Plasma and skeletal muscle free amino acids in type I, insulin-treated diabetic subjects.

Insulin-dependent diabetes mellitus (IDDM) induces plasma amino acid (AA) abnormalities, including low alanine and high branched-chain (BCAA). While insulin treatment restores plasma AA pattern, proline, methionine, valine, isoleucine, and total BCAA remain elevated in skeletal muscle intracellular water. This suggests that the restoration of plasma AA concentrations is not a satisfactory index of recovered AA metabolism in IDDM.

Perioperative management of diabetic subjects. Subcutaneous versus intravenous insulin administration during glucose-potassium infusion.

The purpose of this study was to validate methods for the perioperative management of diabetic patients that meet the prerequisites of simplicity, applicability in the absence of a diabetologist, and flexibility, to rapidly meet changing metabolic requirements. The patients were divided into two groups that were comparable for age, sex distribution, type of diabetes, and type of surgical procedures. The results show that intravenous insulin administration achieved better glycemic control during the intraoperative period, whereas it did not offer advantages over the subcutaneous route during the pre- and postoperative periods. The satisfactory degree of steady glycemic control achieved and the absence of hypoglycemic episodes indicate that the separate administration of insulin and glucose plus electrolytes is an effective and safe management modality for diabetic patients undergoing major surgery.

Response of growth hormone to thyrotropin-releasing hormone during fetal life.

The effect of TRH administration to the term pregnant women on the GH response in cord blood (CB) was evaluated in 138 subjects. Previous studies have demonstrated that TRH readily crosses the placenta. TRH (400 microgram) was administered iv to 59 pregnant women just before delivery. CB samples were obtained at delivery and assigned to 6 groups, depending upon the duration of time between TRH injection and CB sampling. The control group comprised 79 pregnant women who received saline. A progressive rise and then a fall in the CB GH concentration were observed after TRH administration. Values were significantly elevated 61-90 min after TRH administration compared to values in saline-treated subjects (19.3 +/- 3.1 vs. 13.1 +/- 0.9 ng/ml; P less than 0.05). The present study is the first report of the effect of TRH on the GH concentration in CB and suggests that TRH stimulates GH release in the fetus.

Renal metabolism of C-peptide in man.

Renal metabolism of C-peptide was studied in nine nondiabetic nonobese patients with normal renal function by the arterial-venous difference technique before and after the oral administration of an amino acid mixture simulating an animal protein meal. In the basal state, the kidney removed 25.7 +/- 7.5% (+/- SD) of the arterial plasma C-peptide. Renal uptake was approximately 7-fold greater than urinary excretion, and thus, more than 85% of the amount extracted was metabolized by the kidney. Renal C-peptide clearance was very high and approximated the glomerular filtration rate, whereas urinary C-peptide clearance was only 14% of its renal clearance. Shortly after amino acid ingestion, arterial C-peptide levels increased by 107%, and C-peptide renal fractional extraction, uptake, and net metabolism also increased markedly (67%, 278%, and 328%, respectively); urinary clearance and excretion did not change. Renal clearance became 2-fold greater than the glomerular filtration rate, indicating that in this phase the kidney removed substantial amounts of C-peptide from peritubular blood as well as by filtration. Both renal uptake and urinary excretion of C-peptide were related to its arterial levels (P less than 0.001 and P less than 0.05, respectively), but renal uptake increased much more than urinary excretion for each increment in arterial C-peptide levels. These results indicate that renal C-peptide metabolism is considerable in the postabsorptive state and is even more marked during the postprandial period. The kidney, therefore, plays a key role in both the regulation of circulating plasma levels and the metabolic clearance of C-peptide.

Human cord blood concentrations of thyrotropin, thyroglobulin, and iodothyronines after maternal administration of thyrotropin-releasing hormone.

TRH or saline was administered to 214 term pregnant women at various time intervals (8-820 min) before delivery. Cord blood (CB) was obtained, and plasma TSH, T4, T3, rT3, and thyroglobulin concentrations were measured by specific RIA. CB TSH was significantly elevated within 20 min after TRH administration and remained elevated for 180 min. CB T3 rose significantly by 60 min and remained elevated for 820 min. CB T4 was significantly increased from 120 to 820 min after TRH administration. There was no significant change in the CB thyroglobulin concentration. These findings demonstrate for the first time that TRH crosses the human placenta, that the fetal pituitary is responsive to TRH, and that endogenous TSH stimulates the fetal thyroid.

Diabetic autonomic neuropathy and impaired human pancreatic polypeptide secretion in response to food.

In normal subjects, the early human pancreatic polypeptide (hPP) increase induced by food is mainly dependent on vagal activity. Parasympathetic function and plasma hPP response to a standard mixed meal were evaluated in 10 long term insulin-dependent (type I) diabetic patients (group A), 6 age-matched newly diagnosed type I diabetic patients (group B), and 8 normal subjects. The indices of vagal function (beat to beat heart rate variation during deep breathing and the Valsalva maneuver) were uniformly altered in group A, while they were in the normal range in group B, thus excluding in these latter patients the presence of vagal damage. Plasma hPP in response to standard mixed meal was measured at 5, 15, 30, 60, and 120 min. Fasting plasma hPP concentrations (determined by RIA) in groups A and B (mean +/- SEM, 113 +/- 21 and 83 +/- 21 pg/ml, respectively) did not significantly differ from normal (59 +/- 12 pg/ml). In group A, the initial meal-induced hPP increase was significantly lower than normal (5 min, 139 +/- 12; 15 min, 173 +/- 24; 30 min, 137 +/- 17 pg/ml; P less than 0.01 vs. 5 min, 412 +/- 76; 15 min, 446 +/- 57; 30 min, 325 +/- 56 pg/ml). All group B patients had a marked early increase in the peptide, similar to that in the normal subjects. These results suggest that diabetic autonomic neuropathy is associated with dysfunction of hPP secretion, and the evaluation of hPP in response to SMM may be considered a sensitive and nonstressful method for the assessment of parasympathetic impairment in diabetes.

Goiter size and thyroid function in an endemic goiter area in northern Italy.

Thyroid function was studied in a large number of subjects residing in Varsi, a town in the province of Parma, Italy. In this area, endemic goiter associated with moderate iodine deficiency [59 +/- 3 (+/- SE) microgram iodine/g creatinine], as defined by WHO criteria, affects 65% of the population. Serum T4, T3, thyroglobulin (Tg), and TSH concentrations were measured by RIA in 1218 subjects. The TSH response to TRH was determined in 108 subjects selected randomly from the groups with different grades of goiter. No significant change in serum T4 concentrations was found in subjects with different grades of goiter. Serum T3 concentrations were higher in subjects with the larger goiters. Serum Tg concentration progressively increased, and serum TSH progressively decreased with increasing goiter size. The TSH response to TRH was diminished in subjects with larger goiters. The findings of decreasing serum TSH concentrations and blunted TSH responses to TRH as goiter size increased suggest the possibility of autonomous thyroid function in the larger goiters in subjects residing in this area of moderate iodine deficiency.

Failure of metoclopramide to affect thyrotropin concentration in the term human fetus.

Metoclopramide (MET), a potent dopamine receptor-blocking drug, or saline was administered to 125 term pregnant women at various time intervals (5-412 min) before delivery. Maternal serum was obtained before and after MET injection. Cord blood was obtained at delivery in MET-treated and saline-treated (control group) women. No significant changes in serum TSH, T4, T3, or rT3 concentrations were observed in maternal or cord blood after MET administration. These results suggest that, in contrast to euthyroid nonpregnant women and men, MET administration does not induce a rise in serum TSH concentration in term pregnant women or in the term fetus. Thus, the dopaminergic inhibitory effect on anterior pituitary TSH secretion may not be an important factor in TSH regulation during pregnancy or in the fetus, or the dose of MET employed may be unable to overcome the dopamine inhibitory effect.

Pirenzepine inhibits growth hormone, but not thyrotropin response to thyrotropin-releasing hormone in patients with endogenous depression.

In order to evaluate whether in endogenous depression the anomalous growth hormone (GH) response to thyrotropin-releasing hormone (TRH) is mediated by muscarinic cholinergic receptors, 12 patients were tested with TRH (200 micrograms iv) with and without previous treatment with the muscarinic cholinergic receptor blocker pirenzepine (40 mg iv 10 min before TRH). Control tests with normal saline also were performed. Administration of normal saline did not alter serum GH levels. In contrast, TRH injections significantly increased serum GH concentrations by about three-fold. This response was inhibited by pretreatment with pirenzepine. Another neuroendocrine marker of endogenous depression, the low TSH increase in response to TRH (delta less than or equal to 7 microU/ml), was observed in our patients. Pretreatment with pirenzepine did not modify this response. These data indicate that in patients with endogenous depression a muscarinic cholinergic mechanism is involved in the GH response but not in the TSH response to TRH.

Dopaminergic, but not cholinergic, involvement in regulation of hypoglycemia-induced oxytocin release in man.

The plasma oxytocin response to insulin-induced hypoglycemia was evaluated in 20 normal male subjects in the basal state (insulin tolerance test (ITT) alone) and after pretreatment with the muscarinic antagonist pirenzepine (40 mg IV 10 min before the ITT in six subjects), the nicotinic antagonist trimethaphan (0.3 mg/min IV for 30 min before the ITT in six subjects), and the dopaminergic receptor agonist bromocriptine (2.5 mg PO 1 hr before the ITT in eight subjects). The drugs did not modify arterial blood pressure nor produce side effects capable of altering oxytocin secretion. Neither pirenzepine nor trimethaphan administration changed the oxytocin response to hypoglycemia, whereas bromocriptine significantly reduced the oxytocin increase during the ITT. These data suggest the involvement of dopaminergic, but not of cholinergic, muscarinic or nicotinic, receptors in the oxytocin response to hypoglycemia.

Glucose tolerance in chronic alcoholics after alcohol withdrawal: effect of accompanying diet.

The effect of alcoholism or acute alcohol ingestion on carbohydrate metabolism is not clear. The metabolic features of alcoholics cannot be easily achieved in normal men submitted to investigations concerning the effects of alcohol on glucose tolerance. Undernutrition and/or malnutrition characterize the eating behavior of alcoholics. It is also well-known that diet is an important determinant of carbohydrate tolerance. Thus, we studied the effects of a controlled diet on glucose tolerance and insulin release in a group of chronic alcoholics, with or without withdrawal from alcohol. Twenty-two subjects took part in the study; their mean caloric intake was 2,805 +/- 91 kcal/d, 58% of which was due to alcohol. In all subjects five days after an isocaloric diet and no alcohol, we performed an oral glucose tolerance test (OGTT). After that, the subjects were divided into three subgroups: group A, eight subjects with alcohol withdrawal and an 17.5 kcal/kg/d diet; group B, eight subjects with alcohol withdrawal and a 35 kcal/kg/d diet, and group C, six subjects with a 35 kcal/kg/d diet plus ethanol 200 g/d. After 3 weeks a second OGTT was performed. We found a significant improvement of the glucose tolerance and of the release of insulin in group B as well as group C; the alcohol withdrawal per se was irrelevant to the observed modifications of the glucose tolerance. Our data suggest that a poor diet would be a major cause of carbohydrate intolerance in alcoholics.

Naloxone decreases the inhibiting effect of ethanol on the release of arginine-vasopressin induced by cigarette smoking in man.

In order to establish whether ethanol exerts its inhibiting effect on the nicotine-induced release of arginine-vasopressin (AVP) by interacting with an opioid pathway, six normal volunteers were treated with naloxone (2 or 4 mg as IV bolus, plus 5 or 10 mg infused over 105 minutes) during (2 nonfilter) cigarette smoking and ethanol (50 mL to 110 mL of whiskey) drinking. In addition, control experiments with naloxone, ethanol, or cigarette smoking alone were performed. When given alone, naloxone and ethanol did not modify AVP secretion, whereas nicotine increased plasma AVP levels by about 2.5-fold. This effect was completely blocked by ethanol. In the presence of naloxone, AVP rose only by about 1.7-fold in response to nicotine. Since naloxone only partially reversed the inhibiting effects of ethanol, only a partial involvement of opioid peptides in ethanol action might be supposed. Alternatively, ethanol and naloxone-sensitive opioids might produce their inhibiting effects on AVP rise in response to nicotine through independent pathways.

Naloxone abolishes the inhibiting effect of somatostatin on the release of oxytocin evoked by insulin-induced hypoglycemia in humans.

The effect of somatostatin (SRIH) on the release of oxytocin (OT) in response to hypoglycemia during insulin tolerance test (ITT) was studied in seven normal men. Subjects were injected intravenously with 0.15 U/kg insulin alone (control test) or together with SRIH (4.1 micrograms/min x 90 min), naloxone (10 mg in an IV bolus), or the combination of the two substances. Plasma OT concentrations rose significantly during ITT; the OT response was significantly reduced by the treatment with SRIH and increased in the presence of naloxone. When both SRIH and naloxone were given, the OT response to hypoglycemia did not differ from that observed in the control test. These findings provide evidence that the effect of hypoglycemia on plasma OT levels is sensitive to the inhibition by SRIH and by naloxone-sensitive endogenous opioids. Because naloxone reversed the inhibiting effects of SRIH, an involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opioids might produce their inhibiting effects on OT rise in response to hypoglycemia through independent pathways.

Nicotinic-cholinergic involvement in arginine-vasopressin response to insulin-induced hypoglycemia in normal men.

In order to establish whether arginine-vasopressin (AVP) release in response to insulin-induced hypoglycemia is mediated by a muscarinic and/or nicotinic cholinergic pathway, 12 normal men had an insulin tolerance test (ITT) in basal conditions and after treatment with the muscarinic receptor blocker pirenzepine (40 mg IV (intravenously) ten minutes before ITT in six subjects) or the nicotinic receptor antagonist trimethaphan (0.3 mg/min X 30 min IV before ITT in six subjects). The drugs did not modify arterial blood pressure nor produce side effects capable of altering AVP secretion. Pirenzepine administration did not change AVP response to hypoglycemia, whereas trimethaphan significantly reduced AVP increase by about 50% during the ITT. These data suggest the involvement of a cholinergic-nicotinic mechanism in regulation of AVP response to hypoglycemia.

Oxytocin enhances thyrotropin-releasing hormone-induced prolactin release in normal menstruating women.

The effects of oxytocin (OT) on basal thyrotropin-releasing hormone (TRH)-stimulated thyrotropin (TSH) and prolactin (PRL) secretion were evaluated in normal menstruating women during follicular, periovulatory, and luteal phases. Two different studies were performed. In one study, 15 subjects were treated with OT or saline; in the other study, 20 women were tested with TRH alone or in combination with OT. Results during follicular, periovulatory, and luteal phases were similar. OT did not produce any effect on basal serum TSH and PRL levels and on the TRH-stimulated TSH secretion, whereas it significantly enhanced the PRL response to TRH. At all examined phases during the menstrual cycle, the mean peak PRL response was reached within 20 minutes after TRH injection, and the peak was about three times higher than basal value when TRH was given alone and about four times when OT was present. These data suggest that in normal women OT is not involved in the control of basal and TRH-stimulated TSH secretion and of basal PRL release. In contrast, the enhancement of the TRH-induced PRL release suggests that OT plays a role in the control of the acutely stimulated PRL secretion. Because results were similar regardless of the phase of the menstrual cycle, estrogen and/or progesterone do not appear to be involved in the effect of OT on the TRH-induced PRL release.

Abnormal thyroid stimulating hormone, prolactin, and growth hormone responses to thyrotropin releasing hormone in abstinent alcoholic men with cerebral atrophy.

The thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) responses to thyrotropin releasing hormone (TRH), the Wechsler Adult Intelligence Scale (WAIS) for cognitive impairment, and computed tomographic scans were evaluated in 15 nondepressed alcoholic men after 4 weeks of abstinence and in 10 normal controls. Both cognitive impairment and cerebral atrophy were found in 13 of the alcoholics. Eight alcoholics (seven with cerebral atrophy) had blunted TSH and PRL responses to TRH and a TRH-induced paradoxical increase of GH. This study demonstrates that besides affecting the TSH response to TRH, alcoholism often induces alterations of the PRL and GH secretory patterns in response to TRH. The severe brain damage caused by long-term alcoholism might be involved in the pathogenesis of these neuroendocrine alterations.

Dopaminergic control of TSH secretion in endogenous depression.

To evaluate whether the inhibitory control exerted by endogenous dopamine on thyroid-stimulating hormone (TSH) secretion is altered in patients with major depressive disorder, 11 depressed patients and 9 normal controls were tested with the dopaminergic receptor antagonist domperidone (10 or 20 mg i.v.). The administration of domperidone induced a significant increase in circulating TSH levels in the normal controls, but not in the depressed patients. These data excluded the possibility that the dopaminergic inhibition of TSH secretion is enhanced in depression. To establish whether domperidone failure was due to a reduced dopaminergic tone, domperidone was administered before stimulation of TSH secretion with thyrotropin-releasing hormone (TRH) (200 micrograms i.v.). The TSH response to TRH was significantly lower in the depressed than in the control subjects, regardless of domperidone priming. However, in both groups domperidone enhanced the TRH-induced TSH release by 50%. These data suggest that the dopaminergic control of TSH secretion is not altered in patients with endogenous depression and that a reduced capacity of the pituitary to secrete TSH might be responsible for the reduced TSH responsiveness to TRH and domperidone.

[Severe diabetic retinopathy and renal function in non-insulin-dependent (type-2) diabetes mellitus]. / Retinopatia diabetica ingravescente e funzionalità renale nel diabete mellito non insulino-dipendente (tipo 2).

The existence of a linkage between retinal and renal microvascular complications in type 2 diabetes has been so far little investigated. For this purpose we evaluated the presence and degree of renal dysfunction in the most serious clinical conditions of diabetic retinopathy. On the basis of the alterations evidenced by fluorescein angiography 73 type 2 diabetic patients were recruited and divided into the following groups: 19 patients were affected by "clinically significant" Macular Edema (ME), 25 subjects had Preproliferative Retinopathy (PrePR) and 29 patients showed Proliferative Retinopathy (PR). Mean values (M +/- SD) of glycosylated hemoglobin, plasma basal C-peptide, lipid profile, blood pressure, glomerular filtration rate, body mass index, age and known duration of diabetes were similar between the groups. Urinary albumin excretion rate (UAE) was determined for each patient on three consecutive overnight collections (pg/min). Even though the distribution of normo (UAE < 20 micrograms/min), micro (UAE:20-200) and macroalbuminuric (UAE > 200) patients did not significantly differ between the groups, mean values of UAE increased significantly in PrePR (371.1 +/- 532.2) and PR (300.7 +/- 717.3) with respect to ME (35.4 +/- 73.1; p < 0.05). The evaluation of all patients recruited for the study, independently of the kind of retinal alteration, showed that 56.8% of them had no sign of even incipient renal dysfunction, in spite of the advanced retinal damage. When considering those patients affected by both retinal and renal complications (43.2%) the prevalence of renal involvement resulted different in the three conditions investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

[Use of floctafenine in toothaches in adults and children (a controlled study). II]. / Impiego della floctafenina nei dolori odontostomatologici degli adulti e dei bambini (studio controllato). Seconda parte.

A double-blind study was made of the activity and tolerance of 400 mg Floctaphenine versus 400 mg Acetylsalicylic Acid (ASA) on ordinary random administration. 48 patients received Floctaphenine and 50 ASA. Menstruating women were included, but not children aged less than 12 yr. Periodontitis, pulpitis, abscesses, extractions and dysodontiasis were the most frequently represented sources of pain. Subjects completing the study were divided into groups: those already treated with other analgesics in the previous 24 hr, those with uninterrupted pain, those with attacks of pain, those for whom one administration was sufficient, menstruating women. Account was also taken of the effect of treatment before or after meals, and the influence of a simultaneously administered antibiotic (the same one in each case). Statistical assessment showed that both drugs were analgesic, but that Floctaphenine was significantly (P < 0.01) better than ASA. The same was true with regard to latency time, duration of the effect, clinical assessment, need for support from other analgesics. The antibiotic appeared to have no appreciable influence of the activity of the two drugs, nor did the time of administration (before or after meals). Much the same picture was apparent in each group. Menstrual status was devoid of influence, though it cannot be stated with equal certainty that whether secondary effects were more frequent. Floctaphenine was very well tolerated. There were 4 somewhat doubtful cases of somnolence (8.33%). It was not certain, in fact, whether this was not an outcome of the relief from pain. ASA was accompanied by stomach pain in 9 cases (18%). This was much more common when it was taken on an empty stomach.

[Use of floctafenine for dental pain of adults and children; a controlled study. I]. / Impiego della floctafenina nei dolori odontostomatologici degli adulti e dei bambini; studio controllato. - Prima parte.

The analgesic activity and tolerance of a new non-narcotic synthetic analgesic derive from quinoline has been experimented in a double blind study. Phloctaphenin (200 mg) was compared with 200 mg of Acetylsalicylic acid (ASA). Administration of the drug was randomized: 41 patients received Phloctaphenin and 37 ASA. In addition to normal patients, the study also included menstruating women and, after paediatric check-up, children (i.e. under-12's). The conditions treated included periodontitis, pulpitis, abscesses, caries (with extraction), dysodontiasis and traumas. Patients were subdivided into groups (already treated with analgesics in the previous 24 h, not treated in the previous 24 h, affected by continuous pain, affected by fits of pain, subjects in whom a single drug administration was sufficient, patients in their menstrual period). Account was also taken of the outcome of treatment in relation to meals and of the influence of the association of an antibiotic (always the same). The study showed that both drugs possess analgesic activity but that of Phloctaphenin is statistically superior (almost always highly significant, i.e. P < 0.01) compared to ASA. The same applies to latency and the duration of the effect, the clinical judgment ad the need to administered other drugs. Association with the antibiotic has no influence whatever as might have been presumed considering the period of administration and the times of assessing the pain killing action of the two drugs. Administration before or after meals was irrelevant for both drugs. Statistical study of individual groups confirmed these results. From the viewpoint of side-effects, Phloctaphenin is better tolerated: with this new analgesic, in effect, only 2 debatable cases (4.87%) of side-effects (somnolence) were observed while 6 of the patients treated with ASA (16.20%) presented side-effects: 3 cases of gastric pyrosis (8.10%) before meals and 3 cases (8.10%) of hyperhydrosis after meals.