Magnetic Resonance Spectroscopy (MRS) studies have suggested that exposure to recurrent hypoglycemia (RH) reduces brain cortical Pyruvate Dehydrogenase (PDH) flux in animal models. Examination of rat cortical RNA for inhibitory PDH kinase (PDK) isoform expression patterns identified a two-fold upregulation of PDK4 (p>0.01) after three episodes of hypoglycemia. To date no study has examined the functional role of PDH complex inhibition in the cognitive deficits associated with hypo in patients with T1DM. In a randomized controlled cross-over trial of 11 intensively treated T1DM subjects we examined whether PDK inhibition by dichloroacetate (DCA; 12.5mg/kg), which maintains PDH in its active state might restore cognitive function, counterregulatory hormonal responses and symptoms during clamped hypoglycemia (target 50mg/dL). Cognitive testing included measures of visual matching ability and short term visual and auditory memory as well as the ability to manage conflicting information while ignoring task-irrelevant information. Symptom ratings during hypoglycemia were measured using a modified Edinburgh scale. We found that DCA ingestion is associated with increased performance related to visual memory (DCA: 89% correct vs. Placebo: 69% correct, p=0.049), as well as a faster response time during the multitasking test (549ms DCA vs. 603ms placebo; p=0.028). On the Edinburgh scale, patients reported lower ratings of warmness during hypoglycemia with DCA vs. Placebo (2.5 vs. 3.6; p=0.075). Furthermore, we did not observe an effect of DCA on CRR hormonal responses. These results suggest that inhibition of PDH flux by enhanced PDK activity significantly contributes to cognitive impairment under hypoglycemia and may contribute to subjective symptoms and possibly hypoglycemia awareness. We therefore conclude that strategies focusing on reactivation of oxidative glucose metabolism in the brain may play an important role in mitigating the negative impact of hypoglycemia on cognitive function.
D. Groskreutz: None. D. Trico: None. N. Tai: None. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitchens, Inc. J. Leventhal: None. W. Lam: None. M. Knight: None. J. Gannon: None. R.I. Herzog: Consultant; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc.