HYPOGLYCEMIA

ACUTE COMPLICATIONS OF DIABETES

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HYPOGLYCEMIA Pathophysiology and Treatment Gayla Herbel, MD, and Patrick J. Boyle, MD

In the adult patient with type 1 or type 2 diabetes, optimal control of glucose concentrations to near the upper end of the normal range will prevent long-term comp1ications.l.42, 83, 89, lol Clearly, insulin replacement schemes are unlike normal endogenous insulin secretion, leaving the clinician with the dilemma of how to obtain normoglycemia. Although normoglycemia has a critical role in the prevention of chronic complications, patients with diabetes must constantly walk a tight rope, balancing high and low glucose concentrations. Beyond the question of how to pulse insulin physiologically to cover carbohydrate intake acutely, clinicians are challenged by the lack of accurate background insulin replacement. Declining insulin concentrations that normally occur during postprandial periods are difficult to generate outside of insulin pump therapy and, even then, ramping the insulin infusion rate up and down occurs in the absence of feedback on changes in glucose concentration. In addition to problems with insulin replacement, lack of education in regards to counting the grams of carbohydrate accurately sets the stage for excess insulin administration. Factors under the patient’s control and beyond the patient’s control are responsible for the frequency of hypoglycemia that is the focus of this article. Early in the development of intensive diabetes treatment strategies,

This work was supported by grant K24 NS02097-02 and by a grant from General Clinical Research Program, DRR, National Institutes of Health 5 M01 RROO997-25, Bethesda, Maryland.

From the Department of Internal Medicine, Division of Endocrinology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 29 * NUMBER 4 DECEMBER 2000

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health care providers and investigators noted a diminution in the symptoms of hypoglycemia as patients approached near normoglycemia." l2 Symptoms were reduced, and the glucose concentration required to trigger them fell also. Amiel and colleagues4demonstrated an associated failure in epinephrine secretion that made patients vulnerable to what is now known as hypoglycemia unawareness.56Even a single episode of hypoglycemia is sufficient to partially attenuate epinephrine secretion and the symptoms associated with hypoglycemiaa; however, generally, and certainly in clinical practice, more than one episode leads to autonomic failure.= In the fasted subject, portal vein insulin concentrations determine the endogenous rate of hepatic glucose One of the fundamental roles of insulin is to reduce the rate of gluconeogenesis and gly~ogenolysis.7~ Of the glucose produced from the liver, 55% is consumed by the brain, and the remainder by skeletal muscle and the renal medulla.= Of these three tissues, the brain has an absolute dependence on glucose and is inca able of storing more than a few minutes of glucose as glycogen.= &en the glucose supply is interrupted, the classic symptoms of hypoglycemia stem from neuroglycopenia, which, in turn, triggers many of the hormonal responses (counterregulation).92Unfortunately, the counterregulatory responses are often insufficient to stimulate endogenous glucose production to offset the brain's fuel shortage, and a critical threshold is passed beyond which normal brain function is interrupted. For this reason, in more than 1 million patients with type 1 diabetes, hypoglycemia is a common limiting factor preventing them from achieving the tight metabolic control that is necessary to prevent complications. The patient with type 2 diabetes is also at some risk, but the mechanisms leading to low glucose concentrations diverge somewhat in the two forms of the disease. In either case, the net result is that, during critical deficits of glucose provision to the brain, the patient loses consciousness or experiences a seizure. Understanding brain glucose handling is a cardinal requirement to understanding the intricacies of the pathophysiology and treatment of hypoglycemia. THE BRAIN: AN OBLIGATE GLUCOSE CONSUMER

The brain is the major consumer of glucose in the body in the fasting state. Under normal conditions, the brain transports roughly three times more glucose from the circulation across the blood-brain barrier than is needed to satisfy normal metabolism.= Under conditions such as prolonged fasting the brain can convert to lactate oxidation." At a critical glucose concentration, the brain receives inadequate glucose to support its metabolic needs. The uptake of glucose by the brain begins with transport of glucose across the blood-brain barrier. This insulin-dependent process is facilitated by the glucose transport protein GLUTI.85*86 Although the factors that regulate the expression of GLUT1 have not been elucidated, clearly, hypoglycemia is a direct or

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indirect factor. After traversing the capillary endothelial surface, the glucose molecule has two potential fates: (1) it can be taken up by the glial elements and processed to lactate for presentation to the neuron, The glucose or (2) it can be directly taken up by neuronal cells.lOO,lm transport protein GLUT3 is responsible for the neuronal cell's capacity to transport glucose directly from the interstitium.'Ol Increasing evidence suggests that the majority of glucose that crosses the blood-brain barrier is processed by astrocytes to lactate, and that this three-carbon fragment serves as the actual fuel for the neuron.&,100, lo3 The hypoglycemiainduced epinephrine secretion can be attenuated by supplying large amounts of infused lactate, presumably by meeting brain energy demands using lactate as an alternate fuel from the circulation.76,104 The quantity of lactate involved is generally well in excess of the concentration observed in normal humans except after intense exercise. Similarly, the provision of ketones by infusion can lead to diminished epinephrine responses to hypoglycemia, presumably through maintenance of better brain energy balance." lo3 It has been known for some time that the brain can directly modulate systemic glucose concentrations.%Critical centers in the hypothalamus are most likely responsible for sensing the fall in systemic glucose concentrations, and, when a critical glucose threshold is reached, there is a triggering of epinephrine and glucagon release.'" 15, l6 Using a canine model, Biggers and co-workersgexplored the role of the central nervous system in regulating the counterregulatory hormone response. Glucose was infused directly into the vertebral and carotid arteries at a rate calculated to maintain brain normoglycemia while the systemic glucose concentration was permitted to fall. Control animals were allowed to experience normal central nervous system hypoglycemia. In the animals in whom the brain had normal glucose concentrations maintained, the epinephrine and glucagon responses were significantly attenuated in comparison with control animals. Additional evidence exists to support a role of the brain in regulating glucagon release?* These observations suggest that the brain serves a critical role directing and initiating some of the counterregulatory responses. More precisely, this central nervous system glucose-sensing seems to occur in the ventromedial hypothalamic The nucleus and results in counterregulatory epinephrine se~reti0n.l~ genesis of the epinephrine response is critical to understanding hypoglycemia pathophysiology given that the bulk of the symptoms of hypoglycemia are caused by increased adrenergic tone, with the remainder occurring secondary to neurog1ycopenia.w Several investigations have suggested that the liver may have a primary glucose sensory role, but this theory remains controversial.31.43,N59.64 GLUCOSE COUNTERREGULATION

Despite the difficulties of insulin replacement, the body has an amazing capacity to limit the fall in glucose concentration and restore

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the glucose concentration to the normal range.33,34*55 A hierarchy of responses exists, resulting in a reproducible sequence of hormonal responses intended to forestall, prevent, and restore glucose concentrations 92 During the initial reducto a level that will satisfy brain metabolism?** tion in glucose concentration, there is an early reduction in endogenous insulin release.18This reduction explains the more limited amounts of hypoglycemia in patients with type 2 and has a critical role in the prevention of hypoglycemia during prolonged fasting.18,25 Without P-cell mass, the patient with type 1 diabetes has no capacity to decrease the systemic insulin concentration, and further decrements in glucose concentrations ensue. Glucagon secretion is generally considered the front-line defense against hypoglycemia in normal individual^?^, 9o The release of glucagon serves primarily to initiate glycogenolysis and gluconeogenesis in the liver.28Following the glucagon response, adrenomedullary epinephrine release is triggered in normal individuals at a blood glucose concentration of approximately 70 mg / dL.Q92 Minimal perturbations in lucose homeostasis lead to the release of hormones that are critical to tk e restoration of normal glucose concentrations. Epinephrine release is accompanied by many classic symptoms of hypoglycemia, that is, shakiness, trembling, nervousness, and tachycardia.* Additionally, epinephrine serves three other important functions during hypoglycemia: (1)it drives the breakdown of glycogen, (2) it stimulates gluconeogenesis in the liver, and (3) it decreases peripheral glucose uptake by 74 Epinephmuscle so that brain glucose uptake can be preserved.3Or 39, rine release is not normally critical to restoration of normoglycemia during hypoglycemia. In contrast, glucagon release seems to be the driving force in restoring glucose homeostasis.33,57, 9o In patients with type 1 or type 2 diabetes, glucagon secretion becomes defective in response to hypoglycemia, and, in this setting, epinephrine secretion becomes the critical counterregulatory factor.57In the patient with type 1 diabetes, P cells are obliterated, and the 01 cells are left intact, but they may not retain full glucagon release owing to changes in autonomic tone.97Autoimmune destruction is not the explanation for the lack of glucagon response; rather, an acquired defect may be related to the loss of cell function. Indeed, the basal level of glucagon in patients with type 1diabetes is often normal or elevated. Apparently related to the duration of diabetes, this selective loss of glucagon release in response to hypoglycemia may be the result of a local loss of paracrine influence of the P cells?* Intra-islet insulin concentrations should fall as the glucose concentration decreases, but when all P cells have been destroyed by the autoimmune event, hypoglycemia is the direct result of excessive pharmacologic replacement of insulin; therefore, the 01 cells may be tonically ir~hibited.9~ Each of the previously mentioned hormonal responses seems to occur independent of the rate of fall in glucose Concentration? Growth hormone and cortisol have important roles in supporting glucose production and lipolysis; however, in the setting of an acute episode of 493

hypoglycemia, increments in these hormones are not clinically relevant.l3! 18, 91 During protracted hypoglycemia (over 10 hours), both hormones have a relevant role in supporting systemic glucose production to limit severe hypoglycemia.17, 38 Hypophysectomized patients undergoing insulin-induced hypoglycemia demonstrate a glucose profile indistinguishable from that of normal persons during the initial hours of an insulin infusion. Similarly, glucagon and epinephrine concentrations during these initial hours are comparable between normal individuals and hypophysectomized patients (i.e., there is no more exuberant epinephrine or glucagon release to compensate for the absence of growth hormone and cortisol). In the sixth through tenth hours of modest hyperinsulinemia, simulating what might occur during a night of sleep in patients with type 1 diabetes, growth hormone-and cortisol-deficient patients have significantly lower glucose concentrations than normal controls. Growth hormone also has an important role in the etiology of the increased insulin requirements observed in the period just before awakening (the dawn phenomena)." Patients with growth hormone deficiency and type 1 diabetes have minimal insulin requirements to maintain normoglycemia at the end of a normal night of sleep; thus they are prone to nocturnal hypoglycemia.u As a final mechanism of protection, the liver is capable of autoregulating its glucose production independent of hormonal signals. This autoregulation is only initiated at critically low glucose concentrations." Patients with type 2 diabetes do not seem to have the same magnitude of risk for hypoglycemia. In several clinical trials attempting to achieve near normalization of glucose concentrations in patients with type 2 diabetes, remarkably few hypoglycemic events have occurred, even in patients managed exclusively with i n s ~ l i n . ' , Two ~ ~ ,factors ~ ~ ~ are relevant to this observation. First, because these major studies failed to achieve full normalization of hemoglobin A,, whether hypoglycemia would have become more common if the patients had completely attained normoglycemia remains to be seen. Second, and likely more important, the average patient with type 2 diabetes is insulin resistant, and the endogenous insulin secretory responses are left intact. Under these circumstances, the patient with type 2 diabetes and modest hyperglycemia exuberantly increases endogenous insulin release to compensate for insulin resistance. If insulin is given exogenously, the subsequent fall in glucose concentration into the normal range or slightly below leads to a feedback decrease in endogenous insulin release from the p cell^.'^ If a sulfonylurea was used in combination with any of the other active glucose-lowering compounds, hypoglycemia could still occur.1*lo2 The p cells are driven to continue insulin release secondary to binding of sulfonylureasto their receptors. In a large study conducted in Veterans Administration hospitals extensively using sulfonylureas in patients with type 2 diabetes, the observed frequency of severe hypoglycemia was less than 1%of the frequency seen in the Diabetes Control and Complications Trial (DCCT).I Again, because the glycemic control in these patients was not driven into the nondiabetic range, it remains

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to be seen whether hypoglycemia would be more common had full normalization been achieved. MODULATION OF BRAIN GLUCOSE UPTAKE: IMPACT ON SYMPTOMS AND COUNTERREGULATION The mechanism by which changes in ambient glucose levels lead to altered rates of brain glucose extraction was initially explored by Matthaei and colleague^.^^ Their studies evaluated the possibility that chronic hyperglycemia would lead to a decrease of glucose transport capacity in capillary endothelial cells in the brain. Diminished concanavalin B binding, an indirect marker of glucose transporter number, was documented in brain homogenates of chronically hyperglycemic animals. These early findings were later confirmed by decreased brain glucose extraction in the setting of poorly controlled diabetes in rodents.s0The clinical importance of this finding relates to anecdotal observations that patients with poorly controlled type 1 diabetes experience symptoms of hypoglycemia at higher glucose concentrations than do nondiabetic individuals. Indeed, studies of such patients demonstrate that their threshold for perception of the onset symptoms of hypoglycemia is shifted to a higher glucose concentration than is classically observed in nondiabetic volunteers (from 54 to 75 mg/dL in normal versus patients with diabetes, respectively).22Although it would seem logical, the hypothesis that the level of glycemia required to impair brain glucose uptake is shifted in poorly controlled humans with type 1 diabetes has not been confirmed. As might be expected from the preceding data on hyperglycemia, chronic or recurrent hypoglycemia leads to enhanced rates of glucose extraction in rodents,79and the glucose transporter number increases in 73, 98 Although isolated capillary endothelial cells deprived of glucose.71* the precise molecular biology leading to this adaptation remains to be elucidated, it is associated with increased mRNA content for the GLUT1 transporter protein in brain capillary endothelial cells.'O Enhanced glucose uptake at the blood-brain barrier leads to maintenance of normal energy metabolism despite chronic hypoglycemia.79This normalization of brain energy state is best demonstrated in animals implanted with insulinoma who have brain ATP and glucose-6-phosphate levels within the normal range despite dramatically low glucose concentration^.^^ Investigations in humans that complement these findings are limited. Using "C-glucose and position emission tomography, Gutniak and co-workers60, found no differences in the rates of brain glucose metabolism during hypoglycemia in well-controlled patients with type 1 diabetes when compared with nondiabetic subjects; however, the basal rates of brain glucose metabolism during normoglycemia were approximately half the rate traditionally observed, placing these findings in question. By directly measuring cerebral blood flow coupled with arteriovenous glucose differences across the brain in humans, the authors established

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that the mechanism for the development of hypoglycemia unawareness occurred through enhanced brain glucose uptake.2OS 21 An increase of transporter number was presumed not to be an instantaneous process; rather, it would require a finite amount of time to develop. A period of 56 hours of episodic hypoglycemia was selected in the authors’ first investigations in light of the in vitro experiments of Takakura and colleagues98who had demonstrated that this amount of time was sufficient to induce a 60% increase in GLUT1 protein content in isolated brain capillary endothelial cells deprived of glucose. The baseline day of study was conducted in 12 nondiabetic subjects who had retrograde internal jugular and radial arterial cannulas placed before lowering the glucose concentrations in a step-wise fashion from 4.7 to 2.5 mmol/L in five, 1-hour long steps.2l Brain glucose uptake was maintained at normal rates at 4.7 and 4.2 mmol/L but fell sigruficantly at 3.6 mmol/L (Fig. 1). One potential mechanism for increasing the rate of brain glucose uptake would be through increments in brain blood flowz9;however, in none of the authors’ studies did cerebral blood flow increase, even with a glucose concentration of 3.5 mmol/ L. These observations have been validated elsewhere using positron emission tomography to determine flow.= In a follow-up study, the authors used similar methodology in 24 patients with type 1 diabetes having varying degrees of metabolic 50

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Nominal Arterial Glucose Step (mg/dL) Figure 1. On day 1 (Open bar), rates of brain glucose uptake are normally impaired as the systemlc arterial glucose concentration falls from 75 to 65 mg/dL (* P < 0.03). On day 4 (solid bar), following 56 hours of intermittent hypoglycemia, brain glucose uptake is maintained even to an arterial glucose concentration of 45 mg/dL. (From Boyle PJ, Nagy R, OConnor AM, et al: Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci U s A 91:9352, 1994; with permission.)

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Figure 2. Change from baseline, euglycemic values are shown. Rate of brain glucose uptake falls by over 20% as the systemic glucose concentration falls from 85 to 55 mg/dL in normal subjects (lightly shaded bar). A similar reduction is seen in patients with type 1 diabetes in the upper two-thirds of hemoglobin A,, (HbA,,) values. Patients in the lowest third of HbA,, values ,experienced no reduction in brain glucose uptake during relative systemic hypoglycemia. In concordance with reduced rates of brain glucose uptake, central nervous system-driven epinephrine and pancreatic polypeptide release occurs; however, in subjects with the lowest HbA,, values and normal rates of brain glucose uptake during systemic hypoglycemia, no counterregulatory response is seen. IDDM = insulin-dependent diabetes mellitus. Asterisks denote significant differences compared with patients with IDDM in the lowest third of HbAlc concentrations. (From Boyle PJ, Kempersi SF, O’Connor AM, et al: Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependentdiabetes mellitus. N Engl J Med 333:1726, 1995; with permission.)

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control.20Patients in the middle and upper tertiles of glycemic control y hemoglobin Al, concentration experienced reductions in as assessed b rates of brain glucose uptake at 54 mg/dL that were equivalent to the reductions in nondiabetic subjects at the same glucose concentration (Fig. 2). In patients in whom the hemoglobin Al, concentration most nearly approached normal (and who coincidentally experienced the highest rates of clinical hypoglycemia), no decrease in brain glucose uptake was observed during hypoglycemia. In addition, these bettercontrolled patients had fewer symptoms of hypoglycemia when compared with less well-controlled patients or normal subjects. The counterregulatory responses (epinephrine, growth hormone, and cortisol) were all attenuated in these best-controlled patients. Such studies do not directly assess glucose transporter number or function but give an overall quantification of the rate of whole brain glucose uptake. One conclusion from these investigations is that humans do increase brain glucose uptake as a consequence of recurrent hypoglycemia. At glucose concentrations classically associated with the onset of symptoms of hypoglycemia, brain energy metabolism in the patient with recurrent hypoglycemia is maintained; consequently, a signal is not sent to direct the epinephrine response from the adrenal glands. Because epinephrine is directly involved in generation of the tachycardia and nervousness that many patients rely on to detect the onset of hyp~glycemia?~ loss of the catecholamine release can contribute to the loss of awareness of hypoglycemia. This alteration in brain glucose uptake is adaptive and maladaptive. From the standpoint of the brain, enhanced glucose uptake permits neurons to function during periods of repeated, low-grade hypoglycemia. From the standpoint of patient safety, the adaptation leads to a narrow window of opportunity to recognize hypoglycemia and treat it before the patient reaches a critically low glucose concentration that causes loss of consciousness. The finite number of minutes required to treat an insulin reaction with ingestion and gut absorption of glucose must be built into this time line. Often, a spouse or significant other becomes the best judge of the onset of hypoglycemia and may simply note a distant look in the patient’s eye or the onset of typical idiosyncratic behaviors (e.g., blinking, loss of word choice, agitation, deeper breathing). When these changes are coupled with tasks of daily living (e.g., driving, operating heavy equipment, practicing medicine, flying airplanes), the risk of an accident must be considered. Patients with well-controlled diabetes who monitor their glucose levels frequently during more demanding activities are often able to troubleshoot hypoglycemia before it occurs. REVERSAL OF HYPOGLYCEMIA UNAWARENESS

Fortunately, the development of hypoglycemia unawareness is not a permanent event. Just as the brain can increase production of the GLUT1 transport protein during repeated hypoglycemia, it can likely

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reverse this alteration in transport when hypoglycemia is carefully avoided. Agreeing to raising the patient's target glucose level may lead to a slight rise in glycosylated hemoglobin; however, by avoiding hypoglycemia, patients regain their ability to appreciate the onset of symptoms of low glucose concentration at a point where treatment can be successful.3z37,46.47,81In a clinical trial conducted over several months, patients who had lost their awareness to hypoglycemia and who had limited epinephrine secretion during insulin reactions were intensively managed with frequent phone calls from physicians to avoid hypoglycemia.&,47 On repeat testing, the patients had regained their awareness and hormonal counterregulatory capacity for epinephrine secretion. Independent corroboration of the reversibility of hypoglycemia unawareness was provided by a presurgical and postsurgical study of patients with insulinoma. These patients had experienced repeated bouts of hypoglycemia mediated by autonomous, endogenous insulin secretion noted to be associated with a loss of symptoms of hyp~glycemia.~~ Removal of the tumor restored epinephrine secretory capacity and awareness of symptoms.8l PREDICTING, PREVENTING, AND TREATING HYPOGLYCEMIA

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Given the reversible adaptations in the central nervous s stem, the best treatment might come in the form of prevention. Alt ough the optimal treatment of either form of diabetes is beyond the scope of this article, a few guiding principles are worth reviewing. When insulin is required, the ideal insulin replacement scheme should attempt to mimic normal human physiology. By delivering the total daily dose with larger preprandial boluses and smaller amounts of longer-acting insulin, the patient can avoid supraphysiologic insulin concentration during interprandial periods.66,67 Although the patient may initially balk at the need to perform more than two injections, the benefit in terms of reducing the frequency of hypoglycemia and the improved ability to predict glucose concentrations generally result in the patient accepting the multiple injection scheme. Most severe insulin reactions occur during the night." 41 During that time of the day, two questions should be considered: (1) how does one produce a portal insulin concentration that suppresses hepatic glucose production on awakening (8 hours after the last opportunity to inject insulin unless the patient is using an insulin infusion pump); and (2) how does one prevent nocturnal hypoglycemia when insulin concentrations in excess of metabolic needs arise during the early hours of sleep as a consequence of currently available crystal insulin preparations? The answer is the same for both questions given the fact that all available intermediate and long-acting insulin preparations overinsulinize the patient during the early hours of slee sufficient insulin is available on awakening. The prevention of cemia becomes entirely dependent on the prescription of nigttime snacks. In even the most intensive multiple-injection insulin strategies,

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a maximum of 20 to 25 g of carbohydrate is required at bedtime. The composition of the snack has an important role in the prevention of nocturnal hypoglycemia. Quickly absorbable sources of glucose, such as fresh fruit, are cleared from the gut before peak insulin absorption occurs, leading to nocturnal hypoglycemia. In contrast, foods hi her in fiber or foods containing protein and fat (e.g., cottage cheese fruit) offer a source of sustained carbohydrate absorption that can coincide with later peaks in insulin concentration from regimens that incorporate bedtime injections of NPH insulin.'j9 Exercise is another potential factor that can increase the risk for hypoglycemia.68,77 Although it is generally agreed that exercise is a critical element of every diabetes prescription, such activity leads to enhanced insulin sensitivity up to 36 hours after each exercise b o ~ t . 7 ~ The insulin requirement in the period immediately following exercise may need to be reduced because muscle continues to have an elevated rate of glucose uptake during the cool-down period. Additionally, patients should be advised to add slightly more starch to their bedtime snack after a day including substantial exercise or heavy labor. Nevertheless, risk factors for severe hypoglycemia, such as exercise, skipping meals or snacks, and alcohol intake, explained only 7% of the severe hypoglycemia in the DCCT and the development of hypoglycemia unawareness through repeated episodes of hypoglycemia.4l

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ORAL TREATMENT

One of the fundamental symptoms of hypoglycemia is hunger. When patients are confronted with an adrenergically driven urge to eat, limiting food intake to appropriate amounts is often difficult. The average insulin reaction with a glucose concentration near 50 mg/dL is commonly dealt with by having the patient take in 20 to 30 g of ~arbohydrate.6~ Eating more does not accelerate the rate of recovery to normal and may cause hyperglycemia in the hours following the reaction. It is essential that patients be taught not to panic and to use fingerstick glucose concentrations to ensure that their glucose concentration is rising after an oral treatment has been completed. The choice of the carbohydrate will depend on what is available to the patient at the time of the low glucose concentration. Six to 8 ounces of milk will restore the glucose concentration to normal as rapidly as juice. The advantage of drinking milk is the longer duration in the rate of starch absorption owing to the protein and fat in addition to the ~arbohydrate.6~ Acutely, the glucose concentration returns to normal, but, rather than potentially dropping again several hours later (a common occurrence when treating nighttime insulin reactions), the glucose can be stabilized for several hours after the reaction. Because milk is not generally available when patients are at work or school, the authors recommend boxed juices that do not require refrigeration (each contains 15 to 20 g of carbohydrate). Prepackaged boxes of juice also take the

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guesswork out of treating the reaction. Decision makin and logic regarding how much oral sugar is needed to overcome e reaction are regularly lost as hypoglycemia deepens. Canned regular sodas usually contain 60 g of starch (generally twice the amount needed to treat a reaction adequately). With cognitive impairment, judgment to consume only one-half of the volume of the can may be challenging. Patients must be educated not to overtreat insulin reactions when they later feel the need to correct for hyperglycemia, or the process of low followed by high glucose concentrations may be HYPOGLYCEMIA AND TYPE 2 DIABETES

The vast majority of patients with diabetes have type 2 disease. Their treatment regimens are directed toward dealing with insulin resistance rather than insulin deficiency, except in the later phases of living with the condition. The traditional first-line treatment for patients with type 2 diabetes includes compounds that induce insulin release. Sulfonylureas are among the mostly widely prescribed medications in the United Statesmand have become a routine adjunct to therapy in patients failing to achieve adequate glycemic control with either metformin or the insulin-sensitizingcompounds from the thiazolidinedione family of medications. These agents generate hypoglycemia by blocking potassium channels on p cells, ultimately changing membrane potentials and leading to the release of insulin. The second-generation compounds in the sulfonylurea family potentiate insulin release more specifically in the presence of glucose entering the system from the gut, whereas the firstgeneration compounds stimulate insulin release often independently of the systemic glucose concentration or food consumption.m Serious hypoglycemia from these agents is a greater problem in the elderly patient who may eat meals on a more sporadic ba~is.9~ Although the Physician’s Desk Reference recommends treatment with repeated boluses of hypertonic glucose followed by intravenous infusion of dextrose for sulfonylurea-inducedhypoglycemia,7 this approach may not be the best method. Such therapy creates repeated pulses in glucose concentration that are well above normal. In response to hyperglycemia, the p cells (whose function is potentiated by sulfonylurea) release even more insulin,resulting in a recurrence of hypoglycemia. Beta cells are exquisitely sensitive to even modest degrees of hyperglycemia. If the lucose concentration derived from an intravenous infusion even slig tly exceeds 90 to 100 mg/dL, hyperinsulinemia returns, and the dextrose infusion requirement increases gradually. Furthermore, the hypertonicity of the infused dextrose solution usually mandates placement of a long-arm or central access intravenous line. In addition, given the amount of free water infused with 20% or 50% dextrose administration, one must watch for signs and symptoms of fluid overload or hyponatremia in the susceptible patient (e.g., the elderly). Alternatively, diazoxide, an antihypertensive agent that prevents

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insulin release, can be given intra~enously.8~ In studies by the authors, this therapy was only partially successful, and dextrose supplementation was still required. Because the drug falls out of solution if it is mixed with dextrose, it must be given through a separate intravenous line. Hypotension was not a problem in the authors’ experimental overdose situation in which young volunteers participated; however, caution should be exercised in the patient on concomitant antihypertensive agents. The preceding two methods for treating what can be a protracted event are not optimal, especially if overdose is from longer-acting oral agents such as chlorpropamide. Odreotide offers another therapeutic option. Octreotide is a somatostatin derivative usually used to reduce growth hormone secretion in patients with acromegaly. Octreotide is also a potent inhibitor of insulin and glucagon release from the p cell.” Following an intentional overdose of 100 mg of glipizide, normal subjects had this somatostatin analogue infused, and dextrose infusion requirements fell to zero.19 On a more practical note, odreotide can be given subcutaneously. Anecdotally, the authors have found that 50 pg given every 6 to 8 hours provides the same result as a continuous infusion of the drug and may obviate the need for dextrose The major acute side effect of octreotide therapy observed during the authors’ studies was fat malabsorption; thus, low-fat meals are generally recommended when this medication is administered. FACTORS AFFECTING SEVERE INSULIN-INDUCED HYPOGLYCEMIA

The families and significant others of patients with type 1 diabetes should be educated regarding the use of glucagon for the treatment of severe hypoglycemia. Glucagon is supplied in a vial as the lyophilized powder, which must be reconstituted with a diluent that comes preloaded in a syringe or must be drawn up from a separate vial with a syringe. Glucagon should be administered only when the patient has lost consciousness or is so close to doing so that he or she has lost the ability to coordinate swallowing; therefore, the spouse, parent, or sigruficant other, and not the patient, must be trained to administer the injection. The injection can be given subcutaneously or intramuscularly, and the onset of action for the recovery is not greatly different between these two injection methods.2 In most cases, this hormone is given when the patient is seizing from a low glucose concentration; thus any convenient limb-muscle group (deltoid or gluteous) is appropriate. The 1-mg amount provided in the vial in available preparations is more than sufficient to raise the glucose concentration well above normal.2 The person giving the dose must understand that 10 to 20 minutes must elapse for the dose to be absorbed and for glycogen to be mobilized subsequently from the liver. The duration of action of this treatment is 60 to 120 minutes. The major adverse effect of using glucagon is a

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decrease in gut motility. Most patients experience transient nausea, and many vomit. Because this peptide causes only a transient increase in glucose concentration, patients should eat some starch to prevent recurrence of the hypoglycemia several hours later. The need for starch is especially important when the severe hypoglycemia occurs during the early part of the night (and the patient hopes to sleep safely for the remainder of the night). Alcohol consumption is a common coincident risk factor for emergency room visits for hypoglycemia in patients using insulin.@Alcohol inhibits hepatic glucose production by pathways similar to those affected by in~ulin.7~ Any patient using insulin in an intensified treatment schedule who consumes alcohol should be advised about the increased risk of hypoglycemia that does not generally occur during the time when the alcohol is being consumed but, instead, many hours afterwardyo Beta-adrenergic blockade is relatively contraindicated in patients with diabetes owing to an increased risk of hypoglycemia unawareness. Although the adrenergic response is key to much of the initial symptom recognition in patients experiencing hypoglycemia, the postganglionic parasympathetic-mediated sweating remains unaffected and, in fact, is amplified in the setting of P-adrenergic blockade." When chronotropic control is needed in the presence of angina or tachydysrhythmia in the patient with diabetes, the patient should be warned that the usual symptoms of shakiness, nervousness, and hunger will be blunted, whereas sweating will be more profound." Patients with renal insufficiency present a sigruficant challenge in diabetes care. The kidney is a sigruficant sight of glucose 27 As renal parenchymal mass shrinks, renal gluconeogenesis and renal insulin clearance are lost. Although the liver can increase clearance of insulin, the most likely defect leading to hypoglycemia in azotemic patients is loss of glucose production. In the setting of azotemia, epinephrine- and glucagon-induced increments in glucose production are diminished.5O Further exacerbating this problem, the average patient with end-stage renal disease is under significant protein restriction, and the conversion of alanine to glucose is limited by substrate intake. In addition, the conversion of alanine to glucose is most likely impaired.% Prevention of hypoglycemia by reducing insulin dose is of paramount concern. As is true in other complications of diabetes, after a major complication of diabetes has occurred, the diabetes care team must consider whether the benefit of proceeding with intensified diabetes management outweighs the risk. The person with modest renal insufficiency and microalbuminuria may still benefit from intensified management, but the increased risk of hypoglycemia must be considered. SUMMARY

Hypoglycemia is a common consequence of many diabetes treatments. As is true for many therapies for diseases with major pathologic

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consequences, the benefits and risks of treatment must be balanced. In intensified diabetes management, hypoglycemia is not an insurmountable problem but is unfortunately inevitable using the methods of glucose control currently available. Patients with type 1 diabetes seem to be at greater risk than patients with type 2 disease. The health care team must strive to help the patient maintain normoglycemia. The results of the DCCT and the United Kingdom Prospective Diabetes Study prove that near normoglycemia is clearly in the patient's best interest. Patient education has become focused on minimizing hyperglycemia; counseling on the dangers of hypoglycemia has not been given the same stature. Emphasis must be placed on minimizing even minor subclinical hypoglycemia because it will contribute to a vicious cycle of hypoglycemia begetting hypoglycemia.35 References 1. Abreira C, Colwell JA, Nuttall FQ, et al: Veterans Affairs Cooperative Study on glycemic control and complications in type 11 diabetes (VA CSDM): Results of the feasibility trial. Veterans Affairs Cooperative Study in Type 11Diabetes. Diabetes Care 18:1113, is95 in childhood diabetes. II. Effect of subcutaneous or 2. Aman T. Wranne L HvDoelvcemia ,I ", intramGscular injection of different doses of glucagon. Ada Pediatr Scand 77548,1988 3. Amiel S, Archibald H, Chusney G, et al: Ketone infusion lowers hormonal responses to hypoglycemia: Evidence for acute cerebral utilization of a non-glucose fuel. Clin S a 81:189, 1991 4. Amiel SA, Tamborlane WV, Simonson DC, et ak Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus. N Engl J Med 3161376, 1987 5. Amiel SA, Sherwin RS, Simonson DC, et ak Effect of intensive insulin therapy on glycemic thresholds for counterregulatoryhormone release. Diabetes 37901, 1988 6. Amiel SA, Simonson DC, Tamborlane WV, et al: Rate of glucose fall does not affect counterregulatory hormone responses to hypoglycemia in normal and diabetic humans. Diabetes 36:518, 1987 7. Arky R The Physicians' Desk Reference, ed 52. Montvale, NJ, Medical Economics Company, 1998, pp 145-1446 8. Bendtson I, Kvemeland A, Pramming S, et al: Incidence of nocturnal hypoglycemia in insulin-dependent diabetic patients on intensive therapy. Ada Med Scand 223:543, 1988 9. Biggers DW, Myers SR, Neal D, et al: Role of brain in counterregulation on insulininduced hypoglycemia in dogs. Diabetes 38:7, 1989 10. Boado RJ, Pardridge WM: Glucose deprivation causes post-translationalenhancement of brain capillary endothelial glucose transporter gene expression via GLUT1 mRNA stabilization. J Neurochem 602290,1993 11. Bolli G, De Feo ,'F Perriello G, et ak Role of hepatic autoregulation in defense against hypoglycemia in humans. J Clin Invest 751623,1985 12. Bolli GB, Dimitriadis GD, Pehlmg GB, et ak Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med 310:1706, 1984 13. Bolli GB, Gottesman IS, Cryer PE, et ak Glucose counterregulation during prolonged hypoglycemia in normal humans. Am J Physiol247E206, 1983 14. Borg M, Sherwin R, Borg W, et al: Local ventromedial hypothalamus glucose perhsion blocks counterregulation during systemic hypoglycemia in awake rats. J Clin Invest 99361, 1997

-

_-

740

HERBEL & BOYLE

15. Borg W, During M, Sherwin R, et al: Ventromedial hypothalamus lesions in rats suppress counterregulatory hormone responses to hypoglycemia. J Clin Invest 93:1677, 1994 16. Borg W, Sherwin R, During M, et ak Local ventromedial hypothalamus glycopenia triggers counterregulatoryhormone release. Diabetes 44180, 1995 17. Boyle PJ: Cushing's disease, glucocorticoid excess, glucocorticoid deficiency and diabetes. Diabetes Metab Rev 1:301, 1993 18. Boyle PJ, Cryer PE Growth hormone, cortisol, or both are involved in defense against, but are not critical to recovery from, hypoglycemia. Am J Physiol26OE395, 1991 19. Boyle PJ, Justice K, Krentz AJ, et al: Odreotide reverses hyperinsdinemia and hypoglycemia induced by oral sulfonylurea overdose. J Clin Endocrinol Metab 76:752,1993 20. Boyle PJ, Kempers SF, OConner, et al: Brain glucose uptake and unawareness of hypoglycemia in patients with insdin dependent diabetes mellitus. N Engl J Med 3333726, 1995 21. Boyle PJ, Nagy R, (YConnor AM, et al: Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci USA 91:9352, 1994 22. Boyle PJ, Schwartz NS, Shah SD, et ak Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 318:1487,1988 23. Boyle PJ, Smith L, Avogaro A, et al: Absence of the dawn phenomenon and abnormal lipolysis in patients with type I diabetes and chronic growth hormone deficiency. Diabetologia 35:372, 1992 24. Burge hlR, Schmitz-FiorentinoK, Fischette C, et al: A prospective trial of risk factors for sulphonylurea-inducedhypoglycemia in type 2 diabetes mellitus. JAMA 279137, 1998 25. Cahill GG Jr: Starvation in man. N Engl J Med 282668,1970 26. Cersosimo E, Garlick P, Ferretti J: Insulin regulation of renal glucose metabolism in humans. Am J Physiol276E78, 1999 27. Cersosimo E, Garlick P, Ferretti J: Renal glucose production during insulin-induced hypoglycemia in humans. Diabetes 48:261, 1999 28. Cherrington A, Chiasson J., LiljenquistJE, et al: The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive state. J Clin Invest 581407,1976 29. Clarke DD, Sokoloff L Circulation and energy metabolism of the brain. In Sigel GJ, et al (eds): Basic Neurochemistry: Molecular, Cellular and Medical Aspects, ed 5. New York, Raven Press, 1994, p 645 30. Clutter WE, Rizza RA, Gerich JE, et a1 Regulation of glucose metabolism by sympathochromaffin catecholamines.Diabetes Metab Rev 41, 1988 31. Connolly CC, Myers SR, Neal DW, et al: In the absence of conterregulatory hormones, the increase in hepatic glucose production during insulin-induced hypoglycemia in dogs is initiated in the liver rather than in the brain. Diabetes &1805,1996 32. Cranston I, Lomas J, Maran A, et ak Restoration of hypoglycemia unawareness in patients with long duration insulin-dependent diabetes mellitus. Lancet 344283, 1994 33. Cryer PE: Glucose counterregulationin man. Diabetes 30:261, 1981 34. Cryer PE Hypoglycemia: Pathophysiology, Diagnosis and Treatment. New York, Oxford University Press, 1997 35. Cryer PE: Iatrogenic hypoglycemia as a cause of hypoglycemia associated autonomic failure in IDDM A vicious cycle. Diabetes 41255, 1992 36. Dagogo-Jack S, Craft S, Cryer PE: Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. J Clin Invest 91:819, 1993 37. Dagogo-Jack S, Rattarasarn C, Cryer PE: Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 431426, 1994 38. De Feo P, Perriello G, De Cosmo S, et al: Comparison of glucose counterregulation during short-term and prolonged hypoglycemia in normal humans. Diabetes 35:563, 1986 39. De Feo F, Perriello G, Torlone E, et ak Contribution of adrenergic mechanisms to glucose counterregulationin humans. Am J Physiol261:E725, 1991

40. De Feo P, Perriello G, Torlone E, et al: Demonstration of a role for growth hormone in glucose counterregulation.Am J Physio1256E835,1989 41. Diabetes Control and Complications Trial Research Group: Epidemiology of severe hypoglycemia in the DCCT. Am J Med 90450,1991 42. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329977, 1993 43. Donovan CM, Halter JB, Bergman RN: Importance of hepatic glucoreceptors in sympathoadrenal response to hypoglycemia. Diabetes 40:155, 1991 44. Donovan CM, Hamilton-Wessler M, Halter JB, et al: Primacy of liver glucosensors in

the sympathetic response to progressive hypoglycemia. Proc Natl Acad Sci USA 91:2863, 1994 45. Dringen R, Gebhardt R, Hamprecht 8:Glycogen in astrocytes: Possible function as lactate supply for neighboring cells. Brain Res 623:208, 1993 46. Fanelli C, Pampanelli S, Epifano L, et ak Long-term recovery from unawareness, 47.

48. 49. 50. 51. 52. 53.

54. 55. 56.

deficient counterregulation, and lack of cognitive dysfunction during hypoglycemia following institution of rational intensive therapy in IDDM. Diabetologia 371265,1994 Fanelli CG, Epifano L, Rambotti AM, et al: Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 42:1683,1993 Fischer KF, Lees JA, Newman JH: Hypoglycemia in hospitalized patients. N Engl J Med 3151245, 1986 French EB, Kilpatrick R The role of adrenaline in hypoglycaemic reactions in man. Clin Sci 14639, 1955 Frizell M, Larsen PR, Field JB: Spontaneous hypoglycemia associated with chronic renal failure. Diabetes 2 4 9 3 , 1974 Frizzell RT, Jones EM, Davis SN, et ak Counterregulation during hypoglycemia is directed by widespread brain regions. Diabetes 42A253, 1993 Frohman L, Nagai K Central nervous system-mediated stimulation of glucagon secretion in the dog following 2-deoxy-glucose. Metabolism 25:1449, 1976 Garber AJ, Bier DM, Cryer PE, et al: Hypoglycemia in compensated chronic renal ins~ciency.Diabetes 23:982, 1974 Garber AJ, Cryer PE, Santiago Jv, et al: The role of adrenergic mechanisms in the substrate and -hormonal response to insulin induced hypoglicemia in man. J Clin Invest 587, 1976 Gerich J, Davis J, Lorenzi M, et al: Hormonal mechanisms of recovery from insulininduced hypoglycemia in man. Am J Physiol236E380, 1979 Gerich J, Mokan M, Veneman T, et al: Hypoglycemia unawareness. Endocr Rev

12356, 1991 57. Gerich JE, Cryer P, Rizza RA: Hormonal mechanisms in acute glucose counterregulation: The relative roles of glucagon, epinephrine, norepinephrine, growth hormone and cortisol. Metabolism 291165, 1980 58. Gerich JE: Oral hypoglycemic agents. N Engl J Med 321:1231,1989 59. Hamilton-Wessler M, Bergman RN, Halter JB, et al: The role of liver glucosensors in

the integrated sympatheticresponse induced by deep hypoglycemia in dogs. Diabetes 43:1052, 1994 60. Grill V, Gutniak M, Bjorkman 0, et al: Cerebral blood flow and substrate utilization in insulin treated diabetic subjects. Am J Physiol 258:805, 1990 61. Gutniak M, Blomqvist G, Wid& L, et al: D-[U-T] glucose uptake and metabolism in the brain of insulin-dependent diabetic subjects. Am J Physiol 258 (Endocrinol Metab 21):E805, 1990 62. Hardy KJ, Burge MR, Boyle PJ, et ak A treatable cause for recurrent severe hypoglycaemia. Diabetes Care 177:722, 1994 63. Heller SA, Cryer PE Reduced neuroendocrine and svmutomatic resuonse to subse-

quent hypogiycemia after one episode of hypogly&ia in nondi'abetic humans. Diabetes 40223, 1991

742

HERBEL & BOYLE

64. Hevener AL, Bergman RN, Donovan CM Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes 461521,1997 65. Hirsch IB, Boyle PJ, Craft S, et ak Higher glycemic thresholds for symptoms during P-adrenergic blockade in IDDM. Diabetes 401177, 1991 66. Hirsch IB, Farkas-Hirsch R Type I diabetes and insulin therapy. Nurs Clin North Am 289, 1993 67. Hirsch IB, Farkas-Hirsch R, Skyler JSIntensive insulin therapy for treatment of type I diabetes. Diabetes Care 13:1265, 1990 68. Hirsch IB, Marker JC, Smith LJ, et ak Insulin and glucagon in prevention of hypoglycemia during exercise in humans. Am J Physiol260 (5 Pt 1):E695, 1991 69. Jenkins DJ, Jenkins AL Nutrition principles and diabetes: A role for "lente carbohydrate?'' Diabetes Care 18:1491, 1995 70. Kerr D, Macdonald IA,Heller SR, et ak Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent)diabetes. Diabetologia 33:216, 1990 71. Koryanyi L, Bourey RE, James D, et al: Glucose transporter gene expression in rat

brain: Pretranslational changes associated with chronic insulin-induced hypoglycemia, fasting and diabetes. Mol Cell Neurosci 2:244, 1991 72. Krentz AJ, Boyle PJ, Schade DS Octreotide: A long-acting inhibitor of endogenous hormone secretion for human metabolic investigations.Metabolism 4324,1994 73. Kumagai AK, Kang YS, Boado RJ, et ak Upregulation of blood-brain barrier GLUT1 glucose transporter protein and mRNA in experimental chronic hypoglycemia. Diabetes 44.1399, 1995 74. Lecavalier L, Bolli G, Cryer P, et ak Contributions of gluconeogenesis and glycogenolysis during glucose counterregulationin normal humans. Am J Physio1256:E844,1988 75. MacDonald MJ: Postexercise late-onset hypoglycemia in insulin-dependent diabetic patients. Diabetes Care 10584, 1987 76. Maran A, Cranston L, Lomas L, et al: Protection by lactate of cerebral function during hypoglycaemia. Lancet 34316, 1994 77. Marker JC, Hirsch IB, Smith LJ, et ak Catecholamines in prevention of hypoglycemia during exercise in humans. Am J Physiol260(5 Pt 1):E705, 1991 78. Matthaei S, Horiuk R, Olefsky JM: Decreased number of glucose transporters at blood-brain barrier. Diabetes 35:1181, 1986 79. McCall AL, Fixman LB, Fleming N, et al: Chronic hypoglycemia increases brain glucose transport. Am J Physiol251:E42,1986 80. McCall AL, Millington WR, Wurtman RJ: Metabolic fuel and amino acid transport into the brain in experimentaldiabetes mellitus. Proc Natl Acad Sci USA 795406,1982 81. Mitrakou A, Fanelli C, Veneman T, et al: Reversibility of hypoglycemia unawareness. N Engl J Med 329834, 1993 82. Mitrakou A, Ryan C, Veneman T, et al: Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260E67, 1991 83. Ohkubo Y, Kishikawa H, Araki E, et ak Intensive insulin therapy prevents the

progression of diabetic microvascular complications in Japanese patients with noninsulin-dependent diabetes mellitus: A randomized prospective &year study. Diabetes Res Clin Pract 28:103, 1995 84. Owens OE, Morgan AP, Kemp HG, et al: Brain metabolism during fasting. J Clin Invest 461589, 1967 85. Pardridge WM: Brain metabolism: A perspective from the blood-brain barrier. Physiol Rev 63:1481, 1983 86. Pardridge WM, Boado RJ, Farrell CR Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier: Studies with quantitative Western blotting and in situ hybridization. J Biol Chem 265:18035,1990 87. Pfeiffer MA, Wolter CF,Samols E: Management of chloropropamideinduced hypoglycemia with diazoxide. South Med J 71:606, 1978 88. Powers WJ, Boyle PJ, Hirsch IB, et ak Unaltered cerebral blood flow during hypoglycemic activation of the sympathochromaffin system in human subjects. Am J Physiol 265R883, 1993

HYPOGLYCEMIA

743

89. Reichard P, Nilsson BY, Rosenqvist U The effect of long-term intensified insulin

treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 329304, 1993 90. Rizza RA, Cryer PE, Gerich JE,et ak Role of glucagon, catecholamines and growth hormone in human glucose counterregulation. J Clin Invest &62, 1979 91. Santiago JV,Clarke WL, Shah SD, et ak Epinephrine, norepinephrine, glucagon, and growth hormone release in association with physiological decrements in the plasma glucose concentration in normal and diabetic man. J Clin Endocrinol Metab 51:877, 1980 92. Schwartz N, Clutter W, Shah S, et al: Glycemic thresholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79:777, 1987 93. Service EJ, Dale AJD, Elveback LR, et ak Insulinoma: Clinical and diagnostic features of 60 consecutive cases. Mayo Clinic Proc 51:417, 1976 94. Shimazu T, Fukuda A, Ban T Reciprocal influence of the ventromedial and lateral

hypothalamic nuclei on blood glucose level and liver glycogen content. Nature 210:1178, 1966 95. Shorr RI: Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr SOC44:751, 1996 96. Stagner JI, Samols E: The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41:93, 1992 97. Taborsky JG Jr, Ahren B, Have1 PF Autonomic mediation of glucagon secretion during hypoglycemia: Implicationsfor impaired alpha-cell responses in type 1 diabetes. Diabetes 47995, 1998 98. Takakura Y, Kuentzel SL, Raub TJ, et ak Hexose uptake in primary cultures of bovine microvessel endothelial cells. I. Basic characteristics and effects of D-glucose and insulin.Biochim Biophys Acta 1070:1, 1991 99. Towler DA, Havlin CE, Craft S, et a1 Mechanism of awareness of hypoglycemia: Perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes 42A791, 1993 100. Tacopolous M, Magistretti PJ: Metabolic coupling between glia and neurons. J Neurosci 16:887, 1996 101. Uehara Y, Nipper V, McCall AL Chronic insulin hypoglycemia induces GLUT-3 protein in rat brain neurons. Am J Physiol272E716, 1997 102. United Kingdom Prospective Diabetes Study (UKPDS) Group: Intensive blood glu-

cose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 52837, 1998 103. Vannuca SF, Maher F, Simpson IA:Glucose transporter proteins in brain: Delivery of glucose to neurons and glia. Glia 212, 1997 104. Veneman T, Mitrakou A, Mokan M, et ak Effect of hyperketonemia and hyperlacticaci-

demia on symptoms, cognitive dysfunction and counterregulatoryhormone responses during hypoglycemia in normal humans. Diabetes 43:1311, 1994 Address reprint requests to Patrick J. Boyle, MD Department of Internal Medicine5ACC Division of Endocrinology University of New Mexico Health Sciences Center 2211 Lomas Boulevard, NE Albuquerque, NM 87122-5217

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