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

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.