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BACKGROUND Type 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function. METHODS We therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions. RESULTS Insulin deprivation in T1D increased blood glucose, and β-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition. CONCLUSION Transient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation. TRIAL REGISTRATION ClinicalTrials.gov NCT03392441. FUNDING Clinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

Introduction: Diabetes is associated with impaired cognition but the effect of the transient insulin deprivation on cognition and its underlying mechanisms remain unclear. Objective: We determined whether transient insulin deprivation in type 1 diabetic adults (T1D) and adolescents alters brain structure, functions and blood flow compared to nondiabetics (ND). Methods: We performed structural MRI, phosphorous31 NMR spectroscopy, and neuropsychiatric testing at baseline and following 6 hours of insulin deprivation in 14 adolescent (14-17 years) and adult (18-44 years) T1D and age- sex- and BMI-matched ND controls. Results: There were no significant changes on baseline structural MRI between the groups. After insulin deprivation, T1D had a significantly greater blood glucose (272 vs. 85 mg/dL), greater beta hydroxybutyrate (1.45 vs. 0.3 mmol/L), and decreased bicarbonate level (25.5 vs. 21.5 mmol/L) at six hours compared to ND. Following insulin deprivation, there was a significant difference in T1D left cortical volume compared to ND. On diffusion tensor imaging at baseline and after insulin deprivation, T1D had a higher fractional anisotropy compared to ND. T1D also had a significant decline in phosphocreatine/ATP after insulin deprivation compared to ND. Lastly after insulin deprivation, T1D failed to have learned improvement on repeat neuropsychiatric testing, with ND having significantly greater improvements in executive function, attention and working memory compared to T1D. Conclusion: Transient hyperglycemia and insulin deprivation caused a significant decline in some important aspects of cognition and brain energy metabolism, indicating that even transient insulin deprivation affects brain function and morphology. This may have important clinical implications as many diabetic patients inadvertently have occasional periods of transient insulin deprivation. Disclosure A. Creo: Consultant; Self; Ultragenyx. T.M. Cortes: None. A.R. Huebner: None. A. Lteif: None. J. Port: None. K. Nair: None.