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C Cobelli

Publications and source records attributed to C Cobelli.

At least 127 records · Page 7Linked to original sources
PubMed1990

Glucose disposal, beta-cell secretion, and hepatic insulin extraction in cirrhosis: a minimal model assessment.

Factors controlling glucose metabolism after IV load were studied in nine patients with compensated cirrhosis and in six age-matched controls. The time courses of glucose, insulin, and C peptide were analyzed by means of the minimal model technique. In cirrhosis, insulin sensitivity was reduced by approximately 70% and glucose-dependent glucose uptake (glucose effectiveness) by 45%. Decreased glucose effectiveness explained 65% of the variance of glucose disappearance and correlated with the ratio of urinary creatinine to height, an independent measure of muscle mass (r = 0.839). beta-cell responsiveness to glucose, measured on C-peptide kinetics, was variable and increased on average by 170% and 107% (first-phase and second-phase, respectively). The total amount of insulin secreted by beta-cells in the course of the study was nearly doubled, whereas the basal insulin secretion rate was in the normal range. The time courses of hepatic extraction of insulin did not differ between groups, and basal extraction was on average 58% in controls and 56% in patients with cirrhosis. It was reduced to 30% in a single patient who had severe hepatocellular failure and large spontaneous portosystemic shunting. We conclude that the alterations in glucose metabolism of cirrhosis include a decreased insulin sensitivity, a reduced glucose effectiveness, and an increased pancreatic responsiveness to glucose, leading to hyperinsulinemia. The hepatic extraction of insulin is reduced only in the very advanced stages of the disease, possibly because of a large reserve capacity of the hepatic parenchyma.

Adult↗
PubMed1990

Heart rate spectral analysis for assessing autonomic regulation in diabetic patients.

Spectral analysis of the R-R variability signal has been used for assessing the autonomic regulation of heart rate in control subjects and in diabetic patients affected by autonomic neuropathy. Modifications of the parasympathetic-sympathetic balance following postural changes, as observed in normal subjects, were not significant in autonomic patients. In addition, the overall reduction of power occurring in diabetics at all frequencies indicates the impairment of both autonomic components.

Diabetes Mellitus↗
PubMed1990

Pseudoketogenesis in hepatectomized dogs.

Overestimation of ketone body turnover in vivo, measured by tracer kinetics, could occur if specific activity or molar percent enrichment is diluted in extrahepatic tissues by label exchange via reversal of 3-oxoacid-CoA transferase, a process we call pseudoketogenesis. To test this hypothesis, euglycemic hepatectomized dogs were injected with a bolus of acetoacetate (0.8 mmol/kg), 32% enriched in [3,4-13C2]acetoacetate. Concentrations and labeling patterns of blood acetoacetate and R-3-hydroxybutyrate were measured by selected ion-monitoring gas chromatography-mass spectrometry. During the 60 min after bolus injection of [3,4-13C2]acetoacetate, the molar percent enrichment of blood [3,4-13C2]acetoacetate decreased to 73 +/- 3% (n = 5) in controls and to 11.5 +/- 0.8% (n = 3) during infusion of dichloroacetate, an activator of pyruvate dehydrogenase. The enrichment of R-3-hydroxy-[3,4-13C2]butyrate followed closely that of [3,4-13C2]acetoacetate. These dilutions occurred despite a net uptake of ketone bodies. Concomitantly, 10.6 +/- 2.2 (n = 5) and 6.0 +/- 2.9% (n = 3) of [13C]acetoacetate molecules were labeled on all four carbons in control and dichloroacetate-treated dogs, respectively. This uniformly labeled acetoacetate arises from partial equilibration between [3,4-13C2]acetoacetate and [1,2-13C2]acetyl-CoA via the reactions catalyzed by 3-oxoacid-CoA transferase and acetoacetyl-CoA thiolase. Our data demonstrate the reversibility of the 3-oxoacid-CoA transferase in intact extrahepatic tissues and support the concept of pseudoketogenesis. This phenomenon has been quantitated by kinetic analysis of the data.

3-Hydroxybutyric Acid↗
PubMed1990

Myocardial metabolism in insulin-deficient diabetic humans without coronary artery disease.

Eleven insulin-dependent diabetes mellitus (IDDM) patients with angiographically normal coronary arteries and a normal hemodynamic response to an echocardiographic-dipyridamole test and 12 normal controls were studied at rest and after atrial pacing simultaneously sampling arterial and coronary sinus blood. In IDDM patients, despite hyperglycemia [10.0 +/- 2.0 (SE) mmol/l], myocardial glucose uptake was slightly lower than in controls. This process was significantly activated in both groups during atrial pacing. The isotopically calculated net flux of lactate across myocardium, in agreement with the net balance value based on unlabeled lactate-pyruvate arteriovenous differences, showed a net uptake in controls (3.5 +/- 0.6 mumol.min-1.1.73 m-2) and a net release in IDDM (12.4 +/- 2.6; P less than 0.01). Atrial pacing stimulated lactate uptake in both groups. Myocardial uptake of ketone bodies was significantly higher in IDDM (37.0 +/- 6.3 mumol.min-1.1.73 m-2) than in controls (10.1 +/- 3.4 mumol.min-1.1.73 m-2; P less than 0.01). Free fatty acid uptake was also significantly greater in IDDM than in controls (44.1 +/- 7.0 vs. 24.1 +/- 5.1 mumol.min-1.1.73 m-2; P less than 0.01). Alanine and branched amino acids were released by diabetic but not by control hearts at rest. The normalization of blood glucose concentrations restored normal patterns of lactate and ketone body kinetics across diabetic myocardium. In conclusion, 1) at rest, myocardial lactate and amino acid uptake is markedly impaired in IDDM without coronary artery disease, and 2) the metabolic abnormalities of the diabetic myocardium are not a primary phenomenon but rather a consequence of hypoinsulinemia and hyperglycemia because insulin administration, resulting in euglycemia, restored normal patterns of cardiac metabolism.

Adult↗
PubMed1990

Constant specific activity input allows reconstruction of endogenous glucose concentration in non-steady state.

In vivo studies on the glucose system often require its perturbation by an exogenous input of glucose, whereas glucose turnover is assessed by infusing a glucose tracer. The constant infusion represents the usual format of tracer administration, but it has no clear advantage other than simplicity. Here we propose a different tracer infusion format. It consists of infusing the tracer in parallel with unlabeled glucose so as to maintain a constant specific activity in the infusate. This protocol does not increase experimental complexity and provides new information on the glucose system in non-steady state by allowing reconstruction of the endogenous component of glucose concentration. This reconstruction only requires very general assumptions, such as tracer-tracee indistinguishability and mass conservation; in particular it is independent of the glucose model structure, i.e., number of compartments and their interconnections. A proof of the result is given for a general nonlinear model of the glucose system. The constant specific activity input is also advantageous for non-steady-state calculations, because it reduces the variation in the measured plasma glucose specific activity. The glucose system has served as the prototype, but the protocol is applicable to other blood-borne substances. The radioactive tracer case has been considered, but the same results apply to stable isotope tracers as well; in this case they also become relevant in a somewhat different context, i.e., kinetic studies in steady state.

Animals↗
PubMed1990

Modeling glucose metabolism in man: theory and practice.

Quantitative assessment of whole-body and regional glucose metabolism from in vivo kinetic data requires a model of the system, i.e. specific assumptions about the structure and functioning of the system. We discuss here models which allow the measurement and understanding of the kinetics of glucose metabolism in vivo in man and of the effect of insulin upon them. Discussed models include: a whole-body description of glucose distribution and metabolism to quantitate insulin effect; a model to measure in vivo glucose transport in the forearm; physiological models to assess glucose kinetics in the non-steady state; the insulin and C-peptide IVGTT minimal models to assess beta-cell function; the labelled IVGTT minimal models to assess insulin sensitivity and hepatic production. Emphasis is on models of the compartmental type and on the crucial role of modeling methodology. Aspects of improved experiment design are also discussed.

Biological Transport, Active↗
PubMed1989

Optimal design of sampling schedules for studying glucose kinetics with tracers.

Minimum size sampling schedules for estimating glucose kinetic parameters from an impulsive (bolus) tracer injection in normal humans and rats are presented. Glucose kinetics are described by a two-compartment linear model, and reference values of the parameters are estimated from a data base with many samples. The optimal sampling schedule (OSS) is determined in each individual by using a D-optimal criterion and consists of four samples. A population optimal sampling schedule (POSS) applicable to all the individuals of a given population is then determined, and its reliability and efficiency in recovering kinetic parameters (e.g., rate constants, plasma clearance rate, and mean residence time) is assessed. The influence of model and measurement error on OSS is discussed. Moreover, the adoption of an enhanced POSS (EPOSS, 8 samples) is shown to improve accuracy and precision of parameter estimates in a predictable manner. Finally some suggestions are given for obtaining more information from turnover studies using a constant infusion of tracer, with or without a priming pulse of tracer.

Animals↗
PubMed1989

A compartmental model to quantitate in vivo glucose transport in the human forearm.

Glucose transport is a critical step in the control of glucose disposal that, until presently, has not been quantitated in vivo in humans. We have employed the perfused forearm and euglycemic insulin-clamp techniques in combination with a dual-tracer injection to measure basal and insulin-mediated glucose transport in six normal subjects. L-[3H]glucose, which is not transported, was used to trace extracellular glucose kinetics; 3-O-[14C]-methyl-D-glucose, transportable but not metabolizable, was used to monitor glucose movement across the cell membrane. After bolus intra-arterial injection of the two tracers, plasma samples were obtained every 15-30 s for 10 min from a deep forearm vein to determine the washout curves. A linear compartmental model was developed that accounts for blood flow heterogeneity. It consists of three parallel, two-compartment chains merging into the sampling compartment to which cellular compartments are appended. A priori identifiability analysis was performed. The uniquely identifiable parameterization includes the transport rate constants of glucose into and out of the cell. The model was identified using nonlinear least-squares parameter estimation. Transport parameters are estimated with very good precision, and their reproducibility is satisfactory. The model also allows the estimation of the mean arteriovenous transit times of both the extracellular and the transported tracer. The compartmental model provides a novel approach to investigate glucose transport in vivo in humans.

3-O-Methylglucose↗
PubMed1989

Stable-label intravenous glucose tolerance test minimal model.

The minimal model approach to estimating insulin sensitivity (Sl) and glucose effectiveness in promoting its own disposition at basal insulin (SG) is a powerful tool that has been underutilized given its potential applications. In part, this has been due to its inability to separate insulin and glucose effects on peripheral uptake from their effects on hepatic glucose inflow. Prior enhancements, with radiotracer labeling of the dosage, permit this separation but are unsuitable for use in pregnancy and childhood. In this study, we labeled the intravenous glucose tolerance test (IVGTT) dosage with [6,6-2H2]glucose, [2-2H]glucose, or both stable isotopically labeled glucose tracers and modeled glucose kinetics in six postabsorptive, nonobese adults. As previously found with the radiotracer model, the tracer-estimated S*l derived from the stable-label IVGTT was greater than Sl in each case except one, and the tracer-estimated SG* was less than SG in each instance. More importantly, however, the stable-label IVGTT estimated each parameter with an average precision of +/- 5% (range 3-9%) compared to average precisions of +/- 74% (range 7-309%) for SG and +/- 22% (range 3-72%) for Sl. In addition, because of the different metabolic fates of the two deuterated tracers, there were minor differences in basal insulin-derived measures of glucose effectiveness, but these differences were negligible for parameters describing insulin-stimulated processes. In conclusion, the stable-label IVGTT is a simple, highly precise means of assessing insulin sensitivity and glucose effectiveness at basal insulin that can be used to measure these parameters in individuals of all ages, including children and pregnant women.

Adult↗
PubMed1988

Insulin sensitivity and beta-cell responsivity are not decreased in elderly subjects with normal OGTT.

Glucose intolerance has been observed often in elderly subjects, but it is not yet clear whether this impaired metabolic state is due to the aging process itself or is secondary to the appearance of other age-related variables. This study attempts to elucidate the effect of age in itself on factors controlling glucose tolerance. Several metabolic parameters were measured in 10 young male controls (23-29 yr) and 17 nonhospitalized, healthy, nonobese, old (60-80 yr) male subjects. Insulin binding to circulating cells was performed along with the intravenous glucose tolerance test, and the data were analyzed by the minimal model method. This approach yields the following measures: tissue insulin sensitivity (SI), fractional glucose disappearance at basal insulin (glucose effectiveness, SG), and first (phi 1) and second (phi 2) phase beta-cell responsiveness to glucose. Insulin-binding capacity to monocytes and erythrocytes was respectively 6.03% +/- 0.57% and 5.96% +/- 0.53% (elderly), 5.97% +/- 0.39% and 5.36% +/- 0.57% (young); SI was 6.20 +/- 0.59 X 10(4) min-1/(microU/mL) (elderly) and 6.35 +/- 0.30 (young); SG was 0.016 +/- 0.002 min-1 (elderly) and 0.019 +/- 0.003 (young); phi 1 was 1.84 +/- 0.29 min-1 (microU/mL)/(mg/dL) (elderly) and 3.37 +/- 0.84 (young); phi 2 was 13.80 +/- 1.78 X 10(4) min-2 (microU/mL)/(mg/dL) (elderly) and 9.59 +/- 2.65 (young). These results show no change with aging of tissue insulin sensitivity and an intact beta-cell activity, suggesting that age per se does not contribute to the deterioration of glucose tolerance when the effect of other age-related variables, eg, obesity and physical inactivity, is precluded.

Adult↗
PubMed1988

Porcine and human insulin absorption from subcutaneous tissues in normal and insulin-dependent diabetic subjects: a deconvolution-based approach.

The mechanisms of sc insulin absorption are not understood, and models for interpreting in vivo data cannot be developed without gross simplification. To overcome this difficulty we developed a new approach which makes use of deconvolution analysis and does not require any model of the sc tissue. In five normal subjects and seven insulin-dependent diabetic (IDDM) patients endogenous insulin secretion was suppressed by means of a hypoglycemic glucose clamp procedure (approximately 2.8 mmol/L) sustained by a continuous insulin infusion (approximately 4 pmol/min.kg). A bolus injection of insulin (5.4 nmol) was administered iv, and plasma insulin concentrations were measured frequently for 2 h to assess iv insulin kinetics. Insulin then was injected sc in the abdominal region, and plasma insulin concentrations were measured for 8 h. Each subject was studied twice, with porcine and semisynthetic human insulin (Actrapid, Novo). The rate of insulin absorption was reconstructed by deconvolution from the plasma concentrations and iv insulin kinetic data. Linearity of the iv insulin kinetics, essential for deconvolution analysis, was confirmed by a dose-response study in the range of the measured concentrations (150-1800 pmol/L). In most instances, a two-compartment model was adequate to describe the iv response. The mean plasma insulin clearance rates were 15.5 +/- 1.9 (+/- SD) mL/min.kg (porcine) and 17.2 +/- 6.0 (human) in normal subjects and 20.7 +/- 8.8 (porcine) and 20.9 +/- 9.1 (human) in the IDDM patients. The rate of appearance of human insulin from sc tissue was faster than that of porcine insulin in both normal and IDDM subjects, but no significant differences were found in bioavailability, which was 55 +/- 12% (+/- SD; porcine) and 61 +/- 34% (human) in the normal subjects, and 84 +/- 28% (porcine) and 86 +/- 23% (human) in the IDDM patients. The rate of absorption and bioavailability were higher in the IDDM patients than in the normal subjects, a difference possibly related to increased sc blood flow in the IDDM patients. No differences were found with regard to glucose requirement values, normalized to plasma insulin concentrations, in agreement with the finding that the bioavailability of the two insulin species was similar.

Adolescent↗
PubMed1988

Insulin secretion and hepatic extraction in humans by minimal modeling of C-peptide and insulin kinetics.

Methods for measuring insulin secretion and hepatic insulin extraction in vivo, e.g., hepatic vein catheterization, are invasive, and can be applied during steady state only. We introduce a noninvasive method for measuring in vivo insulin secretion and its extraction by the liver during an intravenous glucose tolerance test (IVGTT). This method is based on a minimal model of C-peptide secretion and kinetics that is used for interpreting plasma C-peptide concentration data during an IVGTT in normal humans. The model allows the reconstruction of the time course of insulin secretion and, used in conjunction with a minimal model of insulin delivery and kinetics (described in a previous study), provides a noninvasive measure of the time course of hepatic insulin extraction [H(t)]. The C-peptide model also provides a direct prehepatic measure of beta-cell sensitivity to glucose, expressed by two parameters related to first (phi IC)- and second (phi IIC)-phase insulin secretion. In the 11 healthy volunteers we studied, these parameters were 61 +/- 11 pM.min-1.mg-1.dl and 0.0154 +/- 0.0034 pM.min-2.mg-1.dl, respectively. H(t) showed an initial decrement for approximately 30-50 min (from a fasting value of 63 +/- 8% to a nadir of 53 +/- 9%) after the glucose stimulus, then a steady value of approximately 62% was reestablished and maintained throughout the experiment. The validity of the C-peptide model was further assessed by comparing its estimate of the fractional plasma clearance rate (k01) with that obtained in experiments in which biosynthetic human C-peptide was administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Glucose and ketone body turnover in carnitine-palmitoyl-transferase deficiency.

Most of the patients with carnitine-palmitoyl-transferase deficiency (CPT) show reduced levels of blood ketone bodies in the postabsorptive state. In the present study, we have evaluated ketone body and glucose kinetics in patients with CPT deficiency. Intermediate metabolites of carbohydrate and lipid metabolism have also been studied. Ketone body (KB) turnover was measured by means of sequential intravenous bolus injections of 3-14C acetoacetate and 3-14C D(-) 3-hydroxybutyrate in four patients with liver, platelet, and muscle deficiency of CPT system and in eight normal overnight fasting subjects. 6-3H glucose was also injected, along with 3-14C ketone bodies to measure glucose turnover rate. Three out of four CPT deficiency patients had normal KB turnover, despite a marked reduction in liver CPT activity. Only one subject, with severe defect of CPT activity in liver, showed a significantly reduced, but still present rate of de novo synthesis of acetoacetate and 3-hydroxybutyrate (40 and 51 mumol/m-2/min-1 respectively) in comparison with control subjects (103 +/- 14 and 157 +/- 22 mumol/m-2/min-1). Blood concentrations of dicarboxylic adipic and suberic acids were significantly higher in CPT deficiency patients (0.035 +/- 0.007 and 0.021 +/- 0.005, mmol/L respectively) than in control subjects (0.008 +/- 0.008 and 0.006 +/- 0.003 respectively). Basal glucose turnover was increased in CPT deficiency patients (505 +/- 13 mumol/m-2/min-1) in comparison with normal subjects (433 +/- 18 mumol/m-2/min-1; P less than .01) as well as clearance rates (127 +/- 3 mL/m-2/min-1 and 91 +/- 11 mL/m-2/min-1, respectively; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗