Hypothalamic-pituitary activation does not differ during human and porcine insulin-induced hypoglycemia in insulin-dependent diabetes mellitus (original) (raw)
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Diabetologia, 1988
Acute insulin-induced hypoglycaemia in humans provokes autonomic neural activation and counterregulatory hormonal secretion mediated in part via hypothalamic stimulation. Many patients with Type I (insulin-dependent) diabetes have acquired deficiencies of counterregulatory hormonal release following hypoglycaemia. To study the integrity of the hypothalamic-pituitary and the sympatho-adrenal systems, the responses of pituitary hormones, beta-endorphin, glucagon and adrenaline to acute insulin-induced hypoglycaemia (0.2 units/kg) were examined in 16 patients with Type l diabetes who did not have autonomic neuropathy. To examine the effect of duration of diabetes these patients were subdivided into two groups (Group 1:8 patients<5 years duration; Group 2:8 patients > 15 years duration) and were compared with 8 normal volunteers (Group 3). The severity and time of onset of hypoglycaemia were similar in all 3 groups, but mean blood glucose recovery was slower in the diabetic groups (p <0.01). The mean responses of glucagon, adrenaline, adrenocorticotrophic hormone, prolactin and be-
Human insulin and awareness of acute hypoglycaemic symptoms in insulin-dependent diabetes
Lancet, 1991
Some insulin-dependent diabetic patients who have clear symptoms of hypoglycaemia during animal insulin treatment have reported loss of these symptoms when human insulin preparations are introduced. A survey of Mersey Region, UK, identified eleven patients whose awareness of hypoglycaemia was lost after introduction of human insulin but returned with animal insulin treatment; seven took part in the study. Acute hypoglycaemia was induced in these patients on two occasions by intravenous infusion of porcine or human soluble insulin (2·5 mU. kg-1, min-1) in random order. There was no significant difference between porcine and soluble insulin in the plasma glucose profile; mean (SEM) plasma glucose fell from 7·1 (0·4) mmol/l to a nadir of 1·5 (0·1) mmol/l with porcine insulin and from 7·1 (0·5) mmol/l to 1 & m i d d o t ; 6 (0·2) mmol/l with human insulin. An acute autonomic reaction occurred in all seven patients, at a similar plasma glucose concentration (1·9 [0·1] mmol/l with porcine insulin; 2·0 [0·2] mmol/l with human insulin). There were no significant differences in the frequency of symptoms or signs of hypoglycaemia between the two insulin species, nor any consistent differences in plasma glucagon, cortisol, growth hormone, adrenaline, or noradrenaline responses to hypoglycaemia. Symptomatic and hormonal responses to acute hypoglycaemia induced by porcine and human soluble insulins therefore seem to be almost indistinguishable, even in patients carefully selected for their apparent loss of hypoglycaemia awareness with human insulin.
Journal of Clinical Investigation, 1976
determinations of glucose outflow and inflow, and rates of gluconeogenesis from alanine, before, during and after insulin-induced hypoglycemia were obtained in relation to alterations in circulating epinephrine, norepinephrine, glucagon, cortisol, and growth hormone in six normal subjects. Insulin decreased the mean (+SEM) plasma glucose from 89+3 to 39+2 mg/dl 25 min after injection, but this decline ceased despite serum insulin levels of 153±22 gtU/ml. Before insulin, glucose inflow and outflow were constant, averaging 125.3±7.1 mg/kg per h. 15 min after insulin, mean glucose outflow increased threefold, but then decreased at 25 min, reaching a rate 15% less than the preinsulin rate. Glucose inflow decreased 80% 15 min after insulin, but increased at 25 min, reaching a maximum of twice the basal rate. Gluconeogenesis from alanine decreased 68% 15 min after insulin, but returned to preinsulin rates at 25 min, and remained constant for the next 25 min, after which it increased linearly. A fourfold increase in mean plasma epinephrine was found 20 min after insulin, with maximal levels 50 times basal. Plasma norepinephrine concentrations first increased significantly at 25 min after insulin, whereas significantly increased levels of cortisol and glucagon occurred at 30 min, and growth hormone at 40 min after insulin. Thus, insulin-induced hypoglycemia in man results from both a decrease in glucose production and an increase in glucose utilization. Accelerated glycogenolysis
AJP: Regulatory, Integrative and Comparative Physiology, 2005
Recently, we established that hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia were impaired in uncontrolled streptozotocin (STZ)-diabetic (65 mg/kg) rats and insulin treatment restored most of these responses. In the current study, we used phloridzin to determine whether the restoration of blood glucose alone was sufficient to normalize HPA function in diabetes. Normal, diabetic, insulin-treated, and phloridzin-treated diabetic rats were either killed after 8 days or subjected to a hypoglycemic (40 mg/dl) glucose clamp. Basal: Elevated basal ACTH and corticosterone in STZ rats were normalized with insulin but not phloridzin. Increases in hypothalamic corticotrophin-releasing hormone (CRH) and inhibitory hippocampal mineralocorticoid receptor (MR) mRNA with STZ diabetes were not restored with either insulin or phloridzin treatments. Hypoglycemia: In response to hypoglycemia, rises in plasma ACTH and corticosterone were significantly...
Symptoms of insulin-induced hypoglycemia in normal subjects
Journal of Psychosomatic Research, 1988
In order to better characterize the psychobiology of hypoglycemic symptom production, six normal subjects had physiological/biochemical and symptom ratings at 20, 30 and 40 min after six different doses of intravenous regular insulin (0.0, 0.5, 1.0, 2.0, 3.0 and 4.0 units, in a Latin-square design); subjects also indicated after each dose whether they believed they had received an active or an inactive substance. Choice response switched from inactive to active substance when plasma glucose fell to the mid to high 50s mg/dl (i.e. whole blood glucose of approximately 50), and plasma epinephrine levels rose to between 100 and 200 pg/ml. Adrenergic symptoms and 'weakness' were most strongly associated with choice; other symptom variables had weaker associations. Symptoms were more strongly correlated with epinephrine than glucose levels, but anxiety was not strongly correlated with the epinephrine increases.
Diabetes, 1993
The aim off this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia in normal humans. Experiments were conducted in 9 normal, lean men, who had fasted overnight. Insulin was infused in two separate, randomized protocols so that steady-state levels of 486 ± 33 (low) and 3056 ± 236 pM (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.07 mM/min) and hypoglycemic plateau (2.8 ± 0.1 mM) were similar. Despite similar plasma glucose levels, EPI (8.7 ± 0.7 vs. 5.5 ± 0.7 nM), NE (3.3 ± 0.3 vs. 2.3 ± 0.2 nM), and cortisol (811 ± 36 vs. 611 ± 72 nM) significantly increased during high compared with low insulin infusion, respectively (P < 0.05). Glucagon, growth hormone, and pancreatic polypeptide levels increased briskly and significantly but were not different during the two insulin infusions. HGP rose significantly from 12.1 ± 0.3 to 18.1 ± 1.1 (imol • kg" 1 • min~1 in response to the high insulin level (P < 0.05) but remained unchanged (12.1 ± 0.4 and 11.7 ± 1. 4 fjtmol • kg" 1 • min~1) in the presence of the low insulin level. GR a increased significantly during high insulin levels (3.4 ± 0.3 to 4.8 ± 0.7 jimol • kg" 1 • min~\ P < 0.05) but remained at a basal rate (3.0 ± 0.3 to 2.7 ± 0.6 jxmol • kg" 1 • min" 1) in the presence of low insulin levels. sBP and heart rate
Role of brain in counterregulation of insulin-induced hypoglycemia in dogs
Diabetes, 1989
The role of the brain in directing counterregulation during hypoglycemia induced by insulin infusion was assessed in overnight-fasted conscious dogs. Concomitant brain and peripheral hypoglycemia was induced in one group of dogs (n = 5) by infusing insulin peripherally at a rate of 3.5 mU k g 1 mirr 1. In another group (n = 4), insulin was infused as described above to induce peripheral hypoglycemia, and brain hypoglycemia was minimized by infusing glucose bilaterally into the carotid and vertebral arteries to maintain the brain glucose level at a calculated concentration of 85 mg/dl. Glucose was also infused peripherally as needed so that the peripheral glucose levels in both of the protocols were similar (45 ± 2 mg/dl with and 48 ± 3 mg/dl without brain glucose infusion, both P < .05). The responses (in terms of change of area under the curve) of epinephrine, norepinephrine, cortisol, and pancreatic polypeptide when brain glycemia was controlled during insulin infusion were only 14 ± 6, 39 ± 12, 17 ± 8, and 9 ± 4%, respectively, of those present during insulin infusion without concomitant brain glucose infusion (all P < .05). Of particular interest was the glucagon response that occurred when head hypoglycemia was minimized; the glucagon level was only 21 ± 8% of that present when marked brain Alanine Cortisol Epinephrine Glucagon Glucose Glycerol
The Journal of Clinical Endocrinology & Metabolism, 2003
Hypoglycemia unawareness is thought to be the consequence of recurrent hypoglycemia, yet the underlying mechanism is still incompletely understood. The aim of the present study was to determine the role of antecedent elevated adrenaline in the pathogenesis of hypoglycemia unawareness. Sixteen healthy volunteers (eight of either sex) participated in two experiments, performed in random order and at least 3 wk apart. During the morning, three consecutive doses of 0.04, 0.06, and 0.08 g⅐kg ؊1 ⅐min ؊1 of adrenaline or matching placebo (normal saline) were infused for the total duration of 1 h. Three hours later, a hyperinsulinemic (360 pmol⅐m ؊2 ⅐min ؊1 ) two-step hypoglycemic (5.0 -3.5-2.5 mmol⅐liter ؊1 ) clamp study was performed. During hypoglycemia, hypoglycemic symptoms, counterregulatory hormones, cardiovascular responses, and cognitive function were monitored. Hypoglycemia in-duced similar responses of autonomic and neuroglycopenic symptoms, counterregulatory hormones, and lengthening in reaction time on the choice reaction time task, irrespective of antecedent infusions. However, prior adrenaline was associated with higher exogenous glucose requirements at hypoglycemic nadir (10.1 ؎ 1.3 vs. 7.3 ؎ 1.3 mol⅐kg ؊1 ⅐min ؊1 , P ؍ 0.017), an attenuated hypoglycemia-induced fall in blood pressure (mean arterial pressure, ؊13 ؎ 2 vs. ؊8 ؎ 2 mm Hg, P ؍ 0.006), and preserved cognitive function as assessed by the symbol digit test during hypoglycemia, when compared with prior placebo. We conclude that elevated adrenaline attenuates the responsiveness to, but not the release of counterregulatory hormones during subsequent hypoglycemia. As such, adrenaline's role in the development of hypoglycemia unawareness is limited. (J Clin Endocrinol Metab 88: 5462-5467, 2003)
Diabetes, 2001
Adrenergic responsiveness to acute hypoglycemia is impaired after prior episodes of hypoglycemia. Although circulating epinephrine responses are blunted, associated alterations in adrenal sympathetic nerve activity (SNA) have not been reported. We examined adrenal nerve traffic in normal conscious rats exposed to acute insulin-induced hypoglycemia compared with insulin with (clamped) euglycemia. We also examined adrenal SNA and catecholamine responses to insulin-induced hypoglycemia in normal conscious rats after two antecedent episodes of hypoglycemia (days ؊2 and ؊1) compared with prior episodes of sham treatment. Acute insulin-induced hypoglycemia increased adrenal sympathetic nerve traffic compared with insulin administration with clamped euglycemia (165 ؎ 12 vs. 118 ؎ 21 spikes/s [P < 0.05]; or to 138 ؎ 8 vs. 114 ؎ 10% of baseline [P < 0.05]). In additional experiments, 2 days of antecedent hypoglycemia (days -2 and -1) compared with sham treatment significantly enhanced baseline adrenal SNA measured immediately before subsequent acute hypoglycemia on day 0 (180 ؎ 11 vs. 130 ؎ 12 spikes/s, respectively; P < 0.005) and during subsequent acute hypoglycemia (229 ؎ 17 vs. 171 ؎ 16 spikes/s; P < 0.05). However, antecedent hypoglycemia resulted in a nonsignificant reduction in hypoglycemic responsiveness of adrenal SNA when expressed as percent increase over baseline (127 ؎ 5% vs. 140 ؎ 14% of baseline). Antecedent hypoglycemia, compared with sham treatment, resulted in diminished epinephrine responsiveness to subsequent hypoglycemia. Norepinephrine responses to hypoglycemia were not significantly altered by antecedent hypoglycemia. In summary, prior hypoglycemia in normal rats increased adrenal sympathetic tone, but impaired epinephrine responsiveness to acute hypoglycemia. Hence, these data raise the intriguing possibility that increased sympathetic tone resulting from antecedent hypoglycemia downregulates subsequent epinephrine responsiveness to hypoglycemia. Alternatively, it is possible that the decrease in epinephrine responsiveness after antecedent hypoglycemia could be the result of reduced adrenal sympathetic nerve responsiveness.
Metabolism Clinical and Experimental, 2003
We previously showed, through direct neural recording in conscious rats, that hypoglycemia increases adrenal sympathetic nerve activity (SNA) both acutely and 24 hours following the second of 2 daily antecedent hypoglycemic episodes. Nonetheless, antecedent hypoglycemia impaired catecholamine responsiveness to subsequent acute hypoglycemia. Here we hypothesized that antecedent, nonhypoglycemic adrenal sympathetic stimulation by leptin would impair acute adrenal catecholamine responsiveness to subsequent hypoglycemia. We also hypothesized that acute leptin administration (after 2 days of antecedent hypoglycemia) would enhance adrenal SNA and thereby enhance catecholamine responsiveness to concurrent hypoglycemia. Leptin or saline was administered to normal rats in repeated subcutaneous injections for 2 days prior to acute insulin-induced hypoglycemia. In contrast to our hypothesis, antecedent leptin did not change catecholamine responsiveness or glycemic change in response to subsequent acute insulin administration. In additional studies, intravenous leptin or saline was acutely administered beginning 1 hour before insulin-induced hypoglycemia. All rats had been exposed to antecedent hypoglycemia. In these experiments, acute leptin did not alter catecholamine responses to insulin or glycemic change during or after termination of insulin. We conclude that antecedent nonhypoglycemic sympathetic stimulation by leptin does not alter subsequent catecholamine or glycemic responses to insulin. Moreover, concurrent leptin does not enhance catecholamine responses to insulin in rats exposed to antecedent hypoglycemia.