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Biomedical subjects

J Radziuk

Publications and source records attributed to J Radziuk.

At least 19 recordsLinked to original sources
PubMed1995

Distinguishable substrate pools for muscle glyconeogenesis in lactate-supplemented recovery from exercise.

The formation of muscle glycogen from substrates other than glucose (glyconeogenesis) has now been demonstrated 1) from circulating lactate when this lactate is elevated and 2) from intramuscular substrate, which equilibrates with the products of local glucose metabolism but not with circulating lactate [Am. J. Physiol. 267 (Endocrinol. Metab. 30): E210-E218, 1994]. The purpose of the present studies was to examine the interaction of recovery from low-intensity exercise (4-h swim) and supplementation with exogenous lactate in determining the distribution of carbon flux between these two pathways for the glyconeogenic process in the gastrocnemius muscles. Ten protocols were defined using [14C]bicarbonate (no local incorporation into glycogen), [U-14C]lactate (tracks circulating lactate), and recycled [1-14C]glucose (tracks local substrate formation and glyconeogenesis). During recovery, lactate was infused to increase circulating concentrations 15- to 20-fold. Glucose and saline infusions during recovery were used as controls. The results indicate that prior exercise primarily promotes the local incorporation of recycled glucose label produced within the muscle into glycogen. Exogenous lactate stimulates the incorporation of circulating lactate into muscle glycogen. The contribution of the two substrate pools to glycogen synthesis appears to be additive, indicating the independence of muscle glycogenesis from these two sources.

Animals↗
PubMed1995

Hemipancreatectomy, peripheral diversion of pancreatic venous drainage, and insulin sensitivity.

It has been previously noted that a mild insulin deficiency could increase insulin sensitivity in rats. The data shown here are consistent with such an observation in that the insulin resistance, which was induced by diversion of pancreatic venous drainage to the peripheral circulation, was corrected by the insulin deficiency which was secondary to the hemipancreatectomy performed. These results also help to explain some of the apparent inconsistencies that appear to be present in the comparison often made of insulin sensitivity following various transplantation procedures. Both the site of pancreatic venous drainage and any decrease in beta-cell mass which may accompany pancreas or islet transplantation appear to have independent and opposite effects on insulin sensitivity.

Animals↗
PubMed1994

Differential effects of a graded selective suppression of insulin secretion with galanin on glucose production and removal in dogs.

The metabolic response to graded decreases in insulin concentration was evaluated by measuring the concentration, production, and metabolic clearance rate of glucose in response to the infusion of different galanin doses (1-12 micrograms/kg/h) in 18-h fasted dogs. Peripheral and portal concentrations of insulin and glucagon were measured simultaneously before, during, and after galanin infusions. No increases in portal or peripheral glucagon levels were seen at any dose of galanin infused but, in contrast, dose-dependent decreases of insulin levels occurred in both circulations. The metabolic clearance rate of glucose fell by approximately 25-30% at each dose of galanin infused; suggesting that the maximum effect was reached at the lowest dose. The rate of glucose production increased in a dose-dependent manner with integrated responses of 210 +/- 170, 620 +/- 80, 1,330 +/- 440, 1,920 +/- 310, 1,940 +/- 170, and 1,970 +/- 600 mg/kg at galanin doses of 1, 2, 4, 7, 10, and 12 micrograms/kg/h respectively; saturation of this response occurs at the 7 micrograms/kg/h dose of galanin. The changes in glucose production reflect most closely changes in the fractional decrease in insulin levels both in the portal and peripheral circulations. These changes appear to be mediated by insulin acting directly on the liver, because no alterations in the concentrations of the glucogenic substrates, lactate and glycerol, were seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

An adaptive plasma glucose controller based on a nonlinear insulin/glucose model.

The design of plasma glucose controllers traditionally relies on linear approaches. The implementation of an appropriate nonlinear model of the insulin/glucose regulatory system into an adaptive controller should predict the insulin-dependent glucose removal more reliably and hence provide better control over a wide spectrum of insulin signals. A discretized form of the model leads to a two-step procedure. First, the measured plasma glucose levels associated with the exogenous glucose infusion rates are used in the estimation of the past removal rates which, in turn, can be expressed as a weighted sum of past insulin inputs and previous values of the removal rate. Parameters of the sum are adjusted on-line by a recursive method of estimation which features a prefiltering of data to account for a corrupting coloured process noise. The same equation is in turn used to predict the time course of the insulin-dependent fractional rate of glucose removal. The performance of the controller, tested in vivo in three pigs, is presented for various intravenous or subcutaneous rapid injections and staircase infusions of insulin. Plasma glucose is maintained at an average level of 99.9 +/- 8.7% of the target value (% set point +/- coefficient of variation). The controller reacts promptly to large and rapid variations in insulin action. Although control improves with the number of glucose measurements, the prediction of glucose removal allows for some flexibility in the monitoring of the plasma glucose. Sampling frequency varied from a 2 min interval during transient periods to 7 min as steady states were reached.

Algorithms↗
PubMed1994

Coordinated regulation of hepatic glycogen formation in perfused rat liver by glucose and lactate.

Lactate has been found to enhance the formation of glycogen from both glucose and lactate as substrate (Z. Zhang and J. Radziuk. Biochem. J. 280: 415-419, 1991). To evaluate the relative importance of its role as substrate and regulatory factor, a dual dose-response evaluation was done by adding variable amounts of glucose and lactate to the medium in a recirculating perfused rat liver preparation. Nine groups of perfusions were performed utilizing three different levels of carbon infusion into the system: 0.25, 1.0, and 2.0 mg/min. These levels of carbon infusion were further subdivided into different relative amounts of glucose and lactate. Lactate uptake by the perfused liver was linearly related with net glucose output, regardless of the glucose concentrations. In contrast to this, the effect of lactate uptake on the rate of glycogen synthesis is saturable. Moreover, the rate of glycogen formation at which this saturation occurs is dependent only on the mean perfusate glucose concentration. The highest amount of glycogen formed in a 2-h period was 50 +/- 7 mg and the lowest 3.4 +/- 0.3 mg. A family of dose-response curves was generated describing this dual dependence of glycogen formation (both direct and gluconeogenetic pathways) on lactate and glucose.

Animals↗
PubMed1994

Splanchnic and systemic absorption of intraperitoneal insulin using a new double-tracer method.

The absorption of a bolus of intraperitoneal insulin into the splanchnic and peripheral circulations was separately assessed in dogs using an infusion of two insulin tracers (A1-[3H]insulin and B1-[3H]insulin). One tracer was infused into the superior mesenteric artery and the second into the jugular vein. Serial samples were taken before and after an injection of insulin (1 U/kg ip). Sampling was from the portal vein and the inferior vena cava. By using the principle of equivalent entry of tracer and unlabeled material, we developed two simultaneous equations for the rate of splanchnic and peripheral insulin absorption at each time point. These were solved to yield the two rates. Mean concentrations in the portal vein were approximately 25% higher than in the inferior vena cava, reflecting the splanchnic absorption. This rate accounted for almost half (51 +/- 9%) of the insulin absorbed. The remainder of the absorption was peripheral. The total recovery of intraperitoneal insulin, absorbed by either route, was 88 +/- 11%. Portal absorption peaked earlier than peripheral. Absorption by both routes was 90% complete within approximately 2 h (131 +/- 16 min). In summary, therefore, intraperitoneal insulin is rapidly and almost completely absorbed, with absorption split between the splanchnic and peripheral routes of entry.

Absorption↗
PubMed1994

Muscle glyconeogenesis during recovery from a prolonged swim in rats.

Glyconeogenesis in muscle was assessed during a 3-h recovery period after prolonged submaximal exercise represented by a 4-h swim. Rats fasted for 12 h and previously catheterized underwent this protocol with the concomitant infusion of [6-3H]glucose and one of the following: 1) [14C]bicarbonate, 2) [U-14C]lactate, and 3) [1-14C]glucose. Rested rats served as controls. The incorporation of 14C label ([14C]bicarbonate and [U-14C]lactate) or its transfer to the sixth position of glucosyl units of glycogen, over and above that taken up from circulating glucose (and determined from [6-3H]glucose uptake), was used as an index of muscle glyconeogenesis. 14C from 14CO2 is not expected to be incorporated into glycogen in muscle, and any incorporation that is not from circulating glucose is used to define experimental error. [14C]lactate incorporation measures equilibration with circulating lactate, and label randomization in glucosyl units beyond that seen in plasma glucose is taken as evidence of glyconeogenesis from locally accumulated glycolytic products. The results of these studies demonstrate 1) no glyconeogenesis in the soleus; 2) in the red and white gastrocnemii, glyconeogenesis takes place only from glycolytic products within the muscle. Approximately 35-40% of the [6-14C]glucose in glycogen can only be accounted for by muscle glyconeogenesis. The substrate does not equilibrate with circulating lactate to a detectable extent. 3) Glyconeogenesis appears to persist throughout the recovery period and uses substrate at the level of pyruvate. This is consistent with a continuing elevation of glycolysis during this period.

Animals↗
PubMed1994

Insulin sensitivity and glucose tolerance following transposition of pancreatic venous drainage to the systemic circulation.

In these studies it has been demonstrated that the diversion of pancreatic venous drainage to the systemic circulation (1) increases the peripheral insulinemia and metabolic clearance of glucose under basal conditions; (2) decreases insulin sensitivity, as measured by the hyperinsulinemic euglycemic clamp, more than 2-fold; and (3) decreases peripheral insulin sensitivity and the suppression of endogenous glucose production during exogenous glucose infusion. In spite of these changes, tolerance to the intravenously infused glucose improves. This is accounted for by higher insulin concentrations following diversion, more than compensating for decreases in insulin sensitivity and the suppression of endogenous glucose production. Data on insulin sensitivity and glucose tolerance after pancreas transplantation are not completely consistent, as discussed above. When the site of venous drainage of the pancreas was the only factor altered in the experimental model, unequivocal insulin resistance resulted. This occurred in a relatively short period (ie, 2 weeks). The results here are consistent with a number of studies that have demonstrated normal glucose tolerance coupled with hyperinsulinemia in a partially pancreatectomized dog model as well as in human pancreas transplants. Data presented here imply that the hyperinsulinemia which results after surgical diversion of the pancreatic venous drainage from the portal to the systemic circulation causes an important degree of insulin resistance. Physiological insulin delivery and therefore portal drainage during transplantation may therefore be relevant for the complete normalization of glucoregulation in diabetes. The reduction of hyperinsulinemia may also be important in light of the recent emphasis on the role that this and insulin resistance may play in the development of complications such as cardiovascular disease or hypertension.

Animals↗
PubMed1993

Substrates and the regulation of hepatic glycogen metabolism.

Glycogen metabolism is a complex process which depends on the metabolic circumstances and the hormonal milieu. In this overview an intriguing new possibility has been emphasized--the possible central role of lactate in coordinating, with glucose, the net synthesis of glycogen. Since lactate changes acutely under many physiological circumstances, it would be a logical candidate for a signal which communicates to the liver the metabolic states of the periphery. It would then acutely determine the synthetic rate of glycogen synthesis within the range determined by the glucose concentrations which in turn could be said to reflect the nutritional state of the system. Interestingly, after oral glucose loading, portal glucose levels would be about 25% higher (Radziuk et al., 1978) relative to arterial. As seen from Figs 8 and 9 however the glycogen synthetic rate appears very sensitive to glucose (at a given lactate uptake). Everything else being assumed equal therefore, more glycogen would be synthesized than during intravenous loading with an equivalent peripheral concentration. This is indeed the case (Shulman and Rossetti, 1989). On the other hand, during equivalent loads, peripheral glucose levels are higher and the same quantity of glycogen is synthesized (Radziuk, 1989a, 1989b). If lactate is typical of other glucogenic substrates, then it is also logical that mixed meals with higher levels of portal substrate would maximize glycogen synthetic rates. Similarly, in diabetes where hyperglycemia and hyperlactatemia prevail, gluconeogenesis plays a predominant role in glycogen synthesis (Giaccari and Rossetti, 1992).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Comparison of the continuously calculated fractional splanchnic extraction of insulin with its fractional disappearance using a new double-tracer technique.

These studies were designed to calculate the fractional disappearance rate (FDR) and splanchnic extraction of insulin in response to an exogenous (intraperitoneal) input of insulin. A double-tracer technique using insulin tritiated on both the A1 and B1 positions was introduced for the measurement of hepatic extraction. The A1 tracer, not previously characterized in vivo, was compared in terms of its kinetics with H3-B1-insulin and unlabeled insulin. The metabolic clearance rates (MCR) of the three insulins were identical, as were the decay curves of the two tracers. To measure splanchnic insulin extraction, one tracer was infused systemically to evaluate the FDR of insulin, and the second was infused into the splanchnic circulation (superior mesenteric artery) and its peripheral appearance was calculated. Splanchnic extraction was determined from the difference between this rate of appearance and the rate of infusion of the mesenteric tracer. After intraperitoneal insulin injection, insulin levels increased to peaks of 549 +/- 93 microU/mL (portal vein) and 473 +/- 99 microU/mL (inferior vena cava) and decreased to basal levels over 3 hours. The FDR decreased from 0.295 +/- 0.051 min-1 to 0.125 +/- 0.026 min-1, and splanchnic extraction decreased from 0.534 +/- 0.06 to 0.232 +/- 0.088. The latter returned to near-basal values more rapidly than did the FDR. In conclusion, the kinetics of insulin both in and out of the steady state have been shown to be nonlinear through physiological insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Glucose dynamics and gluconeogenesis during and after prolonged swimming in rats.

Glucose fluxes and, in particular, gluconeogenic rate were examined during and after prolonged submaximal exercise represented by a 4-h swim and 3-h recovery in 12-h-fasted previously catheterized rats. The metabolic clearance rate and production rate of glucose were measured using an infusion of [6-3H]glucose, and gluconeogenesis was assessed from the incorporation of 14C from [14C]bicarbonate into glucose. Immediately after exercise and after the 3-h recovery, liver glycogen was also determined. During exercise, euglycemia was maintained while glucose production and utilization doubled from 1.58 +/- 0.17 to 3.58 +/- 0.21 mg/min. During recovery, glucose concentrations increased to 131.0 +/- 5.8 vs. 110.8 +/- 5.1 mg/dl for controls (P < 0.05), because the decline in glucose production rate lagged behind the decline in metabolic clearance rate. The index of gluconeogenesis coupled with a metabolic correction factor indicates that gluconeogenesis was the primary source of glucose during swimming and recovery and that the principal substrates were at the level of pyruvate. CO2 production rates calculated using plasma CO2 and label concentrations doubled during exercise. Little repletion of liver glycogen was seen after exercise, indicating that the increased production of glucose after exercise is directed primarily toward the repletion of muscle glycogen. Swimming is therefore a useful model of low-intensity exercise easily implemented in untrained animals. [14C]bicarbonate can be used in the estimation of gluconeogenic rates during exercise.

Animals↗
PubMed1993

The effect of systemic venous drainage of the pancreas on insulin sensitivity in dogs.

To assess the metabolic consequences of the diversion of the pancreatic venous drainage to the systemic circulation, the pancreaticoduodenal and gastrosplenic veins were anastomosed to the inferior vena cava in nine normal dogs. This procedure maintained the integrity of the entire pancreas while shunting the hormonal output of the pancreas to the periphery. The metabolic effects were assessed from the sensitivity to insulin during a euglycemic hyperinsulinemic glucose clamp using an insulin infusion of 800 microU/kg per min. The studies were controlled by their duplication in seven dogs identically treated but with the pancreatic veins reanastomosed to the portal vein. No differences in systemic insulin levels or insulin sensitivity before and after surgery were seen under these circumstances. After diversion, however, basal insulin levels rose from 4.5 +/- 1.0 to 11.5 +/- 2.5 microU/ml. Basal glucose metabolic clearance rate (MCR) rose to 3.0 +/- 0.4 from 2.0 +/- 0.3 ml/kg per min. On insulin infusion, maximal stimulation of MCR within the 2-h infusion period was to 15.2 +/- 2.5 ml/kg per min preoperatively and to 7.2 +/- 0.8 ml/kg per min after diversion. Using ratios of MCR-to-insulin concentration as an index of insulin sensitivity, it was demonstrated that this index decreased by at least 50% after diversion. These data imply that portal venous drainage of the pancreas is an important factor in the determination of peripheral insulin sensitivity.

Anastomosis, Surgical↗
PubMed1992

Posthepatic rate of appearance of insulin: measurement and validation in the nonsteady state.

To assess the accuracy with which insulin appearance rates in the peripheral circulation can be measured out of steady state, seven conscious dogs were simultaneously infused with somatostatin and insulin at known variable rates. Tritiated insulin was infused concurrently at a constant rate. Insulin rates of appearance were estimated continuously on the basis of a two-compartment model for systemic insulin kinetics. The calculations were performed assuming that insulin kinetics were linear (tracer data not used) and nonlinear or time varying (tracer data used to assess the variation). The average error in areas under the curve was -3.5 +/- 2.5 and 27.0 +/- 14.2% when nonlinear or linear kinetics were assumed. The maximal errors when linearity was assumed was 39.9 +/- 11.3% and decreased to 16.3 +/- 2.6% when the tracer data was used to account for changes in the fractional removal rate of insulin. The accuracy of the linear estimates improved as the fractional removal rate remained closer to constant. These data suggest that a priori assumptions should not be made on the linearity of the insulin system in a given experimental situation.

Animals↗
PubMed1991

Effects of lactate on pathways of glycogen formation in the perfused rat liver.

In order to investigate the roles of lactate as substrate and regulator of hepatic glycogen synthesis, two groups of rat livers were perfused with oxygenated blood for 2 h. The initial perfusate glucose and lactate concentrations of Group I and II were 245 +/- 6.8 and 254 +/- 12.9 mg/dl and 49 +/- 2.6 and 54 +/- 2.2 mg/dl respectively. Labelled glucose was added to the perfusate to assess direct glycogen formation. Either additional glucose (Group I) or lactate (Group II) was added (1 mg/min) to a recirculating liver-perfusion system. Initial lactate uptake and glucose formation was identical in the two groups of studies. For Group I, both glucose and lactate uptake by the liver fell to nearly zero, in spite of increasing glucose concentrations. However, with lactate infusion (Group II), its uptake by the liver was maintained at 0.89 +/- 0.14 mg/min after 120 min. In total, 6.2 +/- 0.7 mg (Group I) or 20.2 +/- 3.9 mg (Group II) of glycogen was formed, 4.0 +/- 0.7 mg or 9.2 +/- 2.0 mg by direct synthesis from glucose and 2.2 +/- 0.3 mg or 11.0 +/- 2.1 mg by gluconeogenic formation, in Groups I and II respectively. With the provision of additional lactate, its uptake by the perfused liver tripled, as did glycogen synthesis. Glucose production doubled when lactate was added instead of glucose. Gluconeogenic formation of glycogen increased by 400%. Surprisingly, direct synthesis from glucose also rose by 130%. These data indicate that continued lactate uptake by the liver with gluconeogenic glycogen formation determines the amount of glycogen formed not only by this route, but also by direct synthesis from glucose.

Animals↗
PubMed1990

Distribution and kinetics of glucose in rats analyzed by noncompartmental and compartmental analysis.

The steady-state kinetics and distribution of glucose were assessed using noncompartmental and various two-compartment models in rats that were infused with insulin (+/- euglycemic clamping), methylprednisolone (MP), or phlorizin (PHL) as well as rats injected with protamine-zinc-insulin (PZI) or rendered diabetic. Decreases in clearance of glucose (PCR) were greatest with insulin infusion, followed by PHL, MP, and PZI treatments. PCR decreased in diabetes to 25% of normal. With hyperinsulinemia and euglycemia, turnover rates were 1.18 times the rate of glucose infusion. In normal rats the ratio of the contents of the two compartments was 0.6-0.8 (depending on the model). Significant increases, of between 2.8 and 5.2, were observed with insulin infusion and between 0.8 and 1.8 with PHL, again depending on the model. Because PHL-induced changes in PCR are renal, these data suggest that variations in glucose distribution depend on changes in PCR as well as insulin. The intercompartmental rate constant decreased, and the noncompartmental volume of distribution increased to reflect the above changes. In non-steady-state studies, glucose release increased in response to insulin but not to PHL in contrast to other species.

Animals↗
PubMed1990

Tracer studies of liver metabolism.

We have attempted to show a number of uses of tracers both as enhancing the information obtained in arterio-venous difference studies and in allowing the collection of data on hepatic metabolism--glucose production, glycogen formation, etc. in a noninvasive fashion. We have demonstrated, using these methods, that (1) The fractional extraction of glucose by the liver during glucose loading is about 5%; (2) This extraction can lead to significant hepatic glucose uptake (25 g after 100 g glucose load); (3) Only some of this glucose (10 g) is taken up directly into glycogen; (4) The remainder of the glycogen formed following a glucose load (15 g) is synthesized by gluconeogenetic pathways; (5) This gluconeogenesis takes place primarily from lactate which is taken up avidly by the liver--50-60% extracted; (6) This lactate arises from the gut (40%) and from the liver itself (at least 10%) with the remainder from other peripheral obligate lactate producing tissue; (7) It was also shown that the amount and pathways of hepatic glycogen production after oral and intravenous glucose loading is very similar and that the major effects on glucose tolerance take place in peripheral tissues such as the forearm.

Animals↗
PubMed1989

Hepatic glycogen in humans. I. Direct formation after oral and intravenous glucose or after a 24-h fast.

The formation of hepatic glycogen by the direct pathway is assessed in humans 1) after a 12-h fast and oral loading (100 g) or 2) intravenous infusion (90 g) and 3) after a 24-h fast and the same oral glucose load. The methodology used is based on the double tracer method. [3-3H]glucose is infused at a constant rate for the determination of the metabolic clearance of glucose. [1-14C]glucose is administered with the glucose load. One hour after absorption or the intravenous glucose infusion is terminated, a glucagon infusion is initiated to mobilize the glycogen labeled with [1-14C]glucose and formed during the absorptive period. At this time a third tracer, [6-3H]glucose, is administered to measure glucose clearance. It was found that after the 12-h fast and oral glucose loading 7.2 +/- 1.1 g of hepatic glycogen appears to be formed directly from glucose compared with 8.4 +/- 1.0 g after the same load and a 24-h fast and 8.5 +/- 0.4 g after a 12-h fast and an equivalent intravenous glucose infusion. When the amount of label ([14C]glucose) mobilized that was not corrected for metabolic recycling was calculated, the data suggested that the amount of glycogen formed by gluconeogenic pathways was probably at least equal to that formed by direct uptake. It was also approximately 60% greater after a 24-h fast. It can be concluded that the amount of hepatic glycogen formed directly from glucose during glucose loading is not significantly altered by the route of entry or the extension of the fasting period to 24 h. The data suggest, however, that gluconeogenetic formation of glycogen increases with fasting.

Adult↗