Effect of antrectomy on gastric secretion induced by insulin hypoglycemia in dogs]

Antrectomy was shown to cause a sharp and stable suppression of the secretory reaction of the fundal glands of the stomach in response to insulin hypoglycemia. Acid and pepsin secretion was reduced two-fold (on the average) as compared to that after histamine stimulation. A tendency to restoration of the secretory parameters was seen in 3 to 5 months; the next 7 months they persisted on a constant level.     

Hepatic glucagon clearance during insulin induced hypoglycemia

Studies concerning the importance of glucagon secretion in hypoglycemic counterregulation have assumed that peripheral levels of glucagon are representative of rates of pancreatic glucagon secretion. The measurement of peripheral levels of this hormone, however, may be a poor reflection of secretion rates because of glucagon's metabolism by the liver. Therefore, in order to understand the relationship between pancreatic glucagon secretion and levels of glucagon in the peripheral blood during hypoglycemia, we evaluated hepatic glucagon metabolism during insulin induced hypoglycemia. Four dogs received an insulin infusion to produce glucose levels less than 50 mg/dl for 45 minutes. In response to this, the delivery of glucagon to the liver increased from 36.7 +/- 5.9 ng/min in the baseline to 322.6 +/- 6.3 ng/min during hypoglycemia. Hepatic glucagon uptake increased proportionally from 13.6 +/- 7.2 ng/min to 103.1 +/- 28.3 ng/min and the percentage of delivered hormone that was extracted did not change (30.8 +/- 13.8% vs 32.9 +/- 11.6%). The absolute amount of glucagon metabolized by the liver was dependent on the rate of delivery and was not directly affected by plasma glucose level per se. To directly study the effect of hypoglycemia on hepatic glucagon metabolism, five dogs were given an exogenous infusion of somatostatin followed by an infusion of glucagon and then administered insulin to produce hypoglycemia. The percent of glucagon extracted by the liver (19.5 +/- 4.9% and 21.3 +/- 6.4%) was not affected by a fall in the plasma glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Impaired pancreatic polypeptide response to insulin hypoglycemia in obese subjects

We have studied the effect of insulin hypoglycemia on the secretion of pancreatic polypeptide (PP) in 14 obese subjects with normal glucose tolerance and in 6 normal controls. Infusion of insulin 0.1 U/kg/h in controls and 0.12 U/kg/h in the obese, for one hour, produced a progressive hypoglycemia, similar in both groups (nadir 2 mmol/l at 50 min). The secretion of PP was less in obese subjects than in controls (peak 116 mmol/l vs 184 pmol/l, P less than 0.01) (integrated secretion sigma delta PP 288 vs 472 pmol/l, P less than 0.01) and was also delayed in the obese subjects beginning at 50 min instead of 40 min. The secretion of glucagon and of C-peptide were not different in the two groups, but the integrated response of ACTH was higher in the obese (sigma delta ACTH 52 pmol/l vs 25 pmol/l, P less than 0.01). The secretory response of growth hormone (STH) was smaller in the obese group (peak 8.6 +/- 1.28 vs 21.4 +/- 6.4 ng/ml, P less than 0.01). The reduced secretion of PP in obese subjects could be due to impaired sensitivity to hypoglycemia of the central control mechanism for PP release. The similarity of the reductions in the secretion of both PP and STH support this hypothesis, although a reduction in the secretory capacity of pancreatic PP cells cannot be excluded.     

Brain serotonin in response to the hypothalamo-hypophyseal-adrenal system to insulin hypoglycemia

The response of hypothalamus-pituitary-adrenal system to insulin administration was studied in the male Wistar rats submitted to a strong and prolonged blockade of serotonin brain synthesis by repetitive injections of p-chlorophenylalanine (PCPA) a 5-hydroxytryptophan inhibitor. After 24, 48, 72 or 96 hours of either one or two doses of PCPA (250 mg/kg, i.p.) were administered with insulin (0.25 UI/kg s.c.), the plasmatic glucose and corticosterone levels being estimated at 0, 30 and 60 minutes. When PCPA was injected twice, the lapse between them was 48 hours. Insulin produced decrease of plasmatic corticosterone values and inhibition of the response to insulin, specially between 48 and 72 hours, for a single management of PCPA, and stronger and more prolonged for the double dose. The fall of serotonin content in brain maintained great correlation with effects referred above. The results support that stimulatory action of insulin on the pituitary-adrenal system is mediated by central serotoninergic neurons and reaffirms the hypothesis that serotonin (5HT) positively modulates the activity of hypothalamus-pituitary-adrenal system.     

Permanence of the cell-to-cell transmission of insulin induced hormonal imprinting

When insulin-treated (imprinted) Chang liver cell cultures were mixed with cultures which did not receive insulin treatment the information of imprinting was transmitted to the cultures which were not in direct contact with insulin. The ability of the cells to transmit imprinting was long lasting and could be detected even after four weeks, when it was nearly of the same degree as at the first measurement. Difference was found between the binding capacity of the receptors of the plasma membrane and those of the nuclear membrane.     

The erythrocyte insulin receptor response to insulin induced hypoglycaemia

The response of the erythrocyte insulin receptor to a prolonged intravenous infusion of insulin has been measured in normal individuals during hypoglycaemia and when hypoglycaemia was prevented by the concurrent infusion of glucose. When euglycaemia was maintained, mean (+/- S.D.) specific insulin binding following the 5 hour insulin infusion was unchanged (6.9 +/- 2.1 to 6.65 +/- 2.2% bound per 2.25 X 10(9) erythrocytes). In the presence of mild hypoglycaemia, mean (+/- SD) specific insulin binding rose from 6.6 +/- 2.3 to 7.6 +/- 2.5% bound per 2.25 X 10(9) erythrocytes (P less than 0.01), after 5 hours. This increase was due to increased receptor affinity. It was not correlated with the increase in the concentration of any individual counter-regulatory hormone. Initial insulin receptor binding correlated strongly with the subsequent decline in plasma glucose concentration (r = 0.9527; P less than 0.01). Thus, acute hyperinsulinaemia, when associated with hypoglycaemia, does not result in downregulation of insulin receptors on erythrocytes but rather results in increased receptor binding. Consequently, the insulin receptor may not play an active role in protecting the individual against acute hypoglycaemia.     

Cerebrolysin inhibits lipid peroxidation induced by insulin hypoglycemia in the brain and heart of mice

As a consequence of enhanced production of oxygen free radicals, lipid peroxidation leads to the degradation of membrane lipids and disturbances of membrane permeability. Lipid peroxidation increases under stress conditions such as hypoxia, ischemia or acidosis as well as in metabolic diseases, e.g. diabetes mellitus. We have shown that subcomatous doses of insulin (6.0 IU/kg) significantly increase thiobarbituric acid reactive substances (TBARs), especially malondialdehyde (MDA) - the endproduct of lipid peroxidation, in the brain and heart of mice. In our model of insulin-induced hypoglycemia, mice were treated with the neuroprotective, peptide-containing drug Cerebrolysin (100 mg/kg b.w.). Animals were sacrificed by decapitation two or three hours after the injection of tested substance and samples were taken to determine several serum parameters (glucose, total protein, triglycerides and lactic acid) and TBARs in the brain and heart. Although Cerebrolysin was not able to affect serum parameters after subcomatous insulin injection, the drug significantly influenced lipid peroxidation. A single injection of Cerebrolysin already decreased TBARs levels in the brain and heart tissue. Presuming that an increase of TBARs reflects disturbances of the cell membrane, we have documented a promising effect of Cerebrolysin on cell integrity.     

Ovarian response,embryo production and hormonal profile in superovulated goats treated with insulin

The influence of insulin on ovarian response and embryo production was investigated in 30 mixed breed goats, divided randomly into three equal (n=10) groups. Goats in Group 1 (control) were superovulated using 20 IU FSH i.m. in six divided descending doses, i.e. 4/4, 3/3 and 3/3 IU at 12 h interval for three consecutive days and were not given insulin treatment. Goats in Group 2 (insulin pretreatment) were pretreated with long acting purified bovine insulin 0.2 IU/kg body weight per day s.c. on Days 7, 8 and 9 of the estrous cycle prior to initiation of superovulatory treatment as in Group 1. Animals in Group 3 (insulin cotreatment) were treated as in Group I, but in addition received long acting purified bovine insulin 0.2 IU/kg body weight per day s.c. as a cotreatment along with the first, third and fifth FSH treatments on three consecutive days. Total ovarian response (corpus luteum and unovulated large follicle (UOLF)) was significantly (P<0.05) higher in insulin pretreatment (17.90+/-3.08) than in the cotreatment (11.50+/-2.34) and control (11.90+/-1.87) groups. The number of UOLF was significantly higher (P<0.05) in the insulin pretreatment (10.2+/-1.67) than the cotreatment (4.9+/-1.14) and control (3.6+/-1.09) groups. The mean transferable quality of embryos did not differ significantly among treatments. Progesterone concentration on the day of PGF(2)alpha treatment was not different (P>0.05) between the insulin treatment groups (5.28+/-0.79; 5.30+/-0.66 ng/ml). Estradiol-17beta concentration was significantly (P<0.05) higher on the day of PGF(2)alpha treatment in both the insulin treatment groups (36.67+/-6.40; 34.33+/-4.33 pg/ml) as compared to the control group (20.00+/-2.73 pg/ml). There is ample evidence to indicate beneficial effect of insulin on folliculogenesis and steroidogenesis in superovulated goats.     

Contribution of hepatic glycogenolysis and gluconeogenesis in the defense against short-term insulin induced hypoglycemia in rats

In this study, the contribution of liver glycogenolysis and gluconeogenesis in the defense against short-term insulin induced hypoglycemia (IIH) was investigated. For this purpose, we used an experimental model in which IIH was obtained by administering an IP injection of a pharmacological dose (1 U/kg) of regular insulin to rats that had been deprived of food for a period of six hours. This experimental model is suitable to study the simultaneous participation of glycogen breakdown and gluconeogenesis in the defense against IIH. The livers of IIH rats showed insignificant changes in the glycogen concentration, total phosphorylase, active phosphorylase, and percent of active phosphorylase. Our results also indicated that the livers of IIH rats that received the concentration of L-alanine, L-glutamine, L-lactate, or glycerol found in the blood during IIH (basal values) showed negligible glucose production. Nonetheless, glucose, urea, and pyruvate production increased (P<0.05) if the livers were perfused with a saturating concentration of gluconeogenic precursors. In agreement with these results, IIH rats that received intragastric L-alanine, L-glutamine, or L-lactate showed increased (P<0.05) glycemia 30 min after the administration of these substances. However, when using glycerol, higher glycemia (P<0.05) was observed at 2 and 5 min, but not 30 min after the administration of this hepatic gluconeogenic precursor. Thus, we can conclude that the oral availability of gluconeogenic precursors could allow for their use as important antidote in the defense against IIH.     

Glucose turnover and hormonal changes during insulin-induced hypoglycemia in trained humans

Eight athletes (T), studied the third morning after the last exercise session, and seven sedentary males (C) (maximal O2 consumption 65 +/- 4 vs. 49 +/- 4 (SE) ml X kg-1 X min-1, for T and C men, respectively) had insulin infused until plasma glucose, at an insulin level of 1,600 pmol X l-1, was 1.9 mmol X l-1. Glucose turnover was determined by primed constant rate infusion of 3-[3H]glucose. Basal C-peptide (0.46 +/- 0.04 vs. 0.73 +/- 0.06 pmol X ml-1) and glucagon (4 +/- 0.4 vs. 10 +/- 2 pmol X l-1) were lower (P less than 0.05) and epinephrine higher (0.30 +/- 0.06 vs. 0.09 +/- 0.03 nmol X l-1) in T than in C subjects. During and after insulin infusion production, disappearance and clearance of glucose changed identically in T and C subjects. However, in spite of identical plasma glucose concentrations, epinephrine (7.88 +/- 0.99 vs. 3.97 +/- 0.40 nmol X l-1), growth hormone (97 +/- 17 vs. 64 +/- 6 mU X l-1), and pancreatic polypeptide (361 +/- 84 vs. 180 +/- 29 pmol X l-1) reached higher levels (P less than 0.05) and glucagon (28 +/- 3 vs. 47 +/- 10 pmol X l-1) lower levels in T than in C subjects. Blood pressures changed earlier in athletes during insulin infusion, and early recovery of heart rate, free fatty acid, and glycerol was faster. Responses of norepinephrine, cortisol, C-peptide, and lactate were similar in the two groups. Training radically changes hormonal responses but not glucose kinetics in insulin hypoglycemia.