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G M Steil

Publications and source records attributed to G M Steil.

35 records · Page 2Linked to original sources
PubMed1996

Transendothelial insulin transport is not saturable in vivo. No evidence for a receptor-mediated process.

In vitro, insulin transport across endothelial cells has been reported to be saturable, suggesting that the transport process is receptor mediated. In the present study, the transport of insulin across capillary endothelial cells was investigated in vivo. Euglycemic glucose clamps were performed in anesthetized dogs (n = 16) in which insulin was infused to achieve concentrations in the physiological range (1.0 mU/kg per min + 5 mU/kg priming bolus; n = 8) or pharmacologic range (18 mU/kg per min + 325 mU/kg priming bolus; n = 8). Insulin concentrations were measured in plasma and hindlimb lymph derived from interstitial fluid (ISF) surrounding muscle. Basal plasma insulin concentrations were twice the basal ISF insulin concentrations and were not different between the physiologic and pharmacologic infusion groups (plasma/ISF ratio 2.05 +/- 0.22 vs 2.05 +/- 0.23; p = 0.0003). The plasma/ISF gradient was, however, significantly reduced at steady-state pharmacologic insulin concentrations (1.37 +/- 0.25 vs 1.98 +/- 0.21; P = 0.0003). The reduced gradient is opposite to that expected if transendothelial insulin transport were saturable. Insulin transport into muscle ISF tended to increase with pharmacologic compared with physiologic changes in insulin concentration (41% increase; 1.37 +/- 0.18 10(-2) to 1.93 +/- 0.24 10(-2) min-1; P = 0.088), while at the same time insulin clearance out of the muscle ISF compartment was unaltered (2.53 +/- 0.26 10(-2) vs 2.34 +/- 0.28 10(-2) min-1; P = 0.62). Thus, the reduced plasma/ISF gradient at pharmacologic insulin was due to enhanced transendothelial insulin transport rather than changes in ISF insulin clearance. We conclude that insulin transport is not saturable in vivo and thus not receptor mediated. The increase in transport efficiency with saturating insulin is likely due to an increase in diffusionary capacity resulting from capillary dilation or recruitment.

Animals↗
PubMed1996

Extracellular glucose distribution is not altered by insulin: analysis of plasma and interstitial L-glucose kinetics.

We examined the effects of insulin on leg blood flow, whole body extracellular glucose distribution, and glucose diffusion into the interstitial fluid (ISF) surrounding skeletal muscle cells in anesthetized dogs. Extracellular glucose distribution and glucose diffusion into the muscle ISF were assessed by studying the kinetics of L-[1-14C]glucose in plasma and hindlimb lymph. Femoral artery blood flow was not increased with insulin (7.9 +/- 0.7 vs. 7.1 +/- 1.4 ml.min-1.kg-1; P = 0.54). Plasma and lymph dynamics of L-glucose after intravenous administration were superimposable between saline and insulin infusion experiments, indicating that insulin did not affect L-glucose disappearance from plasma or appearance in muscle ISF. Plasma L-glucose kinetics were best described by a four-compartment model, and one of the remote pools (intermediate) predicted the lymph L-glucose dynamics well. Estimation of maximum glucose diffusion capacity indicated that this pool, rather than the slowest pool, represents insulin-sensitive tissues. In conclusion, our data indicate that insulin does not increase transcapillary glucose diffusion to insulin-sensitive cells. In addition, hindlimb lymph represents primarily skeletal muscle ISF, which is represented by an intermediate, rather than the slowest, remote pool from whole body compartmental analysis.

3-O-Methylglucose↗
PubMed1995

OOPSEG: a data smoothing program for quantitation and isolation of random measurement error.

We describe a data smoothing program, OOPSEG, which automatically quantitates and filters the random measurement error in a given data series. The measurement error is initially guessed, and the Optimal Segments technique is used to filter a corresponding amount of variation from the data, thus generating a relatively smooth curve. The residuals about this smooth curve are tested for serial correlation. If correlation is detected, a new measurement error is guessed, and the data are filtered again. This process continues until a smooth curve has been found for which the residuals do not exhibit serial correlation. Such residuals represent the random component of the data, i.e. (presumably) the measurement error. The corresponding smooth curve thus approximates the original, error-free curve. The smooth curve and the estimated coefficient of variation of the data are returned. OOPSEG handles end effects by performing an expansion of the data set, smoothing this expanded data set, then deleting the artificial points before assembling the final, smooth curve. Also, data may be smoothed as a sequence of independent regions to accommodate time courses with known changes in experimental conditions. We suggest that OOPSEG may have numerous applications in data analysis and experimental design.

Algorithms↗
PubMed1995

Assessment of extracellular glucose distribution and glucose transport activity in conscious rats.

The effects of insulin on extracellular glucose distribution and cellular glucose transport activity were studied by simultaneously analyzing the plasma kinetics of L-[1-14C]glucose and 3-O-[3H]methylglucose after an intravenous injection during saline or insulin infusion (euglycemic glucose clamp) in conscious rats (n = 7 for each). The time profiles of plasma L-glucose were almost superimposable in the two protocols, and compartmental analysis showed that neither distribution volumes nor distribution rate constants were affected with insulin (P > 0.05 for all), suggesting that glucose distribution within the extracellular space was not influenced with insulin. In contrast, the time profile of plasma 3-O-methylglucose (3-MG) was markedly altered with insulin; the initial decrease was much faster during insulin infusion than during saline infusion, indicating stimulation of 3-MG transport into intracellular spaces with insulin. The 3-MG data were analyzed using a comprehensive model separately describing extracellular distribution and cellular transport of 3-MG by incorporating information on extracellular distribution kinetics obtained from L-glucose data. The combined L-glucose and 3-MG kinetic analysis precisely estimated insulin's effect in vivo to stimulate glucose transport into and out of intracellular spaces. We conclude that 1) insulin does not affect extracellular glucose distribution kinetics or volumes in conscious rats and 2) insulin's effects on cellular glucose transport in vivo can be assessed by simultaneous analysis of plasma L-glucose and 3-MG kinetics.

3-O-Methylglucose↗
PubMed1995

Insulin sensitivity accounts for glucose and lactate kinetics after intravenous glucose injection.

Mathematical modeling was used to explore the interaction between glucose, insulin, and lactate during the frequently sampled intravenous glucose tolerance test (FSIGTT). Insulin-modified FSIGTs were performed in 25 lean volunteers, and an additional 5 volunteers underwent FSIGTs with glucose injection alone to illustrate the effect of insulin on both glucose and lactate kinetics. The model chosen as the best representation of the system extended the minimal model of glucose kinetics (MM) by including a two-compartment model of lactate kinetics. The model accounted for both glucose and lactate kinetics, provided traditional MM parameters of insulin sensitivity and glucose effectiveness, and descriptive parameters of lactate kinetics. Modeling suggested that lactate production was limited by the rate of glucose disappearance, with no indication of direct effects of insulin on lactate. Inclusion of lactate kinetics had no adverse effect on MM parameters (SG: 0.023 +/- 0.009 vs. 0.023 +/- 0.010 min-1, SI: 1.01 +/- 0.70 vs. 1.03 +/- 0.71 x 10(4).min-1.pmol-1.1; P > 0.50, lactate model vs. MM), and indicated that approximately 1.2% min-1 of total glucose disappearance during the FSIGT is converted to lactate. An additional benefit of including lactate kinetics was the significant improvement in precision in MM parameter estimates as reflected by the fractional standard deviations (FSDs). This effect was most prominent for SG, in which a threefold improvement in parameter precision was observed (FSD: 13.5 +/- 3.1 vs. 42.5 +/- 48.5; means +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin.

Overproduction of glucose by the liver in the face of insulin resistance is a primary cause of hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). However, mechanisms involved in control of hepatic glucose output (HGO) remain less than clear, even in normal individuals. Recent results have supported an indirect extrahepatic effect of insulin as the primary locus of insulin action to restrain HGO. One suggested extrahepatic site is the pancreatic alpha-cell. To examine whether insulin's extrahepatic site is independent of the alpha-cells, HGO suppression was examined independent of changes in glucagon secretion or insulin antagonism of glucagon action. Euglycemic glucose clamps (n = 40) with somatostatin infusion were performed in conscious dogs (n = 5). Paired experiments were conducted in which insulin was infused either portally (1.2, 3.0, 6.0 pmol.min-1.kg-1) or peripherally at half the portal infusion rate (0.6, 1.5, 3.0 pmol.min-1.kg-1). Additional zero and saturating portal-dose experiments (100 pmol.min-1.kg-1) were also performed. For the paired experiments, portal insulin infusion resulted in portal insulin concentrations approximately two to three times higher than in the corresponding peripheral insulin infusion experiments, while at the same time peripheral insulin concentrations were approximately matched. Equal peripheral insulin concentration resulted in equivalent HGO suppression irrespective of the portal concentrations. Thus, insulin affects a signal at a peripheral site, other than alpha-cell, that in turn suppresses hepatic glucose production. To investigate the nature of this signal, we measured alanine, lactate, and free fatty acids (FFAs).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1994

Repeatability of insulin sensitivity and glucose effectiveness from the minimal model. Implications for study design.

To determine the repeatability of insulin sensitivity measurements generated by the minimal model, we subjected 11 normal men to 3 frequently sampled intravenous glucose tolerance tests (FSIGTs) over the course of 12 days under conditions of fixed diet and limited physical activity. FSIGTs were analyzed by the minimal model using a full, 30-sample data set, as well as a reduced, 12-sample data set that has been proposed for population studies. Minimal model insulin sensitivity index (SI) calculated from the 30-sample data set averaged 0.8 +/- 0.083 x 10(-4) min-1.(pmol/l)-1 (range 0.10-1.64 x 10(-4) min-1.(pmol/l)-1 with an average interday coefficient of variation (CV) of 20.2 +/- 3.2% (range 6-44%). Glucose effectiveness (SG) was slightly less repeatable, with an average interday variability of 25.1 +/- 8.8%. The mean CVs for first-phase insulin secretion (20.1 +/- 3.5%) and total insulin secretion (21.4 +/- 3.2%) were similar to the CV for SI. Mean insulin sensitivity calculated from the 12-sample data set (0.82 +/- 0.08 x 10(-4) min-1.(pmol/l)-1 was not significantly different from the mean calculated from the full data set (P = 0.37, paired Student's t test). However, the mean CV of SI calculated from the reduced data set tended to be greater than that calculated from the full data set (27.7 +/- 5.4% vs. 20.2 +/- 3.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Dynamics of glucose production and uptake are more closely related to insulin in hindlimb lymph than in thoracic duct lymph.

We previously reported a striking similarity between the dynamics of both glucose turnover and thoracic duct lymph insulin during euglycemic clamps (J Clin Invest 84:1620, 1989), which suggested that transendothelial insulin transport (TET) is rate-limiting for insulin action in vivo. Thoracic duct lymph, however, is primarily derived from insulin-insensitive tissues, which raises questions as to the physiological significance of this relationship. The relationship between glucose turnover and TET was thus examined in insulin-sensitive tissues by the simultaneous measurement of insulin in plasma, thoracic duct lymph, and hindlimb lymph during euglycemic clamps in normal anesthetized dogs (n = 8). Clamps consisted of two 3-h phases: a 0.6 mU.min-1.kg-1 insulin infusion (activation phase) followed by termination of the insulin infusion (deactivation phase). Lymph insulin was less than plasma insulin during both phases (P < 0.01) with steady-state hindlimb (120 +/- 12 pM) and thoracic duct lymph insulin (138 +/- 12 pM) 38 and 45%, respectively, lower than steady-state plasma insulin (222 +/- 24 pM) at the end of the activation phase (P < 0.05). Also, the rate of increase of lymph insulin was slower than plasma insulin during hormone infusion; half-time to steady-state was 8.8 +/- 2.0 min for plasma insulin, but longer for thoracic (25.8 +/- 3.5) and hindlimb lymph insulin (40.7 +/- 5.7 min). A very close relationship was observed during activation between the rate of increase of glucose uptake (Rd) and the increase in hindlimb lymph insulin (r2 = 0.92); this relationship was weaker for thoracic lymph (r2 = 0.74) and much weaker between glucose uptake and plasma insulin (r2 = 0.35). These data support the concept that interstitial insulin (represented by hindlimb lymph) is the signal that determines glucose uptake by insulin-sensitive tissues and that the rate of increase of glucose uptake is determined by transendothelial insulin transport into insulin-sensitive tissue. Also, during activation, hindlimb lymph insulin was a very strong predictor of the rate of suppression of hepatic glucose output (HGO) (r2 = 0.96), and the correlation with HGO was stronger than that for thoracic lymph (r2 = 0.85). The evidence that the rate of increase of Rd and the rate of suppression of HGO during insulin infusion are very strongly predicted by the time course of insulin in hindlimb lymph is consistent with the single-gateway hypothesis: the insulin transport rate across endothelium in insulin-sensitive tissue (skeletal muscle) determines the rate of glucose utilization and the suppression of hepatic glucose output.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗
PubMed1993

Quantitation of measurement error with Optimal Segments: basis for adaptive time course smoothing.

We introduce a novel technique for estimating measurement error in time courses and other continuous curves. This error estimate is used to reconstruct the original (error-free) curve. The measurement error of the data is initially assumed, and the data are smoothed with "Optimal Segments" such that the smooth curve misses the data points by an average amount consistent with the assumed measurement error. Thus the differences between the smooth curve and the data points (the residuals) are tentatively assumed to represent the measurement error. This assumption is checked by testing the residuals for randomness. If the residuals are nonrandom, it is concluded that they do not resemble measurement error, and a new measurement error is assumed. This process continues reiteratively until a satisfactory (i.e., random) group of residuals is obtained. In this case the corresponding smooth curve is taken to represent the original curve. Monte Carlo simulations of selected typical situations demonstrated that this new method ("OOPSEG") estimates measurement error accurately and consistently in 30- and 15-point time courses (r = 0.91 and 0.78, respectively). Moreover, smooth curves calculated by OOPSEG were shown to accurately recreate (predict) original, error-free curves for a wide range of measurement errors (2-20%). We suggest that the ability to calculate measurement error and reconstruct the error-free shape of data curves has wide applicability in data analysis and experimental design.

Animals↗
PubMed1993

Reduced sample number for calculation of insulin sensitivity and glucose effectiveness from the minimal model. Suitability for use in population studies.

The FSIGT has been extensively applied to the minimal model of glucose kinetics to obtain noninvasive measures of Sl. The protocol has been modified by the addition of a bolus tolbutamide or insulin injection 20 min after glucose. Although the modified protocol has improved the Sl estimate, the method still requires a relatively large number of samples (n = 30). To reduce the total number of samples, we choose a sample schedule that minimizes the variance of the parameter estimates and the error in reconstructing the plasma insulin profile. With data from 10 subjects (BMI 30 +/- 7 kg/m2; Sl 0.9-10.2 x 10(-4) min-1.microU-1 x ml-1), a schedule consisting of 12 samples (0, 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 min) was obtained. Estimates of Sl obtained from the reduced sampling schedule were then compared with those obtained with the full sampling schedule. In all 10 individuals, the Sl estimates were almost identical. A second, much larger data base consisting of 118 modified FSIGTs performed in 87 subjects (67 men, 20 women; BMI from 19.6 to 40 kg/m2 for men and 26.7 to 52.5 for women; Sl from 0.35 to 14.1 x 10(-4) min-1 x microU-1 x ml-1) was then used to independently assess the efficacy of the reduced sampling protocol. For this data base, the correlation between Sl, which was calculated from the full versus the reduced sampling schedule, was 0.95. The mean relative deviation was -1.5% (not significantly different from zero), and the SD of the relative deviation was 20.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Thoracic duct lymph. Relative contribution from splanchnic and muscle tissue.

We have shown previously that thoracic duct lymph insulin dynamics are well correlated with tracer-determined whole-body glucose uptake and have suggested that thoracic duct lymph insulin is representative of insulin concentration in muscle interstitial fluid. However, thoracic duct lymph is comprised of interstitial fluid from all sub-thoracic tissue beds. To investigate the relative contribution of muscle interstitial fluid to total thoracic duct lymph flow, the distribution and elimination of [14C]inulin was investigated in eight experiments with conscious dogs. Both plasma and thoracic duct lymph were measured, and a three-compartment model that was hypothesized to consist of plasma, splanchnic interstitial fluid, and muscle interstitial fluid was identified. Identifications were performed with either a bolus protocol (n = 4) or an infusion protocol (n = 4), and the predicted [14C]inulin dynamics in the splanchnic and muscle interstitial fluid compartments were compared with measured values in thoracic duct lymph. Neither compartment predicted the thoracic duct [14C]inulin dynamics; however, a model based on a percentage contribution from each tissue bed fit the thoracic data well. The relative contribution of splanchnic interstitial fluid to the total thoracic duct lymph flow averaged 78 +/- 5% for the bolus protocol and 54 +/- 5% for the infusion protocol. Thus, we conclude that in the conscious animal, approximately 25-50% of thoracic duct lymph originates from muscle interstitial fluid.

Animals↗
PubMed1991

Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport.

To study the route by which plasma insulin enters cerebrospinal fluid (CSF), the kinetics of uptake from plasma into cisternal CSF of both insulin and [14C]inulin were analyzed during intravenous infusion in anesthetized dogs. Four different mathematical models were used: three based on a two-compartment system (transport directly across the blood-CSF barrier by nonsaturable, saturable, or a combination of both mechanisms) and a fourth based on three compartments (uptake via an intermediate compartment). The kinetics of CSF uptake of [14C]inulin infused according to an "impulse" protocol were accurately accounted for only by the nonsaturable two-compartment model (determination coefficient [R2] = 0.879 +/- 0.044; mean +/- SEM; n = 5), consistent with uptake via diffusion across the blood-CSF barrier. When the same infusion protocol and model were used to analyze the kinetics of insulin uptake, the data fit (R2 = 0.671 +/- 0.037; n = 10) was significantly worse than that obtained with [14C]inulin (P = 0.02). Addition of a saturable component of uptake to the two-compartment model improved this fit, but was clearly inadequate for a subset of insulin infusion studies. In contrast, the three-compartment model accurately accounted for CSF insulin uptake in each study, regardless of infusion protocol (impulse infusion R2 = 0.947 +/- 0.026; n = 10; P less than 0.0001 vs. each two-compartment model; sustained infusion R2 = 0.981 +/- 0.003; n = 5). Thus, a model in which insulin passes through an intermediate compartment en route from plasma to CSF, as a part of a specialized transport system for the delivery of insulin to the brain, best accounts for the dynamics of this uptake process. This intermediate compartment could reside within the blood-CSF barrier or it may represent brain interstitial fluid, if CNS insulin uptake occurs preferentially across the blood-brain barrier.

Animals↗
PubMed1988

Underlying neural computations for some visual phenomena.

In this paper we examine how a large array of neurons, and their associated neural circuitry, may determine known receptive field profile types and some well-known visual phenomena including Mach bands, edge enhancement, and visual masking of one signal by another. The neural model has a spatio-temporal structure and is described by a nonlinear integropartial differential difference equation with an isotropic Gabor kernel - a Gaussian apertured cosine modulation. Several simulations are presented.

Computer Simulation↗
PubMed1987

On the identification of neural responses.

The most common form of measuring electrical responses of nerve cells is the recording of a given cell's "spike train" profile to the parameters of a given input signal. In this paper we consider the conditions under which it is possible to relate such response measures to the properties of the cell's underlying activity characteristics, the neural network, and the input signal.

Mathematics↗
PubMed1986

Control mechanisms of a neural network.

In this paper we consider some classical control theoretic properties of a nonlinear neural network proposed by Oğuztöreli (1979) to represent the activities of constituent neurones in terms of the input signals and coupling (associative) properties. By breaking the network into linear and nonlinear components we have been able to localize the nonlinearities in the individual neural response latencies through the system.

Animals↗
PubMedDate not supplied

Improved vascularization of planar membrane diffusion devices following continuous infusion of vascular endothelial growth factor.

Improving blood vessel formation around an immunobarrier device should improve the survival of the encapsulated tissue. In the present study we investigated the formation of new blood vessels around a planar membrane diffusion device (the Baxter Theracyte System) undergoing a continuous infusion of vascular endothelial growth factor through the membranes and into the surrounding tissue. Each device (20 microl) had both an inner immunoisolation membrane and an outer vascularizing membrane. Human recombinant vascular endothelial growth factor-165 was infused at 100 ng/day (low dose: n = 6) and 500 ng/day (high dose: n = 7) for 10 days into devices implanted s.c. in Sprague-Dawley rats; noninfused devices transplanted for an identical period were used as controls (n = 5). Two days following the termination of VEGF infusion, devices were loaded with 20 microl of Lispro insulin (1 U/kg) and the kinetics of insulin release from the lumen of the device was assessed. Devices were then explanted and the number of blood vessels (capillary and noncapillary) was quantified using morphometry. High-dose vascular endothelial growth factor infusion resulted in two- to threefold more blood vessels around the device than that obtained with the noninfused devices and devices infused with low-dose vascular endothelial growth factor. This increase in the number of blood vessels was accompanied by a modest increase in insulin diffusion from the device in the high-dose vascular endothelial growth factor infusion group. We conclude that vascular endothelial growth factor can be used to improve blood vessel formation adjacent to planar membrane diffusion devices.

Animals↗