A Bariatric Surgery Derived Gut Metabolite is a Potent Single and Combination Oral Therapy for Type 2 Diabetes (T2D)
Andrei Moscalu1, Yingjia Chen1, Snehal N. Chaudhari2, Renuka S. Haridas3, James N. Luo1, Cullen Roberts1, Mehran Karvar1, Ali Tavakkoli1, Sloan Devlin2, Eric G. Sheu1
1Brigham and Women's Hospital, Boston, MA; 2Harvard Medical School, Boston, MA; 3Affinivax Cambridge, MA
INTRODUCTION: Bariatric surgery is the most effective therapy for T2D. We previously discovered cholic-acid-7-sulfate (CA7S), a gut-restricted metabolite that is upregulated by sleeve-gastrectomy in both mice and humans. CA7S lowers blood glucose by inducing secretion of glucagon-like-peptide-1 (GLP-1) in the gut. Sitagliptin is an approved T2D drug that prolongs GLP-1 half-life by inhibiting its degradation. Here, we investigate the antidiabetic efficacy of CA7S alone or in combination with sitagliptin.
METHODS: 16-week-old male, diet-induced-obese, insulin-resistant C57BL/6J-mice, were weight and fasted-glucose matched and received PBS, CA7S (100 mg/kg), sitagliptin, or CA7S (100 mg/kg) + sitagliptin. An incremental dose of sitagliptin was used: 0.1, 1 and 100 mg/kg. Fasted mice were orally-gavaged with the indicated compound(s), and 3-hours later, subjected to an oral-glucose-tolerance-test (OGTT). Active, serum GLP-1 was measured 15 minutes after glucose administration.
RESULTS: CA7S alone reduces peak-blood-glucose-levels (p-BGL) by 26.6% (p<0.01) decreasing the total-area under the curve (t-AUC) by 30.5% (p<0.05) when compared to control. A similar effect is seen after 1mg/kg of sitagliptin (p<0.01). Co-administration of CA7S and sitagliptin drops p-BGL by 63.7% and t-AUC by 60.1% (p<0.001, Fig.1A-D). GLP-1 increases by 233% after CA7S (p<0.01); 352% after 1mg/kg of Sitagliptin (p<0.001) and 600% after combination the two (p<0.0001) when compared with control (Fig.1C).
CONCLUSIONS: Single and combination therapy of CA7S, a surgically induced, gut-restricted metabolite and sitagliptin improves glucose tolerance and augments GLP-1 secretion.
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