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.

Specific aim 4: Determine whether transient insulin deprivation in T1DM adults alters the
skeletal muscle proteome homeostasis especially those involved in fission and fusion

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