Investigation Into the Effects Upon Brain Response to Change in Cirucating Glose Levels in Diabetes Mellitus

Previous studies have shown that a person with type 1 diabetes is less likely to suffer the
long term microvascular complications of diabetes (eye, kidney and nerve damage) if they
strive to achieve as near normal a blood glucose as possible. Unfortunately the tighter the
blood glucose control is, the more likely the subject is to suffer episodes of hypoglycemia.
Hypoglycemia is often the aspect of diabetes management most feared by people with diabetes
and may cause more anxiety than the threat of advanced complications.

For many people with diabetes the problem of hypoglycemia is compounded by the development of
the syndrome of hypoglycemia unawareness. One aspect of hypoglycemia unawareness is
impairment of the hormones normally released as blood glucose falls. Hypoglycemia triggers a
release of such insulin antagonists as epinephrine, norepinephrine, glucagon, growth hormone
and cortisol. These hormones act synergistically with the autonomic nervous system to raise
blood glucose, counteracting insulin and restoring normoglycemia. These homeostatic
mechanisms are also responsible for some of the early symptoms of low blood glucose,
providing a warning to insulin-treated diabetics as glucose falls. A number of studies
including research from this unit have established that strict metabolic control is
associated with impairment of the normal counterregulatory response to hypoglycemia and a
loss of hypoglycemia awareness.

The brain is central to the recognition of hypoglycemia and the coordination of the
counterregulatory response. Neural tissue depends mainly on glucose for its energy supply. As
circulating glucose falls beneath the level needed to maintain glucose transport across the
blood-brain barrier, a variety of defense mechanisms are activated, including symptoms of
cognitive dysfunction. However, the precise nature and causes of the adverse CNS effects of
hypoglycemia are not well understood.

Functional magnetic resonance imaging (fMRI) provides a tool to measure the effects of
hypoglycemia on the patterns and magnitudes of neuronal activation in the human brain, in
both normal and diabetic subjects.

Inclusion Criteria:

- All subjects:

- on a weight maintaining diet

- ability to read and speak English fluently

- For All Type 1 Diabetics all of the above inclusion criteria AND C-peptide negative
AND no evidence of neuropathy or proliferative retinopathy

- Only for Type 1 Diabetics in the intensively treated group: HbA1c < 7.5% AND
documented hypoglycemia at least once per week over at least 4 weeks of frequent daily
self monitoring

- Only for Type 1 Diabetics in the conventionally treated group:HbA1c ≥ 8.5%

- Age 18-40 years in the groups 1,2, and 3. Age 18-50 in groups arm 2 obese and control.

- BMI <30 in the groups 1,2, and 3; BMI >18.4 but < or = 25 in the arm control group;
and BMI > or = 30kg/m2 in the obese group.

Exclusion Criteria:

- Pregnancy

- History of neurologic or cardiovascular disease