title: Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice.
abstract: OBJECTIVE
  The Sirt1/AMPK signaling pathway is a key sensor of energy status and regulates glucose and lipid metabolism. Leucine (Leu) activates Sirt1 by lowering its Km for NAD(+) and potentiates other sirtuin/AMPK-activators, resulting in improvement of insulin sensitivity. Since metformin (Met) converges on this pathway, we hypothesized that leucine would amplify its gluco-regulatory effects.
  
  
  METHODS
  The effects of Leu (24 g/kg diet)+Met (0.05-0.5 g/kg diet) combinations were compared to standard therapeutic Met (1.5 g/kg diet; ~300 mg/kg BW) on glycemic control in high fat diet induced insulin resistant mice for 6 weeks. The effects of Leu on Met stimulation of Sirt1 and AMPK activities were further evaluated in adipocytes.
  
  
  RESULTS
  Sub-therapeutic levels of Met combined with Leu resulted in increases in Sirt1 activity and in tissue P-AMPK/AMPK ratio and corresponding dose-responsive improvements in fasting and post-prandial glucose, in glucose response to an insulin tolerance test and in the area under the curve in glucose tolerance tests. Changes were evident within 7 days of treatment and sustained throughout the 6-week study duration. The Leu+Met (0.25 g/kg)-combinations produced a comparable effect to a standard therapeutic Met dose, while the Leu+Met (0.5 g/kg diet) resulted in greater improvements. Since resveratrol also synergizes with leucine to augment sirtuin signaling and insulin sensitivity, we tested the addition of resveratrol to Leu-Met and found no additional benefit.
  
  
  CONCLUSIONS
  These data demonstrate that adding Leu to Met enables a dose reduction of 66% with improved efficacy and of 83% with comparable efficacy to standard metformin in diet-induced obese mice, and addition of resveratrol does not provide further benefit.
authors: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA.
authors: Lizhi
authors: L
authors: Fu
authors: NuSirt Biopharma Inc., Knoxville, TN.
authors: Antje
authors: A
authors: Bruckbauer
authors: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA.
authors: Fenfen
authors: F
authors: Li
authors: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA.
authors: Qiang
authors: Q
authors: Cao
authors: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA.
authors: Xin
authors: X
authors: Cui
authors: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA.
authors: Rui
authors: R
authors: Wu
authors: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA.
authors: Hang
authors: H
authors: Shi
authors: NuSirt Biopharma Inc., Knoxville, TN.
authors: Michael B
authors: MB
authors: Zemel
authors: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA. Electronic address: bxue@gsu.edu.
authors: Bingzhong
authors: B
authors: Xue
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005215:Fasting / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007930:Leucine / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D007930:Leucine; D005947:Glucose
keywords: AMPK; Diabetes; Leucine; Metformin; Sirt1