Introduction & Objective: Prenatal hyperglycemia exposures (PHGE) are at a higher risk of developing metabolic disorders, including obesity and impaired glucose tolerance. However, the precise mechanisms underlying these disorders remain unclear. We aimed to elucidate the pathogenesis of impaired glucose tolerance in PHGE from the experimental results we have obtained so far, focusing on GLP-1 sensitivity.
Methods: Six-week-old female ICR mice were received single intraperitoneal (i.p.) injection of streptozotocin (STZ) at 150 mg/kg or citric acid buffer. Their offspring were crossbred with another normal glucose-tolerant dams to establish PHGE and Control. Control and PHGE were subjected to OGTT at 50 days of age and intraperitoneal glucose tolerance test (IPGTT) at 60 days of age, and were divided into two subgroups, one receiving 1.8 mg/60 kg (0.03 mg/kg) i.p. of liraglutide (Lira) 30 minutes before the loading test and the other receiving the same volume of phosphate buffer solution (PBS). The insulin secretion induced by Lira administration was evaluated as Control-Lira, Control PBS, PHGE-Lira, and PHGE-PBS. Immunohistological analyses were also performed using P80 pancreatic samples.
Results: In PHGE, hyperglycemia with decreased insulin secretion in OGTT alone was observed, and immunohistological analyses showed no difference in islet cell count and insulin-positive cell area, suggesting GLP-1 involvement. The total GLP-1 and active GLP-1 secretion were confirmed, but the secretion was rather increased, suggesting a decreased sensitivity of PHGE to GLP-1. Confirming the susceptibility of our models to Lira, in Control, Lira treatment significantly increased insulin secretion in both OGTT and IPGTT (OGTT: p < 0.0001, IPGTT: p < 0.01), but not in both in PHGE.
Conclusion: Impaired glucose tolerance in PHGE was shown to be partly due to decreased insulin secretion caused by reduced GLP-1 sensitivity.
G. Tomizawa: None. M. Aierken: None. J. Sasaki: None. K. Ishii: None. G. Li: None. K. Sugai: None. H. Suwanai: None. M. Odawara: Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Daiichi Sankyo, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim, MSD Life Science Foundation, AstraZeneca, Kowa Company, Ltd. Research Support; Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company. Other Relationship; Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Daiichi Sankyo, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim. R. Suzuki: Speaker's Bureau; Novo Nordisk Pharma, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., Kowa Company, Ltd., MSD, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited. Research Support; Sumitomo Dainippon Pharma Co., Ltd.
