Min In Normal Subjects Research Articles

Measuring pre-hepatic insulin secretion using a population model of C-peptide kinetics: accuracy and required sampling schedule.

The accuracy of calculations of pre-hepatic insulin secretion were investigated, to provide independent validation of a population model of C-peptide kinetics. The effects of sampling frequency were also assessed. Five normal subjects (aged 28 to 43 years; BMI (kg/m2) 20.5 to 24.5) and five subjects with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone (aged 34 to 57 years; BMI 22.6 to 25.6) were given a variable intravenous infusion of biosynthetic human C-peptide (BHCP) (t=-60 to 240 min) mimicking meal stimulated C-peptide secretion, with short-term oscillations (peak approximately every 12 min) superimposed on the infusion profile. Plasma C-peptide was measured every 5 min (t=0 to 240 min). The BHCP infusion was reconstructed from C-peptide measurements using a population model of C-peptide kinetics and a deconvolution method. Bias, defined as the percentage difference between the total amount of calculated BHCP and the total amount of infused BHCP (t=0 to 240 min), indicated that overall C-peptide secretion can be measured with 14% [95% confidence interval (CI) -11 to 39%] and 21% (95% CI -3 to 45%) accuracy in normal subjects and subjects with NIDDM respectively. Accuracy was not reduced by reducing the sampling frequency to every 30 min. The root mean square error, measuring the average deviation between the infused and normalised calculated BHCP profiles, was also independent of the sampling frequency [mean (95% CI) 0.9 (0.3 to 1.6) pmol/kg per min in normal subjects; 1.0 (0.9 to 1.1) pmol/kg per min in subjects with NIDDM]. Deconvolution employing a population model of C-peptide kinetics can be used to estimate postprandial total C-peptide secretion with biases of 14% and 22% respectively in normal subjects and subjects with NIDDM. Plasma C-peptide samples need only be drawn every 30 minutes.

An electronic device measuring the frequency of spontaneous swallowing: Digital Phagometer

A new and portable electronic device called the "Digital Phagometer" is described for the time based counting of spontaneous swallowing. This device is composed of a piezoelectric sensor and a digital event counter/ recorder which can be downloaded to any IBM-compatible PC. The sensor of Digital Phagometer is placed and fixed on the coniotomy region between the cricoid and thyroid cartilage. In this way, it is capable of sensing each upward and downward movement of the larynx produced by spontaneous movement as a function of time. Spontaneous swallowing was measured 1-4 h after lunch in 21 normal subjects and 21 patients with Parkinson's disease (PD). The mean frequency of spontaneous swallowing was 0.8 counts/min in PD patients and 1.18 counts/ min in normal subjects (p < 0.05). During the intake of 200 ml water, the mean frequency of voluntary swallowing did not differ significantly between the two groups (24.6 counts/min in normals vs. 22.3 counts/min in PD patients), but the time necessary to swallow the same volume of water was longer in the PD group.

Oscillatory Insulin Secretion After Pancreas Transplant

In vivo studies of beta-cell secretory function have demonstrated the existence of rapid insulin oscillations of small amplitude recurring every 8-15 min in normal subjects. This study evaluated the effects of pancreas transplant on rapid insulin oscillations. Samples for glucose, insulin, and C-peptide were drawn during constant glucose infusion at 2-min intervals for 90 min from six successful Px patients with type I diabetes mellitus, from six normal nondiabetic control subjects, and from three Kx subjects. A computerized algorithm (ULTRA) was used for pulse detection. In the Px group, the average insulin pulse period was significantly shorter than in both the control and Kx groups (Px 8.1 +/- 0.5, control 12.5 +/- 0.7, Kx 12.4 +/- 0.5 min, P < 0.0005). By contrast, the C-peptide pulse periods (Px 16.8 +/- 2.3, control 14.7 +/- 1.2, Kx 15.3 +/- 1.5 min) were similar in the three groups. Spectral analysis confirmed that the frequency of the insulin pulses was increased in the Px group. The absolute amplitude of the insulin pulses was greater in the Px group (P < 0.001) while the amplitude of the C-peptide pulses did not differ between the groups. Cross-correlation analysis demonstrated maximal correlation coefficients at a lag of 0 min between insulin and C-peptide (control r = 0.33, P < 0.0001; Kx r = 0.17, P = 0.06) and between insulin and glucose (control r = 0.21, P < 0.001; Kx r = 0.20, P < 0.02) in the control and Kx groups, respectively, whereas no significant correlations were observed at any lag in the Px group.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between Skin Fluorescence and Blood Flow in Normal and in Chronically Ischemic Subjects Dosed with Fluorescein

To elucidate parameters diagnostic of chronic ischemia, the fluorescence of skin on the foot, leg, arm, and forehead of six chronically ischemic patients and six normal subjects injected with fluorescein was measured serially using a surface-measurement fluorometer (dermofluorometer). Simultaneously collected plasma samples were assayed spectrofluorometrically for unmetabolized fluorescein. The time courses of plasma fluorescein content and dermofluorometer readings were jointly analyzed by combining a standard pharmacokinetic model, a model predicting skin site from plasma concentrations of fluorescein, and a model predicting the dermofluorometer response to those skin concentrations. Fluorescein plasma clearance (0.22 ± 0.06 versus 0.46± 0.20 LVh/kg) in ischemic patients was only half, and half-life was double (2.4 ± 1.0 versus 1.3 ± 0.3 h) those in normal subjects, with volume of distribution (Vdss = 0.46 L/kg) being similar. Despite the ischemia diagnosis for all patients involving claudication of the lower extremities, patients could be distinguished statistically from normal subjects on the basis of fluorescence readings taken on the arm, but not those using the foot or leg. The rate constant describing flux of fluorescein from the arm skin site in patients was only half that in normal subjects, and the peak reading on the arm occurred at 42 ± 14 min after fluorescein injection in patients, but at only 15 ± 6 min in normal subjects. Lack of discrimination between subject groups via leg and foot readings may be due to several physiologic and/or experimental factors, including the need to take skin surface readings much earlier than previously recognized. As might be expected on optical grounds, the model predicted that the dermofluorometer is less sensitive to similar skin concentrations of fluorescein in people of black as compared with white ethnic background.

Blood lactate behavior after glucose load in diabetes mellitus.

The aim of this study was to evaluate the relationships between blood lactate and plasma glucose, insulin (IRI) and C-peptide (IRCP) during the first hour of an oral glucose load (OGTT, 100 g). Twelve controls, sixteen non-insulin-dependent (NIDDM) and four insulin-dependent (IDDM) diabetic subjects were studied. A significant increase in blood lactate was observed at 15 min in normal subjects, whereas there was a delayed increase at 45 min in NIDDM subjects, in the presence of IRCP increments of 0.31 nmol/l. In order to have a minimum significant lactate increment, the threshold value of peripheral IRCP increment was about 0.30 nmol/l. In IDDM subjects, despite considerable hyperglycemia, blood lactate concentration remained unchanged throughout the test. In normal and NIDDM subjects there was a significant negative correlation between delta lactate and delta glucose (r = -0.89, p less than 0.001) and a significant positive correlation between delta lactate and delta IRCP (r = 0.78, p less than 0.001). In conclusion, hyperglycemia itself and the lack of increase in insulin secretion do not affect blood lactate increase during OGTT; blood concentration of this metabolite depends mainly on an early insulin secretion apt to enhance tissue glucose uptake and to inhibit gluconeogenesis.

Measurement of gastric emptying time by real-time ultrasonography

This paper describes an ultrasound method of assessing gastric emptying time based on measurements of the gastric antrum, which is visible in almost all subjects before and after meals. A total of 54 subjects were examined including 18 normal subjects and 36 subjects with idiopathic functional dyspepsia. The emptying time was determined in all subjects by measuring the changes in the crosssectional area of the gastric antrum. In a subgroup of 34 subjects the volume of the whole antropyloric region was also considered. Measurements were taken by the same observer after fasting and at regular 30-min intervals after a standard 800-cal meal. Final emptying time (calculated in relation to the start of the meal) was considered to be the time at which the antral area or volume returned to basal value. Final emptying time (mean ± SD) was 248 ± 39 min in normal subjects and 359 ± 64 min in patients with functional dyspepsia (p < 0.001). A significantly higher degree of dilatation of the gastric antrum was found in dyspeptic patients than in control subjects. Barium x-ray of the stomach in 19 subjects always confirmed the ultrasound finding on the presence or absence of contents within the stomach. We conclude that this kind of ultrasound study of the antropyloric region allows accurate determination of total gastric emptying time.

Lack of in Vivo Insulin Resistance in Controlled Insulin-Dependent, Type I, Diabetic Patients*

Although type I diabetic patients are clearly insulin deficient, it is unclear whether they have normal in vivo sensitivity to insulin. Recent studies which suggested that insulin resistance is a common feature of insulin-dependent diabetics have not taken into account their degree of metabolic control or the presence of circulating antibodies. In the present study, we performed multiple euglycemic glucose clamp studies to construct insulin dose-response curves in 5 well controlled and 5 poorly controlled type I diabetic patients and 21 age-matched normal subjects. Each study was performed on a separate day at insulin infusion rates of 15, 40, 120, 240, or 1200 mU/M2 X min. During the 40 and 120 mU/M2 X min infusions, steady state insulin levels of 96 +/- 8 (+/- SE) and 285 +/- 27 microU/ml respectively, were achieved within 25 min in normal subjects. In contrast, diabetic subjects did not achieve steady state insulin levels (62 +/- 8 and 212 +/- 16 microU/ml) until 90 min of infusion, and insulin antibodies were detectable in the serum of all these patients. The dose-response curve for insulin stimulation of glucose disposal in well controlled diabetic subjects was comparable to that in normal subjects, with half-maximally effective insulin levels of 84 microU/ml in the diabetic patients compared to 70 microU/ml in normal subjects and virtually identical maximal rates of glucose disposal (433 +/- 11 vs. 411 +/- 17 mg/M2 X min in controls). In contrast, the dose-response curve for poorly controlled diabetic subjects was significantly right-shifted (half-maximally effective insulin level, 112 microU/ml), with marked reduction in the maximal glucose disposal rate (324 +/- 25 vs. 411 +/- 17 mg/M2 X min in normal subjects). Basal hepatic glucose output was increased in both poorly controlled and well controlled type I diabetic patients (132 +/- 7 and 101 +/- 16 mg/M2 X min, respectively) compared to normal subjects (76 +/- 7 mg/M2 X min). However, during each insulin infusion, hepatic glucose output was virtually 100% suppressed in all 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of acute hyperglycaemia on plasma potassium and aldosterone levels in type 2 (non-insulin-dependent) diabetes.

Potassium homeostasis during a 50-g oral glucose tolerance test was studied in 14 newly diagnosed, untreated Type 2 (non-insulin-dependent) diabetics. They showed a rise in plasma potassium from a mean +/- SEM basal of 3.9 +/- 0.1 to 4.4 +/- 0.1 mmol/l at 60 min and to 4.6 +/- 0.1 mmol/l at 90 min (p less than 0.01), whereas no change was seen in a group of 14 normal subjects. A possible role of mineralocorticoids was sought by measuring simultaneous serum aldosterone and deoxycorticosterone levels. Aldosterone was reduced after the glucose load in all subjects studied, falling to 73% of basal at 60 min in diabetics (p less than 0.01), and to 61% of basal at 90 min in normal subjects (p less than 0.001). Serum deoxycorticosterone showed a similar pattern. Thus it is unlikely that the rise in plasma potassium seen in the diabetic patients was due to abnormal levels of mineralocorticoids. Since the diabetic subjects were found to have an intact insulin response to the glucose load, it is suggested that resistance to insulin-stimulated potassium uptake into cells might be involved in the pathogenesis of the paradoxical hyperkalaemia induced by acute hyperglycaemia.

Glycine stimulated growth hormone release in man.

The influence of glycine, the simplest amino acid, on pituitary function has been investigated in the present study. Different doses (4, 8, or 12 g) of glycine were intravenously infused over 15 or 30 min in normal subjects. Serum levels of GH (growth hormone) and Prl (prolactin) were measured before and after the infusion, and also blood sugar levels were determined. The dose of 4 or 8 g glycine induced a significant increase in serum GH (P less than 0.05 or P less than 0.001, respectively); however, a more pronounced and significant increase in serum GH levels was observed after infusion at a dose of 12 g glycine (P less than 0.001). It was clearly observed that the dose-dependent GH release to intravenous glycine occurred in normal subjects. On the contrary, serum Prl level was not changed significantly, and blood sugar level was transiently, but significantly (P less than 0.05), increased after the infusion of 12 g glycine. The present data suggest that glycine might play an important role in the control of hypothalamic-pituitary function.

Metabolic effects of glucagon in endogenous hypertriglyceridemia

The metabolic effects of glucagon, administered i.v. in doses of 1 microgram/kg, were evaluated in two groups of patients with endogenous hypertriglyceridemia (Types IV and V according to Fredrickson) with normal and reduced glucose tolerance and in a control group. Glucagon had a lipolytic effect, evaluated as the plasma increase of free fatty acids (FFA) during the first 20 min in normal subjects, but not in the two hyperlipemic groups. A negative correlation was observed between fasting IRI level and FFA mobilization. The ketogenic and hypotriglyceridemic effects of glucagon were demonstrated in normal and hyperlipemic groups. It would seem, therefore, that at the pharmacological doses injected, there is no resistance to the hypotriglyceridemic effect of glucagon in endogenous hypertriglyceridemia.

Metabolic Clearance and Plasma Half Disappearance Time of Exogenous Gonadotropin Releasing Hormone in Normal Subjects and in Patients with Liver Disease and Chronic Renal Failure

The metabolic clearance rate (MCR) and half disappearance time (t 1/2) of gonadotropin releasing hormone (GnRH) has been measured during and after cessation of constant infusion of exogenous GnRH. Studies were performed on normal subjects and patients with severe renal and liver disease. GnRH was quantified by a sensitive and specific radioimmunoassay which does not measure GnRH fragments. The MCR of GnRH in normal subjects was 1640+/-59.7 ml/min (23.7+/-1.8 ml/min/kg), similar to values found in 4 patients with liver disease. However in chronic renal failure an MCR of only 631+/-62 ml/min (9.1+/-0.7 ml/min/kg) was obtained. The t1/2 of GnRH after infusion was linear for 8-10 min, after which a much slower component was observed. The t1/2 of the first component ranged from 5.5 to 8 min in normal subjects, 6.5-8 min in patients with liver disease but prolonged (12-16.5 min) in patients with renal failure. It would appear that GnRH is cleared rapidly in normal subjects, that moderate liver dysfunction does not alter this, but that impaired renal function significantly prolongs the t1/2 and lowers the MCR. The kidney might be an important catabolic organ for infused GnRH; alternatively, uremia might impair catabolism non-specifically.

Pharmacokinetics of Intravenously Administered Tobramycin in Normal Volunteers and in Renal-Impaired and Hemodialyzed Patients

The pharmacokinetics of intravenously administered tobramycin, an aminoglycoside antibiotic, were studied in 16 volunteers with normal renal function and 10 patients with different degrees of renal impairment. In all subjects, the disappearance of tobramycin from serum followed first-order kinetics, and the elimination rate constant decreased proportionally with increasing degree of renal impairment. The half-life average 82 min in normal subjects (endogenous creatinine clearance, greater than 80 ml/1.73 m2 per min) and was 33.7 hr in a totally anephric subject. Linear relations were defined between the half-life of tobramycin in serum and the reciprocal of the endogenous creatinine clearance and between the half-life of the drug and the concentration of serum creatinine. These relations may be used for dosage adjustment in patients with renal impairment. In hemodialyzed patients, the half-life decreased six- to ninefold during dialysis for 6 hr. The extent of tobramycin elimination by hemodialysis may be predicted from relations established between the elimination of tobramycin and that of creatinine and blood urea nitrogen. Dosage schedules must be compatible with the pharmacologic and pharmacokinetic properties of the antibiotic.

Studies of splenic function in the myeloproliferative disorders and generalized malignant lymphomas.

Summary.The relative importance of splenic red‐cell pooling, sequestration and cell destruction in the causation of anaemia has been studied in 29 patients—16 with generalized lymphoproliferative disease, 12 with myeloproliferative disease and one with idiopathic autoimmune haemolytic anaemia.A scanning method with [11C]carbon monoxide was used for direct in vivo measurement of splenic red‐cell volume, and the spleen was delineated by‐a scan after injection of 81Rb‐labelled red cells, damaged with non‐radioactive 1‐mercuri‐2‐hydroxypropane (MHP). The clearance time of the damaged cells from the circulation was used as an index of splenic function. The fraction of red cells in the spleen varied from 2.9% to 32% and the splenic red‐cell volume ranged from 38 to 1000 ml. In patients with lymphoproliferative disorders their spleens contained a smaller proportion of red cells, relative to splenic size, than patients with myeloproliferative disease. Clearance of cells damaged with 1‐mercuri‐2‐hydroxypropane (MHP) was 30–60 min in normal subjects. Slow clearances were found in some patients with lymphosarcoma; fastest clearances occurred in patients with obvious haemolytic anaemia. No clear relationship was noted between the rate of clearance and splenic size or splenic red‐cell volume.

Skin capillary blood flow in scleroderma.

Skin blood flow was measured by the clearance of radioactive xenon ((133)Xe) injected intracutaneously in eight patients with scleroderma and nine control subjects under conditions of controlled temperature and humidity. Scleroderma patients, on being cooled 1 hr at 18 degrees C, had a rate constant of (133)Xe clearance from the dorsal finger skin which was 0.04 +/-0.07 min(-1) (mean +/-SD), compared with 0.23 +/-0.15 min(-1) in normal subjects (P < 0.005). The corresponding mean cutaneous blood flows were 2.9 ml/100 g per min in the scleroderma patients and 16.4 ml/100 g per min in normal subjects. After reflex warming by waterbath, clearance was similar in the two groups (0.33 +/-0.1 vs. 0.40 +/-0.09); these data suggest that diminished clearance in scleroderma patients on cooling resulted, at least in part, from functional or reversible interruption of the circulation. The skin temperatures of scleroderma patients after reflex warming remained lower than those of normal subjects, despite similar increases in sublingual temperatures. The dissociation of (133)Xe clearance and skin temperature in scleroderma patients (i.e. subnormal skin temperatures with normal (133)Xe clearance after reflex warming) suggests either abnormal thermal properties of scleroderma skin or selective vasoconstriction of the vessels which regulate heat exchange. The demonstrated interruption of the capillary circulation on cooling of the skin in patients with scleroderma may be important in the pathogenesis of this disorder. After oral pretreatment with guanethidine, five patients with scleroderma had increased (133)Xe clearance and calculated blood flow on cooling, rising to normal in three of these patients. The potential of this technique for the quantitative sequential evaluation of skin blood flow in subjects with scleroderma and for the evaluation of empirical therapy is suggested.