Hypoglycemia In Humans Research Articles

Leucocyte Mobilization and Release of Neutrophil Elastase Following Acute Insulin‐induced Hypoglycaemia in Normal Humans

Insulin-induced hypoglycaemia in humans is associated with the rapid mobilization of leucocytes in peripheral blood. The aim of the present study was to determine whether neutrophil activation, manifested in plasma by neutrophil elastase concentration, occurs in response to insulin-induced hypoglycaemia. Acute hypoglycaemia (mean blood glucose 1.3 +/- 0.2 mmol l-1; mean +/- SD) was induced with intravenous insulin in 15 normal human subjects, and provoked an increase in the neutrophil count from 3.4 (range 1.9-6.5) to 10.7 (9.4-16.3) X 10(9) l-1 (p less than 0.001), and in the total leucocyte counts from 5.7 (4.1-8.1) to 12.8 (11.3-18.6) X 10(9) l-1 (p less than 0.001), with associated elevations in plasma neutrophil elastase concentration from 21 (12-34) to 29 (14-70) micrograms l-1 (p less than 0.05), and in total neutrophil elastase concentration from 5.90 (3.13-8.20) to 25.20 (23.00-52.00) mg l-1 (p less than 0.001). As neutrophil elastase is implicated in the development of vascular disease, this rise in response to hypoglycaemia may be of pathological importance in insulin-treated diabetic patients.

Effect of Angiotensin-Converting Enzyme Inhibition on Pituitary Hormone Responses to Insulin-Induced Hypoglycemia in Humans*

Renin, angiotensin-II, and angiotensin-converting enzyme (ACE) have been found in the hypothalamus and pituitary in rats, and renin, angiotensinogen, and ACE have been found in human pituitary lactotrophs. To determine the physiological relevance of the renin-angiotensin system in the pituitary hormone response to stress in humans, we created significant inhibition of ACE by administering a clinically used dose (10 mg) of enalapril (E) 4 h before measuring the stress hormone responses to insulin-induced hypoglycemia. Eight fasting lean healthy males (aged 20-35 yr) were given either placebo (P) or E (10 mg, orally) in two studies separated by at least 5 days in a blinded study design. Glucose, ACTH, cortisol, PRL, and GH levels were measured before E or P and at 20-min intervals beginning 20 min before insulin administration. ACE levels were similar at baseline (E, 21.6 +/- 2.7; P, 22.4 +/- 2.4 mU/mL/min), but were significantly lower at the time of insulin injection with E treatment (E, 2.9 +/- 0.5; P, 20.9 +/- 2.5 mU/mL/min; P less than 0.001). The mean of the total area under the curve of PRL secretion was significantly lower for the E group (E, 3767.2 +/- 710.7; P, 4554.9 +/- 650.1 micrograms/L.min; P less than 0.05). Although the mean peak PRL levels were lower for the E group, this did not reach statistical significance (E, 53.0 +/- 9.7; P, 64.4 +/- 9.4 micrograms/L; 0.05 less than P less than 0.10). These differences in PRL responses appeared to be due primarily to substantial decreases in PRL responses with E in three of the eight subjects. No significant differences were found with ACTH, cortisol, or GH for basal levels, peak levels, or areas under the curve.

Cardiac responses to acute insulin-induced hypoglycemia in humans

The effects of acute hypoglycemia on the heart and cardiovascular system were examined in humans using radioisotopic techniques, complemented by measurement of heart rate and blood pressure. The heart rate increased from 62 +/- 3 to 87 +/- 3 beats/min in response to hypoglycemia; this increase was accompanied by a significant increase in systolic blood pressure, a fall in diastolic blood pressure, with no change in the mean arterial blood pressure. The left ventricular ejection fraction increased from 47 +/- 3 (SE) to 72 +/- 5% in response to hypoglycemia. The increases in heart rate and ejection fraction were abolished during parenteral nonselective beta-adrenergic blockade with propranolol but were unaffected by either alpha-adrenergic blockade with phentolamine or cholinergic blockade with atropine. During beta-adrenergic blockade, there were significant increases in diastolic and mean arterial blood pressure in response to hypoglycemia. During alpha-adrenergic blockade the systolic, diastolic, and mean arterial pressures fell significantly after hypoglycemia. The blood pressure responses to hypoglycemia were unaffected by cholinergic blockade. Thus the increases in ejection fraction and in heart rate in response to hypoglycemia are mediated by beta-adrenoreceptors, whereas the blood pressure responses to hypoglycemia are mediated by alpha- and by beta-adrenoreceptors.

Splenic responses to acute insulin-induced hypoglycaemia in humans

1. The effects of acute hypoglycaemia on the spleen were examined in normal humans using radioisotopic techniques, complemented by ultrasonic examination of the spleen. Hypoglycaemia had a modest effect on splenic area, measured by ultrasonography, which declined to 62 +/- 6% (mean +/- SEM) of the basal value after the onset of the acute hypoglycaemic reaction. 2. Hypoglycaemia had a pronounced effect on the splenic radioactivity, which decreased significantly to a mean of 10 +/- 7% of basal radioactivity at 15 min after the onset of hypoglycaemia. The splenic image completely disappeared at some time after hypoglycaemia in all subjects. 3. The reduction of splenic radioactivity was abolished during non-selective alpha-adrenergic blockade with phentolamine, but was unaffected by beta-adrenergic blockade with propranolol, or cholinergic blockade with atropine, which suggests that the response of vessels perfusing the spleen is mediated by alpha-adrenoceptors.

Effect of Plasma Amino Acid Replacement on Glucagon and Substrate Responses to Insulin-Induced Hypoglycemia in Humans

A defective glucagon response impairs glucose recovery from insulin-induced hypoglycemia in some insulin-dependent (type I) diabetic patients. Our objective was to determine whether the glucagon response to insulin-induced hypoglycemia could be stimulated in nondiabetic humans. Because insulin reduces plasma amino acid concentrations, and amino acids are known to stimulate glucagon secretion, we investigated the effect of amino acid replacement during insulin infusion on the glucagon response to hypoglycemia in six healthy nondiabetic subjects. In two separate studies, blood glucose was clamped at the postabsorptive level during a constant infusion of insulin (0.05 U.kg-1.h-1) for 3 h. Blood glucose was then reduced to 45 mg/dl over 20 min. Hormone and substrate concentrations during recovery from hypoglycemia were monitored for 2 h. In the control study, normal saline was infused, and in the other study, an amino acid mixture was infused to prevent the insulin-induced fall in plasma amino acids. Amino acid replacement did not change the basal glucagon levels but resulted in a more robust glucagon response to hypoglycemia (from 184 +/- 24 to 292 +/- 36 pg/ml) than in the control study (from 176 +/- 30 to an average 229 +/- 32 pg/ml, P less than 0.01). Plasma concentrations of epinephrine, norepinephrine, cortisol, and growth hormones increased during hypoglycemia, but the magnitude of the response was not different between the control and amino acid-replacement studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of plasma amino acid replacement on glucagon and substrate responses to insulin-induced hypoglycemia in humans

Effect of plasma amino acid replacement on glucagon and substrate responses to insulin-induced hypoglycemia in humans

The effect of α‐adrenergic blockade on responses of peripheral blood cells to acute insulin‐induced hypoglycaemia in humans

Acute hypoglycaemia provokes rapid changes in peripheral blood cell counts. To examine possible adrenergic mechanisms modulating these changes, counts of peripheral blood cells including lymphocytes, granulocytes and erythrocytes were measured in response to acute hypoglycaemia in a group of six normal subjects in control conditions (study 1), and during alpha-adrenergic blockade with phentolamine (study 2). In study 1 hypoglycaemia provoked a biphasic leucocyte response, with an early rise in lymphocyte count and a later rise in granulocyte count. The erythrocyte count increased modestly following hypoglycaemia. During alpha-adrenergic blockage, the rise in total leucocyte count was diminished, with the rise in the lymphocyte count being greatly obtunded. These findings suggest that the increments of peripheral lymphocyte and erythrocyte counts in response to acute insulin-induced hypoglycaemia are mediated via alpha-adrenoreceptors.

Change in hexose distribution volume and fractional utilization of [18F]-2-deoxy-2-fluoro-D-glucose in brain during acute hypoglycemia in humans

Change in hexose distribution volume and fractional utilization of [18F]-2-deoxy-2-fluoro-D-glucose in brain during acute hypoglycemia in humans

Change in Hexose Distribution Volume and Fractional Utilization of [18F]-2-Deoxy-2-Fluoro-D-Glucose in Brain During Acute Hypoglycemia in Humans

We used positron emission tomography (PET) to study the effects of mild hypoglycemia on cerebral glucose uptake and metabolism. Nine healthy men were studied under basal saline-infusion conditions, and during euglycemic and hypoglycemic clamp studies. Insulin was infused at the same rate (1 mU.kg-1.min-1) in both clamp studies. In euglycemic clamp studies, glucose was infused at a rate sufficient to maintain the basal plasma glucose concentration, whereas in hypoglycemic clamp studies, the glucose infusion rate was reduced to maintain the plasma glucose at 3.1 mM. Each study lasted 3 h and included a 30-min baseline period and a subsequent 150-min period in which insulin or glucose was administered. Blood samples for measurement of insulin, glucose, cortisol, growth hormone, and glucagon were obtained at 20- to 30-min intervals. A bolus injection of 5-10 mCi [18F]-2-deoxy-2-fluoro-D-glucose (2-DFG) was administered 120 min after initiation of the study, and plasma radioactivity and dynamic PET scans were obtained at frequent intervals for the remaining 40-60 min of the study. Cerebral regions of interest were defined, and concentrations of radioactivity were calculated and used in the three-compartment model of 2-DFG distribution described by Sokoloff. Glucose levels were similar during saline-infusion (4.9 +/- 0.1 mM) and euglycemic clamp (4.8 +/- 0.1 mM) studies, whereas the desired degree of mild hypoglycemia was achieved during the hypoglycemic clamp study (3.1 +/- 0.1 mM, P less than 0.05). The insulin level during saline infusion was 41 +/- 7 pM.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma volume changes during hypoglycaemia: The effect of arterial blood sampling

To investigate whether previously reported changes in venous blood volume and composition induced by acute hypoglycaemia in humans are representative for the entire body we measured erythrocyte 51Cr content, haematocrit, plasma volume, intravascular albumin content and transcapillary escape rate of albumin in arterial and venous blood in seven healthy subjects before and during insulin-induced hypoglycaemia. In both vascular sites blood 51Cr content and the haematocrit increased, plasma volume and intravascular albumin content decreased and the transcapillary escape rate of albumin increased during hypoglycaemia. The magnitude of the changes in arterial and venous blood were not significantly different. These results indicate that the above changes in blood volume and composition are whole-body phenomena: furthermore, the major part of the changes are likely to occur in tissues other than upper extremity muscles.

Naloxone abolishes the inhibiting effect of somatostatin on the release of oxytocin evoked by insulin-induced hypoglycemia in humans

The effect of somatostatin (SRIH) on the release of oxytocin (OT) in response to hypoglycemia during insulin tolerance test (ITT) was studied in seven normal men. Subjects were injected intravenously with 0.15 U/kg insulin alone (control test) or together with SRIH (4.1 μg/min × 90 min), naloxone (10 mg in an IV bolus), or the combination of the two substances. Plasma OT concentrations rose significantly during ITT; the OT response was significantly reduced by the treatment with SRIH and increased in the presence of naloxone. When both SRIH and naloxone were given, the OT response to hypoglycemia did not differ from that observed in the control test. These findings provide evidence that the effect of hypoglycemia on plasma OT levels is sensitive to the inhibition by SRIH and by naloxone-sensitive endogenous opioids. Because naloxone reversed the inhibiting effects of SRIH, an involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opioids might produce their inhibiting effects on OT rise in response to hypoglycemia through independent pathways.

Contribution of cortisol to glucose counterregulation in humans.

To test the hypothesis that cortisol secretion plays a counterregulatory role in hypoglycemia in humans, four studies were performed in eight normal subjects. In all studies, insulin (15 mU.m-2.min-1) was infused subcutaneously (plasma insulin 27 +/- 1 microU/ml). In study 1, plasma glucose concentration and glucose fluxes [( 3-3H]glucose), substrate, and counterregulatory hormone concentrations were simply monitored, and plasma glucose decreased from 89 +/- 2 to 52 +/- 2 mg/dl for 12 h. In study 2, (pituitary-adrenal-pancreatic clamp), insulin and counterregulatory hormone secretion (except for catecholamines) was prevented by somatostatin (0.5 mg/h, iv) and metyrapone (0.5 g/4 h, per os), and glucagon, cortisol, and growth hormone were infused to reproduce the concentrations of study 1. In study 3 (lack of cortisol increase), the pituitary-adrenal-pancreatic clamp was performed with maintenance of plasma cortisol at basal levels, and glucose was infused, whenever needed, to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. Isolated lack of cortisol increase caused a approximately 22% decrease in hepatic glucose production (P less than 0.01) and a approximately 15% increase in peripheral glucose utilization (P less than 0.01), which resulted in greater hypoglycemia (37 +/- 2 vs. 52 +/- 2 mg/dl, P less than 0.01) despite compensatory increases in plasma epinephrine. Lack of cortisol response also reduced plasma free fatty acid, beta-hydroxybutyrate, and glycerol concentrations approximately 50%. We conclude that cortisol normally plays an important counterregulatory role during hypoglycemia by augmenting glucose production, decreasing glucose utilization, and accelerating lipolysis.

Demonstration of a role for growth hormone in glucose counterregulation

To test the hypothesis that growth hormone secretion plays a counterregulatory role in prolonged hypoglycemia in humans, four studies were performed in nine normal subjects. Insulin (15 mU.M-2.min-1) was infused subcutaneously (plasma insulin 27 +/- 2 microU/ml), and plasma glucose decreased from 88 +/- 2 to 53 +/- 1 mg/dl for 12 h. In study 1, plasma glucose, glucose fluxes (D-[3-3H]glucose), substrate, and counterregulatory hormone concentrations were simply monitored. In study 2 (pituitary-adrenal-pancreatic clamp), insulin and counterregulatory hormone secretions (except for catecholamines) were prevented by somatostatin (0.5 mg/h iv) and metyrapone (0.5 g/4 h po), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of growth hormone increase), the pituitary-adrenal-pancreatic clamp was performed with maintenance of plasma growth hormone at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. Isolated lack of a growth hormone response caused a decrease in hepatic glucose production and an increase in glucose utilization that resulted in an approximately 25% greater hypoglycemia despite compensatory increases in plasma catecholamines. Plasma free fatty acid, 3-beta-hydroxybutyrate, and glycerol concentrations were reduced approximately 50%. It is concluded that growth hormone normally plays an important counterregulatory role during hypoglycemia by augmenting glucose production, decreasing glucose utilization, and accelerating lipolysis.

Relationship between changes in glucose production and gluconeogenesis during mild hypoglycemia in humans

We measured 14C-alanine conversion to 14C-glucose (an index of gluconeogenesis) and glucose production in six healthy volunteers during low-dose insulin infusion (0.3 mU/kg · min for four hours). Insulin rose from 7 ± 2 to 20 ± 2 μU/mL, and plasma glucose fell to a plateau of 65 to 70 mg/dL after 60 minutes. Glucagon and catecholamines increased after 60 minutes, whereas C-peptide decreased immediately. Glucose production decreased transiently by 43% and then returned to baseline after 45 minutes. In contrast, 14C-alanine conversion to 14C-glucose was unchanged for 120 minutes, but then rose twofold above baseline by 240 minutes. Our data suggest that early recovery of glucose production during mild hyperinsulinemia occurs independent of changes in gluconeogenesis. However, gluconeogenesis plays an increasingly more important role in maintaining glucose production when mild hypoglycemia is prolonged.

Maintenance of high-energy brain phosphorous compounds during insulin-induced hypoglycemia in men. 31P nuclear magnetic resonance spectroscopy study.

31P nuclear magnetic resonance (NMR) spectroscopy allows noninvasive studies of cerebral energy-rich phosphorous compounds in humans. In an attempt to characterize the relationship between peripheral blood glucose concentrations and whole-brain phosphate metabolism during insulin-induced hypoglycemia, 31P NMR spectra were obtained before and after intravenous injection of insulin (0.15 IU/kg body wt) in six men. Compared with prehypoglycemic measurements, no significant changes were found in brain content of Pi, sugar phosphates, phosphocreatine, phosphodiesters, and ATP, and brain pH remained constant during the experiment. These results show that the integrated brain profile of energy-rich phosphorous compounds is unaffected by experimental insulin-induced hypoglycemia in humans.

Bombesin inhibits growth hormone response to insulin-induced hypoglycemia in humans

Intravenous administration of bombesin (5ng/kg/min× 2.5h) significantly reduced growth hormone (GH) response to insulin-induced (0.15 U/kg, i.v.) hypoglycemia in 8 male volunteers without affecting its basal plasma levels. These data, together with the presence of bombesin-like immunoreactivity in the human brain, suggest that — as in experimental animals — this neurogastrointestinal peptide may be of physiological significance in the control of GH secretion also in man.

Role of hepatic autoregulation in defense against hypoglycemia in humans.

To assess the role of hepatic autoregulation in defense against hypoglycemia, we compared the effects of complete blockade of glucose counterregulation with those of blockade of only neurohumoral counterregulation during moderate (approximately 50 mg/dl) and severe (approximately 30 mg/dl) hypoglycemia induced by physiologic hyperinsulinemia during subcutaneous infusion of insulin in normal volunteers. Compared with observations in control experiments, neurohumoral counterregulatory blockade (somatostatin, propranolol, phentolamine, and metyrapone), during which identical moderate hypoglycemia was achieved using the glucose clamp technique, resulted in suppressed glucose production (0.62 +/- 0.08 vs. 1.56 +/- 0.07 mg/kg per min at 12 h, P less than 0.01) and augmented glucose utilization (2.17 +/- 0.18 vs. 1.57 +/- 0.07 mg/kg per min at 12 h, P less than 0.01). Complete blockade of counterregulation (neurohumoral blockade plus prevention of hypoglycemia) did not further enhance the suppressive effects of insulin on glucose production. However, when severe hypoglycemia was induced during neurohumoral counterregulatory blockade, glucose production was nearly two times greater (1.05 +/- 0.05 mg/kg per min at 9 h) than that observed during complete counterregulatory blockade (0.58 +/- 0.08 mg/kg per min at 9 h, P less than 0.01) and that observed during mere neurohumoral blockade with moderate hypoglycemia (0.59 +/- 0.06 mg/kg per min at 9 h, P less than 0.01). These results demonstrate that glucose counterregulation involves both neurohumoral and hepatic autoregulatory components: neurohumoral factors, which require only moderate hypoglycemia for their activation, augment glucose production and reduce glucose utilization; hepatic autoregulation requires severe hypoglycemia for its activation and may thus serve as an emergency system to protect the brain when other counterregulatory factors fail to prevent threatening hypoglycemia.

Diabetes Mellitus Following Pentamidine-induced Hypoglycemia in Humans

Four patients, treated with pentamidine because of Pneumocystis carinii pneumonitis, displayed severe fasting hypoglycemia during this treatment. Diabetes mellitus appeared later, requiring insulin therapy in the three of them who survived more than a few weeks. The metabolic study, performed in two cases during the hypoglycemic period, demonstrated inappropriately high insulin levels in the postabsorptive state. 28 +/- 1 microunits/ml (blood glucose 41 +/- 4 mg/dl) and 86 +/- 5 microunits/ml (blood glucose 15 +/- 5 mg/dl) vs. 15 +/- 3 microunits/ml in 10 control subjects and 55 +/- 3 microunits/ml in 6 patients with a verified B-cell tumor, respectively. Poor B-cell secretory responses followed the stimulations by oral glucose (maximal increment over basal: +5 microunits/ml vs. + 40 microunits/ml in control group and +77 microunits/ml in the insulinoma group), by i.v. arginine (maximal increment + 10 and +28 microunits/ml, respectively, vs. +55 in the controls and +90 microunits/ml in the insulinoma group) and by i.v. glucagon (+10 and +23 microunits/ml, respectively) vs. +40 microunits/ml in both the control and the insulinoma groups). Plasma cortisol and glucagon, and the A-cell response to arginine were higher than normal. These high, nonsuppressible, nonstimulable insulin levels and the sequence of hypoglycemia followed by insulin-dependent diabetes mellitus is consistent with the hypothesis of a selective toxicity turned towards the B-cells. In vitro incubation of islets with pentamidine 10(-10) M produced a passive release of insulin, followed by a significant decrease in B-cell response to glucose + theophylline. It is suggested that pentamidine can induce hypoglycemia because of an early cytolytic release of insulin, and then diabetes mellitus because of B-cell destruction and insulin deficiency.

Diabetes mellitus following pentamidine-induced hypoglycemia in humans

Diabetes mellitus following pentamidine-induced hypoglycemia in humans

Pyloric pressure response to insulin-induced hypoglycemia in humans.

The pyloric pressure response to insulin-induced hypoglycemia was studied. Studies were performed in 102 experiments on 38 normal subjects. During insulin-induced hypoglycemia, pyloric pressure increased from 5.5 +/- 1.2 to 10.8 +/- 1.1 mmHg (P less than 0.02). This increase in pyloric pressure ws not due to a direct effect of insulin, duodenal acidification, or the release of corticosteroids or growth hormone. Glucagon doses of 2 and 5 micrograms . kg-1 . h-1 increased pyloric pressure from 4.7 +/- 1.1 to 6.7 +/- 0.5 mmHg (P less than 0.05) and from 4.7 +/- 1.1 to 8.5 +/- 1.1 mmHg (P less than 0.02), respectively. Pyloric pressures were increased to 10.8 +/- 0.9 (P less than 0.01) and 13.0 +/- 1.4 mmHg (P less than 0.01) at 0.1 and 0.2 micrograms . kg-1 . min-1 of epinephrine, respectively. Neither cholinergic blockade nor alpha-adrenergic blockade significantly affected the pyloric pressure response to insulin hypoglycemia. beta-Adrenergic blockade abolished the pyloric pressure responses to both insulin hypoglycemia and epinephrine. Neither beta- nor alpha-adrenergic stimulation altered the basal pyloric pressure. In contrast, the combination of isoproterenol and phenylephrine increased the pyloric pressure significantly from 4.2 +/- 0.8 to 12.0 +/- 1.7 mmHg ( P less than 0.01). These observations suggest that insulin hypoglycemia increases pyloric pressure by an adrenergic mechanism that requires stimulation of both alpha- and beta-receptors.