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PubMed1993

Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia.

We hypothesize that in patients with insulin-dependent diabetes mellitus (IDDM), recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure, a disorder distinct from classical diabetic autonomic neuropathy (CDAN), and that hypoglycemia-associated autonomic failure, by reducing both symptoms of and defense against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. We used the hyperinsulinemic (12.0 pmol.kg-1.min-1) stepped hypoglycemic clamp technique to assess autonomic and symptomatic responses to hypoglycemia and the insulin infusion test (4.0 pmol.kg-1.min-1) to assess defense against hypoglycemia on mornings before and after clamped afternoon hypoglycemia (approximately 2.8 mmol/liter) and hyperglycemia (approximately 11.1 mmol/liter) in patients with IDDM. Compared with nondiabetic subjects, IDDM with or without CDAN exhibited reduced epinephrine (P = 0.0222 and 0.0040) and pancreatic polypeptide (P = 0.0083 and 0.0056) responses to hypoglycemia. After afternoon hypoglycemia, lower plasma glucose concentrations were required to elicit autonomic and symptomatic responses during morning hypoglycemic clamps in patients without CDAN. At the 2.8 mmol/liter step, mean (+/- SE) epinephrine levels were 1,160 +/- 270 and 2,040 +/- 270 pmol/liter (P = 0.0060), pancreatic and total symptom scores were 22 +/- 3 and 41 +/- 7 (P = 0.0475) after afternoon hypoglycemia and hyperglycemia, respectively. During morning insulin infusion tests after afternoon hypoglycemia, nadir plasma glucose concentrations were 2.6 +/- 0.2 mmol/liter compared with 3.3 +/- 0.3 mmol/liter (P < 0.001) at the corresponding time points after afternoon hyperglycemia. Thus, we conclude: (a) elevated glycemic thresholds for autonomic responses to hypoglycemia are a feature of IDDM per se, not classical diabetic autonomic neuropathy; and (b) a single episode of afternoon hypoglycemia results in both elevated glycemic thresholds for autonomic and symptomatic responses to hypoglycemia and impaired physiological defense against hypoglycemia the next morning in IDDM.

3-Hydroxybutyric Acid↗
PubMed1977

[On the syndrome of childhood-hypoglycemia. I. Definition of hypoglycemia in different age-groups and problems of neonatal hypoglycemia (author's transl)].

Hypoglycemia was diagnosed in 118 patients admitted to the University Children's Hospital Basel over 13 years, altogether 137 times. A definition of infantile and childhood hypoglycemia is discussed. Hypoglycemia was accepted as the correct diagnosis in 72 cases (group I), where 2 or more blood sugar values or at least one blood sugar value and one glucose value in the cerebrospinal fluid were below the limit for the age-group. In 46 cases only one abnormal blood sugar value vas documented (group II). In 19 cases no value was found to be definitely below the normal range. 58 patients were newborns up to 10 days of age. 34 patients (43 hospital admissions) were children in the agegroup after the newborn period. 65% of the newborns in group I and 58% of them in group II showed clinical symptoms concomitant with hypoglycemia. Convulsions (62%) were the most frequent feature. In more of the 76 patients was hypoglycemia documented as an isolated symptom. 75% of newborns were premature and/or of low birth weight. 50% had hypoglycemia and 20% verified central nervous system disease. 4 patients (5%) died in the hospital for reasons other than hypoglycemia. 15% (11 patients) had definite neurological symptoms when discharged from hospital. 30 of the 72 surviving neonates could be reexamined at a mean age of 26,5 months. 18% (13 patients) showed evidence of neurological disorders. 4 patients were readmitted with hypoglycemia at a later age, 3 were diagnosed as idiopathic and one as a ketotic hypoglycemia. One child developed diabetes mellitus at the age of 8 years.

Brain Damage, Chronic↗
PubMed1999

Biopsychobehavioral model of severe hypoglycemia. II. Understanding the risk of severe hypoglycemia.

OBJECTIVE: To evaluate the clinical/research utility of the biopsycho-behavioral model of severe hypoglycemia in differentiating patients with and without a history of severe hypoglycemia and in predicting occurrence of future severe hypoglycemia. RESEARCH DESIGN AND METHODS: A total of 93 adults with type 1 diabetes (mean age 35.8 years, duration of diabetes 16 +/- 10 years, HbA1 8.6 +/- 1.8%), 42 of whom had a recent history of recurrent severe hypoglycemia (SH) and 51 who did not (NoSH), used a handheld computer for 70 trials during 1 month recording cognitive-motor functioning, symptoms, blood glucose (BG) estimates, judgments concerning self-treatment of BG, actual BG readings, and actual treatment of low BG. For the next 6 months, patients recorded occurrence of severe hypoglycemia. RESULTS: SH patients demonstrated significantly more frequent and extreme low BG readings (low BG index), greater cognitive-motor impairments during hypoglycemia, fewer perceived symptoms of hypoglycemia, and poorer detection of hypoglycemia. SH patients were also less likely to treat their hypoglycemia with glucose and more likely to treat with general foods. Low BG index, magnitude of hypoglycemia-impaired ability to do mental subtraction, and awareness of neuroglycopenia, neurogenic symptoms, and hypoglycemia correlated separately with number of SH episodes in the subsequent 6 months. However, only low BG index, hypoglycemia-impaired ability to do mental subtraction, and awareness of hypoglycemia entered into a regression model predicting future severe hypoglycemia (R2 = 0.25, P < 0.001). CONCLUSIONS: Patients with a history of severe hypoglycemia differed on five of the seven steps of the biopsychobehavioral model of severe hypoglycemia. Helping patients with a recent history of severe hypoglycemia to reduce the frequency of their low-BG events, become more sensitive to early signs of neuroglycopenia and neurogenic symptoms, better recognize occurrence of low BG, and use fast-acting glucose more frequently in the treatment of low BG, may reduce occurrence of future severe hypoglycemia.

Adult↗
PubMed2001

Effects of morning hypoglycemia on neuroendocrine and metabolic responses to subsequent afternoon hypoglycemia in normal man.

There is general agreement that prior hypoglycemia blunts subsequent hypoglycemic counterregulatory responses. However, there is considerable debate concerning the timing and number of prior hypoglycemic episodes required to cause this blunting effect. The aim of this study was to determine whether one episode of hypoglycemia could modify neuroendocrine, metabolic, and symptom responses to hypoglycemia induced 2 h later. A total of 24 (12 male and 12 female) young, healthy, overnight-fasted subjects participated in a series of glucose clamp studies. A total of 16 individuals underwent 2 randomized studies of either identical 2-h morning and afternoon hyperinsulinemic (490 +/- 60 pmol/L) hypoglycemia (2.9 +/- 0.1 mmol/L) separated by 2 h or, at least 2 months later, 2-h morning and afternoon hyperinsulinemic (492 +/- 45 pmol/L) euglycemia (5.1 +/- 0.1 mmol/L). A total of 8 other subjects participated in a single experiment that consisted of 2-h morning hyperinsulinemic (516 +/- 60 pmol/L) euglycemia (5.1 +/- 0.1 mmol/L) and 2-h afternoon hyperinsulinemic (528 +/- 66 pmol/L) hypoglycemia (2.9 +/- 0.1 mmol/L) also separated by 2 h. Morning hypoglycemia significantly (P < 0.01) reduced (33-55%) the responses of epinephrine, norepinephrine, glucagon, GH, cortisol, and pancreatic polypeptide during afternoon hypoglycemia. Hypoglycemic symptoms (primarily neuroglycopenic) were also significantly (P < 0.01) reduced during afternoon hypoglycemia. Plasma glucose, insulin, nonesterified fatty acids, glycerol, lactate, beta-hydroxybutyrate (P < 0.01), GH, and cortisol (P < 0.05) levels were significantly increased at the start of afternoon hypoglycemia following morning hypoglycemia. Morning hypoglycemia created an insulin-resistant state during afternoon hypoglycemia. Despite blunted neuroendocrine responses, glucose infusion rates required to maintain hypoglycemia and increases in glucose oxidation were significantly attenuated during afternoon compared with morning hypoglycemia. This was in marked contrast to euglycemic control experiments where glucose infusion rates and nonoxidative glucose disposal were significantly increased during afternoon relative to morning studies. We conclude that in normal man one episode of prolonged, moderate, morning hypoglycemia can produce substantial blunting of neuroendocrine and symptomatic responses to subsequent near-term hypoglycemia, and the induction of posthypoglycemic insulin resistance can compensate for blunted neuroendocrine responses by limiting glucose flux and specifically glucose oxidation during subsequent near-term hypoglycemia.

Adult↗
PubMed1992

Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle.

Three hypoglycemia-associated clinical syndromes in people with insulin-dependent diabetes mellitus (IDDM)--defective glucose counterregulation, hypoglycemia unawareness, and elevated glycemic thresholds for symptoms and activation of counterregulatory systems during effective intensive therapy--have much in common. They segregate together, are associated with increased frequency of severe iatrogenic hypoglycemia, and share several pathophysiological features, including reduced autonomic nervous system responses to a given degree of hypoglycemia. In the setting of reduced glucagon responses, the reduced adrenomedullary epinephrine responses play a key role in the pathogenesis of iatrogenic hypoglycemia in affected patients. Thus, these syndromes are examples of hypoglycemia-associated autonomic failure in IDDM, a disorder distinct from classical diabetic autonomic neuropathy. The pathogenesis of hypoglycemia-associated autonomic failure is not known, need not be the same in all three syndromes, and could be multifactorial even in a given syndrome. The recent finding that short-term antecedent hypoglycemia results in reduced symptomatic and autonomic (including adrenomedullary) responses to subsequent hypoglycemia in nondiabetic humans leads logically to the following hypothesis concerning one potential pathogenetic mechanism: recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure in IDDM, and hypoglycemia-associated autonomic failure, by reducing both symptoms of and defenses against developing hypoglycemia, results in recurrent severe hypoglycemia, thus creating a vicious cycle. If this hypothesis is confirmed, it will suggest strategies to reduce the frequency of iatrogenic hypoglycemia in people with IDDM.

Awareness↗
PubMed1993

Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia.

Hypoglycemia has been incriminated as a possible factor responsible for development of the hypoglycemia unawareness phenomenon in patients with type I diabetes. Many patients with this condition, however, do not have a history of recent hypoglycemia. Because asymptomatic nocturnal hypoglycemia commonly occurs in type I diabetes, we tested the hypothesis that such episodes might be capable of inducing this phenomenon. Accordingly, autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function were assessed during standardized insulin-induced hypoglycemia in 10 normal volunteer subjects on two occasions--once after induction of asymptomatic nocturnal hypoglycemia and once after control studies in which saline rather than insulin was infused overnight. Compared with control experiments, asymptomatic nocturnal hypoglycemia increased the threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction during subsequent hypoglycemia (all, P < 0.05). These results indicate that asymptomatic hypoglycemia may induce hypoglycemia unawareness and, thus, may explain why not every patient with this condition has a history of prior hypoglycemia. Our results therefore support the concept that in type I diabetes this phenomenon may be largely attributable to antecedent hypoglycemia.

Adult↗
PubMed1998

Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus.

We tested the hypothesis that as few as two weekly brief episodes of superimposed hypoglycemia (i.e., doubling the average frequency of symptomatic hypoglycemia) would reduce physiological and behavioral defenses against developing hypoglycemia and reduce detection of clinical hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Compared with nondiabetic controls, six patients with well-controlled T1DM (HbA1c, 7.5 +/- 0.7% [mean +/- SD]) exhibited absent glucagon responses and reduced epinephrine (P = 0.0027), norepinephrine (P = 0.0007), pancreatic polypeptide (P = 0.0030), and neurogenic symptom (P = 0.0451) responses to hypoglycemia as expected. In these patients, 2 h of induced hypoglycemia (50 mg/dl, 2.8 mmol/l) twice weekly for 1 month, compared in a random-sequence crossover design with an otherwise identical 2 h of induced hyperglycemia (150 mg/dl, 8.3 mmol/l) twice weekly for 1 month, further reduced the epinephrine (P = 0.0001) and pancreatic polypeptide (P = 0.0030) responses, tended to further reduce the norepinephrine and neurogenic symptom responses to hypoglycemia, and reduced cognitive dysfunction during hypoglycemia (P = 0.0271), all assessed in the investigational setting. In the clinical setting, induced hypoglycemia did not alter overall glycemic control, but did reduce the total number of symptomatic hypoglycemic episodes detected by the patients from 49 to 30 per month and lowered the mean +/- SE self-monitored blood glucose level during symptomatic hypoglycemia from 51 +/- 2 mg/dl (2.8 +/- 0.1 mmol/l) to 46 +/- 3 mg/dl (2.6 +/- 0.2 mmol/l) (P < 0.01). It also reduced the proportion of low regularly scheduled self-monitored values that were symptomatic by approximately 33%. Thus as little as doubling the frequency of symptomatic hypoglycemia further reduced both the key epinephrine response and clinical awareness of developing hypoglycemia, changes reasonably expected to increase the risk of severe iatrogenic hypoglycemia in T1DM.

Adult↗
PubMed1999

Hypoglycemia per se stimulates sympathetic neural as well as adrenomedullary activity, but, unlike the adrenomedullary response, the forearm sympathetic neural response is not reduced after recent hypoglycemia.

We tested the hypotheses that 1) hypoglycemia per se stimulates the sympathetic neural as well as the adrenomedullary component of the sympathochromaffin system, and 2) sympathetic neural responses to hypoglycemia, like adrenomedullary responses, are reduced after recent hypoglycemia. To this end, we studied 10 healthy young adults on 2 consecutive days on two separate occasions, on one occasion with euglycemia (5.0 mmol/l) and on the other occasion with hypoglycemia (2.8 mmol/l) from 1000 to 1200 and 1400 to 1600 on day 1 of each occasion. On day 2 of each occasion, plasma epinephrine and norepinephrine (NE) concentrations and rates of systemic NE spillover (SNESO) and forearm NE spillover (FNESO) were measured during hyperinsulinemic (12.0 pmol x kg(-1) x min(-1)) euglycemia (5.0 mmol/l) and hypoglycemia (2.8 mmol/l). Compared with values during euglycemia, plasma epinephrine and NE and rates of SNESO and FNESO all increased during hypoglycemia (P < 0.01). After day 1 hypoglycemia, there were reductions during hypoglycemia on day 2 in plasma epinephrine (2,050 +/- 500 vs. 2,960 +/- 400 pmol/l; P < 0.02), plasma NE (1.35 +/- 0.16 vs. 1.92 +/- 0.20 nmol/l; P < 0.01), and SNESO rates (5.13 +/- 0.84 vs. 6.87 +/- 0.81 nmol/min; P < 0.02). However, FNESO rates were unaltered (1.16 +/- 0.25 vs. 1.27 +/- 0.17 pmol x min(-1) x 100 ml tissue(-1). Thus we conclude that 1) hypoglycemia per se stimulates both the sympathetic neural and adrenomedullary components of the sympathochromaffin system and 2) adrenomedullary, but not forearm sympathetic neural, responses to hypoglycemia are reduced after recent hypoglycemia. The extent to which the lower plasma NE levels and reduced SNESO responses to hypoglycemia after day 1 hypoglycemia reflect reduced NE release from the adrenal medullae, sympathetic nerves other than those in the forearm, or both cannot be determined from these data.

Adrenal Medulla↗
PubMed2002

Limited impact of vigorous exercise on defenses against hypoglycemia: relevance to hypoglycemia-associated autonomic failure.

Hypoglycemia-associated autonomic failure (HAAF)-reduced autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia caused by recent antecedent hypoglycemia-plays a key role in the pathogenesis of defective glucose counterregulation and hypoglycemia unawareness and thus iatrogenic hypoglycemia in type 1 diabetes. On the basis of the findings that cortisol infusion mimics and deficient or inhibited cortisol secretion minimizes this phenomenon, it has been suggested that the cortisol response to antecedent hypoglycemia mediates HAAF. We tested the hypothesis that any stimulus that releases cortisol, such as exercise, reduces autonomic and symptomatic responses to subsequent hypoglycemia. Thirteen healthy young adults (four women) were studied on three occasions in random sequence: 1) cycle exercise ( approximately 70% peak oxygen consumption) from 0830 to 0930 h and from 1200 to 1300 h on day 1 and hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic (85, 75, 65, 55, and 45 mg/dl) clamps on day 2, 2) rest on day 1 and identical hypoglycemic clamps on day 2, and 3) hyperinsulinemic-euglycemic clamps. Exercise raised plasma cortisol concentrations to 16.9 +/- 1.9 (0930 h) and 16.6 +/- 1.6 microg/dl (1300 h) on day 1. Compared with rest on day 1, exercise on day 1 was associated with reduced epinephrine (P = 0.0113) responses-but not norepinephrine (P = 0.6270), neurogenic symptom (P = 0.6470), pancreatic polypeptide (P = 0.0629), or glucagon (P = 0.0436, but higher) responses-to hypoglycemia on day 2. However, the effect was small. (The final day 2 hypoglycemia epinephrine values were 765 +/- 106 pg/ml after rest on day 1 and 550 +/- 94 pg/ml after exercise on day 1 compared with 30 +/- 6 pg/ml during euglycemia.) These data are consistent with the hypothesis that the cortisol response to hypoglycemia mediates in part the reduced epinephrine response to subsequent hypoglycemia, one key component of HAAF in type 1 diabetes. However, the small effect suggests that an additional factor or factors may well be involved. These data do not support the hypothesis that the cortisol response to hypoglycemia mediates the reduced neurogenic symptom response to subsequent hypoglycemia, another key component of HAAF in type 1 diabetes.

Adult↗
PubMed1994

Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia.

OBJECTIVE: To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospective assessment. RESEARCH DESIGN AND METHODS: A prospective study was undertaken for 12 months in 60 patients with type I diabetes: 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia. The two groups of patients were matched for age, age at onset of diabetes, duration of diabetes, and glycemic control. Episodes of severe hypoglycemia were recorded within 24 h of the event and verified where possible by witnesses. RESULTS: During the 12 months, 19 (66%) of the patients with impaired awareness had one or more episodes of severe hypoglycemia with an overall incidence of 2.8 episodes.patient-1.year-1. By comparison, 8 (26%) of the patients with normal awareness experienced severe hypoglycemia (P < 0.01) with an annual incidence of 0.5 episode.patient-1.year-1 (P < 0.001). Severe hypoglycemia occurred at different times of the day in the two groups: patients with impaired awareness experienced a greater proportion of episodes during the evening (P = 0.03), and patients with normal awareness experienced a greater proportion in the early morning (P = 0.05). An assessment of fear of hypoglycemia revealed that patients with impaired awareness of hypoglycemia worried more about hypoglycemia than did patients with normal awareness (P = 0.008), but did not modify their behavior accordingly. CONCLUSIONS: This prospective evaluation demonstrated that impaired awareness of hypoglycemia predisposes to a sixfold increase in the frequency of severe hypoglycemia, much of which occurred at home during waking hours.

Adult↗
PubMed2001

Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes.

BACKGROUND: Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes. OBJECTIVE: To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing beta-adrenergic sensitivity in patients with type 1 diabetes. DESIGN: Controlled interventional study. SETTING: Research unit and outpatient diabetes clinic of a university hospital. PATIENTS: 10 men with type 1 diabetes and hypoglycemia unawareness (mean age [+/-SD], 46 +/- 16 years; mean duration of diabetes, 20 +/- 10 years). INTERVENTION: Strict avoidance of hypoglycemia. MEASUREMENTS: beta-Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L [54 mg/dL]) before and after 4 months of avoidance of hypoglycemia. RESULTS: After 4 months, the mean (+/-SE) number of episodes of hypoglycemia (glucose level < 3.9 mmol/L [70 mg/dL]) decreased from 8.4 +/- 0.9 to 1.4 +/- 0.3 per week (P < 0.001). Hemoglobin A(1c) values increased from 0.068 +/- 0.003 (6.8% +/- 0.3%) to 0.077 +/- 0.003 (7.7% +/- 0.3%) (P < 0.001). Autonomic symptom scores during hypoglycemic clamp increased from 1.8 +/- 0.6 to 3.3 +/- 0.7 (P = 0.004) and did not significantly differ from those of normal participants (4.7 +/- 0.8) (P > 0.2). Although catecholamine responses to hypoglycemia were unchanged, the dose of isoproterenol necessary to increase heart rate by 25 beats/min (IC(25)) decreased from 1.96 +/- 0.43 microgram before treatment to 1.09 +/- 0.17 microgram after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 +/- 0.20 microgram) (P > 0.2). Improvements in beta-adrenergic sensitivity (change in IC(25)(-1)) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04). CONCLUSIONS: Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing beta-adrenergic sensitivity.

Adult↗
PubMed1994

Hypoglycemia-induced autonomic failure in IDDM is specific for stimulus of hypoglycemia and is not attributable to prior autonomic activation.

We hypothesized, first, that recent antecedent hypoglycemia causes reduced autonomic responses to subsequent hypoglycemia in patients with well-controlled insulin-dependent diabetes mellitus (IDDM) and that the reduced responses are specific for the stimulus of hypoglycemia while the responses to other stimuli are unaltered and, second, that reduced autonomic responses, specifically sympathochromaffin, so-induced are not simply the result of prior activation of the system. To test the first hypothesis, eight patients with IDDM, selected for HbA1c levels < 8.0% and the absence of classic diabetic autonomic neuropathy, were studied twice. On one occasion, clamped hypoglycemia (approximately 2.8 mM) was produced at 1400-1600 on days 2 and 3; on the other occasion clamped euglycemia (approximately 5.6 mM) was produced at those times. On both occasions, autonomic responses to hypoglycemia (approximately 2.8 mM) were determined the morning of day 3 and those to standing, exercise, and a formula meal the morning of day 4. Following afternoon hypoglycemia, 1) the adrenomedullary epinephrine (EPI) response to hypoglycemia was reduced (P = 0.0397) but that to standing, exercise, and a meal were unaltered; 2) the sympathetic neural norepinephrine (NE) response to standing and to exercise was unaltered; and 3) the partially parasympathetic neural-mediated pancreatic polypeptide response to a meal was unaltered. To test the second hypothesis, seven nondiabetic subjects were studied twice, once with cycle exercise (60% peak VO2 x 60 min) and once without exercise 90 min before clamped hypoglycemia (approximately 2.8 mM). Prior exercise had no effect on the EPI, NE, or pancreatic polypeptide responses to hypoglycemia. We conclude, first, that the phenomenon of hypoglycemia-associated autonomic failure can be induced in patients with well-controlled IDDM and is specific for the stimulus of hypoglycemia and, second, that this is not simply the result of prior activation of the system.

3-Hydroxybutyric Acid↗
PubMed2000

Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans.

The aim of this study was to determine whether the duration of antecedent hypoglycemia regulates the magnitude of subsequent counterregulatory failure. A total of 31 lean healthy overnight-fasted individuals (16 men/15 women) were studied. There were 15 subjects (8 men/7 women) who underwent two separate 2-day randomized experiments separated by at least 2 months. On day 1, 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic (5.2 +/- 0.1 mmol/l) or hypoglycemic (2.9 +/- 0.1 mmol/l) glucose clamps (prolonged hypoglycemia) were carried out in the morning and afternoon. Of the other subjects, 16 participated in a 2-day study in which day 1 consisted of morning and afternoon short-duration hypoglycemia experiments (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 5 min), and 10 of these individuals underwent an additional 2-day study in which day 1 consisted of morning and afternoon intermediate-duration hypoglycemia (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 30 min). The next morning (day 2) all subjects underwent an additional 2-h hyperinsulinemic-hypoglycemic clamp (2.9 +/- 0.1 mmol/l). The rate of fall of glucose (0.07 mmol/min) was carefully controlled during all hypoglycemic studies so that the glucose nadir was reached at 30 min. Despite equivalent day 2 plasma glucose and insulin levels, there were significant differences in counterregulatory physiological responses. Steady-state epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels were similarly significantly blunted (P < 0.01) by the differing duration day 1 hypoglycemia compared with day 1 euglycemia. Muscle sympathetic nerve activity and endogenous glucose production were also similarly blunted (P < 0.01) by day 1 hypoglycemia (relative to day 1 euglycemia). Day 2 hypoglycemic symptoms were significantly reduced (P < 0.01) after day 1 prolonged intermediate- but not short-duration hypoglycemia. In summary, two episodes of short-duration moderate hypoglycemia can produce significant blunting of key neuroendocrine and metabolic counterregulatory responses. Hypoglycemic symptom scores are reduced by prolonged but not short-duration prior hypoglycemia. We conclude that in healthy overnight fasted humans, 1) neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses are sensitive to the blunting effects of even short-duration prior hypoglycemia, and 2) the duration of antecedent hypoglycemia results in a hierarchy of blunted physiological responses with hypoglycemic symptom awareness less vulnerable than neuroendocrine responses.

Adult↗
PubMed1995

Hypoglycemia-induced cognitive dysfunction in diabetes mellitus: effect of hypoglycemia unawareness.

Hypoglycemia results in cognitive dysfunction. The aim of this study was to assess and compare the degree of cognitive dysfunction experienced by insulin-dependent diabetic patients (IDDM) with hypoglycemia unawareness with patients with normal awareness of hypoglycemia. Cognitive function was examined in 10 patients who had normal awareness of the onset of hypoglycemia and 10 patients who had a history of impaired awareness of hypoglycemia. A hyperinsulinemic glucose clamp was used to manipulate blood glucose concentrations. Cognitive function was assessed using Rapid Visual Information Processing (RVIP), Trial Making B (TMB), Paced Auditory Serial Addition Test (PASAT) and Digit Symbol Substitution Test (DSST). Multivariate analysis of variance demonstrated a significant effect of hypoglycemia on cognitive function (p < 0.01). A trend was observed towards an overall effect of awareness on performance (p = 0.08). There were trends in the effects of awareness on RVIP correct responses across time (p = 0.07) and the interaction of awareness by study by TMB (p = 0.08). During hypoglycemia subjects with impaired awareness were less cautious in their responses (RVIP misses p = 0.03) and on recovery from hypoglycemia, their cognitive function remained abnormal (TMB p = 0.04, RVIP correct responses p = 0.02, RVIP misses p = 0.04). Thus, IDDM patients with hypoglycemia unawareness exhibited more profound cognitive dysfunction during acute hypoglycemia which persisted for longer following blood glucose recovery.

Adult↗
PubMed1997

Hierarchy of physiological responses to hypoglycemia: relevance to clinical hypoglycemia in type I (insulin dependent) diabetes mellitus.

Hypoglycemia elicits a characteristic sequence of responses in healthy humans. These responses (and their arterialized venous glycemic thresholds) include: 1) Decreased insulin secretion (approximately 4.5 mmol/L). 2) Increased glucose counterregulatory hormone (glucagon, epinephrine, growth hormone and cortisol) secretion (approximately 3.6-3.8 mmol/L). 3) Symptoms of hypoglycemia (approximately 3.0 mmol/L). 4) Cognitive dysfunction (approximately 2.6 mmol/L). Thus, insulin secretion decreases as plasma glucose levels fall within the physiological range, and counterregulatory hormone secretion increases as plasma glucose levels fall just below the physiological range at substantially higher glucose levels than those required to produce symptoms and impair cognitive function. These data are entirely consistent with the body of evidence that insulin, glucagon and epinephrine stand high in the hierarchy of redundant glucoregulatory factors that prevent, as well as correct, hypoglycemia. When the same methods are used, these thresholds are remarkably reproducible from laboratory to laboratory. Nonetheless, the glycemic thresholds are dynamic rather than static. They vary in relation to recent antecedent glycemia. For example, lower plasma glucose concentrations are required to elicit autonomic, including epinephrine, and symptomatic responses in patients with well controlled IDDM, a phenomenon best attributed to recent antecedent iatrogenic hypoglycemia. This is the basis of the clinical syndrome of hypoglycemia unawareness, which is now known to be reversible with scrupulous avoidance of iatrogenic hypoglycemia. The latter also at least partially reverses reduced epinephrine responses to hypoglycemia, a key component (in the setting of absent glucagon responses) of the syndrome of defective glucose counterregulation. While perhaps seemingly adaptive, these threshold shifts appear to be maladaptive since both defective glucose counterregulation and hypoglycemia unawareness are associated with substantially increased rates of severe iatrogenic hypoglycemia in people with IDDM.

Diabetes Mellitus, Type 1↗
PubMed1991

Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans.

To test the hypothesis that hypoglycemia itself causes reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia, we measured those responses during clamped hypoglycemia (2.8 mM) on consecutive mornings on two occasions, with interval afternoon (1400-1600) hypoglycemia (3 mM) on one occasion and interval afternoon euglycemia (5 mM) on the other, in nine nondiabetic humans. None of the measured responses were reduced by interval euglycemia. In contrast, plasma epinephrine (P less than 0.005), glucagon (P less than 0.005), pancreatic polypeptide (P less than 0.01), cortisol (P less than 0.02), and total (P less than 0.001), neurogenic (P less than 0.001) and neuroglycopenic (P less than 0.05) symptom responses to morning hypoglycemia were reduced after interval afternoon hypoglycemia. Thus, a single episode of hypoglycemia caused a generalized reduction of the neuroendocrine and symptomatic responses to subsequent hypoglycemia, a finding that may be important to the pathogenesis of iatrogenic hypoglycemia in insulin-dependent diabetes mellitus.

Adult↗
PubMed1993

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.

To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 +/- 0.05 to 0.045 +/- 0.03 episodes/patient-day) and an increase in HbA1c (5.8 +/- 0.3 to 6.9 +/- 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.

Adult↗
PubMed1981

Comparison of oral glucose tolerance tests and mixed meals in patients with apparent idiopathic postabsorptive hypoglycemia: absence of hypoglycemia after meals.

The relationship between symptoms of idiopathic postabsorptive hypoglycemia and glucose homeostasis was evaluated by giving oral glucose tolerance tests (OGTT) and mixed meals to 18 patients and 16 controls. Chemical hypoglycemia after OGTT occurred as often in patients referred because of possible hypoglycemia symptoms, 18 out of 80 (23%), as in controls, 4 out of 16 (25%). After glucose, patients showed both clinical and chemical hypoglycemia (mean +/- SE plasma glucose, 48 +/- 3 mg/dl), but insulin, glucagon, and growth hormone responses were similar to controls. After mixed meals, no chemical hypoglycemia occurred in patients (mean plasma glucose, 79 +/- 3 mg/dl), yet 14 out of 18 (78%) had symptoms and/or signs consistent with hypoglycemia. No abnormality of glucose homeostasis was observed after meals that could account for symptoms or signs experienced by patients with idiopathic postabsorptive hypoglycemia. Since factors other than hypoglycemia appear to be involved, the disorder should be termed the idiopathic postprandial syndrome to avoid the connotation of chemical hypoglycemia.

Adult↗