1864-P: Higher Relative Abundance of Bacteroidetes in Gut Microbiota Is Associated with Decreased Insulin Clearance and Insulin Sensitivity after a Short-Term High-Calorie, High-Fat Diet in Healthy Men
Authors: KADOWAKI SATOSHI , TAMURA YOSHIFUMI , SUGIMOTO DAISUKE , SOMEYA YUKI , KAGA HIDEYOSHI , SUZUKI RURIKO , KAKEHI SAORI , YAMASAKI NOZOMU , SATO MOTONORI , KANAZAWA AKIO , KAWAMORI RYUZO , WATADA HIROTAKA 
Published: June 2020

Hyperinsulinemia is observed in obese subject. Even in healthy non-obese subjects, intentional small weight gain by a high-calorie, high-fat diet (HCHFD) resulted in hyperinsulinemia which was caused not by increased insulin secretion but by decreased metabolic clearance rate of insulin (MCRI). In addition, it was reported that in the mice with genetic deletion of CEACAM-1, impairment of MCRI induces hyperinsulinemia and subsequently these mice develop obesity and insulin resistance (IR). Therefore, in healthy subjects, reduction of MCRI could be the primary change that induces hyperinsulinemia, obesity and IR. On the other hand, it has been shown that HCHFD induces enhanced gut permeability and endotoxemia and these changes could be a cause of IR. However, it is totally unknown whether gut microbiota and endotoxemia are related to changes in MCRI as well as insulin sensitivity after HCHFD. To address this, we recruited 21 healthy non-obese men and evaluated metabolic changes and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus 45% energy excess by supplementation with dairy fat. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and tissue specific insulin sensitivity. After the HCHFD, MCRI and muscle insulin sensitivity (M-IS) were significantly decreased by 6% and 4%, respectively. In addition, circulating lipopolysaccharide (LPS) binding protein, a marker of endotoxemia, was significantly increased by 14% after the HCHFD. Baseline relative abundance of Bacteroidetes, LPS-producing Gram-negative gut microbiota, was correlated to changes in MCRI (r=-0.57, p=0.009) and M-IS (r=-0.46, p=0.040), respectively.
In conclusion, short-term HCHFD decreased MCRI and M-IS and those changes were associated with increased marker of endotoxemia after HCHFD and higher baseline relative abundance of Bacteroidetes in gut microbiota.

Disclosure
S. Kadowaki: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. D. Sugimoto: None. Y. Someya: None. H. Kaga: None. R. Suzuki: None. S. Kakehi: None. N. Yamasaki: None. M. Sato: None. A. Kanazawa: Speaker’s Bureau; Self; Novartis Pharma K.K., Sanofi, Takeda Pharmaceutical Company Limited. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding
Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03196)