The impact of diabetes on the CNS.

Perspectives in Diabetes The Impact of Diabetes on the CNS ANTHONY L. McCALL

The brain is not usually thought to be a target of chronic diabetes complications. Nonetheless, substantial evidence, summarized herein, suggests that diabetes causes brain damage. Clinical syndromes of diabetes-related brain abnormalities are discussed along with possible causes. Various physiological effects of diabetes are reviewed, and questions are raised about gaps in our knowledge. Appropriate directions for future research are suggested. Diabetes 41:557-70, 1992

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he impact of diabetes mellitus on the CNS has gained attention only recently (1-3). Peripheral neuropathy has been the primary neuroscience focus of diabetes research. Contrary to some early impressions, however, the CNS is not spared by diabetes (4). Chronically, diabetes mellitus afflicts the CNS in several ways. Diabetes increases stroke risk and damage, overtreatment with insulin or oral agents can permanently damage the brain, and diabetes may increase the prevalence of seizure disorders. Diabetes changes brain transport, blood flow and metabolism, and may produce a chronic encephalopathy. Acutely, glycemic extremes cause coma, seizures, focal neurological deficits, and impaired consciousness. The pathophysiological basis for these marked CNS abnormalities seen in hypoglycemia, hyperosmolar coma, and ketoacidosis are largely unknown. The purpose of this article is to'highlight some of the

From the Diabetes Program, Department of Veterans Affairs Medical Center, Portland; and the Departments of Medicine, Neurology, and Cell Biology and Anatomy, Oregon Health Sciences University, Portland, Oregon. Address correspondence and reprint requests to Dr. Anthony L. McCall, Director, Diabetes Program, Medicine (111-P), Portland VA Medical Center, Portland, OR 97207. Received for publication 5 December 1991 and accepted 27 December 1991.

DIABETES, VOL. 41, MAY 1992

brain abnormalities identified in diabetes mellitus, raise questions about the extent of our knowledge of diabetes and the brain, and draw attention to potentially important future research in relevant interdisciplinary areas. The major focus will be the chronic effects of diabetes on the brain. DIABETES MELLITUS AND STROKE Diabetes increases stroke risk and damage—epidemi-

ology. Epidemiological studies demonstrate that diabetes mellitus carries a two- to sixfold increased risk of thrombotic (but not hemorrhagic) stroke. Diabetes is believed to cause 7% of deaths due to stroke, and cerebrovascular disease may be present in 25% of patients dying with diabetes (5). Because non-insulindependent diabetes mellitus (NIDDM) is underdiagnosed, estimates of the contribution of diabetes to stroke risk may be low. Diabetes increases risk of atherosclerosis in all vascular beds including the brain. Hypertension, a major stroke risk factor, is more common in those with diabetes. However, the increased risk of stroke in diabetic individuals persists even when we correct for other concomitant risk factors, i.e., hypertension, that occur more commonly with diabetes mellitus (6). One noteworthy at-risk group is elderly women. In the Framingham Study, the incidence of atherothrombotic brain infarction rose from ~50/10,000 per yr in nondiabetic women 70-79 yr old to 150/10,000 per yr in diabetic women 70-79 yr old (5). Elderly women represent an increasing proportion of our population. Even modest hyperglycemia increases the risk of stroke significantly. The relative risk of stroke in men increases by approximately threefold when their plasma glucose 1 h, after a 50-g glucose load, rises from 10%) comparable to treated diabetic patients, in 50 patients with stroke or transient ischemic attack (TIA). Excluding known glucose intolerant or diabetic patients, there were 21 of 50 stroke or TIA patients with apparently unrecognized diabetes mellitus. Confirming these data, in a prospective study of 200 acute stroke patients, Gray et al. (17) found that 27% had an HbA! >2SD above the laboratory mean without a history of diabetes. A final, very important possibility is that hyperglycemia predicts excessive stroke morbidity and mortality because glucose acts directly or indirectly to exacerbate brain damage during ischemia. Several human studies have suggested that stroke outcome and severity of residual neurological deficits may be predicted by the glucose concentration in the plasma at the time of stroke and that the damage is due to hyperglycemia per se (11-13,17). The concept of glucose as a potential brain toxin originates largely from animal studies (14). HYPERGLYCEMIA WORSENS ISCHEMIC BRAIN DAMAGE IN ANIMAL MODELS Acute hyperglycemia (usually produced by i.p. injection of glucose) before experimental global or forebrain ischemia (types of brain ischemia similar to that observed after cardiac arrest) increases histological damage to the brain and worsens neurological outcome (14,18-34). In contrast, acute hypoglycemia protects against such damage. Hyperglycemia subsequent to stroke seems less important to neurological morbidity in experimental ischemia; glucose administration and hyperglycemia after the ischemia have little impact. Such findings raise serious questions about whether glucose administration should be omitted routinely from resuscitative measures (35). Fewer studies address whether chronic diabetes in animal models worsens stroke damage. However, those

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that do suggest that brain damage from ischemia is worsened by diabetes (14,36,37). Because damage occurs in the absence of atherosclerosis, these studies implicate hyperglycemia as a possible cause of excessive damage. The relationship of stroke damage and hyperglycemia focuses attention on understanding brain ischemia in metabolic terms and raises the possibility of pharmacological remedies to block critical metabolic abnormalities during ischemia. In particular, aspects of glucose metabolism during ischemia are important for two major pathways thought to be relevant to brain ischemia—the toxic accumulation of metabolic acid and the toxic overstimulation of neurons by excitatory amino acids, glutamate, and aspartate. ACIDOTOXIC BRAIN DAMAGE AND PANNECROSIS The mechanism usually imputed to explain the increased stroke damage after hyperglycemia is cellular acidosis (19,21,38). This "acidotoxicity" hypothesis states that anaerobic metabolism of glucose to lactic acid under conditions of oxygen lack leads to intra- and extracellular acidosis. Indeed, cellular pH after ischemia is a direct function of lactic acid levels in brain. The acidity predicts pannecrosis in the brain, i.e., cellular damage not only to neurons but also to glia and vascular elements. Evidence suggests both pH and lactate levels may independently contribute to cellular damage (39). How lactate or low intra- and extracellular pH cause the damage is not known but will be the focus of much future work. Even a difference of a few millimolars in blood glucose seen after a few days of dexamethasone pretreatment has been invoked to explain more severe stroke damage in rats (20). A major question to be addressed is how such modest hyperglycemia might exert a major effect on stroke outcome (40). Could small increments in glycemia markedly increase lactate-induced brain injury and is this consistent with a mass-action effect? Possibly some other variable or variables serve to amplify the glucose effect. One explanation is that altered glucose transport at the blood-brain barrier or at the plasma membrane of neurons and glia (see below) could serve as such an amplifier, augmenting lactate accumulation during ischemia by increasing glucose delivery to brain. Any theory relating glycemia to stroke damage must explain observations suggesting both possible detriment and benefit of glucose in ischemic brain injury. In animal models of focal brain ischemia (like that seen after thrombotic stroke), there is evidence for worsening (34,41) and some sign of improvement (42) in cellular damage by hyperglycemia. In an area of dense ischemia (the center of an infarct), glucose typically worsens damage. In the penumbra, the ischemic zone that surrounds dense infarction, however, glucose may ameliorate damage. In hypoxia, hyperglycemia may improve brain damage (43). A major question is what relevance data from these animal models have to different types of human cerebral ischemia. Why does hyperglycemia worsen some types of isch-


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emic/hypoxic brain damage but actually improve others (41)? Inefficient ATP generation from glycolysis and toxic buildup of cellular lactate in areas of severe oxygen lack may be the answer. Glycolysis generates a net yield of 2 ATP equivalents compared with as much as 38 for complete glucose oxidation. In addition, a block of pyruvate dehydrogenase characterizes some forms of ischemia (23) and could accelerate cellular accumulation of lactic acid and acidotoxicity. In less hypoxic areas by contrast, more efficient oxidative energy generation and less lactate accumulation could occur. Glucose may benefit the heart, enhancing brain survival by improving cardiac output. Research efforts are needed to address these possibilities. In addition, more studies of how chronic diabetes or glucose intolerance exacerbates neurological damage in animal models of stroke (both focal and global) are needed. Specifically, we would like more information about the dose-response characteristics of the relation between ischemic brain damage and degrees of hyperglycemia and the effect of diabetes treatment on damage. The clinical implications of possible glucose toxicity to brain during stroke are several. If hyperglycemia is implicated in human stroke damage and does not simply reflect unrecognized diabetes or stress hyperglycemia from severe infarction, then what should be done? How tightly controlled should glycemia be in diabetic stroke patients? Does the answer depend on the type of stroke as suggested by Helgason (14)? Should we maintain tight glucose control, potentially risking hypoglycemia in acute stroke patients? What is appropriate nutritional therapy for diabetic stroke patients who can not feed themselves? Should glucose be omitted from their intravenous therapy or should very-low-glucose tube feedings be used when needed? There are no answers to these questions. Clinical studies should address these issues.

EXCITOTOXIC BRAIN DAMAGE

A second type of brain damage occurs during ischemia (and hypoxia or hypoglycemia)—excitotoxicity from acidic amino acids. The characteristic histopathology shows selective neuronal necrosis, with particular neurons in specific brain regions affected but sparing of glial and vascular elements. Biochemical correlates have been sought to explain the selective, regional nature of this brain damage. Most of the focus has been on glutamate toxicity via specific receptors, particularly the A/-methyl-D-aspartate (NMDA) receptor (44), although other receptor types are also involved (45). This receptor, one of the major types of brain glutamate receptors, becomes overstimulated by the release of glutamate from presynaptic neurons during conditions of energy deprivation in the brain. Membrane depolarization occurs, ionic movements follow, and intracellular calcium particularly increases. One attraction of the NMDA toxicity hypothesis is its potential to explain selective neuronal vulnerability. Selective vulnerability should occur where NMDA or other involved glutamate receptors are located postsynapti-


cally. A second appeal is the potential to intervene experimentally with drugs that block the receptors. It is likely, based on in vitro studies of glutamate toxicity in cultured cerebellar neurons, that glucose metabolism is intimately involved in generating the energy locally that determines whether NMDA toxicity occurs (46,47). In particular, glucose oxidation may unblock the magnesium channel in the NMDA receptor. During ischemia or hypoglycemia, glutamate may literally stimulate some neurons to death. Normally, glutamate release would simply cause postsynaptic neurons to receive an excitatory postsynaptic potential and possibly depolarize as a result. Under conditions of energy failure, however, i.e., oxygen or glucose lack, excessive release may occur, with a concomitant failure of the energy-dependent reuptake mechanisms that detoxify glutamate. The result is hyperstimulation of the postsynaptic neuron, a toxic event made worse by inability to restore ionic homeostasis due to the original energy failure. One characteristic consequence of these events is intracellular calcium overload in particular neurons. Cellular calcium overload represents another important biochemical event during ischemia, hypoglycemia, and hypoxia (48). As with the other aspects of excitotoxicity, it may explain the selective nature of neuronal damage. It also offers the possibility of pharmacological intervention to ameliorate the damage. There may be a connection between these different metabolic mechanisms of brain damage. Nimodipine, a calcium-channel blocker, mitigates the acidosis and possibly brain damage caused by hyperglycemia during experimental ischemia (49).

HYPOGLYCEMIA AND BRAIN DAMAGE

Human studies. Hypoglycemia depresses brain metabolism. Based on studies by Kety et al. (50), it became clear that insulin coma, deliberately induced as a therapy for mental disorders (a practice laudably abjured), markedly reduces cerebral oxygen consumption and disproportionately decreases brain glucose metabolism. Hypoglycemia can produce permanent brain damage and death. The cortex, caudate, and hippocampus appear most vulnerable to hypoglycemia. However, confounding variables mar interpretation of some of the human case studies (51). Overall, the brain in humans dying of hypoglycemia may appear either grossly normal or markedly affected, depending on whether the clinical course has been complicated by repeated seizures and cardiac arrest (51,52). Cortical and hippocampal atrophy and ventricular enlargement may occur in long-term survivors. Laminar necrosis occurs in the cerebral cortex, especially in the third and fifth layers. Sometimes, diffuse demyelination is observed. Certain zones of the hippocampus may be characteristically involved. The striatum can be necrotic but involvement of the globus pallidus is uncommon. The cerebellum is relatively spared, especially the Purkinje cells. Animal literature. Animal studies of acute hypoglycemic brain damage, particularly those of Brierley et al. (53) and Auer et al. (56), gave a more controlled examination of histopathological effects of hypoglycemia on the brain.

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Brierley and associates (53,54) argue for the similarity of hypoglycemic brain damage to ischemia and hypoxia, whereas Auer et al. emphasize the differences. Two major types of histological change are observed in hypoglycemia-induced brain damage (55). Cellular shrinkage and condensation of nuclei and cytoplasm and scalloping of the cytoplasmic membrane occur. A second type of histological neuronal injury is swollen neurons, often with vacuolization (probably swollen mitochondria) seen near the cytoplasmic membrane. In any case, selective neuronal necrosis is the most characteristic brain lesion of hypoglycemia. Based on extensive studies in rats with acute hypoglycemia, Auer et al. (56-62) concluded that recognizable neuronal injury leading to cellular death takes place within 2-8 h after hypoglycemia severe enough to produce an isoelectric electroencephalogram (EEG). Cells in the cortex, hippocampus, and caudate are involved in lesions first visible in the dendrites but that comparatively spare axons.

NEUROCHEMICAL EFFECTS OF HYPOGLYCEMIA Acute hypoglycemia produces cerebral energy failure, causes loss of ion homeostasis (especially increases in intracellular calcium) (19,48,63-66), produces membrane depolarization, alters intermediary and amino acid metabolism, depresses protein synthesis (67), increases phospholipid hydrolysis and concentrations of free fatty acids especially arachidonate, and alters cyclic nucleotide metabolism. Moderate hypoglycemia produces a partial energy failure of the CNS through brain fuel starvation or neuroglycopenia, clinically manifest at ~3-mM glucose concn (68-70,214-216). One consequence of the energy failure is synaptic release of glutamate (or aspartate) and a concomitant failure of energy-dependent reuptake of excitatory neurotransmitters. Excitotoxic cellular damage, as with stroke, is mediated via specific receptors, particularly the NMDA receptor (see above). Hypoglycemic brain damage may be prevented by blocking the NMDA receptor. Thus, Wieloch (71) showed in rats that the experimental compound, AP7, inhibits binding of NMDA to its receptor and can prevent almost 90% of the histological damage of hypoglycemia associated with an isoelectric EEG. Auer et al. (72) showed similar protection with a different NMDA blocker (72). Siesjo et al. (48,65,66,73,74) suggested that calciummediated brain damage occurs in hypoglycemia and other brain insults, such as stroke. Selective vulnerability to brain damage may occur because a greater density of calcium channels on some cells permits greater cytoplasmic calcium influx. Intracellular calcium overload activates proteases and lipases, exerting toxic effects through reactions catalyzed by these enzymes and causing mitochondrial swelling and dysfunction. Calcium toxicity may be blocked pharmacologically and potentially prevent the neurotoxic consequences of hypoglycemia (and stroke) to the brain. Thus, even if serious hypoglycemia cannot be avoided, its associated brain damage could be minimized.

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SOME UNANSWERED QUESTIONS Several questions emerge from a review of the neuroscience literature on hypoglycemia. What relationship exists between recurrent clinical hypoglycemia, e.g., repeated bouts of coma or seizures but with apparent neurologic recovery, and long-term brain damage? Frier et al. (75, 76) and others found that repeated hypoglycemia predicts cumulative brain damage (75,76). Do mild bouts of hypoglycemia produce selective neuronal necrosis as in rat studies (56)? If such pathology does not occur, is there some other form of sublethal (e.g., metabolic [77]) neuronal (or glial) injury that impairs neurological function in the long run? Are the brain consequences of hypoglycemia preventable by calcium channel blockers or NMDA receptor blockers? Do some areas of the brain fail to adapt to repeated hypoglycemia (78), although animal studies suggest that much of the brain appears to adapt? What is the role of CNS in counterregulatory hormone defects observed with repeated hypoglycemia (79), and if there is a significant CNS role, what is its neurochemical basis? Is it time for us to design clinical studies in high-risk patients based on our knowledge of the neurochemistry of hypoglycemia in animals? Certain studies, e.g., the use of calcium channel blockers in patients with intensively treated diabetes and hypertension to protect the brain from hypoglycemic damage, seem ethically appropriate. A last question, best addressed in experimental animals, is whether the neurochemistry of hypoglycemia differs in the context of preexisting diabetes. BRAIN TRANSPORT, BLOOD FLOW, AND METABOLISM IN DIABETES AND HYPOGLYCEMIA Transport of glucose and other nutrients into the

brain. Glucose transport into the brain of diabetic animals appears to be depressed as a direct or indirect consequence of hyperglycemia (80-85). With different techniques, several groups have independently reported depressed glucose transport across the blood-brain barrier in experimental diabetes. Early studies by Ruderman et al. (86) found, with cerebral arteriovenous differences, a method influenced by both transport and metabolism, that the net extraction of glucose by the brain is decreased by one-third in uncontrolled diabetes. With the intravenous infusion method to study unidirectional flux of glucose into the brain (a true index of transport), Gjedde and Crone (87) found that chronic hyperglycemia decreased the blood-brain barrier transport of glucose from 44 to 25%. A decreased maximum transport capacity (Tmax) for glucose from 4 to 2.9 ixmol • g~1 • min~1 explains this decrease. When plasma glucose in diabetic rats is lowered to normal values, the glucose transport rate into brain is 20% below that of nondiabetic rats. In extensive physiological studies in diabetic rats, we (81,82) used the Brain Uptake Index method to study transport of several hexoses and other metabolic substrates. Glucose transport into the brain decreases from 40% (control) to 27% (diabetes) in a single cerebral circulation passage. As previously shown (87), the maximal transport rate decreased (from 1.8 to 1.0 ^mol • g~ 1


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• min~1). Hexose transport is symmetrically depressed on both sides of brain capillaries; both efflux and influx of the nonmetabolized hexose analog, 3-O-methyl-D-glucose, are decreased to a similar degree (82). Transport of hexoses into the brain in diabetes is generally but specifically altered. Transport of other nonglucose sugars is depressed by diabetes, whereas that for the ketone body, fj-hydroxybutyrate, is increased in untreated diabetic rats but depressed after insulin treatment (82). Transport of other substrates, e.g., amino acids, or water is unaffected. Chronic changes in antecedent glycemia appear to be the primary stimulus for altered glucose transport into the brain. This conclusion is based on studies showing that glucose transport and glycemia correlate with insulin treatment, sucrose feeding plus insulin treatment, and starvation of diabetic rats (82). The time course of these changes in blood-brain barrier glucose transport is slow, requiring >1 day in rats. Recently, Pardridge et al. (83) confirmed and extended findings on the decrease in blood-brain barrier glucose transport in experimental diabetes mellitus. Choi et al. (84) found increased GLUT1 mRNA levels in the brain capillaries of rats with streptozocin (STZ)-induced diabetes but decreased transport, with the in situ brain perfusion (88) method, and decreased levels of GLUT1 protein (the major blood-brain barrier glucose transporter) in the same brain capillaries (83). They (84) found a 44% decrease in glucose transport and a 77% decrease in GLUT1 immunoreactivity (based on a COOH-terminal and presumably specific antiserum) in isolated cerebral microvessels from rats with experimental diabetes (84). Mooradian and Morin (85) also confirmed the decrease in blood-brain barrier transport but found no change in the number of glucose transport proteins in brain capillaries from diabetic rats. Some controversy has arisen over whether the changes in blood-brain barrier glucose transport are specific or indeed even exist. Harik et al. (89-91) found decreased transport of glucose into the brains of both acutely and chronically hyperglycemic rats but explained the results on the basis of altered cerebral blood flow and/or altered diffusion of L-glucose, their control marker for nonspecific transport. Duckrow (92) found that no transport change exists for glucose at the blood-brain barrier in diabetic rats, whereas, in another study (93), he described a slight decrease. Pelligrino et al. (94) argued against a decrease in glucose transport across the blood-brain barrier in diabetes but found strong direct evidence for increased blood-brain barrier transport in chronic hypoglycemia. Pardridge et al. (83) argued that the methods used in studies failing to find decreased glucose transport in diabetes examine glucose transport into the brain at levels of glucose that largely, if not completely, saturate the carrier proteins. Thus, they would not be able to demonstrate any significant or consistent transport differences. In any case, some controversy will continue, at least until studies are conducted to assess adequately whether such effects occur in humans. In addition, there needs to be more basic information about where glucose


transport proteins are distributed in the brain and how they are regulated. In particular, it seems especially likely that different glucose transport proteins will be differentially regulated.

BRAIN TRANSPORT IN CHRONIC HYPOGLYCEMIA Chronic hypoglycemia increases glucose transport into the brain. Chronic but not acute hypoglycemia increases blood-brain barrier transport of glucose (96). Rats made chronically hypoglycemic by insulinoma implantation, insulin infusion with an osmotic minipump, or daily injections of PZI insulin all have increased brain glucose transport. As in diabetic rats, the changes in blood-tobrain transport in chronic hypoglycemia are specific and rather slow in their onset. Other transport systems are either unaffected (e.g., large neutral amino acids or choline transport) or affected in an opposite fashion (e.g., lactate and pyruvate transport.in insulinoma rats). Furthermore, glucose-6-phosphate, creatine- phosphate, and ATP levels in brain are not significantly lower in insulinoma rats, suggesting the increased glucose extraction at the blood-brain barrier protects brain energy metabolism. Pelligrino et al. (63, 64) similarly found evidence for an increase in blood-to-brain transport of glucose in chronically hypoglycemic rats (78). In these studies, regional analysis suggested that most, although not all, brain areas adapt. The effect of these adaptations are to enhance the cerebral metabolism of glucose. However, note that in chronic hypoglycemia there is less compensatory cerebral blood flow change (97) and, despite adaptation in glucose transport, abnormal mitochondrial respiration remains (77). It appears from the above studies that hyperglycemia and hypoglycemia chronically decrease and increase, respectively, transport of glucose at the blood-brain barrier. Possibly, glycemia similarly affects the cytoplasmic membrane barrier of brain parenchymal cells, particularly glial cells (98,99). Glucose starvation of many tissues and cell types has been repeatedly shown to increase glucose transport and conversely, glucose exposure to decrease glucose transport (100,101). It seems likely that the brain behaves similarly, based on studies performed to date. Regarding controversies in studies of brain transport in diabetes, although we might believe that analysis of glucose transport proteins and mRNA will provide a definitive answer, this may not be. Molecular biology analysis is helpful insofar as it confirms and explains how transport changes. Studies of transport must stand or fall on their own merits. Transport of other substrates and ions in diabetes. Mooradian (102) found that the maximal rate of choline transport across the blood-brain barrier declined from 2.2 to 0.14 nmol • min~1 • g~ 1 in chronically diabetic rats. Insulin therapy for 5 days did not rectify the abnormal choline transport. Because choline may be an important precursor to brain acetylcholine, a neurotransmitter thought to be involved in age- and Alzheimer's diseaserelated memory loss (103), this is an intriguing finding. Mooradian (102) also found that dehydroascorbate,

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but not ascorbate, in vitro was able to compete with glucose for entry into several tissues including the brain. However, it is not clear whether hyperglycemia could cause a deficiency of this vitamin in the brain and lead to dysfunction as a result. Specific abnormalities in sodium transport at the blood-brain barrier in experimental diabetes were observed (104-107). The permeability surface area product (PS) for sodium was determined by infusing 24 Na + i.v. for up to 15 min in diabetic and control rats. The PS decreased from 7.1 in the frontal cortex of control rats to 5.4 x 10~5 • cm" 3 • g " 1 • s" 1 after 2 wk of STZ-induced diabetes (104). Similar decreases occur in occipital cortex after 2 wk of diabetes mellitus. 36CI- and 3 Hsucrose transport do not differ significantly between diabetic and control rats (104), however. Potassium permeability (107) also decreases by 39%, but no difference exists in calcium permeation into the brain. Insulin treatment restores Na+ transport to near-normal values within a few hours (105). Transport changes are not explained by hyperosmolarity because 50% mannitol increases Na+ transport, myo-lnositol treatment normalizes the deficient Na+ transport. It has been postulated that abnormal Na+-K+-ATPase activity in cerebral endothelial cells is the cause of these effects (106). Abnormal permeation of protein into the brains of animals with experimental diabetes mellitus also may occur. Stauber et al. (108) found a selective extravasation of albumin but not IgG or complement (C3) in immunohistochemical studies of the brain in STZ—induced diabetes of 2 wk duration. However, studies by Williamson (109) did not find that 125l-labeled albumin permeation into brain is increased in animal diabetes. Perhaps the latter method is less sensitive than immunohistochemistry. If very poor diabetic control affects microvascular permeability to albumin or sodium of the blood-brain barrier, it could be relevant to the syndrome of cerebral edema that has been observed, particularly in children being treated for diabetic ketoacidosis (110— 114). CEREBRAL BLOOD FLOW AND VASCULAR REACTIVITY CBF probably decreases in animals with poorly controlled, hyperglycemic diabetes (83,89,115-119). Some studies are contradictory (120), perhaps due to experimental design issues such as measurement technique and diabetes duration and severity. CBF may be depressed in a moderate, regionally specific fashion, which depends on the severity of hyperglycemia. Particularly affected is the hindbrain (14% reduction at glucose of 29 mM), with less effect on the forebrain. CBF reduction has been seen in rats with either acute hyperglycemia from intraperitoneal glucose or STZ-induced chronic diabetes (115). It may not be simply an osmotic effect because equiosmotic mannitol yields a more modest decrease. Because the risk and severity of stroke in diabetes is increased, such findings may be mechanistically relevant. If the findings apply to humans with poorly controlled diabetes, they might lead to critically diminished blood flow in certain brain areas, particularly in the presence of extracranial atherosclerosis or thrombosis.

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However, it is not certain whether good-to-moderate glycemic control in people with diabetes produces similarly altered CBF as occurs in these animal models. Some studies find decreased basal CBF in diabetes (121). However, some studies have failed to find such changes or actually found increases in CBF in diabetic humans (122-126), possibly because people are not usually studied in very poor glycemic control. Furthermore, even if CBF is normal under basal conditions, cerebrovascular reactivity is often abnormal in diabetes. Cerebrovascular reactivity may be selectively impaired in long-term experimental and human diabetes (116,120, 127,128). For example, Pelligrino and Albrecht (116) examined CBF responses to hypoglycemia, hypoxia, and hypercarbia after either 6-8 wk or 4 - 6 mo of STZinduced diabetes in rats. In these studies, basal CBF is decreased and vascular reactivity (dilation and increased flow) blunted. Hypoglycemia-induced increases in CBF in long-term diabetic rats are severely impaired. Similarly, human studies of cerebrovascular reactivity, both of dilatation and constriction show abnormal responses (123-126,129,130). The duration of diabetes may be important because not all studies confirm these results. Abnormal cerebrovascular reactivity in people with long-standing diabetes may be specific to certain stimuli (130). There is evidence that clinical diabetic neuropathy predicts the presence of abnormal cerebral vascular reactivity. What is the import of abnormal vascular reactivity in response to hypoglycemia? Increased CBF during hypoglycemia is thought to enhance the supply of glucose to the brain. Impairment of vascular reactivity may blunt this compensatory increase. Cohen et al. (131) obtained evidence for a vascular neuropathy in the carotid arteries of alloxan (ALX)-induced diabetic rabbits (131). Norepinephrine content, release, and uptake are all abnormal in this model. It is not known whether smaller resistance vessels are similarly affected, although evidence exists for their noradrenergic innervation. These investigators also found abnormal cholinergic relaxation in large blood vessels in experimental diabetes, with evidence pointing to abnormal vasoconstrictor prostanoid release as a mechanism (132,133). Although these studies were not performed in brain blood vessels, note that abnormal prostanoid metabolism was found in diabetic brain (134), although not in diabetic brain microvessels (135). DIABETES AND HYPOGLYCEMIA AFFECT MICROVASCULAR METABOLISM IN THE BRAIN The cerebral microvasculature may be a target for chronic diabetic complications. Pericyte loss in brain capillaries was observed in animal models of diabetes (136). However, the effects of diabetes on pericytes in brain capillaries is less well established than effects in retinal capillaries. Reske-Nielsen et al. (137) described brain vascular abnormalities in long-term insulin-dependent diabetes mellitus (IDDM) patients. In addition, in autopsies of humans with IDDM, there is microvascular pathology present including basement membrane thickening (138). Metabolic abnormalities, particularly in energy metab-


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olism (3,14,36,37,139,140), exist in brain microvessels from animals with experimental diabetes. Frequently, altered metabolism of a fuel in vitro by rat brain microvessels correlates with the transport of that fuel in vivo across the blood-brain barrier (82,96,139,140). Thus, diabetes depresses the metabolism of glucose in brain microvessels from rats with STZ-induced diabetes. Microvessel oxidation of glucose decreases by 65-83% and conversion to lactate by 21-61%. As with glucose transport in vivo, prior glycemia is an important regulatory factor for microvessel metabolism. Restoration of euglycemia by insulin treatment or starvation for days both lowers blood glucose levels and rectifies microvessel glucose metabolism. In our studies, [1-14C]lactate oxidation was depressed in brain microvessels from diabetic rats, suggesting impaired flux through the pyruvate dehydrogenase pathway. Restoration of glycemic control improved flux through this pathway. Hingorani and Brecher (141) confirmed and extended work on the abnormal fuel metabolism of cerebral microvessels from diabetic animals in their studies of New Zealand rabbits with 150 mg/kg ALX-induced diabetes. They studied isotopic oxidation of [6-14C]glucose or [1-14C]oleate and the incorporation of radioactivity into CO2, lactate, triglycerides, cholesterol ester, and phospholipids. They found competition between the oxidation of glucose and oleate. Thus, incubation of microvessels with 5.5 mM glucose reduces oleate oxidation by 50%. Conversely, glucose oxidation is reduced by incubation with oleate. Our laboratory found that the oxidation of glucose and p-hydroxybutyrate is altered in a coordinated but opposite direction in brain microvessels of rats with diabetes and chronic hypoglycemia (due to a subcutaneous insulinoma) (139). Glucose oxidation by isolated cerebral microvessels is depressed in diabetes but increased in chronic hypoglycemia, paralleling the transport of glucose in vivo across brain capillaries (82,96). Acutely, insulin treatment has no effect on microvessel metabolism. Oxidation of p-hydroxybutyrate to CO2 by isolated cerebral microvessels is increased in diabetes, as is its transport into brain, whereas, in chronic hypoglycemia, depressed oxidation occurs. The basis for these parallels between fuel transport and metabolism is unknown. It seems implausible that glucose transport by microvessels limits their metabolism because the transport must be abundant enough to provide glucose for the whole brain (151). On the other hand, local (i.e., capillary) metabolism may well influence transport, a notion with considerable precedent in studies of glucose starvation and refeeding in fibroblasts (100,101,142-148). Precise knowledge of the metabolic control mechanisms that regulate transport may in the future permit their deliberate manipulation as therapy. Altered fuel metabolism by brain capillaries does not affect their ATP content or ATP-ADP ratios after 1 or 8 wk of diabetes in rats (139). Although ATP remains unchanged, oxygen consumption by microvessels from diabetic rats increases by 35% compared with controls. The specific metabolic pathways that explain the increased oxidative metabolism are unknown. Possibly, ion


homeostasis in the brain microvasculature of diabetic animals requires a higher rate of respiration. In poorly controlled diabetes mellitus combined with situations of fuel deprivation, e.g., hypoxia or ischemia, excessive oxygen consumption or other abnormalities of fuel use may produce microvascular dysfunction in brain. Future studies should be directed toward looking at the functional consequences of this abnormal fuel metabolism. A major question to be addressed is why there is no obvious clinical syndrome equivalent to diabetic retinopathy that affects the brain, e.g., with hemorrhages. Pericyte density is one possible answer. Retinal capillaries have about four times as many capillary pericytes as the brain. These cells may be a particular target of diabetic microvascular damage. What are the mechanisms involved in CBF changes? No answer is available. If hyperglycemia causes the CBF changes, good control may prevent them. BRAIN ENERGY METABOLISM Kety et al. (149) examined the effects of diabetic coma (ketoacidosis) on brain metabolism in humans. Cerebral metabolic oxygen consumption was reduced by 50%. This reduction probably represents a decrease related to the coma rather than a specific effect of diabetes. Other causes of coma, hepatic failure, uremia, and anesthesia, all produce similar decreases in brain oxygen consumption (150). Ruderman et al. (86) showed that brain fuel metabolism is altered in experimental diabetes. As in starvation, during ketotic diabetes in animals, the brain slowly decreases its utilization of glucose and increases its utilization of the alternate fuels, the ketone bodies, acetoacetate and (3-hydroxybutyrate. This occurs in both anesthetized and unanesthetized rats (152). With arteriovenous differences (86) and sampling of intermediary metabolites in the brain, it was possible to show a glucose-fatty acid cycle in brain during uncontrolled diabetes (153). The effects of poorly controlled diabetes on specific pathways of brain energy metabolism are complex (86,154-156). It seems likely that ketosis engenders a switch from brain utilization of glucose to ketone bodies, much as has been observed in starvation (155,157). Animal and human studies (93,94,155,158-160) have been conflicting on the extent to which nonketotic diabetes influences cerebral metabolism. In humans with well-controlled IDDM, Grill et al. (122) has performed studies of regional CBF and metabolism before and after insulin normalization of glycemia. Before insulin treatment, an increased arteriovenous difference for ketone bodies was seen, as in animal studies. Cerebral nonoxidative metabolism of glucose was increased in IDDM (19 vs. 7% in nondiabetic subjects), and the ratio of glucose to oxygen consumed was altered. The fate of the extra glucose is unknown. Also, which fuel substitutes for glucose oxidation is uncertain. Studies from Jakobsen et al. (117) in diabetic rats suggest that both an increase and then a decrease sequentially in cerebral glucose metabolism may be observed, depending on the time

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course of diabetes (and possibly hyperglycemic severity). More studies need to be done, especially in NIDDM patients. BRAIN NEUROTRANSMITTER METABOLISM Experimental studies indicate that binding and metabolism of neurotransmitters within the brain, especially monoamines, are abnormal in untreated diabetes mellitus. Dopaminergic neurotransmission may be diminished. Lozovsky et al. (161) reported that the number of dopamine receptors, measured by 3H-spiperone binding, is increased by 30-35% in ALX- or STZ-induced diabetic rats. Dopamine receptor ligand binding is normal in diabetic rats treated with insulin, but dopamine metabolism may not be entirely normalized after insulin therapy (162). Similar results are found in animals treated with chronic neuroleptics (dopamine blockers). The accumulation of dopamine metabolites (dihydroxyphenylalanine and homovanillic acid) in the striatum of diabetic rats is decreased after 4 - 6 wk of diabetes (163). Hyperglycemia suppresses dopamine neuronal firing (164). Furthermore, behavioral responses of diabetic rats to drugs acting through dopamine neuronal systems are increased, consistent with a hypersensitivity seen after decreased dopaminergic neurotransmission (165). Regional noradrenergic transmission is altered in diabetes. Trulson and Himmel (166) showed that forebrain norepinephrine content increases with diabetes and decreases after insulin administration. The major metabolite of norepinephrine (3-methoxy-4-hydroxyphenylglycol sulfate) decreases in diabetes and increases after insulin administration, suggesting that diabetes decreases, whereas hypoglycemia increases forebrain noradrenergic neurotransmission. Steger and Kienast (167) found reduced noradrenergic neurotransmission in STZ-induced diabetes to be at least partly correct with insulin therapy (and may relate to hypogonadism). Chu et al. (168), in regional analyses of brain catecholamines and serotonin levels, found lowered catecholamine levels in the hypothalamus but higher levels in the corpus striatum. They (168) also found lower serotonin levels in both hypothalamus and brain stem but not in the corpus striatum. Reversal of these abnormalities occurs with insulin therapy. These authors also noted several neurological or neurobehavioral changes: STZ-induced diabetic rats had thermoregulatory deficits in the cold, they had a higher spontaneous pain threshold but reduced sensitivity to morphine analgesia, and they had decreased spontaneous motor activity but increased motor responses to amphetamines. Garris (169) found that the norepinephrine content rises in several brain regions in db/db mice compared with age—matched controls. Both oc-1 and -2 receptors are elevated, whereas (3-adrenergic receptors are decreased in regional brain samples of diabetic mice relative to controls. Serotonin neurotransmission is abnormal in experimental diabetes. Crandall and Femstrom (170) found that experimental diabetes alters tryptophan content in the brain (the rate-limiting step in serotonin synthesis is thus affected) because of increased competition by other

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large neutral amino acids for entry into the brain. MacKenzie and Trulson (171, 172) suggested that reduced serotonin neurotransmission occurs in STZ-induced diabetic rat brain. King and Rohrbach (173) found reduced serotonin synthesis in the hypothalamus of diabetic mice and related this to reduced gonadotropin levels and infertility. In studies of patients recovering from ketoacidosis, Curzon et al. (174) measured cerebrospinal fluid (CSF) levels of two monoamine precursors, tryptophan (precursor to serotonin), and tyrosine (precursor to brain catecholamines including dopamine, norepinephrine, and epinephrine). CSF tryptophan levels increase in diabetic ketoacidosis as do levels of 5-hydroxy-indoleacetic acid, an indicator of serotonin neurotransmission. In addition to these reports of abnormal monoamine neurotransmission in experimental and occasionally human diabetes, there are various reports of abnormalities in several neuropeptides, including neuropeptide Y, substance P, met-enkephalin, somatostatin, vasoactive intestinal peptide (VIP), p-endorphin, and vasopressin (175-179). These neurotransmitters may affect behavior, mood, appetite, and pain perception. What consequences for clinical care of patients with diabetes emanate from these studies? Altered sensitivity to CNS drugs is one possibility. Ganzini et al. (180) suggested that there is an increased risk of tardive dyskinesia in diabetic patients and an increase in movement disorders in diabetic patients after treatment with metoclopramide, a dopamine receptor blocker used to treat gastroparesis diabeticorum. Perhaps, similar altered noradrenergic or serotoninergic sensitivity will also be found in people with long-standing or poorly controlled diabetes. More neuropharmacological studies in people with diabetes seem warranted given the results in animals. DIABETES AND SEIZURES Several early (181-184) and some recent (185-187) reports suggest EEG abnormalities are more common in people with diabetes. The import for clinical medicine of these findings is unclear. Is there an association between diabetes and seizure disorders other than during glycemic extremes? Some antiseizure medications such as phenytoin are potentially diabetogenic (188). Such an association could account for an apparent relationship between diabetes and seizures. The Diabetes Control and Complications Trial provides evidence that tight glucose control increases the risk of seizures (189,190). Undoubtedly, acute hypoglycemia can produce seizures; it also may produce lasting brain damage. As with insulin overtreatment, poorly controlled diabetes may be clinically manifest by seizures in both ketoacidosis (111) and in hyperosmolar coma (191). Do seizure manifestations caused by uncontrolled glycemia predict any chronic increased risk of seizure disorders? The literature is unclear. We hope this issue will be studied in a more systematic fashion.


A.L McCALL

A CHRONIC DIABETIC ENCEPHALOPATHY Reske-Nielsen (137) described pathological changes in the nervous system of juvenile IDDM patients of long duration. Quantitative analyses of cortical structure in rats with diabetes for 1 yr found decreased brain volume and weight and loss of cortical neurons (192). Many studies in experimental diabetes found structural and biochemical abnormalities as well (175,176,193-198). As reviewed by Mooradian (1), there are many potential causes for brain dysfunction in diabetes mellitus. These include vascular (stroke, altered blood-brain barrier function) and metabolic (altered glycemia, ketosis, hypoxia, electrolyte and neurotransmitter changes) disturbances and the coexistence of other disorders, e.g., renal failure or hypothyroidism. Several studies found evidence of decreased cognitive performance in patients with diabetes mellitus (2). Although global measures such as intelligence (IQ) tests are often normal, more subtle indices of mental efficiency are frequently disturbed in diabetes. The developments in this research area will, we hope, be correlated with the physiological observations made in humans and animals. The possible consequences to human brain function may thus be better understood both descriptively and mechanistically. By doing so, the potential to prevent brain dysfunction in people with diabetes is enhanced. As reviewed by Ryan (2), IDDM patients may exhibit cognitive deficits. Early onset of diabetes may be a particular risk factor for cognitive impairment. IQ and school achievement tests may be abnormal, particularly if school attendance problems occur. For adults with IDDM, as in NIDDM patients, poor metabolic control predicts decreased cognitive performance. In all groups, recurrent and severe hypoglycemia portends poor mental efficiency. As Ryan points out, much more systematic studies need to be done to sort out the several possible causes of chronic brain damage or dysfunction in diabetes. NIDDM patients have reduced performance on measures of verbal learning, memory retrieval, abstract reasoning, and complex psychomotor performance (2, 199-208). However, not all studies found significant differences in performance for diabetic individuals. Explanations for this discrepancy include the complexity and sophistication of the assessment and the types of patients studied. In general, rather subtle dysfunction is noted in those with higher achievement, not likely to affect daily living skills adversely. In other less functional diabetic patients, more pronounced abnormalities are noted. The specific mechanisms involved in decreased cognitive performance are unclear. Many studies found that poor performance is predicted by poor glycemic control. Higher blood glucose levels and elevated HbAi values result in poorer cognitive test efficiency. Hypertriglyceridemia and the presence of peripheral neuropathy also correlate with poor performance in some studies. If poor diabetic control predicts decreased mental efficiency, how does hyperglycemia affect brain performance? What biochemical mechanisms are responsible? Brain tissues may be subject to nonenzymatic glycosyl-


ation (209). The brain seems to be less affected by polyol metabolic abnormalities via the aldose reductase pathway than other tissues (210,211). It is possible that selective CNS cells are impaired, however (212). It would be very helpful if adequate animal models of CNS behavioral dysfunction permitted a more mechanistic determination of involved neurochemical pathways (213). CONCLUSIONS The brain is not spared by diabetes. Clinical complications are manifest in excessive stroke damage, permanent impairment in brain function from hypoglycemia, and a mild chronic encephalopathy. Repeated hypoglycemia as a result of treatment may also interfere with normal protective counterregulatory mechanisms at least partly through CNS effects. It also seems likely that altered responses to neuropharmacological agents and an increased prevalence of seizure disorders may be chronic effects of diabetes on the brain. We understand poorly the basis for these CNS complications of diabetes. Many physiological abnormalities occur in the brain as a chronic consequence of diabetes. CBF is probably decreased by poor diabetes control; cerebrovascular reactivity is clearly impaired in long-standing diabetes mellitus. Neurotransmitter metabolism, action, and binding within the brain are altered at least for monoamines and possibly for other transmitters including neuropeptides. Altered energy metabolism occurs in poorly controlled diabetes. The brain appears to adapt in transport efficiency for metabolic substrates, most notably glucose and ketone bodies, in states of both chronic hyper- and hypoglycemia. This adaptation may partly protect the brain, but it is unlikely that protection is complete. Can we relate the clinical syndromes of CNS complications of diabetes to the physiological changes described? No definitive answers are available. Nonetheless, the evidence suggests that the impact of diabetes on the brain is substantial, although more subtle than some other chronic diabetic complications. Both clinical and basic research needs to be focused on the mechanisms by which abnormal physiology of the brain in diabetes occurs and the best ways to prevent chronic brain damage in patients. Substantial prospects exist to prevent or ameliorate brain damage as a result of diabetes in the future. ACKNOWLEDGMENTS I acknowledge the support of the Juvenile Diabetes Foundation International (JDFI), the joint support of National Institute of Neurological and Communicative Disorders and Stroke, National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung and Blood Institute, and National Institute of Child Health and Human Development (R13-NS-29022), U.S. Public Health Service Grants RO1-NS-22213 and PO1-NS17493, and many colleagues for participation in an International Diabetes Federation Congress Satellite Symposium (29 June to 1 July 1991) on The Central Nervous System and Diabetes from which many ideas for this discussion emanated.

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Particular thanks are expressed to Sara King of the JDFI, Dr. Philip Cryer (Washington Univ., St. Louis, MO), Dr. Robert Sherwin (Yale Univ., New Haven, CT), and the organizing committee members for their help with this symposium.

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DIABETES, VOL 41, MAY 1992

Impact of diabetes mellitus on the outcome of pancreatic cancer.

How fisetin reduces the impact of age and disease on CNS function.

The impact of diabetes on employment in Mexico.

The Impact of Diabetes on Cerebral Structure and Function.

An assessment of the impact of type 2 diabetes on the quality of life based on age at diabetes diagnosis.

The effect of exercise on epigenetic modifications of PGC1: The impact on type 2 diabetes.

The impact of a diabetes local enhanced service on quality outcome framework diabetes outcomes.

In-patient diabetes care: the impact of diabetes outreach team on long-term glycaemic control.

Impact of new technologies on diabetes care.

A systematic review on the impact of diabetes mellitus on the ocular surface.

The Impact of Hepatitis B Vaccination Status on the Risk of Diabetes, Implicating Diabetes Risk Reduction by Successful Vaccination.

Histological investigation of the impact of streptozotocin-induced experimental diabetes on the healthy gingivae of rats.

The impact of type 2 diabetes on the outcome of localized renal cell carcinoma.

Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus.

The Impact of Bariatric Surgery on Type 2 Diabetes Mellitus and the Management of Hypoglycemic Events.

Insight into the impact of diabetes mellitus on the increased risk of hepatocellular carcinoma: mini-review.

Impact of diabetes and peripheral arterial occlusive disease on the functional microcirculation at the plantar foot.

The impact of type 1 diabetes mellitus on corneal epithelial nerve morphology and the corneal epithelium.

The impact of gestational diabetes and maternal obesity on the mother and her offspring.

Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its impact on disease outcome.

The effects of gut microbiota on CNS function in humans.

Effects of viruses and viral vaccines on the CNS.

Effects of propentofylline on CNS remyelination in the rat brainstem.

Letter: On the perception of information in CNS memory mechanism.