Prediction of Neurocognitive Disability with Magnitudes of Insulin Resistance and Glucagon-Like Peptide-1 Secretion in Offspring from Mother with Diabetes

Diabetes during pregnancy has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. However, the correlation between those two phenotypes in offspring from mother with diabetes (OMD) has not been tested. We therefore examined the correlation between motor skill learning and glucose tolerance, including glucagon-like peptide-1 (GLP-1) secretion in OMD. ICR female mice received intraperitoneal injection (i.p.) of 150mg/kg streptozotocin at six weeks old. Control female was administered with the vehicle. Those animals showed over 250mg/dL glucose level at 14 days post injection. Mating was done with normal male and all of pups were born in term. Motor skill learning was tested on accelerated rotarod at postnatal 30 days (P30). A learning index was calculated for each animal by averaging the difference in terminal speed when the mouse fall from the rotor rod. Motor learning is impaired in OMD (P =0.0035). Following the behavior test, insulin tolerance test, oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were performed. Although the weight of OMD is similar to that of control animals at P21, it was significantly increased after P60 (P <0.0001). The glucose level in the plasma of mice is significantly increased in IPGTT (15, 30min post glucose i.p. injection, p <0.0001) at P60. OMD show higher homeostasis model assessment of insulin resistance (OMD 0.93 vs. control 0.84), and reduced secretion of active GLP-1 (aGLP-1) (OMD 6.70 ng/mL vs. control 8.02 ng /mL) in OGTT. Notably, poor learners of motor skill show significantly lower aGLP-1 secretion than the good learners (P =0.0360). Furthermore, in OMD, neuronal morphology was abnormal in the motor cortex that controls the motor skill learning. These results demonstrate that insulin resistance and the aGLP-1 secretion serve as predictors of motor skill learning deficiencies in OMD. Disclosure H. Iwasaki: None. K. Hashimoto-torii: None. M. Odawara: Speaker’s Bureau; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Kyowa Kirin Co., Ltd., MSD Corporation, Novartis AG, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. R. Suzuki: Research Support; Self; Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Speaker’s Bureau; Self; MSD K. K., Novartis Pharma K. K., Novo Nordisk Pharma Ltd., Sanofi K. K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. J. Sasaki: None. K. Sugai: None. M. Ito: None. K. Ishii: None. M. Aierken: None. G. Li: None. H. Suwanai: None. M. Torii: None.