipose tissue diet-induced obesity (DIO) mice were treated using high fat diet formulated with either R118 (200 mg/kg HFD) or metformin (5 g/kg HFD)
Summary
The novel small molecule R118 and the biguanide metformin, a first-line therapy for type 2 diabetes (T2D), both activate the critical cellular energy sensor 5′-AMP-activated protein kinase (AMPK) via modulation of mitochondrial complex I activity. Metformin is thought to elicit its beneficial effects on maintenance of glucose homeostasis primarily though impacting glucose and fat metabolism in the liver. WO 2012/ 016217, February 2, 2012) are both mitochondrial complex I inhibitors [1,2,3] that mediate their beneficial effects on glucose homeostasis partly through modulation of the 5′-adenosine monosphate-activated protein kinase (AMPK), a critical sensor of cellular energy status. R118 is a mechanistic analog of the well-characterized small molecule R419 [4] and activates AMPK by inhibiting mitochondrial complex I with a potency of ~70 nM, comparable to the reported R419 potency of 100 nM. Chronic metformin treatment decreased liver lipid accumulation by AMPK-mediated inhibition of acetyl-CoA carboxylase activity (ACC), which contributes to increased insulin sensitivity [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
