Attenuation of Counterregulatory Responses to Recurrent Hypoglycemia by Active Thalamic Inhibition

Abstract

OBJECTIVE-Hypoglycemia, the limiting factor in the glycemic management of diabetes, is the result of the interplay of therapeutic insulin excess and compromised glycemic defenses. The key feature of the latter is an attenuated sympathoadrenal response to hypoglycemia that typically follows an episode of recent antecedent iatrogenic hypoglycemia, a phenomenon termed hypoglycemia-associated autonomic failure (HAAF) in diabetes. We investigated the role of cerebral mechanisms in HAAF by measuring regional brain activation during recurrent hypoglycemia with attenuated counterregulatory responses and comparing it with initial hypoglycemia in healthy individuals. RESEARCH DESIGN AND METHODS-We used [15 O]water and positron emission tomography to measure regional cerebral blood flow as a marker of brain synaptic activity during hyperinsulinemic hypoglycemic clamps (55 mg/dl [3.0 mmol/l]) in the naïve condition (day 1) and after ϳ24 h of interval interprandial hypoglycemia (day 2) in nine healthy adults.RESULTS-Interval hypoglycemia produced attenuated sympathoadrenal, symptomatic, and other counterregulatory responses to hypoglycemia on day 2, a model of HAAF. Synaptic activity in the dorsal midline thalamus during hypoglycemia was significantly greater on day 2 than day 1 (P ϭ 0.004).CONCLUSIONS-Greater synaptic activity associated with attenuated counterregulatory responses indicates that the dorsal midline thalamus plays an active inhibitory role in reducing sympathoadrenal and symptomatic responses to hypoglycemia when previous hypoglycemia has occurred, the key feature of HAAF in diabetes. Diabetes 57:470-475, 2008 I atrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal. Furthermore, the barrier of hypoglycemia precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the longterm benefits of glycemic control. Finally, episodes of hypoglycemia further impair defenses against falling plasma glucose concentrations and therefore cause a vicious cycle of recurrent hypoglycemia.Hypoglycemia in diabetes is the result of the interplay of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations (1-3). The key feature of the latter is an attenuated sympathoadrenal response to hypoglycemia that causes the clinical syndromes of hypoglycemia unawareness, which is largely the result of a reduced sympathetic neural response (4), and defective glucose counterregulation, which is the result of a reduced adrenomedullary epinephrine response in the setting of absent decrements in insulin and absent increments in glucagon in insulin-deficient diabetes--type 1 diabetes and advanced (i.e., absolutely insulin deficient) type 2 diabetes. These syndromes increase the risk of severe iatrogenic hypoglycemia ϳ6-fold (5) and 25-fold or more (6,7), respectively, in type 1 diabet...

Circulating glucose levels modulate neural control of desire for high-calorie foods in humans

“…The thalamus acts as a relay between subcortical and cortical areas (13), and the hypothalamus is critical for fuel homeostasis and appetite control (1). Consistent with our findings, previous studies have demonstrated thalamic and hypothalamic activation under hypoglycemic conditions (14)(15)(16). The current data demonstrating oppositely directed modulation of PFC and brain reward center activation by circulating glucose support its role in stimulating executive control regions that exert inhibitory control of feeding behavior when glucose is available and promoting survival under hypoglycemic conditions by favoring instinctual motivation for food seeking and consumption when glucose is deficient.…”

Hypoglycemia-Induced Increases in Thalamic Cerebral Blood Flow are Blunted in Subjects with Type 1 Diabetes and Hypoglycemia Unawareness

“…We also observed a reduced activation in left temporal lobe white matter, splenium and body of the corpus callosum of controls as compared with patients. While the involvement of these white matter areas is potentially interesting, the significance of the difference between the groups disappeared in such regions when a large cluster equal to that of other investigators was used for analysis, 1,4,6,7,12 in contrast to what observed in the thalamus. This observation raises questions about the robustness of the findings in the white-matter regions.…”

“…While some studies show less activation during hypoglycemia in several brain areas such as the amygdala and orbitofrontal cortex in patients with T1DM and hypoglycemia unawareness, 6 others have found thalamic activation to be greater during hypoglycemia in human models of HAAF. 7 In both studies, hypoglycemia-induced epinephrine secretion was noted to be reduced in the HAAF group, but direct correlation with regional activation was not reported.…”

The Barrier of Hypoglycemia in Diabetes

“…Discussion of the various theories of the pathogenesis of this key feature of HAAF (1,36 -39) (the systemic mediator, brain fuel transport, and brain metabolism hypotheses) is beyond the scope of this perspective. While much of the neuroscience research into this issue has focused on the hypothalamus (37), recent translational research has raised the possibility that a complex cerebral network normally regulates the hypothalamic (and thus the sympathoadrenal) response to falling plasma glucose concentrations (38,39) and that an inhibitory signal mediated through the thalamus might be involved in the pathogenesis of HAAF (Fig. 3) (39).…”