Introduction and Objective: To amplify insulin secretion from beta cells with nutrient-stimulated hormone (NuSH) receptor agonists (e.g., the GLP-1 RA liraglutide (LIRA)), mitochondria must be energized via substrate-driven ADP privation. Since small-molecule modulators of Pyruvate Kinase (mPK) energize mitochondria via the phosphoenolpyruvate cycle and further boost LIRA-amplified insulin secretion, we hypothesized that mPKs could also optimize obesity treatment with GLP-1 RAs.Methods: DIO C57BL/6J male mice (~45-50 g) treated once daily with placebo (PBO), LIRA (0.4 mg/kg), the mPK TEPP-46 (5 mg/kg), or mPK + LIRA (COMBO) for 5 wks had daily weights and IPGTTs at 1 and 4 wks. DEXA body composition, insulin secretion and Ca2+ oscillations were assessed in isolated islets at study end.Results: PBO-subtracted % change in weight was 4.7% with mPK, 12.3% with LIRA, and 23.6% with COMBO (95% CI for all groups); consequently, COMBO lost nearly twice as much weight as LIRA alone. The mPK only group demonstrated the greatest increase in lean mass (6.5%, p<0.05). COMBO demonstrated preservation of lean mass compared to PBO (lean-to-fat-mass ratio: 5.4 with COMBO vs 3.2 with PBO, p<0.05). By week 1, fasting glucose levels were significantly lower in all treatment groups compared to PBO. IPGTT AUC glucose and 60-min insulins were normalized in both LIRA and COMBO groups. There were no toxicity signals (normal blood gas, electrolytes, LFTs). Islet mass was increased in LIRA and COMBO groups and perifused islet hyperinsulinemia was normalized in all treatment groups. Notably, Ca2+ imaging of isolated islets (in the absence of mPK or LIRA), demonstrated the greatest increase in the duty cycle for the COMBO group, while all groups had markers of improved islet health (decreased amplitude, period, silent phase).Conclusion: Modulation of Pyruvate Kinase synergizes with the NuSH GLP-1 RA, liraglutide, to optimize treatment of obesity in DIO mice, doubling weight loss, while preserving lean mass, as well as improving insulin sensitivity and islet health.
R. Kibbey: Consultant; Structure Therapeutics, Inc. R.L. Cardone: None. I. Ruz-Maldonado: None. X. Zhao: None. S. Brown: None. H.R. Foster: None. M.J. Merrins: None.
National Institutes of Health (R01DK127637)
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