SAAM II: Simulation, analysis, and modeling software for tracer and pharmacokinetic studies

Barrett, P. Hugh R.; Bell, Bradley M.; Cobelli, Claudio; Golde, Hellmut; Schumitzky, Alan; Vicini, Paolo; Foster, David M.

doi:10.1016/s0026-0495(98)90064-6

Cited by 410 publications

(315 citation statements)

References 5 publications

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“…Plasma decay curves were generated by dividing the plasma radioactivity at each time point by the plasma radioactivity determined at the initial 5-min time point after tracer injection. The fractional catabolic rates (FCR) were determined from the area under the plasma disappearance curves fitted to a bicompartmental model using the SAAM II program (35).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I

Tietge¹,

Maugeais²,

Cain³

et al. 2000

Journal of Biological Chemistry

152

135

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Plasma levels of high density lipoprotein (HDL) cholesterol and its major protein component apolipoprotein (apo) A-I are significantly reduced in both acute and chronic inflammatory conditions, but the basis for this phenomenon is not well understood. We hypothesized that secretory phospholipase A 2 (sPLA 2 ), an acute phase protein that has been found in association with HDL, promotes HDL catabolism. A series of HDL metabolic studies were performed in transgenic mice that specifically overexpress human sPLA 2 but have no evidence of local or systemic inflammation. We found that HDL isolated from these mice have a significantly lower phospholipid and cholesteryl ester and significantly greater triglyceride content. transgenic mice was significantly enhanced compared with control mice. In summary, these data demonstrate that overexpression of sPLA 2 alone in the absence of inflammation causes profound alterations of HDL metabolism in vivo and are consistent with the hypothesis that sPLA 2 may promote HDL catabolism in acute and chronic inflammatory conditions. Plasma concentrations of high density lipoprotein (HDL) 1 cholesterol and its major apoprotein apoA-I are inversely associated with atherosclerotic cardiovascular disease (1, 2). The factors responsible for the substantial variation in HDL cholesterol and apoA-I levels in humans remain incompletely understood. Metabolic studies of HDL and apoA-I in humans have established that variation in their levels is due in substantial part to variation in the rate of apoA-I catabolism (3-7). Although the determinants of apoA-I catabolism have not been fully elucidated, the size and lipid composition of HDL have been recognized to substantially influence the catabolic rate of apoA-I (8, 9).One clinical setting that is invariably associated with reduced HDL cholesterol and apoA-I levels is systemic inflammation. Acute inflammatory states such as sepsis are associated with profoundly reduced HDL cholesterol levels (10). Furthermore, chronic inflammatory states such as rheumatoid arthritis and systemic lupus are also associated with reduced levels of HDL cholesterol (11-18), as well as with increased risk of cardiovascular disease (19,20). One of the major factors thought to be implicated in the reduced levels of HDL cholesterol during inflammation is the serum amyloid A (SAA) protein, which increases markedly during acute infection and inflammation and is also elevated in chronic inflammatory states (10,21,22). However, expression of SAA has never been directly demonstrated to alter HDL metabolism in vivo in the absence of systemic inflammation. We recently demonstrated that marked overexpression of human SAA alone in the absence of a generalized acute phase response had no effect on HDL cholesterol and apoA-I levels in human apoA-I transgenic mice (23). This observation raised the question as to whether other factors associated with systemic inflammation may modulate HDL metabolism.Group IIA secretory phospholipase A 2 (sPLA 2 ) is an acute phase protein and plasma leve...

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Section: Methodsmentioning

confidence: 99%

Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I

Tietge¹,

Maugeais²,

Cain³

et al. 2000

Journal of Biological Chemistry

152

135

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“…were estimated by incorporating this model of insulin secretion into the commercially available software SAAM 1.1.2 (Simulation, Analysis And Modelling; SAAM Institute, Seattle, WA, USA) [21].…”

Section: Subjectsmentioning

confidence: 99%

Heritability of model-derived parameters of beta cell secretion during intravenous and oral glucose tolerance tests: a study of twins

et al. 2005

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Aims/hypothesis: The genetic architecture of model-derived parameters of beta cell function has never been assessed. Therefore, we estimated heritability (h 2 ) for model-derived phenotypes of insulin secretion in twins. Methods: Thirty-three monozygotic (MZ) and 23 dizygotic (DZ) twin pairs from the Finnish Twin Cohort Study underwent an OGTT (plasma glucose/C-peptide at 0, 30, 60, 90 and 120 min). A subset of the twin pairs (21 MZ/20 DZ) also underwent an IVGTT (frequent sampling of plasma glucose/insulin from 0 to 60 min) followed by a 160-min euglycaemic-hyperinsulinaemic clamp (45 mU · min −1 ·m −2 ). Mathematical modelling was applied to the IVGTT and the OGTT to assess first-phase (readily releasable insulin [RRI]) and second-phase (sigma) secretion (IVGTT), and a global index of beta cell performance (OGTT beta index). Intraclass correlation coefficients and genetic and non-genetic components for trait variances were computed to assess the h 2 of model-derived parameters. Results: The intraclass correlation coefficients in MZ twins were 0.78 for RRI, 0.67 for sigma and 0.57 for OGTT beta index. In DZ twins the correlation coefficients were 0.23, 0.32 and 0.42, respectively. Using the most parsimonious model for each trait, the h 2 -the proportion of variance accounted for by genetic factors -was 76% (95% CI: 53-88%) for RRI, 28% (34-80%) for sigma and 53% (26-72%) for OGTT beta index. Conclusions/ interpretation: Our findings demonstrate that model-derived parameters of insulin secretion have a substantial genetic component and may be used in the search for genetic determinants of beta cell function in humans.

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“…18 Kinetic analysis of tracer -tracee ratios were made with the simulation analysis modelling SAAM II program 19 (SAAM Institute Inc., Seattle, WA, USA). ApoA-I and B-100 data were analysed using a monoexponential function, assuming that the kinetics of these apolipoproteins are described by one single compartment.…”

Section: Modellingmentioning

confidence: 99%

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

et al. 2002

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AIMS=HYPOTHESIS:Mechanisms responsible for the decreased high-density lipoprotein (HDL) cholesterol level associated with insulin resistance in obese patients are not clearly understood. To determine the influence of insulin resistance at an early stage on HDL metabolism, we performed a stable isotope kinetic study of apolipoprotein (apo) A-I, in five obese insulin resistant women with normal fasting triglycerides and without impaired glucose tolerance, and in five age-matched control women. METHODS: Each subject received a 16 h constant infusion of L-[1-13 C]leucine at 0.7 mg=kg=h following a primed bolus of 0.7 mg=kg. RESULTS: ApoA-I fractional catabolic rate (FCR) was significantly increased in insulin-resistant women compared to controls (0.316 AE 0.056 vs 0.210 AE 0.040 per day, P < 0.01), indicating a significant 50% increase of apoA-I catabolism, leading to an important reduction of plasma apoA-I residence time (3.25 AE 0.59 vs 4.92 AE 1.11, P < 0.01). ApoA-I production rate tended to be higher in insulin resistant women than in controls (364 AE 77 vs 258 AE 60 mg=l=day, P ¼ 0.13), but the difference was not statistically significant. ApoA-I FCR was correlated with triglycerides during the fed state (r ¼ 0.69; P ¼ 0.026) and HDL triglycerides -esterified cholesterol ratio (r ¼ 0.73; P ¼ 0.016), suggesting that alteration of apoA-I metabolism in insulin resistance may be partly related to HDL enrichment in triglycerides. CONCLUSIONS: Our kinetic study shows that patients, at an early stage of insulin resistance (without impaired glucose tolerance nor fasting hypertriglyceridaemia), already have a significant alteration of apoA-I metabolism (increased apoA-I catabolism), which is consistent with the increased risk of atherosclerosis in this population.

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SAAM II: Simulation, analysis, and modeling software for tracer and pharmacokinetic studies

Cited by 410 publications

References 5 publications

Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I

Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I

Heritability of model-derived parameters of beta cell secretion during intravenous and oral glucose tolerance tests: a study of twins

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

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