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Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood...
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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
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Homogeneous Time-resolved F&#246;rster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion
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A Structural Basis for Biguanide Activity.

Scott A Gabel1, Michael R Duff2, Lars C Pedersen1

  • 1Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , 111 T. W. Alexander Drive, Research Triangle Park, North Carolina 27709, United States.

Biochemistry
|August 3, 2017
PubMed
Summary
This summary is machine-generated.

Metformin and related biguanides inhibit dihydrofolate reductase (DHFR), an enzyme crucial for folate metabolism. This competitive inhibition, particularly in the gut microbiome, may contribute to their anti-diabetic effects.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Microbiology

Background:

  • Metformin is a primary treatment for type II diabetes, but its molecular mechanisms remain unclear.
  • Growing evidence suggests biguanides may impact the gut microbiome and folate metabolism.

Purpose of the Study:

  • To determine the structural basis of biguanide interactions with E. coli dihydrofolate reductase (ecDHFR).
  • To investigate the potential of biguanides as folate mimics and their inhibitory effects on DHFR.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy
  • X-ray crystallography
  • Molecular modeling
  • Enzyme inhibition assays

Main Results:

  • Biguanides, including metformin, phenformin, and buformin, form complexes with ecDHFR.
  • Metformin can form ternary complexes within the folate-binding site.
  • Biguanides competitively inhibit ecDHFR activity, with phenformin being a more potent inhibitor than metformin.
  • Inhibition may be significant in the gut microbiome and potentially in intestinal cells.

Conclusions:

  • Biguanides act as competitive inhibitors of DHFR.
  • This DHFR inhibition, especially in the gut, could be a significant mechanism for metformin's anti-diabetic action.
  • Perturbation of folate homeostasis by biguanides may influence cellular metabolism through altered redox ratios.