Small Decrements in Systemic Glucose Provoke Increases in Hypothalamic Blood Flow Prior to the Release of Counterregulatory Hormones

Abstract

OBJECTIVE-The hypothalamus is the central brain region responsible for sensing and integrating responses to changes in circulating glucose. The aim of this study was to determine the time sequence relationship between hypothalamic activation and the initiation of the counterregulatory hormonal response to small decrements in systemic glucose.RESEARCH DESIGN AND METHODS-Nine nondiabetic volunteers underwent two hyperinsulinemic clamp sessions in which pulsed arterial spin labeling was used to measure regional cerebral blood flow (CBF) at euglycemia (ϳ95 mg/dl) on one occasion and as glucose levels were declining to a nadir of ϳ50 mg/dl on another occasion. Plasma glucose and counterregulatory hormones were measured during both study sessions.RESULTS-CBF to the hypothalamus significantly increased when glucose levels decreased to 77.2 Ϯ 2 mg/dl compared with the euglycemic control session when glucose levels were 95.7 Ϯ 3 mg/dl (P ϭ 0.0009). Hypothalamic perfusion was significantly increased before there was a significant elevation in counterregulatory hormones.CONCLUSIONS-Our data suggest that the hypothalamus is exquisitely sensitive to small decrements in systemic glucose levels in healthy, nondiabetic subjects and that hypothalamic blood flow, and presumably neuronal activity, precedes the rise in counterregulatory hormones seen during hypoglycemia. Diabetes 58:448-452, 2009 T he brain relies on glucose as its main energy substrate, and small decrements in circulating glucose provoke an elaborate counterregulatory hormonal feedback response (1,2). Activation of the counterregulatory response requires effective detection of a falling glucose level. Although multiple glucose sensors may be involved (3-7), the hypothalamus has emerged as the dominant brain region responsible for sensing and integrating responses to changes in circulating glucose levels (8 -12). Although most prior studies have relied on animal models to study the neurophysiological response to changes in glucose, newer imaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) provide an in vivo method to study the effect of changes in peripheral glucose levels on human brain activity. Several fMRI studies in humans have demonstrated that a rise in systemic glucose after glucose ingestion leads to an inhibition of hypothalamic activity (13-16). In addition, Musen et al. (17) recently used fMRI based on the blood oxygenation leveldependent (BOLD) contrast mechanism and found that insulin-induced hypoglycemia leads to hypothalamic activation. However, the fMRI-BOLD approach used in that study assesses only relative changes in oxygenated hemoglobin in specific brain regions and does not directly measure tissue perfusion. Magnetic resonance imaging (MRI) pulsed arterial spin labeling (PASL) provides a method for measuring absolute blood flow responses throughout the brain to changes in circulating glucose levels. PASL magnetically tags the arterial blood before entering the brain and then examines t...

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

“…Using PET, Teves et al 1 were the first to find that hypoglycemia activated the thalamus along with the medial prefrontal cortex, right globus pallidus, the right orbital frontal cortex, the right sensory motor cortex, and the periaqueductal gray region in healthy human participants. Others have found the hypothalamus, 3 the anterior cingulate cortex, the bilateral anterior insula, ventral striatum and pituitary, and the posterior parahippocampal gyrus 4 all to show activation at some point during the creation of and recovery from experimental hypoglycemia in healthy human subjects.…”

“…Others have found the hypothalamus to be activated in response to modest hypoglycemia using functional MRI. 2,3 More recently, the dynamics of cerebral activation during the induction of and recovery from hypoglycemia was examined by Teh et al 4 who found that at different times during the experimental period, activation could be observed in various brain areas, including the thalamic pulvinar, anterior cingulate cortex, the bilateral anterior insula, ventral striatum and pituitary, and the posterior parahippocampal gyrus in healthy human subjects.…”

Evolution and resolution of human brain perfusion responses to the stress of induced hypoglycemia

“…In one seminal healthy volunteer study, mild hypoglycemia was associated with medial prefrontal and anterior cingulate cortical and thalamic activation, but the effect of duration of stimulus and recovery was not examined (Teves et al, 2004). A recent study showing regional changes in cerebral perfusion during hypoglycemia using functional magnetic resonance imaging also did not examine their time course (Page et al, 2009). Water positron emission tomography (PET) measures brain regional changes in brain perfusion with excellent signal noise characteristics over short time intervals (Raichle et al, 1983), allowing repeated measures to be made.…”