Insulin Deprivation on Brain Structure and Function in Humans With Type 1 Diabetes

Pilot Study to Evaluate the Effects of Insulin Deprivation on Brain Structure and Function in Humans With Type 1 Diabetes

What are the effects of transient insulin deprivation on brain structure, blood flow, mitochondrial function, and cognitive function in T1DM patients? What are the effects of transient insulin deprivation on circulating exosomes and metabolites in T1DM patients?

Diabetes is associated with impaired cognition, abnormal brain development in children, and dementia in older adults, however the underlying mechanisms remain unclear. Little is known about the brain-specific effects of acute insulin deficiency. Our recent studies in diabetic mice show an overall down regulation of brain mitochondrial ATP production and up regulation of several key mitochondrial proteins, indicating that insulin withdrawal has a profound effect on brain mitochondria as well as proteins implicated in neurodegeneration. Hyperglycemia is known to alter cognitive function, but it is unclear if insulin deprivation independently alters cognitive function and has not been assessed in humans. In order to investigate the effects of insulin deprivation on the human brain, we propose a study involving temporary insulin deprivation in adolescents and adults with type 1 diabetes (T1DM). We will perform brain MRI, phosphorus31 spectroscopy, cognitive testing, circulating blood exosome measurements, and proteomics from muscle biopsy; comparing these measures during insulin treatment and deprivation between diabetic patients and age-, sex-, BMI-matched controls. Specific aim 1: Determine whether transient insulin deprivation in T1DM adults and adolescents alters brain structure, functions and blood flow as assessed by structural/functional MRI. Specific aim 2: Determine whether transient insulin deprivation in T1DM adults and adolescents alters cognitive function. Specific aim 3: Determine whether transient insulin deprivation in T1DM adults and adolescents alters the circulating blood exosome contents and metabolome that can potentially impact brain functions. Specific aim 4: Determine whether transient insulin deprivation in T1DM adults alters the skeletal muscle proteome homeostasis especially those involved in fission and fusion

Insulin Deprivation in Type 1 Diabetic Patients will be performed for a short time period (4-6 hours). Changes to Age, Sex, and Gender matched controls will be compared.

Type 1 Diabetic Patients requiring insulin will have insulin stopped for a short period of time (4-6 hours)

Structural magnetic resonance imaging (MRI) is a non-invasive technique for examining the anatomy and pathology of the brain (as opposed to using functional magnetic resonance imaging [fMRI] to examine brain activity. This produces images which can be used for clinical radiological reporting as well as for detailed analysis.

Inclusion criteria: Male and females age 14-17 years, females must be post-menarcheal Age 18-45 years Able to provide written consent Parents able to provide written consent T1DM treated with CSII or MDI (not degludec) Exclusion criteria: BMI < 20 or > 30 kg/m2 BMI z-score <5th or >95th percentile Celiac disease Pregnancy Smoking Reported history of illicit substance use History of active cardiovascular, cerebrovascular, or peripheral vascular disease Active renal disease evidenced by estimated GFR < 50 mL/min/1.73 m2 History of traumatic brain injury Dementia or any other neurologic disease Psychiatric disease\ Any learning disability Hemoglobin A1c > 8.5% Hemoglobin A1c > 9% T2DM, or impaired fasting glucose

Creo AL, Cortes TM, Jo HJ, Huebner AR, Dasari S, Tillema JM, Lteif AN, Klaus KA, Ruegsegger GN, Kudva YC, Petersen RC, Port JD, Nair KS. Brain functions and cognition on transient insulin deprivation in type 1 diabetes. JCI Insight. 2021 Mar 8;6(5):e144014. doi: 10.1172/jci.insight.144014.