Glucose turnover and metabolic and hormonal changes in ethanol-induced hypoglycaemia.

Infusion of 67 g ethanol over four hours in fasted, non-obese normal men (a) induced hypoglycaemia by inhibiting gluconeogenesis; (b) produced noticeable increases in blood lactate, 3-hydroxybutyrate, and free fatty acid concentrations; (c) depressed plasma growth hormone concentrations, despite hypoglycaemia; and (d) raised plasma cortisol concentrations before significant hypoglycaemia occurred. These metabolic changes were explained by the reduction of redox state which accompanies ethanol oxidation. The pronounced changes in metabolic values recorded during this study suggested that the use of parenteral feeding regimens including ethanol needs to be reconsidered.     

Psychomotor performance during insulin-induced hypoglycemia

Subjects were given intravenous injections of insulin and/or saline on separate occasions and then tested on a pursuit-tracking task. Seven subjects showed clear clinical signs of hypoglycemia which were accompanied by a plasma glucose concentration of 32 mg/dl or less and by impaired tracking performance. Seven subjects showing no hypoglycemic signs despite insulin, and seven subjects receiving saline injections, showed no impairment in tracking. Impairment lasted from about the 15th to the 60th minute following injection, and was more readily apparent in response execution than response selection. There were no changes in accuracy of performance. Possible explanatory mechanisms, including neuroglycopenia, are discussed, and some implications for driving performance are noted.     

Brain angiotensin receptors and sympathoadrenal regulation during insulin-induced hypoglycemia

Simultaneous blockade of systemic AT1 and AT2 receptors or converting enzyme inhibition (CEI) attenuates the hypoglycemia-induced reflex increase of epinephrine (Epi). To examine the role of brain AT1 and AT2 receptors in the reflex regulation of Epi release, we measured catecholamines, hemodynamics, and renin during insulin-induced hypoglycemia in conscious rats pretreated intracerebroventricularly with losartan, PD-123319, losartan and PD-123319, or vehicle. Epi and norepinephrine (NE) increased 60-and 3-fold, respectively. However, the gain of the reflex increase in plasma Epi (Deltaplasma Epi/Deltaplasma glucose) and the overall Epi and NE responses were similar in all groups. The ensuing blood pressure response was similar between groups, but the corresponding bradycardia was augmented after PD-123319 (P < 0.05 vs. vehicle) or combined losartan and PD-123319 (P < 0.01 vs. vehicle). The findings indicate 1) brain angiotensin receptors are not essential for the reflex regulation of Epi release during hypoglycemia and 2) the gain of baroreceptor-mediated bradycardia is increased by blockade of brain AT2 receptors in this model.     

ACTH-, glucose- and lactate-content of swine plasma during insulin-induced hypoglycemia]

The present investigation was undertaken to determine the content of ACTH, glucose and lactate in plasma of 4 pigs (body weight 82--118 kg) during a circadian period and during an insulin hypoglycemia test using 1 IU/kg in 3 pigs (body weight 96--118 kg) and 4 pigs (body weight 20--30 kg). The plasma ACTH level at rest was 57 +/- 27 pg/ml (Mean +/- SE) for all samples in all animals during a circadian period. Significant diurnal changes were not observed. During insulin-induced hypoglycaemia plasma ACTH rose from a mean (+/- SE) basal level of 35 +/- 15 to a maximum of 673 +/- 100 pg/ml at 60 min in heavier pigs and in lighter pigs to 395 +/- 153 at 30 min and 403 +/- 145 pg/ml at 120 min. Initial ACTH responses were evident 30 min (heavier pigs) and between 0 and 15 min (lighter pigs) after insulin administration. Plasma glucose decreased from a mean (+/- SE) basal level of 80 +/- 10 to a minimum of 6 +/- 1 mg/100 ml at 60 min (heavier pigs) and from 88 +/- 3 to 16 +/- 4 mg/100 ml at 60 min (lighter pigs). After its minimum level the glucose concentration showed a slower increment in the heavier pigs as compared to lighter animals. Plasma lactate rose from a mean (+/- SE) basal level of 19 +/- 10 to a maximum of 76 +/- 42 mg/100 ml at 120 min (heavier pigs) and from 12 +/- 3 to 37 +/- 16 mg/100 ml at 150 min (lighter group). In accordance with the changes in the blood plasma levels of ACTH, glucose and lactate, the clinical symptoms of hypoglycaemia in heavier pigs were more intensive.     

Magnesium sulfate attenuates increased blood-brain barrier permeability during insulin-induced hypoglycemia in rats

Magnesium probably protects brain tissue against the effects of cerebral ischemia, brain injury and stroke through its actions as a calcium antagonist and inhibitor of excitatory amino acids. The effects of magnesium sulfate on cerebrovascular permeability to a dye, Evans blue, were studied during insulin-induced hypoglycemia with hypothermia in rats. Hypoglycemia was induced by an intramuscular injection of insulin. After giving insulin, each animal received MgSO4 (270 mg/kg) ip, followed by a 27 mg/kg dose every 20 min for 2.5 h. Plasma glucose and Mg2+ levels of animals were measured. Magnesium concentrations increased in the serum following MgSO4 administration (6.05+/-0.57 vs. 2.58+/-0.14 mg/dL in the Mg2+ group, and 7.14+/-0.42 vs. 2.78+/-0.06 mg/dL in the insulin + Mg2+ group, P < 0.01). Plasma glucose levels decreased following hypoglycemia (4+/-0.66 vs. 118+/-2.23 mg/dL in the insulin group, and 7+/-1.59 vs. 118+/-4.84 mg/dL in the insulin + Mg2+ group, P < 0.01). Blood-brain barrier permeability to Evans blue considerably increased in hypoglycemic rats (P < 0.01). In contrast, blood-brain barrier permeability to Evans blue was significantly reduced in treatment of hypoglycemic rats with MgSO4 (P < 0.01). These results indicate that Mg2+ greatly reduced the passage of exogenous vascular tracer bound to albumin into the brain during hypoglycemia with hypothermia. Mg2+ could have protective effects on blood-brain barrier permeability against insulin-induced hypoglycemia.     

Somatostatin concentration and binding in the rat hypothalamus and striatum during severe insulin-induced hypoglycemia

Hypoglycemia was induced by administration of insulin (40 I.U./kg) to 24 h fasted rats. Somatostatinlike immunoreactivity (SLI) and¹²⁵I-Tyr¹¹-somatostatin binding were measured in the striatum and hypothalamus at the onset of hypoglycemic coma (5–10 min). No significant changes in SLI concentration were detected in either site although the total number of specific somatostatin receptors in the striatum membranes, but not in the hypothalamus, decreased in insulin-injected rats when compared with the control group.     

Metabolic and hormonal parameters after insulin-induced hypoglycemia in man, comparison between biosynthetic human insulin and purified pork insulin

Although clinically undistinguishable, some authors have found important differences in the counterregulatory response between Biosynthetic Human Insulin (BHI) and Purified Pork Insulin (PPI). To reassess the problem 10 healthy volunteers of both sexes underwent paired iv insulin tolerance test with both BHI and PPI (0.10 U/kg b.w.). To check the humoral response the variations of glucose, free fatty acids (FFA), prolactin, growth hormone, ACTH and plasma renin activity were evaluated. Blood glucose depression and further recovery by BHI and PPI administration paralleled each other, so were, prolactin, FFA, and plasma renin activity. A slight section of ACTH, and GH was observed under BHI challenge. There were not statistically significant differences between both insulins on any of the six parameters studied. The data do not confirm earlier published reports indicating hormonal and metabolic differences between human and porcine insulin.     

Increased dopamine and serotonin metabolites in CSF during severe insulin-induced hypoglycemia in freely moving rats

The effect of insulin on dopamine (DA) and serotonin (5-HT) metabolites was determined in the cerebrospinal fluid (CSF) of the rat and compared with glucose levels in blood and CSF. CSF was continuously withdrawn from the third ventricle of freely moving rats at a constant rate of 1 μl/min. Liquid chromatography with electrochemical detection was used for the direct assay of DA and 5-HT metabolites in the CSF. The metabolites were stable during the first hour after insulin injection (6IU/Kg). A progressive increase occurred thereafter in animals which had no access to food during the time of the experiment. The maximal effect was observed 2.5 h after insulin, with respective mean increases of 80% for dihydroxyphenylacetic acid, 47% for homovanillic acid and 33% for 5-hydroxyindolacetic acid. These increases in monoamine metabolites were not observed when rats received glucose (5g/Kg ip) 45 min after insulin or when food was made available. The period for insulin-induced increase in DA and 5-HT metabolites corresponded to a maximal fall of glucose levels both in blood and CSF although the CSF glucose decrease was delayed when compared to the fall of blood glucose. The role of brain glucose and brain insulin in the control of central DA and 5-HT metabolism is discussed.     

Effect of anaesthesia on insulin-induced hypoglycemia in rabbits

The aim of this study was to determine how anaesthetized rabbits survive much longer than awake rabbits after receiving an insulin overdose. Insulin appeared to act in both groups of rabbits because there was a prompt fall in circulating glucose, free fatty acids, and beta-hydroxybutyrate concentrations. Carbohydrate appeared to be the principal energy source for anaesthetized rabbits because their respiratory quotient approached unity. Although the fall in glycemia was similar in both groups of rabbits, the circulating lactate concentration rose only in the anaesthetized group. This rise in lactate in the initial 60 min after insulin was given could account for most of the fall in glycemia if the source of lactate was the glucose pool. The decline in hepatic glycogen was close to 100 mumol/g liver; this would account for about one-third of the total energy turnover and close to one-half of the measured glucose appearance in these anaesthetized rabbits. As judged from the rate of oxygen consumption, muscle glycogen seemed to supply two-thirds of the fuel to be oxidized in these rabbits. However, only one-third of the lactate released from muscle was first converted to glucose and the remainder was oxidized directly to CO2. Although insulin provided the metabolic setting for a rapid rate of glucose oxidation, this rate appeared to be diminished when the overall rate of oxygen consumption was lower during anaesthesia.     

Effects of aging on thermoregulatory responses and hormonal changes in humans during the four seasons in Japan

Physiological functions are impaired in various organs in aged people, as manifest by, e.g., renal and cardiac dysfunction and muscle atrophy. The elderly are also at increased risk of both hypothermia and hyperthermia in extreme temperatures. The majority of those over 65 years old have elevated serum osmolality. Our hypothesis is that the elderly have suppressed osmolality control in different seasons compared to the young. Eight healthy young men and six healthy older men participated in this study. The experiments were performed during spring, summer, autumn and winter in Japan, with average atmospheric temperatures of 15–20°C in spring, 25–30°C in summer, 15–23°C in autumn and 5–10°C in winter. Each subject immersed his lower legs in warm water at 40°C for 30 min. Core (tympanic) temperature and sweat rate at chest were recorded continuously. Blood was taken pre-immersion to measure the concentrations of antidiuretic hormone, serum osmolality, plasma renin activity, angiotensin II, aldosterone, leptin, thyroid stimulating hormone, fT₃ and fT₄. The results suggested that the elderly have suppressed osmolality control compared to the young; osmolality was especially elevated in winter compared to the summer in elderly subjects. Therefore, particularly in the elderly, balancing fluid by drinking water should be encouraged to maintain euhydration status in winter.     

Effects of beta-selective blockade on levels of glucagon in blood plasma during insulin-induced hypoglycemia

The effects of beta-selective blockade with metoprolol on the glucagon blood plasma level during insulin-induced hypoglycemia were studied in 20 control dogs, and 20 alloxan diabetic dogs. The results indicate that the sensitivity to exogenous insulin is increased in alloxan diabetes glucose counterregulatory mechanisms are impaired. After insulin administration glucagon concentration increased much more and quicker in the control group than in diabetic dogs. Beta-blockade with metoprolol increased glucagon secretion in both groups.     

Hormonal and metabolic counterregulation during and after high-dose insulin-induced hypoglycemia in diabetes mellitus type 2.

Non-obese type 2 diabetic subjects in good metabolic control (n=6, HbA1c 7.0 +/- 0.3%, mean diabetes duration: 5.7 +/- 1 years) and matched non-diabetic subjects (control; n = 6) were studied during hyperinsulinemic (approximately 3 nmol/l)-hypoglycemic (approximately 3.1 mmol/l) clamp tests (0-120 min) and the subsequent recovery period (120-240 min). Plasma glucagon rose gradually but not significantly, whereas norepinephrine and epinephrine similarly increased approximately 2 and approximately 25-fold in both groups. Islet amyloid polypeptide (IAPP) decreased to approximately 41% and approximately 24% of basal values during hypoglycemia and rapidly rose approximately 4.7-fold during the recovery period, while plasma C-peptide remained suppressed in both groups. Within 140 min, plasma free fatty acids similarly decreased to approximately 70 micromol/l (p < 0.05), but then rose to values being approximately 50% higher in diabetic than in control subjects (240 min: 907 +/- 93 vs. 602 +/- 90 micromol/l; p < 0.05). Glucose infusion rates were comparable during hypoglycemia, but approximately 40% lower during recovery in diabetic patients (1.88 +/- 0.27 vs. 3.44 +/- 0.27 mg x kg(-1) x min(-1), p < 0.001). These results demonstrate that (i) hypoglycemia induced by high-dose insulin largely abolishes the counterregulatory response of glucagon, but not of catecholamines in nondiabetic and well-controlled type 2 diabetic subjects, (ii) the rapid posthypoglycemic increase of plasma IAPP occurs independently of plasma insulin, and (iii) the superior rise in plasma free fatty acids may account at least in part for the posthypoglycemic insulin resistance of type 2 diabetic patients.     

Cortical and hippocampal mitochondria bioenergetics and oxidative status during hyperglycemia and/or insulin-induced hypoglycemia

This study was undertaken to evaluate the effects of streptozotocin (STZ)-induced hyperglycemia and insulin-induced hypoglycemia in cortical and hippocampal mitochondria bioenergetics and oxidative status. For that purpose we used, citrate (vehicle)-treated Wistar rats, STZ-treated rats [i.p., 50 mg/kg body weight] and STZ-treated rats injected with insulin [s.c., dose adjusted to blood glucose levels] 1 h prior to sacrifice to induce an acute episode of hypoglycemia. Several parameters were analyzed: respiratory chain, phosphorylation system, thiobarbituric acid reactive substances (TBARS) levels, hydrogen peroxide (H₂O₂) production rate, and non-enzymatic and enzymatic antioxidant defenses. Cortical mitochondria from insulin-induced hypoglycemic rats present a significant decrease in the ADP/O index, a significant increase in the repolarization lag phase and a decrease in GSH/GSSG ratio when compared with STZ and control mitochondria. Both STZ-induced diabetes and insulin-induced hypoglycemia promote a significant increase in TBARS levels and a decrease in glutathione disulfide reductase activity. Diabetic cortical mitochondria present a significant decrease in glutathione peroxidase (GPx) activity compared to control mitochondria. In turn, insulin-induced hypoglycemia induced a significant increase in GPx and manganese superoxide dismutase (MnSOD) activities. In hippocampal mitochondria, insulin-induced hypoglycemia increases the respiratory control ratio whereas both situations, hyper- and hypoglycemia, potentiate H₂O₂ production and decrease the activity of MnSOD. These results suggest that the poor glycemic control that occurs in type 1 diabetic patients undergoing insulin therapy may have detrimental effects in brain areas involved in learning and memory.     

Glucose acts in the CNS to regulate gastric motility during hypoglycemia

Our purposes were to 1) develop an animal model where intravenously (iv) administered d-glucose consistently inhibited antral motility, and 2) use this model to assess whether iv glucose acts to inhibit motility from a peripheral or a central nervous system site and to elucidate the factor(s) that determine(s) whether stomach motor function is sensitive to changes in blood glucose. Rats were anesthetized with alpha-chloralose-urethane, and antral motility was measured by a strain-gauge force transducer sutured to the antrum. In some cases, antral motility and gastric tone were measured by monitoring intragastric balloon pressure. Increases in blood glucose were produced by continuous iv infusion of 25% d-glucose at 2 ml/h. Inhibition of antral motility and gastric tone was observed when gastric contractions were induced by hypoglycemia (subcutaneously administered insulin, 2.5 IU/animal). In contrast, no inhibition of gastric motor function was observed when glucose infusion was tested on gastric contractions that were 1) spontaneously occurring, 2) evoked by iv administered bethanechol in vagotomized animals, and 3) evoked by the TRH analog RX77368, microinjected into the dorsal motor nucleus of the vagus. Using the model of insulin-induced hypoglycemia to increase gastric motor activity, we found that neither sectioning the hepatic branch of the vagus (n = 5), nor treating animals with capsaicin to destroy sensory vagal afferent nerves (n = 5) affected the ability of iv d-glucose to inhibit gastric motor function. Our results indicate that an important factor determining whether stomach motor function will be sensitive to changes in blood glucose is the method used to stimulate gastric contractions, and that the primary site of the inhibitory action of iv glucose on gastric motility is the central nervous system rather than the periphery.