Biomedical subjects
Publications and source records attributed to P Cryer.
Blunt trauma to the eye of patients with an artificial intraocular lens may cause globe rupture with all the accompanying sequelae. It must be recognised promptly and dealt with appropriately before urgent referral to ophthalmology.
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The brain usually depends almost exclusively on glucose for its energy requirements. During hypoglycemia associated with prolonged fasting or strenuous exercise, circulating ketone-body and lactate levels increase several-fold; in both situations, certain signs and symptoms of hypoglycemia are diminished. Therefore, to test the hypothesis that hyperketonemia or hyperlacticacidemia of the magnitude seen during certain clinical situations can substitute for glucose as an energy source for the brain and alter physiological responses to hypoglycemia, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function during standardized insulin-induced hypoglycemia in normal volunteers with and without infusion of beta-hydroxybutyrate (BOHB) or lactate designed to reproduce circulating levels of these substrates seen during prolonged fasting and strenuous exercise. Compared with paired control experiments, infusion of BOHB and lactate increased the glycemic threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction (all P < 0.05). The hypoglycemic threshold for autonomic symptoms increased from 3.8 +/- 0.1 to 3.1 +/- 0.2 mmol/l during BOHB infusion and from 3.7 +/- 0.1 to 2.8 +/- 0.1 mmol/l during lactate infusion, and the threshold for neuroglycopenic symptoms increased from 2.8 +/- 0.1 to 2.4 +/- 0.1 and 2.3 +/- 0.1 mmol/l, respectively. The magnitude for autonomic symptoms decreased from 12 +/- 2 and 11 +/- 1 to 6 +/- 2 and 4 +/- 1 during BOHB and lactate infusion, respectively. Neuroglycopenic synptoms decreased from 11 +/- 2 to 3 +/- 1 during both series of experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: To assess the characteristics of patients with hypoglycemia unawareness (development of neuroglycopenia without appropriate prior autonomic warning symptoms) and its predisposing factors. RESEARCH DESIGN AND METHODS: We studied 43 insulin-dependent diabetes mellitus patients who were objectively categorized as having or not having hypoglycemia using the stepped hypoglycemic clamp technique in which plasma glucose was clamped at plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l and a statistical criterion (onset of autonomic warning symptoms at a plasma glucose concentration 2 SD below normal) and examined their clinical characteristics and hormonal, symptomatic, and cognitive responses. RESULTS: Eleven (26%) of the patients were classified as having hypoglycemia unawareness. Compared with the other patients, unaware patients had a lower HbA1c level (P < 0.01), a longer duration of diabetes (P < 0.01), and a history of more severe hypoglycemia (P < 0.003). During experimental hypoglycemia, counterregulatory hormone responses, neuroglycopenic symptoms, and cognitive dysfunction all began at lower plasma glucose concentrations in unaware patients (P < 0.01, 0.03, and 0.01, respectively). Moreover, although the magnitudes of their plasma catecholamine responses and autonomic symptoms were reduced (both, P < 0.01), the plasma catecholamine levels at which autonomic symptoms began was not altered. Finally, as seen from glucose infusion rates necessary to maintain identical plasma glucose levels, patients with hypoglycemia unawareness had increased sensitivity to insulin (P < 0.001). CONCLUSIONS: Our results confirm an association between hypoglycemia unawareness and duration of diabetes, glycemic control, and occurrence of severe hypoglycemia, and in addition provide evidence that both autonomic and neuroglycopenic symptoms are affected and that insulin sensitivity is increased, but beta-adrenergic sensitivity is not diminished.
BACKGROUND: A lack of appropriate autonomic warning symptoms before the development of neuroglycopenia occurs frequently in patients with diabetes mellitus. The pathogenesis of this phenomenon is unclear, but it is associated with intensive insulin therapy, prolonged duration of diabetes, frequent episodes of hypoglycemia, and impaired glucose counterregulation. Recently, it has been proposed that repeated episodes of hypoglycemia may themselves induce the phenomenon. METHODS: To test this hypothesis and to determine whether the phenomenon is reversible, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormonal responses, and cognitive function during stepped hypoglycemic-clamp studies in 6 patients with insulinomas before and approximately six months after curative surgery and in 14 normal subjects matched for age, weight, and sex. RESULTS: Before surgery, the patients with insulinomas had lower scores than the normal subjects for autonomic symptoms (mean [+/- SD], 3.5 +/- 0.8 vs. 9.6 +/- 4.5) and neuroglycopenic symptoms (2.8 +/- 1.5 vs. 8.9 +/- 5.3). The patients also had impaired counterregulatory hormonal responses (their plasma epinephrine, norepinephrine, glucagon, growth hormone, and cortisol responses before surgery were 187 +/- 227 pg per milliliter [1.03 +/- 1.25 nmol per liter], 223 +/- 85 pg per milliliter [1.32 +/- 0.50 nmol per liter], 86 +/- 21 ng per liter, 7.4 +/- 5.2 micrograms per liter, and 12.1 +/- 1.5 micrograms per deciliter [334 +/- 41 nmol per liter], respectively, as compared with 842 +/- 439 pg per milliliter [4.63 +/- 2.41 nmol per liter], 519 +/- 150 pg per milliliter [3.07 +/- 0.89 nmol per liter], 201 +/- 58 ng per liter, 25.3 +/- 13.7 micrograms per liter, and 26.3 +/- 1.2 micrograms per deciliter [726 +/- 33 nmol per liter] in the normal subjects) and less deterioration in cognitive function than the normal subjects during hypoglycemia (sum of z scores for seven tests of cognitive function, 1.7 +/- 1.9 vs. 8.9 +/- 3.5) (P < 0.02 for all comparisons). Surgical cure reversed all these abnormalities (P not significant for all comparisons with the normal subjects). CONCLUSIONS: Hypoglycemia itself can induce unawareness of the autonomic and neuroglycopenic symptoms of hypoglycemia and decrease the counterregulatory hormonal responses to hypoglycemia.
To test the hypothesis that the rate of decrease in plasma glucose concentration may affect the hierarchy of responses to hypoglycemia, we compared plasma couterregulatory hormone concentrations, autonomic and neuroglycopenic symptom scores, and cognitive function test performance in 10 normal volunteers whose plasma glucose concentration was either rapidly (over 30 min) decreased to 3.7 mmol (66 mg/dL) or was slowly decreased in a stepwise manner to plateaus of 4.3 mmol (78 mg/dL), 3.7 mmol (66 mg/dL), 3.0 mmol (54 mg/dL), and 2.3 mmol (42 mg/dL). Comparable plasma counterregulatory hormone concentrations and autonomic symptom scores were observed in both sets of experiments during the 3.7 mmol (66 mg/dL) plateaus. In the stepwise decrement experiments, significant increases in neuroglycopenic symptom scores and deterioration in cognitive performance occurred only during the last glycemic plateau (2.3 mmol, 42 mg/dL). In the rapid decrement experiments, no increase in neuroglycopenic symptom score or deterioration in cognitive performance was observed during the 3.7 mmol (66 mg/dL) plateau. We, therefore, conclude that in normal volunteers the rate of decrease in plasma glucose concentration does not affect the hierarchy of responses to hypoglycemia.
We sought 1) to determine which symptoms of hypoglycemia are reproducible, 2) to pharmacologically distinguish neurogenic (autonomic) from neuroglycopenic symptoms, and 3) to test the hypothesis that awareness of hypoglycemia is the result of perception of neurogenic rather than neuroglycopenic symptoms. Awareness of hypoglycemia and 19 symptoms were quantitated in 10 normal, young adults, each studied on four occasions in random sequence, during 1) clamped euglycemia (approximately 5 mM), 2) clamped hypoglycemia (approximately 2.5 mM), 3) clamped hypoglycemia with combined alpha- and beta-adrenergic blockade (phentolamine and propranolol), and 4) clamped hypoglycemia with pan-autonomic blockade (phentolamine, propranolol and atropine). Significant (ANOVA, P < 0.001) treatment effects on the awareness of hypoglycemia ("blood sugar low") were noted. No change occurred in the score for this during euglycemia, but the mean +/- SE increase was 2.1 +/- 0.4 during hypoglycemia. This increase was not reduced significantly by adrenergic blockade (1.6 +/- 0.5), but was reduced significantly and substantially (approximately 70%) by pan-autonomic blockade (0.6 +/- 0.3). Significant neurogenic symptoms included shaky/tremulous (P < 0.001), heart pounding (P < 0.001), and nervous/anxious (P = 0.002), all adrenergic; and sweaty (P < 0.001), hungry (P < 0.001), and tingling (P = 0.009), all cholinergic. Significant neuroglycopenic symptoms, those produced by hypoglycemia but not reduced by pan-autonomic blockade, included warm (P < 0.001), weak (P = 0.011), difficulty thinking/confused (P = 0.004), and tired/drowsy (P = 0.003). We conclude that muscarinic cholinergic mechanisms mediate an important and previously uncharacterized component of the neurogenic symptoms of hypoglycemia and awareness of hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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.
To test the hypothesis that physiologic hyperinsulinemia activates the sympathetic nervous system in humans, we measured changes in plasma norepinephrine as well as epinephrine concentrations during euglycemic hyperinsulinemic clamp experiments in which normal volunteers were infused with insulin for up to 12 hours, at rates chosen to simulate the basal and postprandial hyperinsulinemia seen in insulin-resistant states. Infusions of insulin increased plasma insulin threefold (to approximately 200 pmol/L) and 15-fold (to approximately 1,000 pmol/L) in simulations of fasting and postprandial hyperinsulinemia. In neither experiment did plasma norepinephrine or epinephrine change significantly. In control experiments in which saline was infused for 12 hours, plasma epinephrine increased twofold (P less than .05), but plasma norepinephrine did not change. Therefore, we conclude that hyperinsulinemia of the magnitude seen in the insulin-resistant humans does not increase sympathetic nervous system activity.
To define glycemic thresholds for activation of counterregulatory hormone secretion, initiation of symptoms (autonomic and neuroglycopenic), and onset of deterioration of cognitive function, we measured indexes of these responses during glycemic plateaus of 90, 78, 66, 54, and 42 mg/dl in 10 normal volunteers, with the use of the hyperinsulinemic glucose clamp technique. Activation of glucagon, epinephrine, norepinephrine, and growth hormone secretion began at arterialized venous plasma glucose concentrations of 68 +/- 1, 68 +/- 1, 65 +/- 1, and 67 +/- 2 (SE) mg/dl, respectively. Autonomic symptoms (anxiety, palpitations, sweating, irritability, and tremor) began at 58 +/- 2 mg/dl, which was significantly (P = 0.0001) lower. Neuroglycopenic symptoms (hunger, dizziness, tingling, blurred vision, difficulty thinking, and faintness) and deterioration in cognitive function tests began at 51 +/- 3 and 49 +/- 2 mg/dl, respectively, values that were both significantly (P = 0.018 and 0.004, respectively) lower than that for initiation of autonomic symptoms. We therefore conclude that there is a distinct hierarchy of responses to decrements in plasma glucose, such that the threshold for activation of counterregulatory hormone secretion occurs at higher plasma glucose levels than that for initiation of autonomic warning symptoms, which in turn occurs at higher plasma glucose levels than that for onset of neuroglycopenic symptoms and deterioration in cerebral function. Such a hierarchy would maximize the opportunity to avoid incapacitating hypoglycemia.
Following 4 h of general anesthesia with halothane [1.5 minimum alveolar concentration (MAC)]-nitrous oxide (50% in oxygen), whole body protein synthesis is decreased and the rate of leucine oxidation is increased in dogs. To evaluate the effects of general anesthesia with isoflurane on whole body fuel metabolism and the effects of duration of anesthesia on these processes, eight dogs were studied, once in the conscious state (over 9 h) and again prior to and during isoflurane anesthesia (1.5 MAC) for 3.5 h (n = 8). Three additional dogs were studied in the conscious state and over 5 h of anesthesia. Changes in protein, fatty acid, and glucose metabolism were estimated using isotope dilution techniques, employing simultaneous infusions of L-[1-14C]leucine, [6-3H]glucose and [9,10-3H]palmitate. Ten minutes after the beginning of the administration of isoflurane, total leucine carbon flux, leucine oxidation, and leucine incorporation into proteins decreased (P less than 0.05), resulting in a slight decrease in the ratio of leucine oxidation to nonoxidative leucine disappearance (LOX/NOLD, P less than 0.05), an indicator of leucine catabolism. Throughout the 5 h of anesthesia, whole body protein synthesis remained decreased (P less than 0.01), whereas leucine flux and oxidation increased progressively throughout the remainder of the study, resulting in a more than 80% increase in the ratio of LOX/NOLD. After 10 min of isoflurane anesthesia, both plasma free fatty acid concentrations and palmitate turnover had decreased by more than 70% (P less than 0.001) and remained suppressed (P less than 0.001) throughout the remainder of the anesthesia, consistent with decreased lipolysis. Glucose production was increased 10 min (P less than 0.05) following induction of anesthesia and peripheral glucose utilization was decreased following 3.5 h of isoflurane anesthesia (P less than 0.05). These data strongly suggest a widespread and immediate metabolic effect of isoflurane anesthesia, which includes peripheral insulin resistance to glucose disposal, decreased lipolysis, and a progressive increase in protein wasting with increasing duration of anesthesia.
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To estimate the relative contributions of gluconeogenesis and glycogenolysis to the increase in hepatic glucose output (HGO) during glucose counterregulation under conditions simulating clinical insulin hypoglycemia, we induced moderate hypoglycemia (approximately 55 mg/dl) with a continuous infusion of insulin that resulted in physiological hyperinsulinemia (approximately 20 microU/ml) in eight normal volunteers and estimated gluconeogenesis by two methods: an isotopic approach in which appearance of plasma glucose derived from lactate was determined and another approach in which we infused alcohol along with insulin to block gluconeogenesis and used the exogenous glucose required to prevent greater hypoglycemia as an index of gluconeogenesis. Both methods gave similar results. Initially glycogenolysis accounted for approximately 85% of HGO; however, once hypoglycemia became established, the contribution of gluconeogenesis increased progressively to 77 +/- 10 (isotopic method) and 94 +/- 10% (alcohol method) of overall HGO. We conclude that in normal humans during moderate protracted hypoglycemia induced by physiological hyperinsulinemia, gluconeogenesis is the predominant factor responsible for the counterregulatory increase in HGO and that increased gluconeogenesis rather than increased glycogenolysis is the primary mechanism preventing development of greater hypoglycemia.
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In man, a decrease in plasma glucose concentration results in a compensatory increase in hepatic glucose release. Studies in vitro have suggested that a low glucose concentration per se may directly stimulate hepatic glucose release, an effect often referred to as autoregulation. Whether autoregulation occurs in man in response to a physiologic decrement in blood glucose is not known. Therefore, seven healthy, nonobese subjects were studied on two occasions to determine the role of autoregulation in mediating the increase in glucose production that accompanies a physiologic decrement in plasma glucose concentration. On both occasions, plasma glucose concentrations were clamped successively at 95, 65, and 95 mg/dl for 2 h each. Insulin (approximately 14 microU/ml) and glucagon (approximately 70 pg/ml) were maintained constant on both occasions by an infusion of somatostatin and insulin. Phentolamine and propranolol also were infused on one occasion to produce combined alpha- and beta-adrenergic blockade. In the absence of adrenergic blockade, glucose production increased by approximately 1.3 mg/kg X min when the plasma glucose concentration was decreased from 95 to 65 mg/dl and decreased by approximately 1.5 mg/kg X min when glucose was increased from 65 to 95 mg/dl. In the presence of adrenergic blockade, the increase and decrease in glucose production averaged 0 and 0.5 mg/kg X min, respectively, representing 70-100% inhibition. We conclude that, in the presence of low physiologic insulin concentrations, autoregulation is not a major contributor to the hepatic response to a physiologic decrement in plasma glucose concentration in man.
To determine the effects of prolonged hyperglycaemia on pancreatic islet A- and B-cell function, plasma glucose was clamped for 12 h at approximately 11 and 5 mmol/l in control experiments by infusing glucose and somatostatin along with replacement amounts of insulin, glucagon, and growth hormone in seven normal volunteers. Following restitution of euglycaemia for 1 h after prolonged hyperglycaemia, termination of the somatostatin-replacement hormone infusions resulted in a sustained decrease in plasma glucose to 3 mmol/l (p less than 0.01). Despite this, plasma glucagon did not increase above values observed in control experiments in which plasma glucose did not decrease; moreover, there was a persistent increase in insulin secretion nearly threefold above that observed in control experiments (p less than 0.01). Plasma growth hormone, cortisol and adrenaline responses were appropriate. This failure of a decrement in plasma glucose to suppress insulin secretion and to stimulate glucagon secretion was not observed when comparable hypoglycaemia was induced by exogenous insulin after a prolonged euglycaemic clamp. Our results indicate that hyperglycaemia can induce altered sensitivity of pancreatic A and B cells to glucose and suggest that abnormal A- and B-cell responses to glucose in diabetes mellitus may not represent a wholly intrinsic defect.
Human pancreatic polypeptide (HPP) increases after insulin-induced hypoglycemia. To determine whether adrenergic mechanisms contribute to this increase in normal man, six subjects were studied on two occasions: once after insulin alone and once after insulin plus simultaneous alpha (phentolamine)- and beta (propranolol)-adrenergic blockade. Despite comparable hypoglycemia (51 +/- 4 vs. 49 +/- 4 mg/dl), the increase in HPP did not differ in the presence or absence of adrenergic blockade (721 +/- 215 vs. 736 +/- 193 pg/ml, respectively). These findings suggest that HPP secretion during hypoglycemia is not dependent on adrenergic mechanisms.