Search PubMed⌕ Search

Biomedical subjects

C Cobelli

Publications and source records attributed to C Cobelli.

At least 145 records · Page 8Linked to original sources
PubMed1987

In vivo glucose metabolism in the awake rat: tracer and insulin clamp studies.

The goals of this study were twofold: (1) to determine the in vivo dose-response relationship in the conscious, unstressed rat between the plasma insulin concentration and total body glucose uptake, and between plasma insulin and suppression of endogenous glucose production; and (2) to develop a physiologic compartmental model to describe the kinetics of plasma glucose in the rat in the basal state. In order to perform repeat insulin clamp studies in the same rat, chronic catheters were implanted in the aortic arch (via the carotid artery) and in the cardiac atrium (via the jugular vein), exteriorized, and fixed to the back of the skull with a dental cement cap. Insulin was infused at rates of 1.2, 2.4, 4.8, 12, and 24 mU/min.kg, and the plasma glucose was held constant at the basal level by a variable glucose infusion (euglycemic insulin clamp). The resulting steady-state plasma insulin concentrations ranged from 40 to 1,300 microU/mL. The dose-response curve for glucose uptake was sigmoidal in shape: in the basal state, total glucose utilization averaged 6.8 mg/min.kg at an insulin concentration of 9 microU/mL, half-maximal glucose uptake (18.3 mg/kg.min) occurred at a plasma insulin concentration between 70 and 80 microU/mL, and maximal uptake (36.6 mg/kg.min) was seen at an insulin level in excess of 100 microU/mL. Residual endogenous glucose production was evaluated by a prime-continuous infusion of (3-3H)-glucose. The dose-response curve for suppression of endogenous glucose output also was sigmoidal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Non-steady state: error analysis of Steele's model and developments for glucose kinetics.

The model proposed by Steele (Ann. NY Acad. Sci. 82: 420-430, 1959) to compute rates of appearance and disappearance in non-steady state is subjected to theoretical analysis. It is shown that this model introduces an error with two components, one dependent on the volume of the compartment, the other related to the complex configuration of the system. The errors depend on the time course of specific activity, change differently with time, and may take the opposite sign but they do not, in general, cancel each other. Corollaries of this analysis are the following: there is no single pool-fraction value satisfactory under all non-steady-state situations; keeping tracer specific activity as constant as possible during the experiment minimizes both errors; and non-steady-state analysis demands proper modeling of the system. Tracer experiments were carried out in five normal volunteers. Plasma [3-3H]glucose concentration was first brought to equilibrium by means of a primed constant 2-h infusion, and then the steady state was perturbed by a 2-h euglycemic insulin (1 mU X min-1 X kg-1) clamp, realizing a transition between a basal and a euglycemic hyperinsulinemic steady state. These data were analyzed with Steele's equation, the two compartment models of Radziuk et al. [Am. J. Physiol. 234 (Endocrinol. Metab. Gastrointest. Physiol. 3): E84-E93, 1978], and a new model based on a study on glucose kinetics carried out in the two steady states separately. Steele's equation yielded negative values for hepatic glucose production already 40 min into the clamp and throughout the study. The average value of glucose production during the 2nd h was -0.88 mg X min-1 X kg-1; the suppression of basal release over the 2-h period was 115%. In contrast, the new model calculated a mean glucose production of 0.37 mg X min-1 X kg-1 during the 2nd h and an overall suppression of 62%; no negative values were obtained.

Female↗
PubMed1987

Models to interpret kinetic data in stable isotope tracer studies.

In contrast to "weightless" radioactive tracers, stable isotope tracers have nonnegligible mass and are naturally present in the system, and the measured variable is a ratio of two isotopic species. These features do not allow stable isotopic tracer data analysis using straightforward analogy with radioactive tracer approaches, even though this practice is common. In this study, we present kinetic variables, models, and measurements for the analysis and interpretation of stable isotope tracer data. Assumptions and mathematical techniques for modeling the data when perturbation is both nonnegligible and negligible are discussed. Emphasis is placed on the rich information content of the dynamic portion of a stable isotope tracer curve and on the role of compartmental and noncompartmental modeling approaches for its interpretation. A presumed and commonly used analogy between the radioactive specific activity and stable isotopic enrichment is shown to be incorrect. We show that the proper analogue of specific activity is the tracer-to-tracee molar ratio. This variable is not a directly measurable one, but a formula is derived that allows its computation from the data. A method for reconstructing the time course in blood of the concentration component due to endogenous synthesis is presented. This allows measurement of the extent of the perturbation in the case where a nonweightless tracer is used. Special attention is given to data analysis originating from a multiple tracer experiment, a configuration necessary for studying more complex systems, e.g., the kinetics of interacting substrates.

3-Hydroxybutyric Acid↗
PubMed1987

Reconstructing the rate of appearance of subcutaneous insulin by deconvolution.

In this paper a deconvolution scheme is presented to reconstruct the rate of appearance of subcutaneously injected insulin. Relevant aspects of experiment design are briefly described. Intravenous insulin kinetics are modeled to determine the impulse response of the system. The deconvolution problem is not ill conditioned and is solved using a least-squares method without imposing constraints on the input. An estimate of the error of the reconstructed input is provided. The reliability of the deconvolution scheme is tested by means of an independent validation study. Finally, the different sources of error that affect the method are discussed, and a figure of the global error is derived.

Humans↗
PubMed1986

Estimation of insulin sensitivity and glucose clearance from minimal model: new insights from labeled IVGTT.

The "minimal model" of glucose disappearance provides noninvasive estimates of insulin sensitivity and glucose effectiveness from an intravenous glucose tolerance test (IVGTT). However, this model does not allow the separation of glucose production from utilization. To overcome this limitation, labeled glucose was injected along with cold glucose in six normal dogs, and both cold and labeled glucose time courses were monitored along with insulin concentration. A revised minimal model was fitted to tracer data to obtain new measures of insulin sensitivity (SI* = 6.41 +/- 0.91 10(-4) min-1 X microU-1 X ml-1) and fractional glucose clearance (SG* = 0.0092 +/- 0.0009 min-1). SG* was compared with a direct measure obtained by a hepatic arterial-venous difference technique, which yielded a value of 0.0097 +/- 0.0002, virtually identical to SG*, thereby validating the model estimate. When the original minimal model was identified from cold data, we obtained S1 = 4.52 +/- 1.39 and SG = 0.042 +/- 0.009. SI* and SG* were different from SI and SG, respectively. In particular SG overestimates fractional glucose clearance by approximately five times. The revised minimal model yields glucose disposal parameters SI* and SG* that are not affected by the confounding effect of insulin and glucose inhibition of glucose production. Limitations inherent in cold IVGTT and original minimal model are overcome by labeled IVGTT and the revised minimal model, while test simplicity remains.

Animals↗
PubMed1985

Ketone body metabolism in normal and diabetic human skeletal muscle.

Although the liver is considered the major source of ketone bodies (KB) in humans, these compounds may also be formed by nonhepatic tissues. To study this aspect further, 3-[14C]hydroxybutyrate (BOH) or [3-14C]acetoacetate (AcAc) were constantly infused after a priming dose and contemporaneous arterial and venous samples were taken at splanchnic, heart, kidney, and leg sites in eight normal subjects (N) undergoing diagnostic catheterization and at the forearm site in five normal and six ketotic diabetic (D) subjects. After 70 min of infusion, tracer and tracee levels of AcAc and BOH reached a steady state in the artery and vein in both normal and diabetic subjects. The venous-arterial (V-A) difference at the forearm step for cold KB was negligible both in normal and diabetic subjects, whereas for labeled KB it was approximately 10-fold higher in diabetic subjects (V-A AcAc, -31 +/- 7 and -270 +/- 34 dpm/ml in N and D, respectively; V-A BOH, -38 +/- 6 and -344 +/- 126 dpm/ml in N and D, respectively). We assumed that the V-A difference in tracer concentration was consistent with dilution of the tracer by newly synthesized tracee inside the muscle and calculated that the forearm muscle produces KB at a rate of 16.2 +/- 3.3 mumol/min in D and 0.9 +/- 0.9 mumol/min in N. These findings can be accounted for by the hypothesis that the disappearance flux of KB from circulation was replaced by an equivalent flux of KB entering the vein at the muscle step in D but not in N. Moreover, in N KB were not only produced but also utilized by the splanchnic area (39 +/- 9 mumol/min).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1985

Acetoacetate and 3-hydroxybutyrate kinetics in obese and insulin-dependent diabetic humans.

[3-14C]acetoacetate (AcAc) and beta-[3-14C]hydroxybutyrate (beta-OHB) administration, measurements of labeled AcAc and beta-OHB in blood, and kinetic modeling have been used to investigate ketone body (KB) metabolism in five normal, five obese, and eight insulin-withdrawn diabetic subjects. Diabetic subjects were divided in mildly ketotic (MKD) and highly ketotic (HKD) patients according to beta-OHB blood level. A four-compartmental model successfully described the tracer kinetic data in obese and normal subjects, whereas in diabetic patients a five-compartmental model was necessary. Obese subjects showed a significantly lower (P less than 0.05) KB de novo synthesis (R30 = 159 +/- 54 (SD) mumol X min-1 X m-2) in comparison with normal subjects (282 +/- 93), but the clearance rates of AcAc (PCR1) and beta-OHB (PCR2) were similar in the two groups. R30 was 596 +/- 534 in MKD and 1,278 +/- 445 (P less than 0.01) in HKD. PCR1 was not significantly different both in MKD and HKD in comparison with normal subjects. In contrast PCR2 was markedly reduced in HKD (0 +/- 0 ml X min-1 X m-2) in comparison with MKD (1,031 +/- 615) and normal subjects (782 +/- 278). The percentage distribution of KB among various tissues inside the organism of diabetic subjects is abnormal. Both AcAc and beta-OHB recycling and mean residence time are not normal in HKD. A significant correlation was found between C-peptide and KB production in diabetes. These results suggest that a selective defect of beta-OHB peripheral utilization is important in determining and maintaining severe diabetic ketoacidosis.

3-Hydroxybutyric Acid↗
PubMed1985

Effect of insulin on the distribution and disposition of glucose in man.

Understanding the influence of insulin on glucose turnover is the key to interpreting a great number of metabolic situations. Little is known, however, about insulin's effect on the distribution and exchange of glucose in body pools. We developed a physiological compartmental model to describe the kinetics of plasma glucose in normal man in the basal state and under steady-state conditions of euglycemic hyperinsulinemia. A bolus of [3-3H]glucose was rapidly injected into a peripheral vein in six healthy volunteers, and the time-course of plasma radioactivity was monitored at very short time intervals for 150 min. A 1-mU/min kg insulin clamp was then started, thereby raising plasma insulin levels to a high physiological plateau (approximately 100 microU/ml). After 90 min of stable euglycemic hyperinsulinemia, a second bolus of [3-3H]glucose was given, and plasma radioactivity was again sampled frequently for 90 min more while the clamp was continued. Three exponential components were clearly identified in the plasma disappearance curves of tracer glucose of each subject studied, both before and after insulin. Based on stringent statistical criteria, the data in the basal state were fitted to a three-compartment model. The compartment of initial distribution was identical to the plasma pool (40 +/- 3 mg/kg); the other two compartments had similar size (91 +/- 12 and 96 +/- 9 mg/kg), but the former was in rapid exchange with plasma (at an average rate of 1.09 +/- 0.15 min-1), whereas the latter exchanged 10 times more slowly (0.12 +/- 0.01 min-1). The basal rate of glucose turnover averaged 2.15 +/- 0.12 mg/min kg, and the total distribution volume of glucose in the postabsorptive state was 26 +/- 1% of body weight. In view of current physiological information, it was assumed that the more rapidly exchanging pool represented the insulin-independent tissues of the body, while the slowly exchanging pool was assimilated to the insulin-dependent tissues. Insulin-independent glucose uptake was estimated (from published data) at 75% of basal glucose uptake, and was constrained not to change with euglycemic hyperinsulinemia. When the kinetic data obtained during insulin administration were fitted to this model, neither the size nor the exchange rates of the plasma or the rapid pool were appreciably changed. In contrast, the slow pool was markedly expanded (from 96 +/- 9 to 190 +/- 30 mg/kg, P less than 0.02) at the same time as total glucose disposal rose fourfold above basal (to 7.96 +/- 0.85 mg/min kg, P less than 0.001). Furthermore, a significant direct correlation was found to exist between the change in size of the slow pool and the insulin-stimulated rate of total glucose turnover (r=0.92, P<0.01). We conclude that hyperinsulinemia, independent of hyperglycemia, markedly increases the exchangeable mass of glucose in the body, presumably reflecting the accumulation of free, intracellular glucose in insulin-dependent tissues.

Adult↗
PubMed1984

Validation of simple and complex models in physiology and medicine.

The problem of assessing the value of mathematical models in physiology and medicine is considered. The role of validation within the modeling process is clearly defined. An appropriate vocabulary and validation procedures to be adopted are outlined for simple and complex models, with these two classes defined operationally on the basis of theoretical identifiability. Some examples illustrating these validation procedures are briefly discussed. It is shown that simple and complex models each have a role both in physiology and clinical application when properly validated.

Animals↗
PubMed1984

Compartmental vs. noncompartmental modeling for two accessible pools.

We examine the limitations of noncompartmental vs. compartmental modeling when two accessible pools are available in kinetic experiments. Focus is on the estimation of mean residence time, whole-body mass, and steady-state equivalent distribution volume. Examples illustrate these points.

Kinetics↗
PubMed1983

Is the "pool-fraction" paradigm a valid model for assessment of in vivo turnover in non-steady state?

Quantification of in vivo turnover of endogenous substances in nonsteady state is of fundamental importance for understanding a variety of physiological and clinical metabolic situations. Toward this end, a pool-fraction model has become a paradigm in the glucose and ketone body areas. We discuss the basic assumptions on which the pool-fraction model is based and the criteria on which it has been validated. Specific comments are then made on its current and potential use for quantifying the non-steady-state turnover of glucose, ketone bodies, and insulin. We conclude that the quantitative reliability of predictions provided by the pool-fraction model is quite poor and that new developments are needed for quantifying the non-steady-state situation.

Animals↗
PubMed1983

Insulin-mediated glucose disposal in type I diabetes: evidence for insulin resistance.

To clarify whether type I diabetes is characterized by insulin resistance, insulin-mediated glucose metabolism (M; milligrams per kg/min) was estimated by means of the glucose clamp technique in five insulin-dependent diabetic patients and six normal subjects. Three glucose clamps were carried out under different metabolic conditions. Free insulin plateaux were similar during each clamp in both groups. The first clamp was performed in normal subjects after an overnight fast [blood glucose, 80 +/- 3 mg/dl (mean +/- SEM)] and in diabetic patients 18 h after insulin withdrawal (blood glucose, 366 +/- 47 mg/dl). Diabetic patients had a M value (4.25 +/- 0.74) not different from normals (5.38 +/- 0.63; P = NS). The second clamp was done with the same glycemic values (approximately 125 mg/dl) in both groups. M increased to 8.07 +/- 1.06 (P less than 0.01) in the normal subjects and decreased to 2.87 +/- 0.50 (P = NS) in the diabetic patients. The M value in the diabetic patients was lower than that in the normal subjects (P less than 0.05). The third clamp was performed in three diabetic patients after 1 month of treatment with continuous sc insulin infusion. The mean blood glucose level was 88 +/- 6 mg/dl, and M was 3.23 +/- 0.38, significantly lower than that of the normal subjects in the basal state (P less than 0.05). No differences were found in insulin binding to erythrocytes. The mean plasma clearance rate (milliliters per m2/min) of free insulin was the same in both groups (428 +/- 113 in normal subjects and 354 +/- 83 in diabetic patients). Basal endogenous glucose production was higher in the diabetics (3.13 +/- 0.48 mg/kg X min) than in the normal subjects (1.71 +/- 0.57). During the clamp, however, endogenous glucose production was similarly inhibited (approximately 95%) in both groups. Multiple glucose clamp studies were also performed at three different insulin infusion rates (21, 73, and 760 mU/m2 X min, respectively) to generate an insulin-dose response curve for glucose disposal in six diabetic patients treated with continuous sc insulin infusion for at least 6 months. This allowed investigation of the effect of chronic strict insulin therapy leading to normal glucose and intermediary metabolite levels and identification of the cellular mechanism of insulin resistance. A significant reduction of the maximal glucose disposal rate (10.7 +/- 0.5 mg/kg X min) was found in these diabetic patients compared to that in normal subjects (14.9 +/- 1.0; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗