Glucose turnover in humans in the basal state and after intravenous glucose: a comparison of two models.

This study investigated the ability of two models to represent glucose kinetics in the basal steady state and during an intravenous glucose tolerance test (IVGTT). Six young nonobese male subjects were studied after an overnight fast. Two bolus injections of [U-13C]glucose were given 150 min apart, the first without and the second together with concomitant injection of unlabeled glucose. [3-3H]glucose was constantly infused throughout the study and served to provide an independent means for evaluation of system responses. A linear time-invariant three-compartmental model and the two-compartment time-variant model proposed by Caumo and Cobelli were used to interpret measured time courses of [U-13C]glucose and to reconstruct endogenous glucose production and glucose removal. The ability of the two models to describe the glucose tracer time course was comparable. Simulation studies showed that the two-compartmental time-variant system better predicted measured [3-3H]glucose concentration profiles than did the three-compartmental time-invariant model. However, endogenous glucose production and the integral of excess glucose removal over basal during the IVGTT derived from the two models were almost identical.

Comparative long-term experience with immunoadsorption and dextran sulfate cellulose adsorption for extracorporeal elimination of low-density lipoproteins.

Two low-density lipoprotein (LDL) apheresis methods allowing a specific extracorporeal removal of atherogenic lipoproteins from plasma were compared concerning their efficacy and safety in the long-term therapy of severe familial hypercholesterolemia. Five patients were treated with immunoadsorption (IMA) at weekly intervals over 3 years each, and three patients received weekly therapy with dextran sulfate cellulose adsorption (DSA) for up to 2 years. The mean plasma volume processed per session to decrease total cholesterol to a target level of 100-150 mg/dl at the end of LDL apheresis was significantly lower in DSA than in IMA: 143% vs. 180% of the individual plasma volume. Both LDL apheresis procedures achieved a mean acute reduction of plasma LDL cholesterol by more than 70%. The average interval concentrations of plasma LDL cholesterol obtained without concomitant lipid-lowering medication were 151 +/- 26 mg/dl compared to 351 +/- 65 mg/dl at baseline in the IMA-treated patients and 139 +/- 18 mg/dl compared to 359 +/- 48 mg/dl at baseline in the DSA-treated patients. Two patients from the DSA group died after 2 years of study participation due to a stroke and a sudden cardiac death several days after the last plasma therapy. Treatment-related side effects were infrequent. Long-term therapy with IMA and DSA was associated with symptomatic improvement of coronary artery disease and mobilization of tissue cholesterol deposits. Analysis of coronary angiograms after 3 years of weekly LDL apheresis with IMA revealed in five patients nearly identical atherosclerotic lesions without definite regression or progression.

Recovery of hypoglycaemia-associated compromised cerebral function after a short interval of euglycaemia in insulin-dependent diabetic patients.

To test the hypothesis that compromised cerebral function, induced by recurrent hypoglycaemic episodes, may recover after a short interval of euglycaemia, we examined electrophysiological activity and symptom awareness during two sequential euglycaemic-hypoglycaemic clamp studies in 11 insulin-dependent diabetic patients without any signs of peripheral or autonomic neuropathy. Neurophysiological testing and evaluation of hypoglycaemic symptoms were performed at stable glycaemic plateaus of 5.6, 3.3, 2.2, and 1.7 mmol/l. The first clamp study was preceded by 3 short-term hypoglycaemic episodes, whereas the second clamp study followed a 2 day interval of strict euglycaemia. The latter caused a recovery of electrophysiological activity, which was demonstrated by recovery of delays of the middle latency auditory evoked potentials (latency shift of the P(a) component, MANOVA, P < 0.01). Reversal of hypoglycaemic symptom unawareness involved the overall symptom perception (MANOVA, P < 0.04), as well as the autonomic symptoms of heart pounding (P < 0.05) and sweating (P < 0.05). We conclude that the previously reported impaired cerebral function, occurring as a consequence of repetitive hypoglycaemic episodes, may recover after a single euglycaemic interval.

Rudimentary second stomach as adrenal incidentaloma.

We present the case of an adrenal incidentaloma of considerable size which turned out to be a stomach-like diverticular mass, probably a malformation arising from the embryonic foregut. We discuss whether results possibly obtained by extensive and costly investigative techniques would have changed the management.

Differential diagnosis of neuropathic lesions in diabetic and alcoholic patients.

Cardiovascular reflex tests are used extensively to screen diabetic patients for autonomic cardiac neuropathy. Since alcohol abuse must often be considered the cause of nerve damage in internally ill patients, we examined 66 nonalcoholic type 1 (insulin-dependent) diabetics and 63 nondiabetic alcoholics matched for age, weight, and duration of disease to determine whether specific patterns of complaints, symptoms, signs, and results of the cardiovascular reflex tests can differentiate between alcoholic and diabetic nerve damages. In these carefully selected diabetic and alcoholic patients the medical history, clinical neurological assessment, and reflex test results all showed significant differences, resulting in different patterns which allow the correct allocation of nerve damage to either diabetic or alcoholic origin with easily available clinical means.

Hypothalamic-pituitary activation does not differ during human and porcine insulin-induced hypoglycemia in insulin-dependent diabetes mellitus.

Although pituitary hormones play only a minor role in acute hormonal counterregulation during insulin-induced hypoglycemia, their concomitant secretion with the profound sympathoadrenal response provides an indicator of hypothalamic-pituitary activation. The release of different amounts of beta-endorphin, growth hormone, and adrenocorticotropin during human (HI) and porcine (PI) insulin-induced hypoglycemia would serve as a pointer to a different insulin species effect on hypothalamic-pituitary response. We performed a controlled, double-blind study with randomization to either HI or PI to compare insulin effects during developing and established hypoglycemia. The glucose clamp technique was used to lower the blood glucose concentration stepwise (3.3, 2.2, 1.7 mmol/l) over similar periods in ten patients with insulin-dependent diabetes mellitus. beta-endorphin, growth hormone, and adrenocorticotropin levels were determined by radioimmunoassay from arterialized blood at the above plateaus. A different action of HI or PI on peripheral glucose metabolism was not found. Pituitary hormones increased significantly during hypoglycemia (analysis of variance for hypoglycemic effects: beta-endorphin, P < 0.02; growth hormone, P < 0.04; adrenocorticotropin, P < 0.05). No insulin species effect was detected. Hypothalamic-pituitary activation during insulin-induced hypoglycemia is independent of the insulin species used, which supports earlier observations of an identical sympathoadrenal response during HI- and PI-induced hypoglycemia.

Different effects of two methods of low-density lipoprotein apheresis on the coagulation and fibrinolytic systems.

OBJECTIVE: Immunoadsorption (IMA) and dextran sulfate adsorption (DSA) are two methods for selective extracorporeal elimination of low-density lipoproteins which are known as LDL apheresis. Their influence on haemostasis until now is widely unknown. DESIGN: The effects of both LDL apheresis procedures on the coagulation and fibrinolytic systems were compared amongst five patients treated with IMA and four patients who received a DSA therapy. SUBJECTS: All patients with severe heterozygous familial hypercholesterolaemia were participants in a long-term LDL apheresis programme with treatments every 1-2 weeks. INTERVENTION: Combined anticoagulation with heparin and citrate in IMA, and also heparin exclusively in DSA were used for the extracorporeal circulation. MEASURES: Blood samples were taken immediately before and after a single LDL apheresis and five times during the weekly interval until the next therapy. RESULTS: DSA had a significantly greater effect on standard clotting tests than IMA at the end of plasma therapy despite identical dosages of heparin. DSA caused a considerable reduction of the coagulation factors V, VIII:C, vWF:Ag, XI, XII, and prekallikrein by 48-99% at the end of apheresis treatment whereas only factor VIII:C showed a marked decrease of 72% after IMA. All abnormalities of the global coagulation tests and of most clotting factors were restored 1 day after treatment in both procedures followed by a moderate rebound phenomenon of single coagulation factors during the next few days in IMA-treated patients. CONCLUSION: DSA exerts a more profound effect on the coagulation system than IMA by a substantial co-elimination of various clotting factors in addition to the desired removal of atherogenic lipoproteins.

Neurophysiological impairments in IDDM patients during euglycemia and hypoglycemia.

OBJECTIVE: To test the hypothesis that latencies of evoked potentials in IDDM patients are delayed compared with healthy control subjects during euglycemia, and that insulin-induced hypoglycemia causes further latency delays of evoked potentials to occur. RESEARCH DESIGN AND METHODS: We recruited 23 IDDM patients (27.9 +/- 1.6 yr of age, HbA1c 6.7 +/- 0.3%, without sensory or autonomic neuropathy) and 26 unequivocally healthy subjects who were carefully matched for sex, age, and body mass index to serve as the control group (18 men and 8 women, 28.4 +/- 1.6 yr of age, 22.6 +/- 0.7 kg/m2), for a controlled, prospective study. Sequential euglycemic-hypoglycemic clamps were performed with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' and healthy control subjects' neurophysiological functions were evaluated. The methodological armamentarium included the measurement of brainstem auditory, middle-latency auditory, and somatosensory evoked potentials that assessed conduction velocity in corresponding neural structures and information processing in the midbrain and auditory cortex. RESULTS: Multiple analysis of variance revealed a significant overall difference of brainstem auditory evoked potential latencies during euglycemia between the study group and healthy control group (F = 3.41, P < 0.03), which was mainly attributable to latency delays of wave III (F = 6.60, P < 0.02), V (F = 9.19, P < 0.01), and interpeak latency I-V (F = 2.82, P < 0.07). Repeated analysis of variance measures detected a significant latency delay of the major wave Pa of the middle-latency auditory evoked potentials during hypoglycemia (F = 4.4, P < 0.02), which rapidly returned to normal after reinstitution of euglycemia. CONCLUSIONS: In IDDM patients, chronic, structural CNS changes already appear at the brainstem level during euglycemia. Functional, reversible CNS changes, however, seem to emerge during acute deviation from glucose homeostasis in more rostral brain regions.

Comparison of a mechanized version of the 'König' reaction and a fluorescence polarization immunoassay for the determination of nicotine metabolites in urine.

Smoking can be detected by the determination of cotinine in urine. We compared the performance of an automated modification of the 'König' reaction adapted to a centrifugal analyzer with an automated commercial fluorescence polarization immunoassay (TDX system). In the latter assay, cotinine, as the primary metabolite of nicotine, can be measured with high specificity. In contrast, the 'König' reaction also detects nicotine metabolites other than cotinine by a group colour reaction. Analysis speed of the 'König' reaction was about 66 samples/h with a detection limit 2 S.D. above the mean value of urine samples of non-smokers. Analysis speed of the TDX system was 41 samples/h. The coefficient of variation (C.V.) of both methods in smokers' urine was 8.6% ('König' reaction) vs. 3.4% (TDX system) in the high range and 16.4% vs. 9.5% in the low range. In a controlled, prospective study recruiting 86 cigarette-smoking volunteers, 83.7% were correctly classified as being smokers by both systems, 13.9% were classified as smokers by the 'König' reaction only and 2.4% were misclassified as non-smokers by both systems. Thus, the sensitivity of the 'König' reaction seems to be higher than in the TDX system (97.6% vs. 83.7%). Of 33 non-smoking individuals, 81.8% were correctly classified as non-smokers by both systems, 18.2 were misclassified as smokers by the 'König' reaction and no person was misclassified by the fluorescence polarization immunoassay. Thus, the specificity of the TDX system seems to be higher than that of the 'König' reaction (100% vs. 81.8%). We conclude that both systems are applicable to detect individuals who smoke regularly by simple urine testing. The higher specificity of the TDX system is outweighed by the higher sensitivity of the 'König' reaction at much lower cost.

Systemic vasculitis positive for circulating anti-neutrophil cytoplasmic antibodies and with predominantly neurological presentation.

A 57-year-old male patient suffering from dramatically deteriorating diffuse and focal central nervous system symptoms was admitted to hospital after a short prodromal period in a somnolent state. He was diagnosed as having systemic vasculitis positive for circulating anti-neutrophil cytoplasmic antibodies, primarily involving the brain, but also most other organ systems. Circulating anti-neutrophil cytoplasmic antibodies are highly specific for Wegener granulomatosis, though they have been detected in rare cases of other vasculitic syndromes. Central nervous system lesions as presenting signs in Wegener granulomatosis have to be regarded as rare. This case nonetheless suggests that Wegener granulomatosis has to be considered in patients with a predominantly cerebral manifestation of a vasculitic syndrome.

Compromised hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients.

To test the hypothesis that recurrent short-term hypoglycemic episodes may impair hormonal counterregulation, symptom awareness, and neurophysiological function during subsequent hypoglycemia, we examined two groups of IDDM patients (n = 18), neither of whom exhibited signs of autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed three days apart with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' awareness of and response to hypoglycemia was evaluated. In the intervention group (n = 11), three short-term hypoglycemic episodes preceded the second clamp study. Counterregulatory hormones increased significantly during hypoglycemia, but adrenaline (P < 0.03), cortisol (P < 0.01), and ACTH (albeit not significant) showed a blunted response after repetitive hypoglycemic events. In this group, the perception of hypoglycemic symptoms was significantly reduced and was most evident for the autonomic symptoms of sweating (P < 0.05), heart pounding (P < 0.01), and warmness (P < 0.03). The deterioration of neurophysiological function, as assessed from the middle latency auditory evoked potentials, was more pronounced in the intervention group (latency shift of the Pa component, P < 0.05). These data suggest that alterations of neuroendocrine counterregulation, symptom perception, and certain aspects of cerebral function may occur as a consequence of recurrent short-term hypoglycemic episodes. These adaptation phenomena may contribute to the increased incidence of severe hypoglycemia in IDDM patients on intensive insulin therapy.

Simple computer-assisted diagnosis of acute myocardial infarction in patients with acute thoracic pain.

In order to minimize the initial diagnostic uncertainty in patients suspected of having acute myocardial infarction, we prospectively extracted predictive variables from previous history, ECG, and clinical chemical parameters of 87 patients, who were admitted for acute thoracic pain. The variables thus extracted were: Thoracic pain in previous history, duration of pain, white blood cell count, blood glucose, creatine-kinase, and S-T elevation in the ECG. These parameters were used for formulating a mathematical model based upon univariate and multivariate statistical methods. The sensitivity of the model in the study population was 95% and the specificity 77%. Correct classification was achieved in 89% of cases. In a second phase, the prognostic index was prospectively evaluated in a second set of 122 consecutive patients. In this test population, the sensitivity was 89% and the specificity 86%. 87% of patients were classified correctly.

Successful treatment of brain abscess caused by Nocardia in an immunocompromised patient after failure of co-trimoxazole.

Disseminated infection caused by Nocardia asteroides is a fairly rare entity occurring mostly in immunocompromised states. Metastatic brain abscesses are a frequent and ominous complication. We report on a patient whose underlying disease was stage II pulmonary sarcoidosis. He acquired disseminated N. asteroides infection while on immunosuppressive therapy with prednisolone. After the generally recommended therapy with co-trimoxazole (trimethoprim/sulfamethoxazole) proved ineffective in controlling his brain abscesses, the lesions of the central nervous system completely resolved under a combination of oral rifampicin with i.v. imipenem, followed by oral rifampicin and ampicillin/clavulanic acid.

Hormonal counterregulation, symptom awareness, and neurophysiological function in type 1 diabetes during insulin-induced hypoglycaemia.

To evaluate a putative differential impact of human (HI) and porcine (PI) insulin on human brain function we examined 10 Type 1 (insulin-dependent) diabetic patients without any signs of sensory or autonomic neuropathy. The glucose clamp technique was applied to achieve stable glycaemic plateaus of 5.6, 3.3, 2.2, and 1.7 mmol l-1 on two occasions with randomized and blinded allocation of either HI or PI. At each of the plateaus, symptom awareness, hormonal counterregulation, and neurophysiological functions (primary sensory information processing of the auditory and somatosensory system) were recorded. The effect of both types of insulin on glucose metabolism and counterregulatory hormone response was almost identical. Catecholamines increased (adrenaline p less than 0.05; noradrenaline p less than 0.02) during hypoglycaemia, independent of the type of insulin being used. Symptom awareness increased significantly during the fall of blood glucose concentration. This effect was more pronounced (total symptom score 26 vs 2, p less than 0.05) with PI, but only during developing hypoglycaemia (3.3 mmol l-1-plateau). For brainstem auditory evoked potentials and somatosensory evoked potentials, all individual and averaged latencies and corresponding amplitudes were within the normal range. No effect of insulin type or blood glucose concentration on neurophysiological measures could be detected. Our results suggest a differential impact of HI and PI on human brain function with regard to symptom awareness, but not hormonal counterregulation. This direct effect of insulin on central nervous function does not involve the afferent transmission in the auditory and somatosensory system.

Increase in glucose consumption by acetylcysteine during hyperglycemic clamp. A study with healthy volunteers.

Thiols have been shown to be related to insulin secretion and to uptake of glucose into tissues. In the present study the effects of i.v. administration of acetylcysteine (N-acetylcysteine, NAC, CAS 616-91-1) on glucose consumption and plasma free thiols were studied in young healthy volunteers during hyperglycemic clamp. NAC (0.5-2.0 mg/kg) significantly increased glucose consumption. This effect was not obvious at higher doses of NAC. Plasma free NAC depended on the dose of NAC injected. The t1/2 of NAC was 11 min. NAC produced significant increases of plasma cysteine concentrations, and a slight but insignificantly increase of plasma glutathione. These data suggest that a moderate increase in plasma thiols augments glucose consumption during hyperglycemic clamp.

Catecholamine response during human and pork insulin-induced hypoglycemia in IDDM patients.

OBJECTIVE: To evaluate the catecholamine response during human and pork insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS: Ten insulin-dependent diabetes mellitus (IDDM) patients without any signs of autonomic neuropathy received either human or pork insulin in a randomized crossover fashion on 2 nonconsecutive days. The glucose clamp technique was applied to achieve stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM. RESULTS: The effect of both types of insulin on glucose metabolism and circulating catecholamines was almost identical. There was a sharp rise of both epinephrine (P less than 0.05) and norepinephrine (P less than 0.02) during hypoglycemia, which did not depend on the type of insulin applicated. Symptom awareness increased significantly during the decrease of blood glucose concentration. Only during developing hypoglycemia (3.3-mM plateau), was this effect more pronounced (cumulative symptom score 2 vs. 26, P less than 0.05) with pork insulin. CONCLUSIONS: AN attenuated catecholamine secretion seems not to be the putative mechanism of a reduced awareness of human insulin-induced hypoglycemia.

Cognitive and psychomotor function during severe insulin-induced hypoglycaemia in insulin-dependent diabetic patients.

Cognitive and psychomotor function, hormonal counterregulation and symptom awareness during severe insulin-induced hypoglycaemia were evaluated in 10 insulin-dependent diabetic patients. The glucose-clamp technique (Biostator) was applied to achieve a stable hypoglycaemic (39 +/- 2 mg/dl) plateau. A battery of 7 neuropsychological tests and a standardized questionnaire assessing hypoglycaemia symptoms were administered during euglycaemia and hypoglycaemia. There was a significant increase in counterregulatory hormone response (cortisol, growth hormone, p less than 0.05). Every patient experienced symptoms during severe hypoglycaemia. Four patients, however, were not aware of this threatening metabolic state. There was a significant performance decrement in all but two neuropsychological tests (Aiming Center I, Aiming Center II, Line Tracing Errors, Reaction Time, p less than 0.01; Digit Symbol, p less than 0.05). Performance of simple motor tasks as well as cognitive tasks requiring complex discrimination deteriorated similarly. Furthermore, the patients' general well-being (subjective condition) worsened considerably. In conclusion, a significant impairment of neuropsychological functions emerged during severe hypoglycaemia in insulin-dependent diabetes mellitus, even in the face of adequate hormonal counterregulation, and did not always coincide with an appropriate patient awareness of the actual metabolic state.

Different awareness of hypoglycaemia induced by human or purified pork insulin in type I diabetic patients.

Recently, there have been reports on a diminished awareness of hypoglycaemia after a switch from purified pork insulin (PPI) to human insulin (HI) in insulin-dependent diabetes mellitus (IDDM). To clarify this phenomenon we investigated nine IDDM patients without signs of autonomic neuropathy. After an overnight euglycaemic clamp, blood glucose was lowered to hypoglycaemic levels by means of an artificial pancreas (Biostator) on 2 days. Insulin was used in a double-blind, randomized, cross-over fashion, either PPI or HI. The symptomatology and the hormonal counterregulation of developing hypoglycaemia was recorded. Venous concentrations of free insulin, cortisol, glucagon, growth hormone and the prevailing blood glucose were similar under both insulins. Eight out of nine IDDM patients felt more symptoms and at a higher blood glucose concentration under PPI than under HI. The first symptom of developing hypoglycaemia appeared at a mean blood glucose concentration of 61.1 +/- 5.4 mg.dl-1 under PPI and 44.4 +/- 5.3 mg.dl-1 under HI respectively (P less than 0.05). We conclude that HI may cause symptoms of hypoglycaemia to appear later and with a lesser number in comparison to PPI.