Targeting the gastrointestinal tract to treat type 2 diabetes

Abstract

The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain–Adipocyte Axis

“…Intestinal hormones have become an important therapeutic target in the management of obesity due to their involvement in energy homeostasis and satiety [1]. Among the intestinal L cell peptides, glucagon-like peptide-1 (GLP-1) has been highlighted because of the success of its recent clinical use in the treatment of diabetes mellitus and obesity [2].…”

A Structural Basis for Biguanide Activity

“…Recent evidence has accumulated implicating the gut microbiome as a significant target of these drugs 16, 18 . The microbiome represents an attractive target for a weakly interactive drug from two points of view: 1) Metformin dosages are typically large, 0.5–2.5 g/day, and gut concentrations are correspondingly elevated, and 2) similar to evolutionarily-related mitochondria, gut microbes typically exhibit high, negative membrane potentials, supporting accumulation of cationic compounds.…”

“…The structural information, binding affinities and inhibition constants for the E. coli DHFR are by far the most extensive data available for interaction of biguanides with any proposed biguanide target. The likely variation of biguanide-DHFR K i values for different species of gut bacteria provides one possible basis for species selection in metformin-treated patients 16, 17 . Indeed, the first, A–B loop in DHFR derived from different species shows extreme sequence variability, and as discussed above, the binding affinity for pABG differs substantially between the E. coli and L. casei enzymes.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…In fact, SFN reduces hepatic glucose production and improves glucose control in patients with T2DM (Axelsson et al, 2017). Interestingly, some evidence suggests that metformin may be effective in preventing other nonglycemic pathophenotypes of the NRF2 diseasome, including cardiovascular (Nesti and Natali, 2017), respiratory (Sato et al, 2016), digestive (Bauer and Duca, 2016), neurodegenerative (Markowicz-Piasecka et al, 2017), autoimmune (Schuiveling et al, 2017), and neoplastic (Heckman-Stoddard et al, 2017) disorders. The mechanism of action of metformin is not completely clear, but it involves inhibition of mitochondrial complex I, thus increasing the AMP/ATP ratio (El-Mir et al, 2000;Owen et al, 2000) and leading to activation of the energy sensor AMPK (Hardie, 2004;Rena et al, 2017).…”