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K Thomaseth

Publications and source records attributed to K Thomaseth.

At least 19 recordsLinked to original sources
PubMed2001

Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD).

We performed an analysis of All cancer and Lung cancer mortality in relation to estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) in the cohort of chemical workers at 12 US plants assembled by the US National Institute for Occupational Safety and Health (NIOSH) (n = 5172). Estimates of cumulative exposure to TCDD were based on a minimal physiologic toxicokinetic model (MPTK) that accounts for inter- and intra-individual variations in body mass index (BMI) over time. Population-level parameters related to liver elimination and background (input or concentration) of TCDD were estimated from separate data with repeated measures of serum TCDD (US Air Force Health Study). An occupational TCDD input parameter was estimated based on one-point-in-time TCDD data available for a subset (n = 253) of the NIOSH cohort. Model-based time-dependent cumulative dose estimates (area under the curve (AUC) of the lipid-adjusted serum TCDD concentration over time) were obtained for members of the full cohort with recorded body height and weight (n = 4049), as this information is required by the MPTK model to compute dose. Missing-value problems arose in the estimation of the occupational input parameter (n = 42) and in TCDD-dose calculation in the full cohort (n = 886) and they were handled with multiple imputation methods. Risk-regression analyses were based on Cox log-linear models including age at entry, year of entry and duration of employment as categorical covariates in addition to the logarithm of cumulative TCDD dose in ppt-years. Risk sets were stratified on birth cohort. Estimates of the unlagged exposure coefficient in these models were 0.1249 [95% confidence interval (CI) 0.0144, 0.2354] for All cancer and 0.2158 (95% CI 0.02376, 0.4078) for lung cancer. A 10-year lag produced an increase in the estimate for all cancer (0.1539, 95% CI 0.0387, 0.2691), whereas, the estimate for lung cancer was not affected much (0.2125, 95% CI 0.0138, 0.4112). At a dose level of 100 times the background the estimates obtained with a 10-year lag translate into a relative risk of 2.03 (95% CI 1.19-3.45) for all cancer and of 2.66 (95% CI 1.07-6.64) for lung cancer. Higher estimates of the exposure coefficients were obtained after imputation of missing values. This increase in risk seemed due to the inclusion of short-term workers, who may exhibit a higher mortality for reasons other than dioxin exposure.

Body Mass Index↗
PubMed2001

Contribution to glucose tolerance of insulin-independent vs. insulin-dependent mechanisms in mice.

To study the contributions of insulin-dependent vs. insulin-independent mechanisms to intravenous glucose tolerance (K(G)), 475 experiments in mice were performed. An intravenous glucose bolus was given either alone or with exogenous insulin or with substances modulating insulin secretion and sensitivity. Seven samples were taken over 50 min. Insulin [suprabasal area under the curve (DeltaAUC(ins))] ranged from 0 to 100 mU. ml(-1). 50 min. After validation against the euglycemic hyperinsulinemic clamp, the minimal model of net glucose disappearance was exploited to analyze glucose and insulin concentrations to measure the action of glucose per se independent of dynamic insulin (S(G)) and the combined effect of insulin sensitivity (S(I)) and secretion. Sensitivity analysis showed that insulin [through disposition index (DI)] contributed to glucose tolerance by 29 +/- 4% in normal conditions. In conditions of elevated hyperinsulinemia, contribution by insulin increased on average to 69%. K(G) correlated with DI but was saturated for DeltaAUC(ins) above 15 mU. ml(-1). 50 min. Insulin sensitivity related to DeltaAUC(ins) in a hyperbolic manner, whereas S(G) did not correlate with the insulin peak in the physiological range. Thus glucose tolerance in vivo is largely mediated by mechanisms unrelated to dynamic insulin and saturates with high insulin.

Animals↗
PubMed2001

Insulin and C-peptide secretion and kinetics in humans: direct and model-based measurements during OGTT.

To directly evaluate prehepatic secretion of pancreatic hormones during a 3-h oral glucose tolerance test (OGTT), we measured insulin and C-peptide in six healthy control, six obese, and six type 2 diabetic subjects in the femoral artery and hepatic vein by means of the hepatic catheterization technique. Hypersecretion in obesity was confirmed (309 +/- 66 nmol in obese vs. 117 +/- 22 in control and 79 +/- 13 in diabetic subjects, P </= 0.01), whereas early phase secretion was impaired in diabetes. We also measured hepatic insulin extraction (higher in diabetic than in control subjects, P = 0.03) and insulin clearance. The measured data were also used to validate a previously proposed mathematical model, developed to quantify prehepatic secretion, hepatic insulin extraction, and insulin clearance during OGTT, when C-peptide and insulin concentrations are systemically measured. We found good correspondence between experimental data and model estimates for prehepatic insulin secretion (P > 0.3, r(2) = 0.93), whereas estimation of hepatic insulin extraction and insulin clearance needs further investigation for improvement.

Adult↗
PubMed2000

Urea as a marker of adequacy in hemodialysis: lesson from in vivo urea dynamics monitoring.

BACKGROUND: "Dialysis dose," a concept developed by Sargent and Gotch based on urea kinetic modeling, is a useful and recognized tool that is used to quantitate and optimize a dialysis-efficacy program. However, it has been shown that oversimplification of the "dialysis adequacy" concept to the Kt/V index might lead to dramatic underdialysis and subsequent deleterious consequences on morbidity and mortality of dialysis patients. With this perspective, the determination of Kt/V must be very cautious and rely on accurate measurement of postdialysis urea concentration and its use integrated as a tool in a quality-assurance process. METHODS: In this study, we analyzed urea dynamics by means of a blood side (ultrafiltrate) continuous online urea monitoring system interfaced with a two-pool model hosted in a microcomputer. The study was designed to provide instantaneous dialysis performances (body and dialyzer clearances, dialyzer mass transfer coefficient) and to determine the in vivo functional permeability characteristics of the patient [intercompartment urea mass transfer coefficient (Kc)]. Thirteen end-stage renal disease patients (age 54 +/- 16 years; 12 male and 1 female) were studied during nine consecutive dialysis sessions (3 weeks). RESULTS: Urea kinetics obtained from the urea monitoring system fitted closely the urea kinetic modeling prediction, confirming the validity of the double-pool model structure. Effective in vivo urea mass transfer coefficient averaged 912 +/- 235 mL/min/1.73 m2, a value close to those reported with more invasive methods. Large variations ranging from 363 to 1249 mL/min were observed among patients, confirming very large interindividual patient permeability differences. Interestingly, the urea mass transfer coefficient was inversely correlated with the postdialysis rebound values. Intraindividual variations were also noted as a function of time denoting functional changes in urea mass transfer coefficient values. The urea distribution volume was 38.1 +/- 7, 8 L (53 +/- 8% body weight). V1 referring to the extracellular volume and V2 to the intracellular volume were 9 +/- 2 L (13 +/- 2% body weight) and 29.2 +/- 6.6 L (41 +/- 1.3% body wt), respectively. The extracellular/intracellular volume ratio was 0.31 (approximately one third) and was not as usually defined by the paradigm 1/2 ratio. CONCLUSION: Online double-pool urea kinetic modeling gave a new insight in urea kinetic modeling approach. Urea dynamics fit perfectly a double-compartment model structure. Accessible extracellular volume to hemodialysis is smaller than expected. The in vivo urea mass transfer coefficient must be considered as an individual and variable characteristic of ESRD patients that should be taken into consideration when prescribing the hemodialysis schedule.

Adult↗
PubMed2000

Power spectral analysis of heart rate in hypothyroidism.

OBJECTIVE: The aim of the present study was to evaluate the impact of hypothyroidism on the autonomic regulation of the cardiovascular system by analysing separately sympathetic and parasympathetic influences on the heart. DESIGN: In seven newly diagnosed untreated hypothyroid patients we analysed power spectral density of heart rate cyclic variations at rest, while lying, and while standing. The same protocol was repeated after the induction of stable euthyroidism by levothyroxine (L-T(4)) treatment. The results were also compared with those obtained from seven age-, sex- and body mass index-matched control subjects. METHODS: Heart rate variability was evaluated by autoregressive power spectral analysis (PSA). This method allows reliable quantification of low frequency (LF) and high frequency (HF) components of the heart rate power spectral density. These are considered to be under mainly sympathetic and purely parasympathetic control respectively. In addition, heart rate variations during deep breathing, lying to standing, and Valsalva's manoeuvre were assessed. RESULTS: PSA showed a sharp reduction in the HF (parasympathetic) component in hypothyroid subjects compared with controls (lying, 29.4+/-5.4 vs 47.7+/-6.3 normalized units (NU) (means +/- s.e.m.), P<0.05; standing, 14.0+/-3.5 vs 32.1+/-3.6NU, P<0.005). Conversely, the LF (mainly sympathetic) component was higher in hypothyroid subjects than in controls (lying, 61.6+/-6.4 vs 45.4+/-6.7 NU; standing, 71.7+/-8.0 vs 53.1+/-5.6NU), this difference being significant in the standing position. Hence, the LF/HF ratio, which is considered an index of sympathovagal balance, was increased in hypothyroid subjects while both lying (2.75+/-0.6 vs 1.16+/-0.3; P<0.05) and standing (10.0+/-3.7 vs 1.85+/-0.3; P<0. 02). Total heart rate variability, expressed as total power spectral density, was lower in hypothyroid patients than in control subjects, this difference being significant in the lying position (574+/-126 vs 2302+/-994ms(2), P<0.05). In patients re-examined after L-T(4) therapy, complete normalization of cardiovascular parameters was observed (LF/HF ratio, lying, 1.26+/-0.4; standing, 2.56+/-0.8, both P<0.01 vs baseline values). The response to conventional cardiovascular autonomic tests was not significantly different between hypothyroid patients and healthy controls, and did not change in patients after therapy. CONCLUSIONS: These results suggest that, contrary to the clinical picture, thyroid hormone deficiency is associated with an increased sympathetic influence on the autonomic cardiovascular system. The changes in sympathetic function could be explained by a secondary adaptation to an altered cardiovascular responsiveness.

Electrocardiography↗
PubMed1999

Design of optimal two-sample bolus injection tests for measuring low plasma clearance rates.

The bolus injection technique is widely used for assessing plasma clearance rates of substances and is based on multiexponential data analysis of multiple concentration measurements. This approach can be simplified to a monoexponential description with only two measurements if intercompartmental mixing occurs at a much faster rate than elimination, i.e. with low plasma clearance rates. In this context initial transients must be ignored because the first measurement time instant affects the accuracy of clearance estimates if mixing is still incomplete. Moreover, measurement noise affects estimation precision which can be optimized by suitable choice of the sampling schedule and of the injected test dose. The aim of this study is to design two-sample bolus injection tests for measuring low plasma clearance rates with preassigned precision and with minimum amount of injected test substance. This paper provides equations for evaluating whether plasma clearance is sufficiently low to allow a monoexponential description of the plasma disappearance curve and for choosing the first sampling time instant. Closed form equations are proposed for determining the optimal test dose and the second sampling time. Result are derived for a particular heteroscedastic measurement noise description, and the problem of robustness with respect to interpatient variability of kinetic parameters is addressed.

Artifacts↗
PubMed1999

Uncertainty in estimating exposure using a toxicokinetic model. The example of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

This paper deals with sources of uncertainty in the use of a minimal physiological toxicokinetic model to obtain dose estimates for a dose-response analysis of cancer in an occupational cohort. Toxicokinetic models make it possible to construct exposure parameters that are more closely related to the individual dose than traditional measures of exposures to toxic agents. However, the process introduces a wide array of sources of uncertainty. Selecting a model structure to describe the kinetics of a toxic agent implies necessarily making simplifications and assumptions that influence the range of applicability of the model. Once a model has been selected, the value of certain model parameters (constants) must be assigned, for example, from anthropometric data. The question then arises of how sensitive the model predictions are to variations in the values of these constants. Other model parameters, typically those describing the kinetics of the agent, are next estimated from actual data. There may be limitations in the data concerning, for example, sparseness (too few observations per subject) or missing values. The methods used for parameter estimation carry their own set of assumptions that need to be appropriate to the situation at hand. In summary, the dioxin example is used to characterize the sources of uncertainty at different levels, such as model structure, methods and data used for parameter estimation, estimation of occupational exposure, and imputation of missing values in exposure indices derived from the kinetic model.

Environmental Exposure↗
PubMed1998

Zinc supplementation improves glucose disposal in patients with cirrhosis.

Zinc deficiency is common in cirrhosis, and was proved to affect nitrogen metabolism. In experimental animals, zinc status may also affect glucose disposal, and acute zinc supplementation improves glucose tolerance in healthy subjects. This study was aimed at measuring the effects of long-term oral zinc supplements on glucose tolerance in cirrhosis. The time courses of glucose, insulin, and C-peptide in response to an intravenous (i.v.) glucose load were analyzed by the minimal-model technique before and after long-term oral zinc supplements (200 mg three times per day for 60 days) in 10 subjects with advanced cirrhosis and impaired glucose tolerance or diabetes. The test was performed using a simplified procedure, based on 20 blood samples collected within 4 hours from the glucose load. Normal values were obtained in 25 age-matched healthy subjects. Zinc levels were low to normal or reduced before treatment, and were normalized by oral zinc. Glucose disappearance improved by greater than 30% in response to treatment. There were no changes in pancreatic insulin secretion and systemic delivery, or in the hepatic extraction of insulin. Insulin sensitivity (SI), which was reduced by 80% before treatment, did not change. Glucose effectiveness (SG) was nearly halved in cirrhosis before treatment (0.013 [SD 0.007] min(-1) v. 0.028 [SD 0.009] in controls; P < .001), and increased to 0.017 (SD 0.009) after zinc (P < .05 v. baseline). The return to normal of plasma zinc levels after long-term zinc treatment in advanced cirrhosis improves glucose tolerance via an increase of the effects of glucose per se on glucose metabolism. Poor zinc status may contribute to the impaired glucose tolerance and diabetes of cirrhosis.

Administration, Oral↗
PubMed1998

Optimal design of a two-sample test for assessing [125I]iothalamate plasma clearance in peritoneal dialysis.

BACKGROUND: Plasma clearance of a tracer in peritoneal dialysis (PD) can be used to assess treatment adequacy without labour-intensive fluid collections. Accuracy and precision of plasma clearance estimates by the bolus injection technique depend on the estimation accuracy of the area under the concentration curve and the measurement precision of plasma concentrations. The first source of error is due to oversimplified, e.g. monoexponential, descriptions of plasma disappearance curves. The second source of error arises from the propagation of measurement errors to the parameter estimates. METHODS: The theoretical bias of parameter estimates is determined first for a monoexponential approximation of a biexponential disappearance curve and as a function of the first sampling time at which mixing is still incomplete. The precision of plasma clearance estimates, expressed as coefficient of variation, is then described as a function of the experimental variables and of the standard deviation of measurement error. This allows the determination of the optimal two-sample test that yields most precise estimates of plasma clearance. RESULTS: The optimal two-sample schedules for assessing plasma clearance of [125I]iothalamate in PD patients vary between subjects according to individual clearances and distribution volumes. Our results suggest collecting the first sample 120 min, and the second 2-4 days, after the bolus injection. CONCLUSIONS: The proposed two-sample test is suitable to be used in clinical routine for assessment of adequacy of PD treatment but requires a priori estimation of individual tracer kinetics and of laboratory measurement errors. A fixed design with the first sample taken after 120 min and the second sample collected 3 days after the bolus injection should yield the best performance.

Adult↗
PubMed1998

Distribution and kinetics of amylin in humans.

The aim of the study was to determine the apparent volume of distribution (VTOT), total body clearance (CL), fractional clearance, and mean residence time (MRT) of the beta-cell hormone amylin. We therefore performed an intravenous injection of 50 micrograms of human synthetic amylin (amlintide) in nine healthy male subjects during suppression of endogenous amylin release by intravenous somatostatin (0.06 microgram.kg-1.min-1). The plasma levels of amylin concentrations over time were analyzed using three-exponential curves. VTOT was 173 +/- 16 ml/kg and was not different from that of insulin reported in the literature (157 ml/kg). MRT was 27.7 +/- 2.1 min and thus two times the reported value for insulin (14.1 min) and C-peptide (16.4 min). CL and fractional CL were 6.2 +/- 0.2 ml.kg-1.min-1 and 0.038 +/- 0.003 min-1, respectively. Fractional CL is therefore definitely lower than that reported for insulin (0.12-0.2 min-1) but is, however, in the range of that of C-peptide (0.05 min-1). In conclusion, clearance of amylin is similar to that reported for C-peptide and much slower than insulin, indicating that the commonly used molar insulin-to-amylin ratio does not reflect the correct relationship of the two peptides.

Adult↗
PubMed1998

Estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin using a minimal physiologic toxicokinetic model.

In this study we investigated estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on a minimal physiologic toxicokinetic model in humans. Our purpose was to obtain a mathematical tool for dose-response studies based on human data. We first simplified an existing model of TCDD kinetics in humans and estimated its parameters (i.e., liver elimination and background input of TCDD) using repeated measures of serum dioxin taken in Vietnam veterans (Ranch Hand data and data from an unexposed reference group). We carried out computer simulation and estimation of the model parameters both under a nonlinear weighted least-squares model (naive pooled data approach) and under a nonlinear mixed-effects model. The best parameter estimates were obtained with log-transformed data under a mixed-effects model: liver elimination parameter kf = 0.022 days-1 (95% confidence interval [CI] = 0.020, 0.024), and background input rate input = 0.1251 pg/kg/day (95% CI = 0.071, 0.179). The dioxin kinetic model and its estimated parameters were then used to provide dose estimates for a cohort of workers with exposure to TCDD at chemical plants in the United States. First, the model was used to estimate the rate of occupational intake of TCDD in a subset of the cohort consisting of 253 subjects for whom one measure of serum TCDD was available. A model of change in body-mass index over time was also identified for this subsample. The occupational exposure rate was estimated by linear regression using the above values of kinetic parameters and assuming an initial condition for serum TCDD of 7 ppt, i.e., the average level found in unexposed workers. The estimate of the occupational exposure parameter was 232.7 pg/kg/day (95% CI 192, 273). This value can be applied to the full cohort to obtain for each cohort member the time course of serum dioxin concentration from which exposure indices can be derived. Sensitivity coefficients to model parameters (background input, kf, occupational exposure, and the assumed TCDD concentration at hire) allow for a convenient recalculation of the serum TCDD curve and of the derived exposure indices for different assumed values of the model parameters.

Humans↗
PubMed1997

Amylin: history and overview.

The presence of amyloid deposits in the pancreas was first described at the beginning of the 20th century. However, it was not until 1987 that the structure of the amylin molecule was identified. Amylin is a 37-amino-acid peptide hormone that is co-secreted with insulin by the pancreatic beta-cells in response to a nutrient stimulus. It is deficient in patients with Type 1 diabetes and elevated in patients in the early stages of Type 2 diabetes, a condition which is characterized by hyperinsulinaemia. Elevation of plasma amylin levels has also been described in patients with impaired glucose tolerance, obese subjects and in pregnant women with both normal glucose tolerance and gestational diabetes mellitus. However, it appears that deficiencies of amylin secretion appear before those of insulin in patients in the later stages of Type 2 diabetes. Early experimental studies suggested that amylin inhibits basal insulin secretion, and induces insulin resistance in skeletal muscle, leading to the hypothesis that it has a role in the aetiology of Type 2 diabetes. However, a number of more recent experimental studies have indicated that amylin is a third active pancreatic islet hormone that works with insulin and glucagon to maintain glucose homeostasis. Amylin appears to regulate glucose inflow to the circulation by influencing the rate of gastric emptying, and thus the rate at which meal-derived glucose enters the system, and also by inhibiting glucose release and hepatic glucose production in the postprandial period.

Amyloid↗
PubMed1997

Amylin release during oral glucose tolerance test.

The role of amylin in the beta-cell dysfunction that occurs in patients with diabetes mellitus may be important. Amyloid deposits are found in the pancreata of subjects with Type 2 diabetes and may contribute to beta-cell death. It is therefore necessary to study amylin secretion and kinetics to determine whether elevated levels of the peptide are due to elevated secretion, reduced clearance or both. The aim of this study was to measure amylin dynamics during an oral glucose tolerance test (OGTT). We also used a mathematical model of beta-cell activity to assess the secretion and kinetics of C-peptide, insulin and amylin in humans during an OGTT. In particular, we were interested in characterizing the physiological meaning of one of the terms in the model, the amylin/C-peptide co-secretion factor (sigma). The model has been used in several pathophysiological conditions and results indicate an elevated secretion and clearance of amylin in glucose-intolerant states. Amylin clearance has been found to be similar to that of C-peptide, and much slower than that of insulin. In this study, direct measurements of insulin and amylin secretion in five obese subjects yielded an estimate of the amylin/insulin co-secretion factor of 0.004 with a standard deviation (SD) of 0.002. The point estimate of hepatic clearance was 80 ml min(-1), which was much lower than that of insulin (507 +/- 94 ml min[-1]). In addition, the estimated hepatic clearance was not significantly different from zero given its high SD of 213 ml min(-1). The absence of hepatic extraction of amylin is therefore a plausible hypothesis, which is also supported by the similarity between amylin and C-peptide clearances. This observation characterizes the physiological meaning of sigma and suggests that this parameter is associated mainly with beta-cell secretion.

Amyloid↗
PubMed1997

Elevated islet amyloid pancreatic polypeptide and proinsulin in lean gestational diabetes.

Recent research indicates that islet amyloid pancreatic polypeptide (IAPP) might have a regulatory effect on beta-cell insulin processing and secretion. To study such interaction in more detail, IAPP secretion and kinetics and the serum concentrations of proinsulin were assessed both before and after delivery in lean pregnant women with gestational diabetes mellitus (GDM patients) in comparison to those with normal glucose tolerance (NGT) and to nonpregnant healthy lean (control) and obese insulin-resistant women during oral glucose tolerance tests. Kinetic analysis of IAPP was performed with mathematical modeling, providing indirect estimates of its secretion and fractional clearance. Total insulin secretion per 180 min was elevated by 30% in GDM patients (35 +/- 3 pmol/l) versus control subjects (27 +/- 1 pmol/l) (P < 0.05), but increased even more (190-250%) in obese insulin-resistant women, compared with all other groups (68 +/- 7 pmol/l, P < 0.0005). Pregnancy induced a more marked fourfold increase in apparent total IAPP secretion rate (TIR) (GDM patients, 172 +/- 31 pmol x 1(-1) x 3 h(-1); NGT subjects, 166 +/- 31 pmol x 1(-1) x 3 h(-1); control subjects, 40 +/- 1 pmol 1(-1) x 3 h(-1)) and a twofold rise in its fractional clearance versus control subjects (P < 0.01), whereas in GDM patients a 30% increase of IAPP secretion and a decreased clearance was found, compared with obese insulin-resistant women (TIR, 112 +/- 14 pmol x 1(-1) x 3 h(-1)). The increase in IAPP secretion in both pregnant groups was much higher than that of the insulin groups, resulting in a marked change of the IAPP-insulin cosecretion factor when compared with lean or obese nonpregnant women (P < 0.0005). Associated serum proinsulin and the postprandial (total divided by 180 min) proinsulin-to-insulin ratio were greater in GDM patients versus NGT and control subjects (0.11 +/- 0.01 vs. 0.07 +/- 0.01 and 0.08 +/- 0.01 pmol/l, P < 0.05), while the fasting proinsulin-to-insulin ratio was only increased in GDM patients versus control subjects (0.22 +/- 0.03 vs. 0.13 +/- 0.01 pmol/l, P < 0.05). After delivery, total IAPP secretion (52.4 +/- 1.5 pmol/l) was completely normalized in the GDM group, as were the clearance rate and the IAPP-insulin cosecretion factor. Similarly, serum proinsulin concentrations returned to normal, whereas proinsulin-to-insulin ratios remained elevated. In conclusion, IAPP hypersecretion is characteristic for pregnancy and might partially decrease hyperinsulinemia in pregnancy by inhibiting insulin secretion. Increased proinsulin concentrations and a raised proinsulin-to-insulin ratio, which did not abate following delivery, are specific to GDM and might thus serve as its marker and potentially even identify subjects at high risk for the development of NIDDM.

Adult↗
PubMed1997

Pronounced insulin resistance and inadequate beta-cell secretion characterize lean gestational diabetes during and after pregnancy.

OBJECTIVE: To evaluate beta-cell secretion and glucose metabolism in lean subjects with gestational diabetes mellitus (GDM) compared with that in subjects with normal pregnancy and obesity. RESEARCH DESIGN AND METHODS: Insulin secretion, insulin sensitivity (S1), and hepatic insulin extraction were assessed in pregnant women with GDM before and after delivery and in those with normal glucose tolerance (NGT) in comparison to healthy nonpregnant lean and obese women. Kinetic analysis of glucose, insulin, and C-peptide plasma concentrations during oral and intravenous glucose tolerance tests was performed by mathematical modeling. RESULTS: S1 was blunted in pregnant women with GDM by 84% and in those with NGT by 66% compared with lean nonpregnant women (P < 0.005 vs. healthy nonpregnant lean control subjects; P < 0.05, GDM vs. pregnant women with NGT), whereas glucose effectiveness was decreased by 33% in both pregnant groups (P < 0.05 vs. healthy nonpregnant lean control subjects). Insulin secretion was 30% higher (P < 0.05) in subjects with GDM than in pregnant women with NGT or in nonpregnant lean women, but decreased (P < 0.005) when compared with obese women with a comparable degree of insulin resistance. Fractional hepatic insulin extraction was similar in both pregnant groups, being lower (P < 0.0001) by 30% versus nonpregnant females. beta-cell sensitivity to glucose for insulin release was decreased in subjects with GDM versus pregnant women with NGT as well as nonpregnant women by 40-50% (P < 0.01). Twelve weeks after delivery, GDM returned to normal glucose tolerance, but S1 remained 50% lower than that in lean nonpregnant women, while beta-cell sensitivity to glucose did not change (P < 0.01 vs. healthy nonpregnant lean control subjects). CONCLUSIONS: Pregnancy is characterized by insulin resistance, diminished hepatic insulin extraction, and glucose effectiveness. Lean subjects with GDM are additionally characterized by having more pronounced insulin resistance and inadequate insulin secretion, which persist after delivery. Compared with other insulin-resistant prediabetic states like impaired glucose tolerance (IGT), defective insulin secretion seems to be a predominant defect in lean GDM subjects, indicating that it might represent a specific prediabetic condition.

Adult↗
PubMed1996

Acute effect of insulin on autonomic regulation of the cardiovascular system: a study by heart rate spectral analysis.

Insulin is suggested to have direct effects on the cardiovascular system but these are not well described. We assessed the possible influence of insulin on autonomic control of heart function. A 2-h hyperinsulinaemic euglycaemic clamp was performed in 10 healthy women (mean age 21.7 +/- 1.3 years), at two different insulin infusion rates: 80 mU m-2 and 400 mU m-2 min-1, in 7 and 3 subjects, respectively. Saline alone was infused in 4 controls. Power spectral analysis (PSA) of heart rate was recorded before and after 90-120 min of insulin infusion, as were blood pressure and heart rate. Although there were no significant changes in heart rate or blood pressure, PSA showed marked reductions of high frequency (HF) bands after insulin (2.60 +/- 0.12 vs 2.09 +/- 0.16 log ms2, p < 0.005), as at both low and high infusion rates (2.46 +/- 0.13 to 2.14 +/- 0.23 log ms2, p < 0.05, and 2.92 +/- 0.18 to 1.98 +/- 0.06 log ms2, p < 0.01, respectively). There were no significant changes of low frequency (LF) bands. Densities at LF and HF did not change significantly in control studies. As HF and LF are considered to reflect parasympathetic and mainly sympathetic control respectively, our observation of an increased LF/HF ratio (0.13 +/- 0.10 vs 0.63 +/- 0.13, p < 0.005) may be considered an index of relative sympathetic predominance induced by insulin infusion. We conclude that insulin affects the cardiovascular system, reducing vagal influence on the heart and inducing a relative hypersympathetic tone.

Adult↗
PubMed1996

Beta-cell activity and hepatic insulin extraction following dexamethasone administration in healthy subjects.

Glucocorticoids induce an increase of hepatic glucose production and peripheral resistance to insulin action. It is further assumed that dexamethasone administration in humans causes insulin hypersecretion, although inferences on beta-cell activity have been made in absolute terms and mostly from observations of systemic insulin concentration. In fact, the role of hepatic insulin extraction in humans treated long-term with glucocorticoids has not been investigated. The aim of the present study was to factor out quantitatively the main components of the insulin pathway that are responsible for the peripheral hypersecretion observed after steroids. Frequently sampled intravenous (FSIGT) and oral (OGTT) glucose tolerance tests were performed in healthy subjects before and after 5 days of oral dexamethasone administration (4 mg/d). Insulin sensitivity, beta-cell secretion, and hepatic insulin extraction were estimated by means of mathematical modeling. After steroids, insulin sensitivity decreased from 6.00 +/- 1.29 to 4.23 +/- 1.04 min-1/(microU/mL) (P < .04). Basal beta-cell secretion increased from 45 +/- 7 to 104 +/- 26 pmol/L . min-1 (P < .004) during the FSIGT and from 40 +/- 6 to 88 +/- 21 (P < .05) during the OGTT; total insulin release increased from 19 +/- 5 to 36 +/- 7 nmol/L in 180 minutes (P < .005) and from 33 +/- 5 to 50 +/- 10 (P < .02), respectively, FSIGT data also showed that first-phase beta-cell sensitivity increased from 236 +/- 39 to 309 +/- 33 pmol/L . min-1/(mg/dL) (P < .04), and second-phase from 631 +/- 154 to 1,103 +/ 196 10(4) pmol/L . min-2/(mg/dL) (P < .03). Posthepatic insulin delivery increased only insignificantly during the FSIGT (from 3.4 +/- 0.6 to 4.5 +/- 0.5 nmol/L, P = .073) due to an augmented hepatic insulin extraction from 73.0% +/- 7.2% to 83.0% +/- 3.5% (P < .05). During the OGTT, posthepatic insulin delivery increased after treatment from 6.6 +/- 1.2 to 11.4 +/- 2.5 nmol/L (P < .035) due to an increase, although slight, of hepatic insulin extraction from 77.4% +/- 1.9% to 79.3% +/- 3.3% (P = .319). The increased overall beta-cell activity during both tests was observed also by analyzing OGTT profiles of islet amyloid polypeptide (IAPP), the secretion of which was higher after steroids (basal, 0.081 +/- 0.012 v 0.272 +/- 0.082 pmol/L/min, P < .02; total, 35 +/- 8 v 116 +/- 48 mpmol/L in 3 hours, P < .05). In conclusion, after dexamethasone administration, peripheral hyperinsulinemia due to marked prehepatic beta-cell insulin hypersecretion is partially ameliorated by a concomitant increase of hepatic insulin clearance, which is more evident during a FSIGT. Model-derived secretion parameters from the OGTT and FSIGT produced comparable results, indicating that both tests, when properly analyzed, are feasible tools to evaluate insulin secretion.

Administration, Oral↗