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IDDM, Counterregulation, and the Brain
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oes the brain of a person with IDDM respond to hypoglycemia differently than the brain of someone without diabetes? This is one of several questions raised by the provocative article by George et al. (1) in this issue. Recognition of hypoglycemia and the counterregulatory defenses against hypoglycemia are thought to be mediated primarily through discrete brain regions (2,3)- If this thinking is correct, might the observation by George and colleagues be explained as an effect of IDDM on the brain signaling? Importantly, experimental studies in animals and humans suggest that both diabetes (2) and hypoglycemia (3) may exert potentially deleterious effects on the brain. The study by George et al. (1) concludes that those with IDDM recover awareness of hypoglycemia more rapidly than do those without diabetes. In this study, moderate hyperglycemia was maintained between hypoglycemic challenges. Two days after a brief period of hypoglycemia, eight subjects with uncomplicated diabetes showed normal responses (except for the peak and threshold norepinephrine response) to being rechallenged with hypoglycemia. This recovery is more rapid than the recovery the authors previously found in nondiabetic subjects. To begin addressing the questions raised by this study, we must understand its clinical background. We also need to review the pathophysiology of how both diabetes and hypoglycemia affect the brain. The important clinical backdrop for this study relates to the good news/bad news conundrum raised by the data from the Diabetes Control and Complications Trial (DCCT) (4) and other similar studies, such as the Stockholm Diabetes Intervention Study (5). The good news, of course, is that substantial and clinically relevant reductions in risk for all of the major chronic metabolic complications of IDDM are achieved with intensive insulin therapy that attains close to normal levels of HbAk (~7%) when compared to less closely regulated glycemia (~9% HbAlc). The less welcome observation is that a threefold increase in the risk of serious hypoglycemia occurs in those with intensive treatment. Serious hypoglycemia in IDDM subjects commonly occurs at night or without typical sympathoadrenal warning symptoms 1228
(hypoglycemia unawareness) that permit patients to rectify glucose levels by taking dextrose or other remedies. These observations have led Cryer (6) to assert that hypoglycemia is the limiting factor in control of IDDM, a judgment now widely accepted. The hypothesis that excess glucose or some factor closely allied with it is toxic is now much better defended than ever; the concern about hypoglycemia is, however, heightened.
HYPOGLYCEMIA AND COUNTERRE6ULATION — The scientific backdrop for the study by George et al. (1) includes clinical investigations showing that in those with IDDM, prior hypoglycemia is the crucial factor predisposing to hypoglycemia unawareness and defective insulin counterregulation (6). It appears that hypoglycemia per se elicits a stimulus-specific autonomic defect in various counterregulatory hormone responses to hypoglycemia, perhaps most importantly in epinephrine and glucagon. This has been shown in those with insulinoma-induced hypoglycemia (7), in nondiabetic individuals made hypoglycemic for periods of 2 h or less (8), and in those with IDDM (9,10). Most studies of induced counterregulatory defects have been either of rather short duration (24 h) or of much longer duration (weeks to months). In consequence, some aspects of the time course of counterregulatory deficits are not clear. Few studies directly compare subjects with and without IDDM; virtually none have studied what occurs in NIDDM. A key observation has been the reversibility of hypoglycemia-induced autonomic failure and its associated hypoglycemia unawareness and defective insulin counterregulation. In patients with insulinoma, reversal occurs after insulinoma resection (7). Meticulous prevention of hypoglycemia in IDDM may also reverse such hypoglycemia-induced abnormalities within as little as 3 weeks in those without long-standing diabetes (11). However, the reversal of hypoglycemia unawareness and defective counterregulation may not always be coincident or complete (12).
SITE OF THE DEFECT— To inter pret the study by George et al. (1), we must
ask, what are the physiological abnormalities that cause hypoglycemia unawareness and/or defective counterregulation? Specifically, we may ask, is it in the brain that hypoglycemia signaling abnormalities occur? Some evidence suggests that liver hypoglycemia may lead to counterregulatory responses (13,14). Moreover, liver autoregulation may be an important, albeit late, fail-safe response to profound hypoglycemia (15). It seems possible, however, that the role of the liver might not be autonomous; it could communicate to the brain through visceral sensory afferent nerves, and its actions may be orchestrated partly through cerebral responses. Despite the potential importance of the liver, the brain may be the primary source for hypoglycemia-induced protective responses. Evidence for the role of the brain in protection against hypoglycemia comes from both clinical and basic studies of hypoglycemia. Clearly, the brain becomes discretely dysfunctional as a result of glucose lowering to levels that are near 3 mmol/1 (54 mg/dl). The brain is subject to many metabolic and neurotransmitter abnormalities as a result of more profound hypoglycemia (3). Excessive release and/or reduced uptake of the excitatory amino acid neurotransmitters, glutamate and aspartate, is believed to mediate much of the hypoglycemic damage to the brain (16,17). After less-profound hypoglycemia, these same compounds could also alter signaling in the brain through such learninglike mechanisms as long-term potentiation. Inhibition of glycolysis and cellular glucopenia have been shown to induce such long-term potentiation (18,19). Brain responses to hypoglycemia may be induced through signaling in several regions, including those involved in the distribution of the carotid and vertebrobasilar cerebral circulation (20,21). Glucose deprivation in discrete brain areas can also trigger counter-insulin hormone responses. Some evidence suggests that the ventromedial hypothalamus (VMH) is particularly important for counterregulatory responses. VMH lesions impair counterregulation induced by hypoglycemia (22). Glucopenia induced in the VMH by local application of deoxyglucose triggers counterregulation hormone responses (23). Glucose perfusion locally
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within this hypothalamic area also blunts counterregulatory hormone responses to systemic hypoglycemia (24). Unfortunately, the relative importance of individual brain areas and neurotransmitters is unknown. Treatment to reverse counterregulatory failure and hypoglycemia unawareness suggests that the brain might be the site of the signaling defect. For example, caffeine has been shown to reverse hypoglycemia unawareness partially or to potentiate awareness of hypoglycemia in nondiabetic individuals (25). In IDDM subjects, reversal of unawareness may be induced by caffeine as well (26). One possible mechanism for these changes is altered cerebral blood flow, which, among other things, could alter the availability of metabolic substrate (i.e., glucose) to the brain. The importance of cerebral blood flow to substrate delivery and hypoglycemic counterregulation has been reinforced by another recent study (27).
DIABETES, HYPOGLYCEMIA, AND SUBSTRATE DELIVERY TO THE BRAIN — Indeed, possible alterations in availability of metabolic substrates for brain energy metabolism have been much studied in hypoglycemia and in diabetes (28,29). Work from Gjedde and Crone (30) and our own lab (31) has suggested that transport of glucose into the brain is reduced in diabetes. This has been a contentious issue (32). Nonetheless, in clinical practice, those with poorly controlled diabetes become symptomatic for hypoglycemia at normal glucose values, and in experimental models, the brain exposed to chronic hyperglycemia needs less-intense hypoglycemia to produce a counterregulatory defensive response (33). In experimental chronic hypoglycemia, adaptations in brain transport of glucose or in glucose transporter expression may occur. Blood-to-brain transport of glucose is increased in chronic hypoglycemia (34,35). The mRNA and protein for GLUT1, the predominant glucose transporter isoform expressed in brain capillary endothelium, are increased by chronic hypoglycemia in rats (36). Work from Boyle et al. (37) has indicated that chronic hypoglycemia also induces altered efficiency of brain extraction of glucose in both nondiabetic subjects and those with tightly controlled IDDM (38), giving credence to the relevance of animal observations. Recently, Uehara et al. (39) have shown that the adaptation of the brain glucose DIABETES CARE, VOLUME 20, NUMBER 8, AUGUST
transporters may be cell- and isoform-specific. Thus, GLUT1 protein expressed in glial cells of brain did not increase after 8 days of hypoglycemia in rats, whereas GLUT1 protein doubled in the brain microvessels of these chronically hypoglycemic rats. Of interest and potential importance to the phenomenon of hypoglycemia unawareness, significant induction of GLUT3, the neuron-specific glucose transporter in brain, occurred as well. This is the first demonstration that neurons may specifically adapt fuel transport to chronic hypoglycemia. Presumably, the increase in neuronal glucose transporter expression may favorably affect neuronal glucose availability, although by itself no increase in overall glucose supply occurs without an increase in blood-brain glucose transport. While it might seem a beneficial adaptation, such increased neuronal transport of glucose (assuming the overexpressed transporters are functional) could be an important factor in delayed neuronal signaling of hypoglycemia.
OTHER FACTORS AFFECTING COUNTERREGULATION — The role of hormones in counterregulatory failure and hypoglycemia unawareness has regained prominence. Davis et al. (40) found that they could mimic hypoglycemia defects in counterregulation with infusion of cortisol in nondiabetic subjects. This same group has work suggesting that insulin itself may modify the counterregulatory response (40,41). Certainly, glucocorticoids in high physiological or pharmacological amounts may alter a variety of brain-mediated responses, including stress responses (42). The role of insulin in modifying brain responses to hypoglycemia could be important but indirect. Figlewicz and colleagues (43-45) have shown that insulin downregulates the expression of the norepinephrine transporter (NET) within the brain and neuronal cells. This neurotransmitter transporter, similar in structure to glucose transporters, acts as the off signal for central noradrenergic neurons by transporting norepinephrine out of synapses. Both diabetes (lack of insulin) and insulin might alter NET expression and by doing so might influence sympathetic neurotransmission in the brain and control of peripheral sympathetic activity. Insulin downregulates NET mRNA; diabetes upregulates it. In summary, hyperglycemia and hypoglycemia induce multiple signaling abnormalities in the brain, and
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these are usually opposite in effect—on substrate transport and on neurotransmitter metabolism.
CONCLUSION— Brain signaling abnormalities occur in hypoglycemia and in diabetes. Both may be important in understanding the physiology of recovery from hypoglycemia in IDDM. Such signaling abnormalities might explain the observations by George et al. (1), particularly if the hyperglycemia in their IDDM study subjects reversed some of the effects of hypoglycemia on the brain. Human and animal studies are often difficult to compare, partly because of differences in the severity or duration of hypoglycemia and in whether comparable hyperglycemia follows hypoglycemia. The precise timing of brain signaling defects resulting from diabetes or hypoglycemia remains incompletely characterized. The duration of the effects of a single bout of hypoglycemia, the timing of brain recovery from hypoglycemia, and the impact of sustained hyperglycemia on brain signaling are all important issues raised by this study (1). To understand fully the signaling defects induced by hypoglycemia will require further research. Such research may need to compare human and animal models more closely and to determine whether the diabetic milieu modifies such signaling. ANTHONY L. MCCALL, MD, PHD From the Diabetes Program and Lipid Clinic, Portland Veterans Affairs Medical Center, and the Department of Medicine, Neurology and Cell and Developmental Biology, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health Sciences University, Portland, Oregon. Address correspondence and reprint requests to Anthony L. McCall, MD, PhD, Associate Professor of Medicine, Neurology and Cell and Developmental Biology, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health Sciences University, Portland, OR 97201. E-mail:
[email protected].
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