Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime.

OBJECTIVE: To establish whether the short-acting insulin analog lispro can be successfully implemented in long-term intensive insulin therapy in type 1 diabetes, and if so, what its effects are on glycemic control and frequency and awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: We randomized 56 type 1 diabetic patients to treatment with either lispro (n = 28) or human regular insulin (Hum-R; n = 28) as mealtime insulin for 1 year (open design, parallel groups). Lispro was injected at mealtime and Hum-R was given 10-40 min before meals (bedtime NPH was continued on both occasions). With lispro, NPH was added at breakfast (approximately 70/30), lunch (approximately 60/40), and supper (approximately 80/20) (mixing percentage of lispro/NPH) to optimize premeal and bedtime blood glucose. RESULTS: Total daily insulin units were no different in the two treatment groups, but with lispro approximately 30% less short-acting insulin at meals and approximately 30% more NPH was needed versus Hum-R (P < 0.05). The bedtime NPH dosage was no different. With lispro + NPH, the mean daily blood glucose was lower than with Hum-R (8.0 +/- 0.1 vs. 8.8 +/- 0.1 mmol/l; P < 0.05), HbA1c was lower (6.34 +/- 0.10 vs. 6.71 +/- 0.11%, mean value over 1 year; P < 0.002), and hypoglycemia (blood glucose < or = 3.8 mmol/l) was less frequent (7.4 +/- 0.5 vs. 11.5 +/- 0.7 episodes/patient-month) and tended to occur more within 90 min after meals than in the postabsorptive state (P < 0.05 vs. Hum-R). After 1 year, plasma adrenaline and symptom responses to experimental, stepped hypoglycemia improved with lispro and were closer to the responses of 12 nondiabetic control subjects versus Hum-R both in terms of thresholds and magnitude (P < 0.05). CONCLUSIONS: We concluded that mealtime injection of lispro + NPH improves the 24-h blood glucose and the percentage HbA1c as compared with Hum-R. The improvement can be maintained long term. Intensive therapy with lispro + NPH results in less frequent hypoglycemia and better awareness and counterregulation of hypoglycemia.

[Oral glucose tolerance and HbA1c in the diagnosis of pregnancy in diabetes]. / Carico orale di glucosio ed HbA1c nella diagnosi di diabete gestazionle.

This study was undertaken in order to evaluate the plasma glucose response to oral glucose tolerance test (OGTT, 100 g) and the HbA1c values in pregnant women at different gestational ages. One-hundred twenty-nine OGTTs have been performed in 75 pregnancies. The results obtained show a decrease in glucose tolerance during pregnancy. Mean HbA1c value was significantly higher in women with gestational diabetes mellitus, but values of subjects with gestational diabetes and normal glucose tolerance overlapped widely. In conclusion, HbA1c is not a sensitive parameter in the diagnosis of gestational diabetes mellitus. Further studies are necessary to evaluate its specificity and prognostic significance.

[Importance of CA-50 detection in malignant gynecologic tumors]. / Importanza della determinazione del CA-50 nei tumori ginecologici maligni.

The role of Tumor Associated Antigens in the diagnosis of neoplasia is now actively investigated. The CA-50 antigen is known to be elevated in different types of gynecological neoplasia. In this study the CA-50 levels have been measured in 70 patients with ovarian, endometrial or cervical cancer. The data obtained show that the CA-50 levels, although elevated above normal in a high percentage of the patients studied, cannot be considered diagnostic for the presence of neoplasia.

[Corticosteroids]. / Corticosteroidi.

Adrenal steroids, particularly glucocorticoids, are used in a variety of conditions ranging from adrenal insufficiency requiring substitution therapy (glucocorticoids and mineral-corticoids), to a wide range of clinical disorders in which undesired inflammatory reactions must be reduced (glucocorticoids). The anti-inflammatory effect, typical of glucocorticoids, is mainly due to the interference with arachidonic acid metabolism, from which both prostaglandins and leukotriens, mediators of inflammation, take origin. ACTH is also employed with the same indications of glucocorticoids, but its use is limited, since its effect depends on the stimulation of cortico-adrenal gland with subsequent release of not only glucocorticoids but also mineral-corticoids and androgens. The therapeutical indications of glucocorticoids are numerous, but dose and duration of treatment vary in relation of the disease that is to be cured. The widespread use of steroids is accompanied by numerous unwanted reactions which depend on their metabolic actions. Therefore corticosteroids must be reserved to well defined clinical conditions and their use should be guided by criteria that are now codified. In this review the physiological and pharmacological effects and the clinical use of corticosteroids have been examined.

Improved column-chromatographic isolation of glycosylated hemoglobin S.

We investigated glycosylated hemoglobin S by means of chromatography on Bio-Rex 70. The selected elution conditions were similar to those described by Trivelli et al. (N Engl J Med 284: 353-357, 1971), except for modified ionic strength and accurate temperature control. This enabled us to isolate a minor hemoglobin fraction whose properties, as determined by chromatography, electrophoresis, and two-dimensional maps of its tryptic peptides, were typical of a hemoglobin S tetramer with blocked N-terminal residues of the beta subunits. The colorimetric test indicated this to be a glycosylated hemoglobin. This procedure is notably improved over previous chromatographic techniques for isolating glycosylated hemoglobin S. Moreover, it can be easily used in any laboratories where Trivelli's method is routinely in use.

Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion.

To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (less than 1 mo); 11 with 2.6 +/- 0.3 (mean +/- SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 +/- 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 X min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80-130 ng/m2 X min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = -0.943; P less than 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.

Continuous subcutaneous insulin infusion treatment in insulin-dependent diabetic patients: a comparison with conventional optimized treatment in a long-term study.

The effects of continuous subcutaneous insulin infusion (CSII) by portable pump (Microjet MC2, Miles) and conventional optimized insulin therapy (OCT) on metabolic control were compared in a group of five insulin-dependent diabetic patients. A group of seven normal volunteers was examined as control. CSII treatment consisted of a basal insulin infusion and three boluses of 60 min, starting 30 min before each main meal. OCT was characterized by three daily s.c. insulin injections: regular insulin before breakfast and lunch, regular plus lente before dinner. Two protocols of study were performed. In the first one the metabolic (blood glucose, NEFA, 3-beta-OH-butyrate) and hormonal (free insulin, pancreatic glucagon, cortisol, growth hormone) profiles were examined in the hospital with the patients connected to a "blood glucose monitor," after 45 days of OCT and CSII treatment, respectively. In the course of CSII treatment, a better blood glucose profile was observed than during OCT (OCT: MBG = 162 +/- 18 mg/dl, M = 43 +/- 11, MAGE = 151 +/- 26 mg/dl. CSII: MBG = 133 +/- 8 mg/dl, M = 29 +/- 5, MAGE = 138 +/- 19 mg/dl: P less than 0.05), although the indices remained higher than in normal subjects (MBG = 85 +/- 3 mg/dl, M = 0.98 +/- 0.18, MAGE = 49 +/- 3.6 mg/dl). CSII treatment was also associated with an improvement of NEFA and 3-beta-OH-butyrate profiles. Plasma "free" insulin (IRI) ranged between 18.2 +/- 5.4 and 32 +/- 5.5 microU/ml during CSII. Plasma glucagon (IRG) concentration after overnight fast was 195 +/- 65 pg/ml and 220 +/- 55 pg/ml during OCT and CSII treatment, respectively, with minor changes throughout the day. (ABSTRACT TRUNCATED AT 250 WORDS)

Important role of adrenergic mechanisms in acute glucose counterregulation following insulin-induced hypoglycemia in type I diabetes. Evidence for an effect mediated by beta-adrenoreceptors.

UNLABELLED: During hypoglycemia induced by an i.v. insulin infusion for 60 min, rates of plasma glucose (PG) decrease and recovery, PG nadir, and plasma counter-regulatory hormone and free fatty acid responses were studied in eight type I uncomplicated diabetic subjects and eight nondiabetic subjects. Each subject was tested three times at two different rates of insulin infusion (25 and 32 mU/m2/min): (1) during infusion of saline, (2) during infusion of phentolamine + propranolol (combined alpha, beta-blockade), and (3) during infusion of propranolol alone (isolated beta-blockade) for 150 min. At the time of the studies, the diabetic subjects had been made euglycemic by an overnight i.v. insulin infusion. During infusion of insulin (25 mU/m2/min) and saline, the rates of PG decrease and recovery were slower (P less than 0.01) and PG nadir was delayed in the diabetic subjects. Moreover, their plasma glucagon response was blunted while plasma epinephrine, norepinephrine, growth hormone, and cortisol responses were similar in both groups. Infusion of insulin at 32 mU/m2/min caused larger decreases in PG than had been observed when insulin was infused at 25 mU/m2/min. Plasma glucagon responses increased in the nondiabetic subjects (P less than 0.05) but not in the diabetic subjects. However, in the diabetic subjects, plasma epinephrine increased more than in the nondiabetic subjects (P less than 0.05). There was an inverse correlation between the individual plasma epinephrine responses and the plasma glucagon responses in the diabetic subjects (r = -0.72) but not in the nondiabetic subjects. Alpha, beta-adrenergic blockade decreased the plasma glucose nadir and impaired the rate at which normoglycemia was restored in the diabetic subjects (P less than 0.005 vs. saline) but not in the nondiabetic subjects. Plasma catecholamine and growth hormone responses were increased and plasma FFA recovery was suppressed in both groups (P less than 0.05 vs. saline), while the cortisol responses were unaltered. During isolated beta-adrenergic blockade, changes in plasma glucose, counterregulatory hormones and FFA were essentially identical to those observed during combined alpha, beta-adrenergic blockade in both groups except that the augmented plasma norepinephrine responses were no longer apparent. CONCLUSIONS: although epinephrine is not essential for prompt restoration of normoglycemia in normal man following insulin-induced hypoglycemia, it plays a major role in glucose counterregulation in diabetics who have an impaired glucagon secretion in response to hypoglycemia. These counterregulatory effects of epinephrine are mediated by beta-adrenoreceptors.

Circulating catecholamine and glucagon responses to insulin-induced blood glucose decrement in a patient with pheochromocytoma.

In a gastrectomized woman with an adrenal pheochromocytoma we observed hypertensive crisis in association with postprandial hypoglycemic episodes. To assess whether hypoglycemia could be responsible for the hypertensive crises, we measured circulating catecholamines and glucagon during an insulin-induced blood glucose decrement carried out by an artificial endocrine pancreas. When the blood glucose level reached 36 mg/dl, a severe hypertensive crisis occurred. At this time, circulating catecholamines increased 2-fold (norepinephrine, from 2200 to 3568 pg/ml; epinephrine, from 950 to 1750 pg/ml), while no changes in glucagon were observed. Our observation suggests that in patients with pheochromocytoma, hypoglycemia may trigger a marked release of catecholamines independent of glucagon secretion. This response probably is mediated by activation of the sympathetic nervous system. Our results also suggest that the pancreatic A-cell response to blood glucose decrement is totally suppressed in patients with pheochromocytoma by the chronically high levels of circulating catecholamines. Thus, hypoglycemia may be added to the list of other well known factors which may provoke hypertensive emergencies in patients with pheochromocytoma.

Lack of glucagon response in glucose counter-regulation in type 1 (insulin-dependent) diabetics: absence of recovery after prolonged optimal insulin therapy.

Mild hypoglycaemia was induced using an artificial pancreas in five normal subjects (from 5.00 +/- 0.15 to 2.83 +/- 0.15 mmol/l) by infusing 28 mU/m2 per min soluble insulin for 60 min. Six Type 1 (insulin-dependent) diabetic patients were stabilized for 14h using an artificial pancreas. They were then rendered hypoglycaemic (from 4.94 +/- 0.09 to 2.89 +/- 0.11 mmol/l) by infusing 28 mU/m2 per min plus 16 +/- 3.8 mU/min insulin for 60 min. Before the study, the diabetic patients were in optimal blood glucose control (mean blood glucose 6.72 +/- 0.11 mmol/l over the previous 14-20 days; HbA1 8.3 +/- 0.1%). During the insulin infusion test, blood glucose decrement was slower in the diabetic patients than in the control subjects. The blood glucose nadir was delayed in the diabetics until 75 min compared with 55 min in the control subjects. Blood glucose recovery rate in the diabetic subjects was severely impaired. In Type 1 diabetes, the counter-regulatory hormonal response to insulin induced hypoglycaemia is similar to that of non-diabetics, except for that of glucagon, the blunted response of which is not reversed by prolonged optimisation of blood glucose control. This impaired response of the A cell does not seem to be a consequence of insulin deficiency.

Analysis of short-term changes in reversibly and irreversibly glycosylated haemoglobin AI: relevance to diabetes mellitus.

We have determined the stable (irreversibly glycosylated) fraction of haemoglobin AI (HbAI) on Bio-Rex 70 after incubation of red blood cells in 0.9 % saline solution for 6 h at 37 degrees C. The total (reversibly + irreversibly glycosylated fractions) HbAI was determined before each incubation. Labile (reversibly glycosylated) HbAI represented the difference between total and stable HbAI fractions. Total and stable HbAI fractions were determined during insulin- or meal-induced blood glucose fluctuations in 24 insulin-dependent diabetics and in seven subjects with impaired glucose tolerance. In the diabetics, the maximal fluctuation of total HbAI was 1.47% over 2-12 h, while the simultaneous plasma glucose variation was 21.5 mmol/l. The stable HbAI fraction did not change significantly. In diabetics the differences between the maximal and minimal values of plasma glucose and total HbAI were significantly correlated. Plasma glucose correlated with simultaneously determined total and labile HbAI fractions, but not with stable HbAI. In subjects with impaired glucose tolerance, similar changes in total but not in stable HbAI were observed during an oral glucose tolerance test. We conclude that, although rapid changes in chromatographically determined HbAI are relatively small, the determination of stable HbAI should be performed to circumvent this problem and to ensure a more accurate index of blood glucose control.

[Early diagnosis of pheochromocytoma in pregnancy]. / Diagnosi precoce di feocromocitoma in gravidanza.

The authors report a case of pheochromocytoma revealed by a de novo appeared hypertension in a young female patient at her 3rd trimester of pregnancy. An early diagnosis and an appropriate medical management allowed a successful maternal outcome. Since maternal and fetal prognosis of pheochromocytoma associated with pregnancy is strictly related to an antepartum diagnosis, the importance of suspecting pheochromocytoma as underlying cause of de novo appearing hypertension (or hypertension of unknown origin) during pregnancy is emphasized. Biochemical tests (plasma and/or urinary catecholamine or metabolite determination) are recommended as the most suitable approach to the screening of pheochromocytoma in pregnancy.