Nasal-Insulin-Induced Change of Functional MRI Signal at the Level of Hypothalamic Nuclei in the Patients with Type 2 Diabetes Mellitus

Insulin resistance in the hypothalamus is related to both increased appetite and systemic metabolic deterioration and may be an essential cause of metabolic diseases. In human studies, hypothalamic activity after intranasal insulin administration (INIA) has been measured by functional MRI (fMRI). However, to date, the resolution of fMRI has not been high enough to assess which neuronal nuclei in the hypothalamus are responsible for insulin. The purpose of this study was to investigate whether we can assess hypothalamic reaction after INIA at the nuclear level using high-resolution fMRI and if so, to examine its association with clinical parameters. Here, we studied 20 men with type 2 diabetes (T2DM) and 20 non-obese men without diabetes (CON). All subjects underwent fMRI with INIA (160 IU human insulin). The average of the cleaned blood oxygenation level-dependent (BOLD) signal from -15 min to 0 min was used as the baseline value in each subject. The signal change compared to the baseline value was calculated at every 5 min after INIA. The mean ages of subjects were both around 50 years and HbA1c levels were 6.88±1.13% in T2DM and 5.24±0.25% in CON (p<0.001). There were significant differences in the BOLD signal changes after INIA in the posterior nucleus (PH) at 5 min and posterior lateral hypothalamic area (LHAp) at 5 and 10 min between T2DM and CON. In other hypothalamic nuclei, there were no significant differences between T2DM and CON in the rate of change of the BOLD signal up to 30 min after INIA. Multiple regression analysis revealed that fasting plasma glucose (FPG) was a significant independent variable for activity change of the PH at 5 min and LHAp at 5 and 10 min, while BMI and HOMA-IR were not. In summary, we successfully detected nasal-insulin-induced change of fMRI signal at the level of hypothalamic nuclei. We found the differences in neural activity in the PH and LHAp early after INIA between those with and without diabetes, which were associated with FPG. Disclosure M.Kiya: None. Y.Tamura: None. H.Kaga: None. N.Ito: None. T.Tajima: None. H.Naito: None. M.Sato: None. S.Kadowaki: None. S.Kakehi: None. H.Watada: Research Support; Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, LifeScan Diabetes Institute, Eli Lilly Japan K.K., Sun Pharmaceutical Industries Ltd., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Sanwa Kagaku Kenkyusho, Speaker's Bureau; Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Novo Nordisk, Abbott Japan Co., Ltd., Astellas Pharma Inc., Merck Sharp & Dohme Corp., Kissei Pharmaceutical Co., Ltd., AstraZeneca, Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Eli Lilly Japan K.K. Funding Japan Society for the Promotion of Science (21H03380, 22K17835); Ministry of Education, Culture, Sports, Science and Technology of Japan; Suzuken Memorial Foundation