Introduction

Results from the Diabetes Control and Complications Trial, (1) the United Kingdom Prospective Diabetes Study (2) and other studies of type 1 (3,4) and type 2 (5,6) diabetes mellitus have consistently documented that improved glycemic control decreases the incidence and progression of retinopathy, nephropathy, and neuropathy in subjects with diabetes. The widespread implementation of regimens to rigorously control blood sugar in patients with diabetes has led to an increased incidence of severe iatrogenic hypoglycemic events. The annual incidence of severe hypoglycemia and coma is increased threefold in intensively treated patients (1,7). This complication of intensive treatment has limited rigorous glycemic management of diabetes.

From: Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition Edited by: A. Veves and R. Malik © Humana Press Inc., Totowa, NJ

The counterregulatory response is triggered by specialized glucose-sensing neurons within the brain and, to a lesser extent, the portal venous system (8). The brain regions that play a critical role in the detection of incipient hypoglycemia localize to the ventromedial hypothalamus—in particular the ventromedial and arcuate nuclei (9,10), and brainstem (11). The molecular mechanisms whereby these neurons detect fluctuations in glucose levels are not fully elucidated. It is suggested that this kinase functions as a intracellular fuel gauge (12) that becomes activated by a decrease in the ATP-to-ADP ratio (13).

Deficient secretion of glucagon and catecholamines is in large part responsible for the morbidity and mortality associated with iatrogenic hypoglycemia. The glucagon response to hypoglycemia is irreversibly attenuated after several years of type 1 diabetes and the adrenergic response becomes the critical defense mechanism against insulin induced hypoglycemia (14). Numerous studies have documented that antecedent hypo-glycemia is a primary cause of the impaired adrenergic response to insulin-induced hypoglycemia. The mechanisms whereby this impairment occurs are not fully elucidated (15,16).

Glucose Counterregulation

Hypoglycemia provokes a sequence of metabolic, neural, and clinical responses (17,18). Insulin secretion decreases whereas glucagon, epinephrine, norepinephrine, pancreatic polypeptide, cortisol, and growth hormone increase. The sympathetic, parasympathetic, and sympatho-adrenal divisions of the autonomic nervous system are activated in response to the falling blood sugar. The autonomic clinical features associated with these metabolic and neural changes include tremor, palpitations, anxiety, diaphoresis, hunger, and paresthesias. Hypoglycemia also impairs neuronal function leading to fatigue, weakness, dizziness, and cognitive and behavioural symptoms. Lower blood sugar levels may cause seizures, coma, and death (19-22).

Studies carried out in several different laboratories have confirmed that diabetic subjects in strict glycemic control or on insulin pump therapy exhibit decreased counter-regulatory responses to hypoglycemia (23-29). In these individuals perception of hypoglycemic symptoms is reduced (27-31) and the glucose threshold at which symptoms of hypoglycemia are perceived is lowered (i.e., a lower blood glucose level is required to elicit symptoms of hypoglycemia) (20,21,28). These adaptations lead to impaired glucose counterregulation and contribute to the increased incidence of severe hypoglycemia during intensive diabetes treatment (30,32). Furthermore, defective coun-terregulatory hormone responses can be partially restored by the meticulous avoidance of hypoglycemia in intensively treated patients with short duration (33-36) and long duration diabetes (37,38).

These studies suggest that an increased incidence of recurrent hypoglycemia is responsible for the induction of altered hormonal counterregulation and symptom perception in patients with diabetes in strict glycemic control. This assertion was confirmed in studies of normal humans without diabetes who were exposed to recurrent hypo-glycemia. These studies showed that recurrent hypoglycemia induced defective hormonal counterregulation, lowered glucose thresholds for symptom perception, and impaired symptom responses to hypoglycemia is similar to those seen in strictly controlled subjects with diabetes (39-43). Similarly, subjects with hypoglycemia because of insulinoma also exhibit blunted counterregulatory responses to hypoglycemia (44). This altered counterregulation was reversed following removal of the insulinoma (44,45).

Compared with men, women demonstrate a significantly lower counterregulatory response to the same hypoglycemic stimulus. Specifically, during hypoglycemia, epinephrine, glucagon, and growth hormone levels in the circulation are lower in women than men. Muscle sympathetic nerve activity and metabolic counterregulatory responses are also reduced in women during hypoglycemia (46). In aggregate these counterregulatory responses to hypoglycemia are 50% greater in men than in women. However, antecedent hypoglycemia produces less blunting of the counterregulatory response to subsequent hypoglycemia in women than in men (46). The gender differences in counterregulation in response to hypoglycemia are not attributable to gendermediated differences in glycemic thresholds, as both men and women have a glycemic threshold for release of neuroendocrine hormones between 71 and 78 mg/dL (47).

Hypoglycemic Autonomic Failure

The spectrum of reduced counterregulatory hormone responses (in particular epinephrine) and decreased symptom perception of hypoglycemia because of decreased autonomic nervous system activation following recent antecedent hypoglycemia has been termed "hypoglycemia induced autonomic failure" (48-50). This leads to a vicious cycle of hypoglycemia unawareness that induces a further decrease in counterregulatory hormone responses to hypoglycemia. This vicious cycle occurs commonly in subjects with diabetes in strict glycemic control. The reduced epinephrine response to antecedent hypoglycemia occurs in the absence of diabetic autonomic neuropathy as measured by standard tests of autonomic function (32,49,51) (see Figs. 1 and 2).

However, the presence of autonomic neuropathy further attenuates the epinephrine response to hypoglycemia in subjects with diabetes after recent hypoglycemic exposure (52-54). The additional downregulation of the epinephrine response is present in patients with parasympathetic nervous system involvement even in the absence of significant sympathetic nervous system deficits (52). This interaction between autonomic neuropathy and the counterregulatory response is seen in most but not all studies (49). Furthermore, patients with abnormal autonomic function have a greater risk for severe hypoglycemia; the odds ratio for severe hypoglycemia in people with abnormal responses in heart rate and blood pressure to standing compared with those with normal responses, was 1.7 (95% confidence interval 1.3, 2.2) after controlling for age, duration of diabetes, glycemic control, and study centre (55).

Although there is consistent evidence that the antecedent hypoglycemia attenuates the sympathoadrenal (epinephrine) and parasympathetic hormonal (pancreatic polypeptide) responses to subsequent hypoglycemia (39,43,49), there is conflicting evidence as to the effect of recent hypoglycemia on sympathetic neural responses. Davis and coworkers reported that antecedent hypoglycemia reduces peroneal muscle sympathetic nerve activity measured with microneurography during subsequent hypoglycemia (43,56,57). In contrast, Paramore and colleagues (58) using another measure of sympathetic activity, forearm norepinephrine spillover rates, observed that antecedent hypoglycemia does not attenuate sympathetic activity during subsequent hypoglycemia. It is possible that differential control of the autonomic nervous

Fig. 1. Hypoglycemia-associated autonomic failure in diabetes. Adapted from ref. 14.

system outflow in response to different stimuli is responsible for these conflicting results (59).

The studies described earlier have established that recent antecedent iatrogenic hypo-glycemia impairs some autonomic responses to subsequent hypoglycemia. It is not clear whether antecedent hypoglycemia has more general effects on autonomic nervous system function, impairing the response to nonhypoglycemic stimuli. Ratarsan and coworkers reported the autonomic impairment was specific to hypoglycemic stimuli. In a study of subjects with type 1 diabetes they observed that, following antecedent hypoglycemia, the epinephrine responses to exercise, standing, and a meal, and the norepinephrine responses to standing and exercise were intact (60). In contrast, data from Kinsley and colleagues from a study of subjects with type1 diabetes suggested that the deficit was more generalized. These investigators noted that the epinephrine and norep-inephrine response to a cold pressor test was reduced in well-controlled subjects with type 1 diabetes in comparison with controls (61).

More recently, Davis and coworkers reported that antecedent hypoglycemia reduces the normal exercise-induced rise in epinephrine, norepinephrine, glucagon, growth hormone, pancreatic polypeptide, and cortisol in healthy individuals (62). These data lend further support to the view that the effects of antecedent hypoglycemia on the autonomic nervous system are more generalized and not specific to subsequent hypoglycemic stimuli. Furthermore, antecedent exercise in normal subjects (two bouts of earlier exercise for 90 minutes at 50% VO2max and for 60 minutes at 70% VO2max attenuate the counter-regulatory responses to subsequent next-day hypoglycemia occurring in nondiabetic subjects (63). A similar although more restricted effect was found by McGregor et al. (64), using a different experimental design (two bouts of cycle exercise at approximately 70% peak oxygen consumption for 1 hour separated by 180 minutes) was associated with reduced epinephrine response to subsequent hypoglycemia (but not norepinephrine, neurogenic symptom, pancreatic polypeptide, or glucagons (64).

Fig. 2. The percentage increase over baseline of plasma epinephrine, norepinephrine, muscle sympathetic nerve activity and pancreatic polypeptide in healthy males during the last 30 minutes of a 2-hour hypoglycemic clamp at 50 mg/dL. Subjects were exposed on the previous day, to either euglycemia, or hypoglycemia of 70, 60, or 50 mg/dL. Data are group means ± SEM. * = p < 0.05 vs 90 mg/dL. From ref. 16.

Fig. 2. The percentage increase over baseline of plasma epinephrine, norepinephrine, muscle sympathetic nerve activity and pancreatic polypeptide in healthy males during the last 30 minutes of a 2-hour hypoglycemic clamp at 50 mg/dL. Subjects were exposed on the previous day, to either euglycemia, or hypoglycemia of 70, 60, or 50 mg/dL. Data are group means ± SEM. * = p < 0.05 vs 90 mg/dL. From ref. 16.

Similar findings may be present in individuals with type 1 diabetes that may play a role in exercise-induced hypoglycemia. The autonomic response (epinephrine, pancreatic polypeptide, and muscle sympathetic nerve activity) and hypoglycemic symptom response to subsequent hypoglycemia was attenuated after two bouts of low-intensity (90 minutes at 30% VO2max) and moderate-intensity (90 minutes at 50% VO2max) exercise separated by 180 mins (65). In contrast, Rattarasarn et al. (60) found that a

60-minutes bout of exercise at 60% VO2max did not attenuate the autonomic response to subsequent hypoglycemia in subjects with typel diabetes. The differences in experimental design may be responsible for the different results.

The Etiology of Hypoglycemia Induced Impairment in the Counterregulatory Response and Hypoglycemia Induced Autonomic Failure

The etiology of hypoglycemia-induced impairment in the counterregulatory response to repeat hypoglycemia has not been established, but does not appear to be because of changes in glucose uptake by the brain (66). A series of studies by Davis and others suggest that the increase in cortisol that occurs during hypoglycemia plays an important role in development of impaired counterregulation to repeat hypoglycemia. Administration of Adrenocorticotropic hormone (ACTH) or cortisol intravenously to achieve blood levels of cortisol similar to those observed during hypoglycemia blunts the counterregulatory response to subsequent hypoglycemia (56,67). Raising cortisol levels through exercise may also blunt the counterregulatory response to subsequent hypoglycemia (63). Finally, patients with Addison's disease who are unable to increase cortisol in response to a hypoglycemic stress, do not show impairment of the counter-regulatory response to repeat hypoglycemia (57).

These results have not been replicated consistently. Whereas, increased endogenous cortisol secretion elicited by an infusion of a pharmacological dose of a-(1-24)-ACTH, which raised plasma cortisol levels to approximately 45 ug/dL, reduced the adreno-medullary (epinephrine), sympathetic (norepinephrine) and parasympathetic (pancreatic polypeptide), and autonomic symptom response to subsequent hypoglycemia (67). However, elevations of antecedent cortisol levels more comparable with those that occur during hypoglycemia were not found to reduce adrenomedullary epinephrine or hypo-glycemia neurogenic symptoms in response to subsequent hypoglycemia (68).

Other elements of the hypothalamic-pituitary-adrenal axis (HPA) axis may be implicated too. Studies in a rodent model support a role for corticotrophin releasing hormone (CRH). Animals pretreated with CRH had impaired release of epinephrine, norepinephrine and glucagon following insulin induced hypoglycemia. This downregulation of the sympathoadrenal response was not present following pretreatment with ACTH or corti-costerone. The impaired release of catecholamines and glucagon was abolished by simultaneous administration of a CRHrl antagonist with CRH (69).

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