The effect of intravenous lactate administration on brain lactate concentrations and pH during euglycemia and hypoglycemia in patients with type 1 diabetes with and without impaired awareness of hypoglycemia

Patients with type 1 diabetes (T1DM) who are unable to perceive symptoms of
hypoglycemia, referred to as impaired awareness of hypoglycemia (IAH), are at
very high risk of severe hypoglycemia. IAH affects approximately 25% of
patients with T1DM. Brain lactate may be involved in the development of IAH. We
found indications of increased brain lactate utilization during hypoglycemia in
T1DM patients with IAH, which did not occur in patients with normal awareness
of hypoglycemia (NAH). Conversely, administration of lactate to patients with
NAH has been shown to attenuate counterregulatory hormone responses to and
symptomatic awareness of hypoglycemia, thus causing a situation that resembles
IAH. It has, however, not been demonstrated whether the excess of lactate is
actually taken up or metabolized by the brain, and if so whether this occurs
under euglycemic or hypoglycemic conditions or both.

This project consists of two related studies. The objective of part 1 is to
investigate the effect of elevated plasma lactate levels that are sufficient to
impair awareness of hypoglycemia on brain lactate concentrations during
euglycemia and hypoglycemia in T1DM patients with NAH. The objective of part 2
is to compare the effect of exogenous lactate on brain lactate concentrations
between T1DM patients with NAH and T1DM patients with IAH. In both studies, we
will also assess changes in brain pH, because lactate administration is known
to alter blood pH levels

Explorative, single-blind placebo controlled, randomized cross-over
intervention study

Part 1: On two separate occasions, patients with T1DM and NAH will undergo
hyperinsulinemic euglycemic-hypoglycemic glucose clamps with or without the
infusion of exogenous lactate. 1H magnetic resonance spectroscopy (MRS) will be
applied to measure brain lactate levels and 31P-MRS will be used to determine
changes in brain pH levels. Part 2: Patients with T1DM and IAH will undergo a
hyperinsulinemic euglycemic-hypoglycemic glucose clamp with infusion of
lactate. 1H- and 31P-MRS will be applied to measure brain lactate
concentrations and changes in brain pH levels, respectively. Data will be
compared with those of lactate administration obtained in patients with NAH
during study 1.

The hypoglycemic condition is likely to produce typical symptoms (e.g.
sweating, feeling hungry, palpitations) in T1DM-NAH patients, but is usually
well-tolerated and less pronounced when lactate is infused. The risk for more
severe hypoglycemia is negligible. The use of venous and arterial catheters may
lead to hematomas and phlebitis, yet this is self-limiting and has in our hands
never lead to permanent damage. 1H- and 31P-MRS are non-invasive methods
involving high magnetic fields, which are not associated with adverse events
other than possible claustrophobia due to lying in the small MR-bore.