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Biomedical subjects

J Radziuk

Publications and source records attributed to J Radziuk.

At least 55 records · Page 3Linked to original sources
PubMed1986

The measurement and validation of the nonsteady-state rates of C-peptide appearance in the dog.

In order to verify the calculation of nonsteady rates of secretion of C-peptide, dog C-peptide was infused into 5 normal conscious dogs at varying rates. Using the decay curve obtained following a preliminary injection of C-peptide in each animal, concentrations during the infusion, and mathematical deconvolution, the rate of appearance of the C-peptide was calculated. This rate was within 12% of the infusion rates, with 94% of the C-peptide infused recovered in the calculation. The metabolic clearance of C-peptide was calculated to be 10.1 +/- 1.0 ml/min following both its injection and constant infusion. In conclusion, within the limits of the errors determined, C-peptide and therefore insulin secretion can be calculated on a continuous basis under nonsteady-state conditions.

Animals↗
PubMed1986

A simplified method for metabolic studies in conscious swine.

Reliable short-term blood access in conscious swine was provided by implanting multiple silastic catheters. Catheters were inserted into the aorta, hepatic vein, portal vein, and inferior vena cava through a midline laparotomy incision. Multiple catheters also were placed into the external jugular vein through a separate cervical incision. Catheter patency rates for blood withdrawal on the sixth post-operative day were: arterial 100%, hepatic 91%, portal 86%, inferior vena cava 71%. No animal had major wound or catheter infection on the seventh post-operative day. The methods described allow metabolic studies, including measurements of splanchnic blood flow, to be carried out either acutely or for up to at least 7 days post-operatively.

Animals↗
PubMed1985

Insulin-mediated and non-insulin-mediated metabolic effects of gastroenteropancreatic peptides in type I and type II diabetes.

In this brief review of regulatory function of gastroenteropancreatic peptides in control of intermediary metabolism in normal and diabetic states, with and without mediation by insulin and/or glucagon, a variety of possible mechanisms have been described. It is apparent that the pharmacologic actions of the peptides identified in various locations provide models for multiple routes of delivery and modes of action of effectors in this control system. Examples already exist of each of the hypothetical mechanisms illustrated in the scheme in Figure 4. It is clear that a great deal of study will be necessary in identification of the active agents and assessment of their importance in the physiology of intermediary metabolism. With respect to the possible pathophysiologic roles of regulatory peptides of the gastroenteropancreatic system other than insulin and glucagon, a number of considerations of Type I and Type II diabetes have been raised. The balance of the evidence suggests that Type I diabetes may be viewed as an insulin deficiency syndrome, so that physiological replacement with insulin may be expected to result in correction of the metabolic abnormalities. Nevertheless, the difficulty of physiologic replacement treatment, which may call for portal delivery of insulin, is well recognized, and abnormalities secondary to insulin deficiency even in "well-treated" Type I diabetes may be compounded by the effects of gastroenteropancreatic peptides other than insulin, exerted through the various mechanisms discussed. In Type II diabetes mellitus, current understanding of the pathophysiology is much less complete and no convincing description of the etiology exists. The various metabolic actions of the gastroenteropancreatic peptides, and their interactions with other endocrine, paracrine and nervous regulatory mechanisms, represent a dauntingly complex control system. The elucidation of this system can provide fertile ground for the development and testing of hypotheses for the pathophysiology of disordered metabolism in Type II diabetes mellitus.

Blood Glucose↗
PubMed1985

Measurement using tracers of steady-state turnover and metabolic clearance of insulin in dogs.

In nine conscious dogs, the steady-state metabolic clearance rate (MCR) and the systemic appearance rate (Ra) of insulin were determined by the tracer dilution method. [3H-PheB1]insulin ([3H]insulin) was infused as a tracer from time 0 at a constant rate. After tracer equilibration was attained, unlabeled porcine insulin was infused at variable constant rates (10.6-279 mU/min) with somatostatin (0.3 microgram . kg-1 . min-1) to suppress endogenous insulin secretion. Glucose was infused to prevent hypoglycemia. Tritiated and immunoreactive insulin (IRI) concentrations were determined in plasma samples after extraction on a C-18 reverse-phase column. Tracer-determined basal Ra of insulin was 2.39 +/- (SE) 0.61 mU/min. The calculated steady-state Ra of insulin for plasma IRI from 20 to 2,300 microU/ml showed good agreement with insulin infusion rates. The mean ratio of these rates was 0.973 +/- 0.018. The MCR of insulin under basal conditions was 29.9 +/- 3.4 ml . kg-1 . min-1, and it decreased with increasing insulin concentrations. It is concluded that 1) insulin turnover rates can be measured accurately using [3H]insulin as a tracer and 2) insulin kinetics are nonlinear.

Animals↗
PubMed1985

Galanin inhibits insulin secretion and induces hyperglycemia in dogs.

Intravenous administration of galanin into fasted conscious dogs produced a dose-dependent hyperglycemia accompanied by decreases in plasma insulin levels, but with no elevation of plasma glucagon levels. Galanin infusions produced greater parenteral glucose-induced rises in plasma glucose levels along with markedly blunted insulin responses compared with glucose and insulin responses to control glucose infusions. Immediately after cessation of the galanin infusions, elevation of plasma insulin levels occurred in the basal state and after parenteral glucose loading. These results suggest that galanin's hyperglycemic activity is predominantly mediated by a reversible inhibition of insulin secretion.

Amino Acid Sequence↗
PubMed1984

The effects of an alpha-glucoside hydrolase inhibitor on glycemia and the absorption of sucrose in man determined using a tracer method.

Acarbose, an alpha-glucosidase inhibitor, lowers the glycemic excursion following the ingestion of carbohydrates, in particular, sucrose. This was confirmed with increasing doses of acarbose (0, 50, and 100 mg) and the causes investigated. The absorption of the glucose moiety of sucrose was determined from plasma tracer concentrations when overnight-fasted normal subjects received a 100-g oral sucrose load labeled with sucrose [(1-14C]glucose and a simultaneous intravenous infusion of [3-3H]glucose. As the dose of acarbose given with the sucrose load was increased from 0 to 100 mg, the percentage of the load appearing in the peripheral circulation decreased from 90% to 62%. Malabsorption was confirmed by the appearance of breath hydrogen. Simultaneously, absorption time increased from 243 to 411 min. Maximal glycemic excursions were therefore lowered from 64 to 31 mg/dl. The plasma concentrations of gastric inhibitory polypeptide and insulin decreased with the acarbose dose so that the fractional disappearance rate of glucose also decreased. However, the concentrations of glucagon-like immunoreactivity (GLI) rose, confirming the ileal appearance of malabsorbed sucrose.

Acarbose↗
PubMed1983

The effects of ingested and intravenous glucose on forearm uptake of glucose and glucogenic substrate in normal man.

The forearm uptake of glucose, lactate, and alanine was determined in overnight fasted man following both oral glucose loading and the intravenous (i.v.) infusion of glucose in an absorption pattern. Arterial glucose concentrations were lower following oral than following i.v. loading and forearm glucose uptake was 50% higher after oral glucose. Arterial insulin levels were higher in the first 2 h during oral loading. Forearm lactate and pyruvate production did not change significantly during glucose administration by either route so that the increased plasma levels are due to splanchnic production.

Administration, Oral↗
PubMed1982

Calculation of the rate of gluconeogenesis from the incorporation of 14C atoms from labelled bicarbonate or acetate.

The rate of gluconeogenesis in vivo may be estimated by the incorporation of 14C atoms from a labelled precursor into plasma glucose or by introducing 14C atoms into the pathway of gluconeogenesis at known stages by metabolites which in themselves do not contribute to the net synthesis of glucose (e.g., bicarbonate or acetate). The purpose of the investigation was to examine some of the assumptions involved in the calculation of gluconeogenic flux by the second approach. [2-14C]acetate or NaH14CO3 was infused to dogs, and the specific activity (SA) of glucose, bicarbonate CO2, urea, and lactate in the plasma was followed. The incorporation of 14C atoms from [2-14C]acetate into glucose allows the calculation of the degree of underestimation of glucose formation due to "metabolic exchange" in the hepatic oxaloacetate pool. The possible error introduced into this calculation by the incorporation of 14C atoms from 14CO2 (a product of acetate oxidation) was found to be negligible, but the heavy labelling of plasma lactate may possibly affect the estimate of metabolic exchange. It is proposed that in the calculation of the rate of gluconeogenesis from infused NaHCO3 the SA of hepatocellular and not of plasma bicarbonate CO2 should be related to that of plasma glucose. This latter is expected to equal the SA of plasma urea, since the sole precursor of its C atom is hepatocellular CO2. The rate of gluconeogenesis estimated from the SA(glucose)/SA(urea) ratio and a previously estimated correction factor for metabolic exchange was 51% of the glucose production in the postabsorptive state. The nearly identical SA(urea)/SA(CO2) ratios, irrespective of the tracer infused, indicated that plasma CO2 is a major precursor of urea C and that a large fraction of injected acetate is oxidized by extrahepatic tissues.

Acetates↗
PubMed1982

Sources of carbon in hepatic glycogen synthesis during absorption of an oral glucose load in humans.

The role of hepatic glycogen is central in the short-term storage and supply of glucose. In the studies described, both glucose and its precursors are labeled and their incorporation into hepatic glycogen is measured during absorption of an oral glucose load in humans. The measurements are accomplished using tracer-determined non-steady-state turnover techniques. Mobilization of newly formed glycogen is achieved by glucagon infusions. After ingestion of a 100-g glucose load in normal fasting (12 h) man, no more than 10 g of the glucose taken up by the liver is converted directly into glycogen. On the other hand, by measuring the uptake of 14C from 14CO2 into glycogen and correcting for Krebs cycle exchange of label, at least an additional 15 g of the glycogen formed can simultaneously be accounted for by new synthesis of glycogen from glucogenic precursors.

Administration, Oral↗
PubMed1982

Developments in the tracer measurement of gluconeogenesis and glycogenesis in vivo: an overview.

In summary, recent developments in the continuing effort to accurately measure gluconeogenetic rates are presented in this symposium. Problems and assumptions are discussed. Mathematical methods that form a basis for further progress are also given. A direct application to the measurement of the gluconeogenetic component of glycogen formation is then described. A further application to the assessment of gluconeogenesis in the fetal component of the fetal-maternal system is discussed. Finally, the importance of tracer sampling and infusion sites in turnover measurement is treated in detail.

Animals↗
PubMed1982

Abnormal oral glucose tolerance and glucose malabsorption after vagotomy and pyloroplasty. A tracer method for measuring glucose absorption rates.

The mechanisms underlying the abnormal glucose tolerance in patients who had undergone vagotomy and pyloroplasty were investigated by measuring the rates of absorption of ingested glucose and the clearance rate of glucose using tracer methods. These methods are based on labeling a 100-g oral glucose load with [1-14C]glucose and measuring glucose clearance using plasma levels of infused [3-3H]glucose. The rate of appearance of both ingested and total glucose is then calculated continuously using a two-compartment model of glucose kinetics. It was found that about 30% of the ingested glucose (100 g) failed to appear in the systemic circulation. That this was due to malabsorption was confirmed using breath-hydrogen analysis. The absorption period is short (101 +/- 11 min) compared with normal values but the clearance of glucose is identical to that in control subjects, and it peaks 132 +/- 7 min after glucose loading. The peak plasma insulin values were more than four times higher in patients than in normal subjects, and this may afford an explanation of rates of glucose clearance that are inappropriate for the short absorption period. The combination of glucose malabsorption and this clearance pattern could yield the hypoglycemia that may be observed in patients after gastric surgery.

Blood Glucose↗
PubMed1981

A qualitative comparison of canine plasma gastroenteropancreatic hormone response to bombesin and the porcine gastrin-releasing peptide (GRP).

The effect on plasma gastroenteropancreatic hormone levels on infusing the porcine gastrin-releasing peptide and bombesin into dogs demonstrated no qualitative difference in the spectrum of activity of the two peptides. Sustained elevation in plasma immunoreactive gastrin, pancreatic polypeptide, enteroglucagon, gastric inhibitory polypeptide, pancreatic glucagon and transient elevations in plasma insulin were seen during infusions of both peptides. The similar spectrum of activities and the structural homology between the two peptides suggests that the porcine gastrin releasing peptide is the porcine counterpart of the amphibian peptide bombesin.

Animals↗
PubMed1980

Pharmacokinetics in nonlinear and partially compartmentalized systems.

The pharmacokinetics of complex systems both linear and nonlinear, compartmentalized, distributed, and partially compartmentalized are reviewed. The two problems considered are: 1) the prediction of concentration or pharmacological effects, and 2) the determination of the input (absorption, dosage schedule) from a given set of measured or desired concentrations. These problems are solved using the super-position integral in linear time-invariant systems by i) integration and ii) deconvolution respectively. Time-varying systems are dealt with by using tracer methods. Nonlinear systems are defined as systems with concentration-dependent parameters. The examples of Michaelis-Menten kinetics, tissue binding, and threshold effects are considered. Approaches to solutions of these problems are generally model-dependent and achieved through i) system identification (parameter estimation), ii) linearization for limiting cases, and iii) tracer techniques. Tracer techniques effectively linearize a nonlinear system so that some variable-dependent parameters can be measured. It is suggested that some of the more general techniques used in the study of metabolic systems may be useful in pharmacokinetics.

Drug Administration Schedule↗
PubMed1979

Hyperglucagonemia in liver cirrhosis with portal-systemic venous anastomoses: responses of plasma glucagon and gastric inhibitory polypeptide to oral or intravenous glucose in cirrhotics with normal or elevated fasting plasma glucose levels.

Plasma immunoreactive glucagon (IRG) was examined in volunteers with biopsy-proven cirrhosis of the liver after recovery from surgical portal--caval anastomosis. A wide range of increased total plasma IRG concentrations was found after overnight fast in groups of cirrhotic subjects with and without fasting hyperglycemia. Gel filtration chromatography of plasma showed a major component in the 3500-mol wt fraction in all cases so studied. Administration of glucose i.v. caused rapid suppression of total plasma IRG in normoglycemic and non-insulin-dependent hyperglycemic cirrhotic subjects. After administration of oral glucose, total plasma IRG was suppressed rapidly in normoglycemic cirrhotic subjects, while non-insulin-dependent hyperglycemic cirrhotic subjects exhibited delayed but prolonged suppression. Chromatography of selected plasma with glucose-suppressed total IRG showed a major decrease in the 3500-mol wt component in every case. Exaggerated increments of plasma gastric inhibitory polypeptide were demonstrable in both groups of cirrhotic individuals after administration of oral glucose, and it is speculated that this peptide may contribute to stimulation of glucagon secretion in liver disease associated with insulin deficiency.

Administration, Oral↗
PubMed1979

Hepatic glycogen formation by direct uptake of glucose following oral glucose loading in man.

The extent of direct uptake of glucose into hepatic glycogen following oral glucose loading in man is determined by mobilizing newly formed glycogen with a glucagon infusion in the immediately postabsorptive period. The amount of glucose flushed from liver glycogen is measured by using "out-of-steady-state" tracer turnover techniques. Following a 93 +/- 1 g load of glucose, at most 7.7 +/- 1 g of ingested glucose is recovered from glycogen. If the unlabelled glucose pool is taken into account, at most 10 g of available glucose can be said to be taken up directly into hepatic glycogen during the absorption of the glucose load.

Administration, Oral↗
PubMed1978

Initial splanchnic extraction of ingested glucose in normal man.

Estimates of initial splanchnic uptake of ingested glucose and the concomitant suppression of endogenous glucose production were obtained in man by validated tracer techniques for non--steady-state turnover measurement. Nine normal volunteers (18--44 yr old) fasted overnight received intravenous infusions of tracer (3-3H-glucose or 1-14C-glucose) and a low (45 +/- 1 g) or high (96 +/- 5 g) oral load of glucose labeled with an alternative tracer (1-14C-glucose or 2-2H-glucose). A two-compartment model was used to derive rates of peripheral appearance (Ra) of glucose from all sources (total) and the Ra of ingested glucose. Ra (total glucose) and Ra (ingested glucose) were integrated from the first appearance of ingested glucose until the basal Ra (total glucose) or 116 +/- 6 (SEM) mg/min was reattained. The total amount of glucose reaching the systemic pool in this time was 95 +/- 4 g and 46 +/- 3 g with high and low doses, respectively. Of these quantities 86 +/- 4 g and 40 +/- 3 g originated in the oral glucose, representing 90% +/- 4% of the administered glucose. The remainder (11% +/- 2% of the total) represented endogenous production, suppressed by 66% +/- 6% relative to basal. Sequestration of ingested glucose and subsequent release did not take place during the study since identical results were obtained with ingested 1-14C-glucose or 2-3H-glucose. The latter label would have been lost if the glucose had entered the hexose--phosphate pool. Thus, in normal man approximately 90% of an ingested glucose load is absorbed and passes through the liver to appear in the systemic pool.

Absorption↗