Hypoglycemia of obscure cause.
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C-Peptide↗
Biomedical subjects
P E Cryer
Publications and source records attributed to P E Cryer.
Absence of the dawn phenomenon and abnormal lipolysis in type 1 (insulin-dependent) diabetic patients with chronic growth hormone deficiency.
To determine the role of growth hormone in overnight insulin requirements and lipolysis, five patients with chronic growth hormone deficiency and Type 1 (insulin-dependent) diabetes mellitus and six control patients with diabetes were each studied on two separate nights. Insulin was infused at a variable rate throughout one night to maintain euglycaemia and fixed at 04.00 hours on another. During the variable infusion, euglycaemia was maintained in control patients by a 36% increase in insulin infusion rate between 03.00 and 08.00 hours while a 46% decrease in the rate was required in growth hormone deficient patients (p less than 0.02). Despite this difference, mean free insulin values were equivalent. This finding is suggestive of increased insulin clearance in growth hormone sufficient patients. Glucose levels rose in control and fell in growth hormone deficient patients when insulin infusion rates were fixed at 04.00 hours. Glycerol production and non-esterified fatty acid concentrations were significantly lower in the growth hormone deficient diabetic patients, p less than 0.001, and when normalized with a heparin infusion, had no effect on insulin requirements. We conclude that: (1) growth hormone contributes to the development of the "dawn phenomenon," possibly by increasing insulin clearance (2) growth hormone helps sustain nocturnal lipolysis in Type 1 diabetes and (3) non-esterified fatty acids are not involved in the dawn phenomenon.
3-Hydroxybutyric Acid↗
Role of GH in regulating nocturnal rates of lipolysis and plasma mevalonate levels in normal and diabetic humans.
To define the role that nocturnal increments in growth hormone (GH) play in maintaining lipolysis, glycerol turnover was measured in six patients with GH deficiency and six normal subjects during sleep. Glycerol production initially decreased in both groups but then increased to 1.44 +/- 0.20 mumol.kg-1.min-1 by 0800 h in normal subjects, whereas GH deficiency was associated with a continuous fall to 0.77 +/- 0.10 mumol.kg-1.min-1, P less than 0.02. Nonesterified fatty acid levels paralleled these changes. Six GH-deficient patients received basal GH replacement including a pulse during sleep, which resulted in normal fasting fatty acid levels (P less than 0.05, replaced vs. chronic deficiency). To assess a possible link between the normal nocturnal increase in plasma mevalonate (the product of the rate-limiting step in cholesterol synthesis) and sleep-associated GH release, 11 GH-deficient patients and 11 normal subjects were studied. Peak nocturnal and fasting mevalonate concentrations were not correlated with GH level. We conclude that nocturnal growth hormone secretion is essential for maintaining lipolysis but that it is not related to normal increments in mevalonate and, by inference, to cholesterol synthesis during sleep.
Adult↗
Epinephrine's ketogenic effect in humans is mediated principally by lipolysis.
To quantify epinephrine's effects on acetoacetate and beta-hydroxybutyrate kinetics, we infused subjects with 0.3 and 2.5 micrograms/min epinephrine, either alone or with a concomitant somatostatin infusion with insulin, glucagon, and growth hormone replaced at postabsorptive levels (islet clamp). Additional subjects received no epinephrine but sequential infusions of heparin plus 10% Intralipid at rates of 0.5 and 3.0 ml/min. Both epinephrine and Intralipid increased ketone body appearance (unaffected by islet clamp), augmented the interconversion rates between ketone bodies and, during the 2.5 micrograms/min infusion, caused a marked increase in beta-hydroxybutyrate appearance. The fraction of plasma free fatty acid (FFA) flux appearing as plasma ketones increased from 6 to 7% in the basal state to 11% at the high-epinephrine infusion. This fraction was also unaffected by the islet clamp and was not different from values obtained at similar Intralipid plus heparin-induced elevations in plasma FFA levels. We conclude that epinephrine's ketogenic effect in humans is primarily the result of its lipolytic effect, is accompanied by a significantly increased rate of ketone body interconversion, is manifest largely as an increase in plasma beta-hydroxybutyrate appearance at high plasma epinephrine values, and is not limited by portal insulin at post-absorptive levels.
3-Hydroxybutyric Acid↗
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↗
Attenuated glucose recovery from hypoglycemia in the elderly.
Advanced age is a risk factor for hypoglycemia caused by sulfonylureas (and insulin) used to treat diabetes mellitus. Therefore, we hypothesized that there is an age-associated impairment of glucose counterregulation and further that this is the result of a sedentary life-style. To test these hypotheses, glycemic and neuroendocrine responses to hypoglycemia, produced by 0.05 U/kg body wt insulin i.v. were measured in nondiabetic elderly subjects (age 65.1 +/- 0.9 yr n = 23)--and in a subset (n = 11) again after 1 yr of physical training (which increased VO2 max by 5.2 +/- 0.9 ml.kg-1.min-1, P less than 0.05)--and compared with these responses in nondiabetic young subjects (23.8 +/- 0.6 yr, n = 18). Recovery from hypoglycemia was attenuated (analysis of variance P less than 0.001) in the elderly (plasma glucose recovery rate 29.4 +/- 2.2 vs. 42.7 +/- 5.0 microM/min, P less than 0.02). This attenuation was the result of a smaller counterregulatory increment in glucose production (maximum increment 13.3 +/- 1.1 vs. 17.2 +/- 1.1 mumol.kg-1.min-1; P less than 0.05) rather than a greater increment in glucose utilization in the elderly. The attenuated glucose recovery was associated with higher plasma insulin concentrations (maximum increment 1385 +/- 122 vs. 940 +/- 72 pM, P less than 0.01) and reduced glucagon responses to hypoglycemia (maximum increment 43 +/- 6 vs. 66 +/- 12 ng/L). The epinephrine, norepinephrine, cortisol, and growth hormone responses were similar, although the epinephrine response was slightly delayed and the growth hormone response appeared smaller in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Hydroxybutyric Acid↗
Subdiaphragmatic vagotomy in rats induces systemic hypertension and sodium retention.
We examined the acute effects of bilateral subdiaphragmatic vagotomy (BSV) on blood pressure and renal function in female Sprague-Dawley rats. Mean arterial pressure was greater (p < 0.0001) in rats with BSV than in sham-operated rats (SOR). Rats with BSV had a significantly lower effective renal plasma flow (p < 0.01), total sodium excretion (p < 0.005), fractional sodium excretion (p < 0.01), urine flow (p < 0.01), and fractional excretion of water (p < 0.02) than SOR. The glomerular filtration rate was not significantly different between the 2 groups of rats. Plasma potassium was greater in rats with BSV than in SOR (p < 0.02). Pretreatment with an inhibitor of the angiotensin-converting enzyme prevented the above changes in rats with BSV. Changes in renal function and mean arterial pressure could not be attributed to antidiuretic hormone since plasma levels of antidiuretic hormone were lower in rats with BSV than in SOR (p < 0.002). In addition, the activity of the sympathetic system was decreased in rats with BSV, as suggested by the lower plasma levels of epinephrine (p < 0.003) and norepinephrine (p < 0.02) and the significantly lower renal tissue concentrations of norepinephrine (p < 0.03). No significant changes in renal tissue concentrations of acetylcholine or choline, its precursor, were observed in BSV rats when compared to SOR, suggesting a lack of renal parasympathetic innervation. Plasma renin activity was lower in rats with BSV (p < 0.02) than in SOR, but this effect was blunted in rats given an angiotensin-converting enzyme inhibitor prior to BSV.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗
Pheochromocytoma.
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Adrenal Gland Neoplasms↗
The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation.
We studied the effect of standard and high doses of epinephrine on coronary perfusion pressure during cardiopulmonary resuscitation in 32 patients whose cardiac arrest was refractory to advanced cardiac life support. Simultaneous aortic and right atrial pressures were measured and plasma epinephrine levels were sampled. Patients remaining in cardiac arrest after multiple 1-mg doses of epinephrine received a high dose of 0.2 mg/kg. The increase in the coronary perfusion pressures was 3.7 +/- 5.0 mm Hg following a standard dose, not a statistically significant change. The increase after a high dose was 11.3 +/- 10.0 mm Hg; this was both statistically different than before administration and larger than after a standard dose. High-dose epinephrine was more likely to raise the coronary perfusion pressure above the previously demonstrated critical value of 15 mm Hg. The highest arterial plasma epinephrine level after a standard dose was 152 +/- 162 ng/mL, and after a high dose, 393 +/- 289 ng/mL. Because coronary perfusion pressure is a good predictor of outcome in cardiac arrest, the increase after high-dose epinephrine may improve rates of return of spontaneous circulation.
Aorta↗
Increased symptoms of hypoglycaemia in the standing position in insulin-dependent diabetes mellitus.
1. To test the hypothesis that patients with insulin-dependent diabetes mellitus perceive the symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position, we assessed symptoms of hypoglycaemia, as well as heart rate and plasma noradrenaline and adrenaline concentrations, in both positions during hyperinsulinaemic glucose clamps on three occasions in seven patients. 2. Plasma glucose concentrations were clamped at 5.0 mmol/l (90 mg/dl) and 5.0 mmol/l on one occasion, at 5.0 mmol/l and 3.9 mmol/l (70 mg/dl) on another occasion, and at 5.0 mmol/l and 2.8 mmol/l (50 mg/dl) on yet another occasion. 3. During euglycaemia there was no effect of position on the symptom panels used to assess the symptomatic response to hypoglycaemia. However, at the plasma glucose concentration of 2.8 mmol/l, total (P less than 0.003) and neurogenic (P less than 0.005), but not neuroglycopenic, hypoglycaemic symptom scores were higher with the patients in the standing than in the lying position. Increments in total hypoglycaemic symptom scores, over those during the corresponding euglycaemic phase, were 5 +/- 2 in the lying position and 11 +/- 2 in the standing position (means +/- SEM, P less than 0.01). 4. Thus patients with insulin-dependent diabetes mellitus perceive symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position because of enhanced neurogenic symptoms.
Adult↗
Perioperative management of surgical patients with diabetes mellitus.
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Ambulatory Surgical Procedures↗
Plasma chromogranin A as a marker of sympathochromaffin activity in humans.
The extent to which the sympathochromaffin system compared with other endocrine/neuroendocrine tissues contributes to the plasma chromogranin A pool has not been defined. To test the hypothesis that the sympathochromaffin system is the major source of circulating chromogranin A only when that system is activated markedly, we measured chromogranin A concentrations in 200 human plasma samples known to have a broad range of norepinephrine and epinephrine concentrations, reflecting therefore a broad range of sympathochromaffin activity at the time of sampling. Plasma chromogranin A and norepinephrine concentrations were highly correlated when the sympathochromaffin system was activated markedly (cardiac arrest samples, n = 13, r = 0.8392, P less than 0.0005) and when there was release of large amounts of norepinephrine from tumors (pheochromocytoma samples, n = 17, r = 0.8132, P less than 0.001). However, when the sympathochromaffin system was activated less markedly, resulting in plasma catecholamine concentrations that spanned the physiological and lower pathophysiological range (nonpheochromocytoma noncardiac arrest samples, n = 170), correlations between plasma chromogranin A and norepinephrine (r = 0.2877, P less than 0.0001) and epinephrine (r = 0.3814, P less than 0.0001) levels were relatively weak, although still statistically significant. Thus, at basal through moderate stress levels, norepinephrine and epinephrine concentrations accounted for only approximately 10-15% of the variance in plasma chromogranin A levels. We conclude that, although plasma chromogranin A concentrations are a valid marker of sympathochromaffin activity in humans, they are not a sensitive marker under physiological conditions.
Adrenal Gland Neoplasms↗
Growth hormone, cortisol, or both are involved in defense against, but are not critical to recovery from, hypoglycemia.
We tested the hypotheses that growth hormone, cortisol, or both are involved in defense against but are not critical to recovery from prolonged hypoglycemia and that the putative roles of these hormones in defense against prolonged hypoglycemia are permissive rather than direct. To do so we studied control subjects (n = 10) and patients with growth hormone and cortisol deficiencies resulting from hypopituitarism both in the untreated state (n = 7) and with prestudy and basal intrastudy growth hormone and cortisol replacement (n = 6). Postabsorptive plasma glucose, insulin, glucagon, and epinephrine concentrations were no different in the untreated patients and controls. Twelve-hour insulin infusions, in low doses adjusted over the 1st 2 h to produce plasma glucose concentrations of 3.6 mmol/l (65 mg/dl) and then fixed at that dose, resulted in significantly (P less than 0.0001) lower late plasma glucose concentrations in the patients, without and with replacement. The 12-h plasma glucose concentrations were 2.9 +/- 0.1 mmol/l (53 +/- 1 mg/dl) in the control subjects, 2.4 +/- 0.1 mmol/l (43 +/- 2 mg/dl; P less than 0.001 vs. control) in the deficient patients, and 2.5 +/- 0.1 mmol/l (45 +/- 2 mg/dl; P less than 0.01 vs. control) in the replaced patients. Rates of glucose recovery from hypoglycemia after discontinuation of insulin were identical in all three studies. Thus growth hormone, cortisol, or probably both play a demonstrable role in defense against prolonged, in contrast to short-term, hypoglycemia in humans. This does not appear to be the result of permissive actions of the hormones and is therefore best attributed to their increments during hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Insulin and glucagon in prevention of hypoglycemia during exercise in humans.
To assess the roles of decrements in insulin and increments in glucagon in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal young men were studied during somatostatin infusions with insulin and glucagon infused to 1) hold insulin and glucagon levels constant, 2) decrease insulin, 3) increase glucagon, and 4) decrease insulin and increase glucagon during exercise. In contrast to a comparison study (saline infusion), when insulin and glucagon were held constant, glucose production did not increase and plasma glucose decreased from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.001) initially during exercise. Notably, plasma glucose then plateaued and was 3.3 +/- 0.2 mmol/l at the end of exercise. This decrease was at most only delayed when either insulin was decreased or glucagon was increased independently. However, when insulin was decreased and glucagon was increased simultaneously, there was an initial increase in glucose production, and the glucose level was 4.5 +/- 0.2 mmol/l at 60 min, a value not different from that in the comparison study. Thus we conclude that both decrements in insulin and increments in glucagon play important roles in the prevention of hypoglycemia during exercise and do so by signaling increments in glucose production. However, since hypoglycemia did not develop during exercise when changes in insulin and glucagon were prevented, an additional counterregulatory factor, such as epinephrine, must be involved in the prevention of hypoglycemia during exercise, at least when the primary factors, insulin and glucagon, are inoperative.
3-Hydroxybutyric Acid↗
Catecholamines in prevention of hypoglycemia during exercise in humans.
To assess the role of catecholamines in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal humans were studied with combined alpha- and beta-adrenergic blockade and with adrenergic blockade while changes in insulin and glucagon were prevented with the islet clamp technique (somatostatin infusion with insulin and glucagon infused at fixed rates). The results were compared with those from an islet clamp alone study. In contrast to a comparison study (saline infusion), adrenergic blockade resulted in a small initial decrease in plasma glucose during exercise, from 5.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l (P less than 0.01), but the level then plateaued. There was a substantial exercise-associated decrement in plasma glucose when insulin and glucagon were held constant, i.e., from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.0001), but the level again plateaued. However, when insulin and glucagon were held constant and catecholamine actions were blocked simultaneously, progressive hypoglycemia, to 2.6 +/- 0.6 mmol/l (P less than 0.001), developed during exercise. Hypoglycemia was the result of an absent increase in glucose production and an exaggerated initial increase in glucose utilization. Thus we conclude that sympathochromaffin activation plays a minor role when insulin and glucagon are operative, but a catecholamine, probably epinephrine, becomes critical to the prevention of hypoglycemia during exercise when changes in insulin and glucagon do not occur.
3-Hydroxybutyric Acid↗
Hypoinsulinemia is not critical to glucose recovery from hypoglycemia in humans.
To test the hypothesis that glucose recovery from hypoglycemia can occur in the absence of decrements in insulin below baseline, we studied nine normal humans on six occasions. In a control study, saline was infused. In five experimental studies, insulin (0.6 mU.kg-1.min-1) was infused from 0 to 80 min, to produce hypoglycemia (approximately 3.3 mM). Then, from 80 to 180 min, insulin was not infused or was infused in four different doses 0.1, 0.2, 0.4, and 0.6 mU.kg-1.min-1), and glucose recovery was assessed. In the recovery periods, approximately fourfold peripheral with approximately twofold portal insulin elevations prevented glucose recovery (glucose = 3.6 +/- 0.1 mM, counter-regulatory hormone levels elevated throughout). However, biological glucose recovery, documented by increments to 4.3 +/- 0.1 mM and decrements in all counterregulatory hormones (glucagon, epinephrine, growth hormone, and cortisol) to control levels, occurred despite nearly twofold peripheral hyperinsulinemia (54 +/- 4 vs. 32 +/- 4 pM, P less than 0.01) in the absence of portal hypoinsulinemia (58 +/- 4 vs. 68 +/- 8 pM). Thus we conclude that, although dissipation of insulin normally plays an important role in the correction of hypoglycemia, biological glucose recovery from hypoglycemia to glucose levels more than sufficient to disengage glucose counterregulatory systems and well above those required to produce symptoms of hypoglycemia can occur in the absence of decrements in portal insulin below baseline and despite mild peripheral hyperinsulinemia.
3-Hydroxybutyric Acid↗
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↗
Multifactorial origin of hypoglycemic symptom unawareness in IDDM. Association with defective glucose counterregulation and better glycemic control.
To assess potential relationships between unawareness of hypoglycemic symptoms and both defective glucose counterregulation and therapy-associated altered glycemic thresholds, symptoms and hormonal responses to hypoglycemia were quantitated during standardized insulin infusion tests in 41 patients with insulin-dependent diabetes mellitus (IDDM). The glycemic thresholds for both neurogenic and neuroglycopenic symptoms (and those for both epinephrine and pancreatic polypeptide release) were at lower plasma glucose concentrations in both patients with defective (n = 9, 22%) and those with adequate glucose counterregulation and, among the latter, in patients with lower compared with higher glycosylated hemoglobin levels. The data are consistent with the concept that both defective glucose counterregulation and improved glycemic control contribute to excessive hypoglycemia in IDDM by reducing awareness of symptoms of developing hypoglycemia and by impairing physiological defenses against hypoglycemia. Thus, hypoglycemic symptom unawareness is multifactorial in origin and may be partly reversible.
Awareness↗