Provocation of postural hypotension by insulin in diabetic autonomic neuropathy

The effect of insulin administration on blood pressure has been investigated in eight diabetes with autonomic neuropathy. Systolic and diastolic pressures fell considerably after insulin in all of them. This effect was aggravated by tilting to the vertical position. Five patients fainted when upright with systolic blood pressures less than 50 mm. Hg. This hypotensive effect of insulin occurs whether it is administered intravenously, intramuscularly, or subcutaneously. The onset of the effect is almost immediate after intravenous insulin, is progressive, and may last for several hours. It coincides with a falling blood glucose level and occurs before hypoglycemic levels are reached, and it may be present when the blood glucose level is still elevated. Diurnal variations of postural hypotension have been recorded in some patients, the standing blood pressure falling with the onset of insulin action and rising again as the latter declines. Some of our patients were unable to differentiate between symptoms of hypoglycemia and hypotension. Postural hypotension may account for some episodes of sudden loss of consciousness without warning, usually attributed to hypoglycemia.     

Cholecystokinin and pancreatic polypeptide release in diabetic patients with and without autonomic neuropathy

The present study was undertaken to investigate postprandial responses of cholecystokinin (CCK) and pancreatic polypeptide (PP) and their interrelationship in patients with diabetes mellitus (DM) with and without autonomic neuropathy (AN). Twenty-two patients with DM (seven with AN and 15 without AN) and 14 age-matched healthy controls were studied. AN was diagnosed according to several tests of cardiovascular autonomic function. CCK and PP plasma levels were measured by specific radioimmunoassays before and at several time points after the oral administration of a test meal. Basal CCK plasma levels in DM patients were normal, whereas basal PP plasma levels were increased (139 +/- 18 vs 72 +/- 7 pg/ml; P < 0.01). Integrated postprandial CCK response was increased in DM patients (208 +/- 27 vs 110 +/- 14 pmol/liter/2 hr; P < 0.05), mainly due to the patients with AN. Postprandial PP response was increased in DM patients without AN (37,273 +/- 5241 vs 13,418 +/- 3299 pg/ml/2 hr; P < 0.001) but not in those with AN (8887 +/- 3461 pg/ml/2 hr). Moreover, PP response was closely (P < 0.002) correlated with the degree of AN. A direct and linear correlation between postprandial CCK and PP responses was found in healthy controls (r = 0.78; P < 0.005) but not in DM patients. We conclude that the CCK response to a meal is increased in diabetic patients with AN, whereas the PP response is increased only with an intact autonomic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired endothelium-dependent relaxation after coronary reperfusion injury: evidence for G-protein dysfunction

This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.     

Influence of long-term human recombinant erythropoietin treatment on secretion of pancreatic polypeptide and gastrin in hemodialysed patients with chronic renal failure

The study aimed to assess the influence of long-term rhu-EPO treatment on secretion of pancreatic polypeptide (PP) and gastrin. A total of 27 haemodialysed patients and nine healthy subjects were examined. Nine patients with uraemic anaemia were treated with rhu-EPO for 12 months (EPO group), while another nine patients did not receive rhu-EPO (non-EPO group), but were monitored biochemically and clinically as patients of the EPO group. The third group (HD) comparised nine haemodialysed patients with a haematocrit value > or = 30% without rhu-EPO therapy. In all subjects plasma levels of PP and gastrin were estimated before and after administration of a test meal. Patients of the EPO and non-EPO group were examined before and after 6 and 12 months of rhu-EPO therapy (EPO group) or clinical monitoring (non-EPO group) respectively, while only one test was performed in patients of the HD group and healthy subjects. Six months rhu-EPO therapy was followed by an decrease of basal plasma level of PP and increased response of gastrin to the test meal. After 12 months of rhu-EPO therapy basal plasma level of PP was still lower, the response of PP secretion to a test meal was higher, while that of gastrin secretion lower that the pretreatment ones. Our results suggest, that rhu-EPO treatment exerts effect on secretion of PP and gastrin. These alterations seem not to be related to improvement of the haematological status.     

Hemodynamic and autonomic effects of intravenous saterinone in patients with chronic heart failure

In this study, the hemodynamic and neurohumoral/autonomic effects of intravenous saterinone (a selective phosphodiesterase type III inhibitor, with additional alpha 1-blocking properties) were evaluated. In a double-blind, placebo-controlled design, 36 patients with moderate to severe heart failure were studied (saterinone, n = 24; placebo, n = 12). Invasive hemodynamic measurements, by using right-heart catheterization, were performed, as well as measurement of plasma neurohormones and analysis of heart rate variability (HRV), to study drug influences on neurohumoral activation and autonomic tone. Systemic vascular resistance significantly decreased during saterinone infusion, accompanied by a decrease in systemic blood pressure (both p values < 0.05) and an increase in heart rate (p = 0.05). Filling pressures also decreased during saterinone, but this was statistically significant only for pulmonary capillary wedge pressure, whereas the cardiac index remained unaffected. Plasma neurohormones (norepinephrine, epinephrine, and renin activity) were not significantly influenced by saterinone. HRV analysis revealed no significant effect of saterinone on autonomic tone. These results suggest that intravenous saterinone has a significant vasodilating effect in patients with moderate to severe chronic heart failure (CHF), without exerting an adverse effect on the autonomic nervous system, as demonstrated by assessment of plasma neurohormones and HRV analysis.     

Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin

OBJECTIVES: To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin. DESIGN: Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin. SETTING: Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital. SUBJECTS: 17 patients with insulin dependent diabetes mellitus of more than five years' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin. MAIN OUTCOME MEASURES: Glycaemic control and frequency of hypoglycaemic episodes during two months' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping. RESULTS: Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness. CONCLUSIONS: These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.     

Selenium deficiency associated with cardiac dysfunction in three patients with chronic respiratory failure

We encountered three patients with chronic respiratory failure who had heart failure of cardiac arrhythmias and low levels of serum selenium. All three had tracheostomies and had received long-term parenteral nutrition that had not included selenium. All three also had refractory cardiac dysfunction, which was manifested in edema, heart failure, and various tachycardias. We suspected that selenium deficiency had caused their cardiac dysfunction. Serum selenium concentrations were found to be much lower than normal in all three, so 100 micrograms/day of selenium was administered in addition to their tube feedings. Cardiac function improved after replacement of selenium. These cases show the need for preventing selenium deficiency in patients with chronic respiratory failure during long-term administration of parenteral nutrition.     

Determination of serum pancreatic polypeptide and its clinical significance in patients with end state renal failure

A screening program for the detection of Tay-Sachs disease (TSD) carriers in the ultra Orthodox community of Ashkenazi Jews has operated in Israel since 1986. The purpose of this program is the prevention of marriages of 2 heterozygotes. The screened individuals are mostly couples in the engagement process or students in religious high schools. Two mandatory requirements guide this program. First, anonymity of the tested individuals who are identified only by code numbers; second completion of the test results of couples in the engagement process within a few days. The screening program is performed by the determination of hexosaminidase A (Hex A) activity in serum which is repeated in serum and leukocyte extracts in couples where both partners were found in the heterozygote range in the initial tests. The minimal carrier frequency was estimated to be 1:26 or higher, which is higher then in the general Jewish Ashkenazi population. This higher carrier frequency apparently stems from the fact that most members of this community originate from central Europe where the TSD carrier frequency was previously reported to be the highest in the Ashkenazi population. Since the beginning of the screening program no TSD child has been born to newlywed couples of this community in Israel.     

Diastolic dysfunction in patients with chronic kidney failure on a hemodialysis program

OBJECTIVE: The aim of this study was to analyse different ultrasound parameters for the assessment of isolated left ventricular diastolic dysfunction (LVDD) in patients with chronic renal failure (CRF) on periodic hemodialysis (HD), comparing pulsed wave Doppler with pulsed tissue Doppler. MATERIALS AND METHODS: Forty-seven patients with CRF on HD (61% were male; mean age was 51.0 +/- 16.5 years, mean HD time--3.7 +/- 3.8 years, 38% had hypertension, 17% had diabetes) were studied by echocardiography (bidimensional, M-Mode, flow pulsed Doppler and tissue Doppler imaging). All patients had symptoms of left heart failure-class II NYHA, were in sinus rhythm and had no symptoms of ischemic heart disease. The presence of abnormal LV regional contractility was the exclusion criteria. According to their mitral inflow profile Doppler characteristics, patients were included in two groups: Group A (E/A > 1; n = 21) and B (E/A < 1; n = 26). We compared: LV dimensions and function, left atrial (LA) dimension. Gaasch index, LV mass index. E and A wave velocities (in flow pulsatile Doppler and tissue Doppler). E/N ratio in tissue Doppler, isovolumetric relaxation time (IVRT) and deceleration time (DT). RESULTS: There were no significant differences in the prevalence of age > or = 65 years male sex, hypertension or diabetes between group A and B patients, and almost all patients were on hemodialytic treatment for more than one year (81% vs 85%: NS). LV hypertrophy was present in almost all group A and B patients (A--95% vs B--85.5%; NS). Group A, compared with group B, had a difference in the Gaasch index (2.45 +/- 0.3 vs 2.08 +/- 0.4; p < 0.05), E wave velocity in flow pulsatile Doppler and tissue Doppler (cm/sec) (110 +/- 27 vs 62 +/- 20; p < 0.001 and 41 +/- 15 vs 28.5 +/- 16; p < 0.05), E/A ratio in tissue Doppler (1.3 +/- 0.4 vs 0.8 +/- 0.3; p < 0.001). IVRT (msec) (80.7 +/- 15.2 vs 113.5 +/- 28.3; p < 0.001) and DT (msec) (189.7 +/- 24 vs 278.2 +/- 17.9; p < 0.001). According to the E'/A' ratio in tissue Doppler, group A patients were divided in another two groups: E'/A' > 1 (13/21--62%) and < 1 (8/21--38%) and a significantly longer IVRT (75.8 +/- 9.3 vs 100.9 +/- 3.2; p < 0.001) and DT (178 +/- 15 vs 240 +/- 20; p < 0.001) and a greater LA dimension (37.6 +/- 6.9 vs 44.6 +/- 6.9; p < 0.05) were found. CONCLUSIONS: Pulsed wave Doppler is the most useful non invasive method for assessment of global diastolic dysfunction. In our study, 17% of the patients had E/A < 1 only in the tissue Doppler study. These patients probably had a pseudonormal mitral pattern.     

Differing haemodynamic and catecholamine responses to exercise in three groups with peripheralautonomic dysfunction: insulin-dependent diabetes mellitus, familial amyloid polyneuropathy and pure autonomic failure

BACKGROUND: The nosological status of postpartum psychoses has remained controversial because of their often 'atypical' symptomatology. A polydiagnostic approach may further clarify this issue. METHODS: In a retrospective study, we applied the ICD-10 and Leonhard's classification to 39 patients with severe postpartum psychiatric disorders. The patients were personally reexamined on average 12.5 years (6-26 years) after the onset of the illness. RESULTS: An acute onset and a polymorphous psychotic symptomatology with rapid changes characterized the majority of our cases. Unipolar depressive disorders (28%) and acute polymorphous psychotic disorders (21%) represented the largest proportions within the ICD-10-classification. Applying Leonhard's classification, over half the patients (54%) suffered from a cycloid psychosis. Among cycloid psychoses, motility psychoses clearly predominated. Schizophrenias occurred rarely (10%) according to both classifications. LIMITATIONS: Due to the unknown prevalence of the various diagnoses among women of child-bearing age, it is impossible to statistically infer a specific association between childbirth and a distinct diagnosis from our data. CONCLUSIONS: Our findings suggest that cycloid psychoses, in particular motility psychoses, account for the majority of postpartum psychoses, and do not support the hypothesis of a nosological independence of postpartum psychoses.     

Cerebrovascular and cardiovascular responses to graded tilt in patients with autonomic failure

BACKGROUND AND PURPOSE: Patients with autonomic nervous system failure often experience symptoms of orthostatic intolerance while standing. It is not known whether these episodes are caused primarily by a reduced ability to regulate arterial blood pressure or whether changes in cerebral autoregulation may also be implicated. METHODS: Eleven patients and eight healthy age- and sex-matched control subjects were studied during a graded-tilt protocol. Changes in their steady state middle cerebral artery mean flow velocities (MFV), measured by transcranial Doppler, brain-level mean arterial blood pressures (MABPbrain), and the relationship between the two were assessed. RESULTS: Significant differences between patients and control subjects (P < .05) were found in both their MFV and MABPbrain responses to tilt. Patients' MFV dropped from 60 +/- 10.2 cm/s in the supine position to 44 +/- 14.0 cm/s at 60 degrees head-up tilt, whereas MABPbrain fell from 109 +/- 11.7 to 42 +/- 16.9 mm Hg. By comparison, controls' MFV dropped from 54 +/- 7.8 cm/s supine to 51 +/- 8.8 cm/s at 60 degrees, whereas MABPbrain went from 90 +/- 11.2 to 67 +/- 8.2 mm Hg. Linear regression showed no significant difference in the MFV-MABPbrain relationship between patients and control subjects, with slopes of 0.228 +/- 0.09 cm.s-1.mm Hg-1 for patients and 0.136 +/- 0.16 cm.s-1.mm Hg-1 for control subjects. CONCLUSIONS: The present study found significant differences between patients and control subjects in their MFV and MABPbrain responses to tilt but no difference in the autoregulatory MFV-MABPbrain relationship. These results suggest that patients' decreased orthostatic tolerance may primarily be the result of impaired blood pressure regulation rather than a deficiency in cerebral autoregulation.     

Hypophosphatemia and glucose intolerance: evidence for tissue insensitivity to insulin

Although hypophosphatemia is commonly present in diabetics, little is known about its isolated effects on glucose and insulin metabolism. We therefore investigated glucose metabolism in six nondiabetic subjects with chronic hypophosphatemia. When glucose was infused to maintain a constant hyperglycemic level (125 mg per deciliter [6.9 mmol per liter] above basal levels), the glucose infusion rate was 36 per cent less in the hypophosphatemic group than in controls (4.90 +/- 0.34 mg per kilogram of body weight per minute vs. 7.64 +/- 0.37, P < 0.001), although responses to endogenous insulin were similar. When exogenous insulin was infused at a constant rate to maintain an insulin level about 100 microU per milliliter (718 pmol per liter) above basal levels and glucose was infused as necessary to maintain fasting glucose levels, the infusion rate of glucose was 43 per cent lower in the hypophosphatemic group than in controls (3.80 +/- 0.58 mg per kilogram per minute vs. 6.70 +/- 0.33, P < 0.001), although the clearance rate of insulin was similar in both groups. These results indicate that hypophosphatemia is associated with impaired glucose metabolism in both the hyperglycemic and euglycemic states, and that this associated primarily reflects decreased tissue sensitivity to insulin. (N Engl J Med. 1980; 303; 1259-63.).     

Modulation of tyrosine kinase activity has multiple actions on insulin release from the pancreatic beta-cell: studies with lavendustin A

The reproductive function of spinal cord injured males is not the primary concern of health professionals responsible for the management of these young adults. However, the fertility of these patients is threatened right from the first days after trauma, as indicated by abnormalities of the sperm count, reflecting the histological alterations observed on testicular biopsy. The factors predisposing to asthenoteratospermia, responsible for impaired fertility, are analysed and discussed. Urinary tract infection is the leading factor. This acute situation must be managed early, by preventing urinary tract infection and by obtaining a semen donation as soon as possible, after improvement of the general status.     

Thyroid dysfunction in uremia: evidence for thyroid and hypophyseal abnormalities

Disturbances in thyroid function and a high prevalence of goiter develop in patients on chronic hemodialysis. This study shows that in patients on dialysis, mean serum thyroxine and triiodothyronine levels are lower than normal. Patients with chronic renal failure not on dialysis, have mean serum thyroxine levels similar to normal subjects and low mean serum triiodothyronine levels. However, both serum thyroxine and triiodothyronine concentrations decrease as the renal failure worsens. In addition, both groups of patients with renal failure have a decreased serum thyroxine response to oxogenous thyrotrophin and a diminished serum thyrotrophin response to thyrotrophin-releasing hormone. These data suggest the presence of an intrathyroidal and an hypophyseal defect in uremic patients. Although serum iodide concentrations are elevated, there is no correlation between the level of serum iodide and the degree of renal failure. Therefore, we have no direct evidence that iodide excess is responsible for the abnormalities observed.     

Plasma lipase, C-peptide reactivity and human pancreatic polypeptide responses after ingestion of elemental diet in patients with chronic pancreatitis

Plasma lipase, C-peptide reactivity (CPR) and human pancreatic polypeptide (HPP) responses after ingestion of elemental diet were studied in 27 patients with chronic pancreatitis. These subjects were classified into 3 groups according to ERP findings; minimum or mild (MIP, n = 17), moderate (MOP, n = 6) and advanced (ADP, n = 4). Basal plasma lipase levels in the MIP and MOP patients were significantly higher than that in the controls (P < 0.05). Plasma CPR response (sigma delta CPR) in MIP cases were significantly higher than that in controls (P < 0.05). Also, plasma HPP (response (sigma delta HPP) in MIP cases were significantly higher than that in controls (P < 0.05). Plasma CPR and HPP responses correlated with the severity of chronic pancreatitis. Fourteen of the 17 MIP patients (82%) showed higher levels of basal lipase or sigma delta HPP in comparison to the respective normal ranges. This study suggested that the ED test may be more sensitive for detection of mild chronic pancreatitis and that it may be useful for evaluating exocrine and endocrine pancreatic functions in various stages of chronic pancreatitis.     

Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance?

The polycystic ovary syndrome (PCOS) is the most common hyperandrogenic disorder among women and is characterized by metabolic and cardiovascular aberrations similar to those seen in the so-called insulin resistance syndrome. The regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 10 nonobese women with PCOS and in 11 age- and body mass index-matched healthy women. Eight PCOS women were reinvestigated after 3 months of treatment with combined oral contraceptives containing ethinyl estradiol and norethisterone, which normalized hyperandrogenicity. The PCOS women showed a marked resistance to the lipolytic effect of noradrenaline due to defects at two different levels in the lipolytic cascade: first, a 7-fold reduction in sensitivity to the beta 2-selective agonist terbutaline (P < 0.005), which could be ascribed to a 50% lower beta 2-adrenoceptor density (P < 0.02) as determined with radioligand binding; there was no difference with regard to dobutamine (beta 1) or clonidine (alpha 2-sensitivity) or beta 1-adrenoceptor density; second, the maximum lipolytic response was also 35% lower (P < 0.02) in the PCOS women compared to that in the healthy women. This was seen with all beta-adrenergic agonists and the postreceptor-acting agents forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating protein kinase). Neither beta 2-adrenoceptor sensitivity or density nor the reduced lipolytic responsiveness was restored by 3 months of oral contraceptives treatment. The results indicate the existence of a marked impairment of catecholamine-induced lipolysis in nonobese PCOS women displaying early features of the insulin resistance syndrome due to multiple lipolysis defects as a lower beta 2-adrenoceptor density and reduced function of the protein kinase, hormone-sensitive lipase complex. These lipolysis defects are identical to those observed in the insulin resistance (metabolic) syndrome and could be a primary pathogenic mechanism for the development of these disorders.     

Impaired release of natural killer cytotoxic factor(s) by peripheral blood lymphocytes in patients with chronic LGL-proliferative disease

BACKGROUND: Chronic LGL-proliferative disease (LGL-PD) is a clonal expansion of cells with large granular lymphocyte (LGL) morphology. In most cases, proliferating cells express both suppressor/cytolytic T-cell and natural killer (NK) cell surface markers, but other cell phenotypes may be observed. LGL-PD lymphocytes have been found to lack or show very low natural killer cell activity (NKa). The aim of the present paper is to investigate the underlying mechanisms responsible for impaired NKa in a homogeneous group of five selected LGL-PD patients with a CD3+, CD8+, CD57+ cell phenotype. RESULTS: In all patients, the expanded cell population expressed very low NKa against K562 cell targets, but this increased significantly with recombinant human interleukin-2 (rhIL-2) and phytohemagglutinin (PHA) activation. Recombinant human alpha-interferon (rhIFN-alpha) had no significant effect on NKa. Cells displayed normal tumor cell binding capacity but failed to release sufficient amounts of functionally active natural killer cytotoxic factor(s) (NKCFs) upon interaction with the NK-sensitive K562 cells targets. However, they did release soluble cytolytic molecules against K562 cells upon activation with PHA. CONCLUSIONS: Our findings provide evidence that the defective NKa in LGL-PD patients with the aforementioned phenotype is probably due, at least in part, to the inability of expanded lymphocytes to release NKCFs upon interaction with NK-sensitive cell targets. Since recognition of target cells by patient lymphocytes is not disturbed and the cells are capable of producing NKCFs upon activation with PHA, it is probable that the cause of this abnormality is located at the level of the activation signal provided by the stimulatory target cells. Studies in subcellular level are certainly needed for a more precise determination of the underlying defect.