Effect of near physiologic insulin therapy on hypoglycemia counterregulation in type-1 diabetes

OBJECTIVES: The aim of this study was to examine hormonal counterregulation during insulin-induced hypoglycemia in type-1 diabetic patients during long-term near normoglycemic insulin therapy and intensive clinical care. METHODS: Type-1 diabetic patients (age 35.3 +/- 2 years, body mass index 22.8 +/- 1 kg x m(-2), mean diabetes duration 13.6 (11-17 years), mean HbA1c during the last year 6.6 +/- 0.1%) and nondiabetic subjects were studied during (0-120 min) and after (120-240 min) hypoglycemic (3.05 mmol/l) hyperinsulinemic (approximately 330 pmol/l) clamp tests. RESULTS: During hypoglycemia peak plasma concentrations of glucagon (199 +/- 16 vs. 155 +/- 11 ng/l, p < 0.05), epinephrine (4,514 +/- 644 vs. 1,676 +/- 513 pmol/l, p < 0.001), norepinephrine (2.21 +/- 0.14 vs. 1.35 +/- 0.19 nmol/l, p < 0.01) and cortisol (532 +/- 44 vs. 334 +/- 61 nmol/l) were reduced in the diabetic patients. Plasma lactate did not change from baseline values (0.51 +/- 0.06 mmol/l) in diabetic but doubled in healthy subjects (1.13 +/- 0.111 mmol/l, p < 0.001 vs. control). During the posthypoglycemic recovery period plasma concentrations of free fatty acids were higher in diabetic patients at 240 min (1.34 +/- 0.12 vs. 2.01 +/- 0.23 mmol/l, p < 0.05). CONCLUSION: Despite long-term near physiologic insulin substitution and the low incidence of hypoglycemia, hormonal hypoglycemia counterregulation was impaired in type-1 diabetic patients after a diabetes duration of more than 10 years.     

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.     

Effect of functional adrenalectomy on glucagon secretion and circulating catecholamines during insulin hypoglycemia in the dog

The present study was carried out to determine whether an increase in the pancreatic immunoreactive glucagon (IRG) secretion during the acute phase of insulin-induced hypoglycemia depends on circulating catecholamines of adrenal origin. Hypoglycemia was induced by a bolus insulin injection (0.15 IU/kg, i.v.) in dogs anesthetized with sodium pentobarbital (35 mg/kg, i.v.). Plasma aortic epinephrine (E) and norepinephrine (NE) concentrations increased significantly 30 min after the injection of insulin. At this time point, a functional adrenalectomy (diversion of bilateral adrenal venous blood from the systemic circulation) was performed for 5 min. The increased aortic E and NE concentrations significantly decreased reaching, within 5 min, a level below the corresponding preinjection control value. The basal output of pancreatic IRG (6.58 +/- 1.12 ng/min, n = 6) significantly increased (24.93 +/- 2.77 ng/min, p less than 0.05, n = 6) 30 min after insulin injection. During the functional adrenalectomy, the increased pancreatic IRG output diminished rapidly, within 5 min, to approximately 50% (11.73 +/- 3.19 ng/min, p less than 0.05, n = 6) of the value observed 30 min after insulin administration. In the other group of dogs receiving sham adrenalectomy, the increased aortic E and NE concentrations and pancreatic IRG output following insulin injection remained elevated above the levels observed immediately before the sham adrenalectomy. The net decrease in IRG output during the adrenalectomy was significant (p less than 0.05) compared with the corresponding net IRG output observed in the sham group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of insulin on low-density-lipoprotein metabolism in human lymphocytes in vitro.

The metabolism of low-density lipoproteins (LDL) in vitro in the presence of insulin was studied in freshly isolated human peripheral-blood lymphocytes. Insulin appeared to decrease the binding affinity of 125I-LDL to its cell-surface receptor, without any change in apparent Vmax or in the number of LDL receptors. As a consequence, the absolute amounts of 125I-LDL internalized and degraded were lower in the presence of insulin than in its abscence, although the fraction of internalized 125I-LDL degraded in either instance was quite similar. 3-Hydroxy-3-methylglutaryl-CoA reductase activity, and hence cholesterol synthesis, were stimulated by insulin. This effect of insulin was independent of the inhibitory effect of LDL on cholesterol synthesis. At the same time, acid cholesterol esterase and acyl-CoA: cholesterol O-acetyltransferase activities were lower in cells incubated with insulin than in controls. The net effect of these metabolic alterations seems to be that cells accumulate greater quantities of free and esterified cholesterol when treated with insulin.     

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)     

Serotonin-induced hypoglycemia and increased serum insulin levels in mice

The effects of serotonin (5-HT) on plasma glucose levels were studied. 5-HT above 20 mg/kg induced apparent hypoglycemia in mice. The hypoglycemic effects of 5-HT were strongly antagonized by methysergide but only partially inhibited by ketanserin. However, ICS 205-930 was without effect. This indicates that the hypoglycemia induced by 5-HT is mediated by both the 5-HT1 and 5-HT2 receptors. 5-HT also produced an increase in serum immunoreactive insulin (IRI) which was completely inhibited by methysergide and partially antagonized by ketanserin. It is suggested that the 5-HT-induced increase in IRI is elicited by the activation of the 5-HT1 and 5-HT2 receptors, which is similar to the results obtained with plasma glucose. These results indicate that the 5-HT receptors may regulate blood glucose levels by modifying the release of insulin.