The relationship between plasma concentration and plasma disappearance rate of immunoreactive insulin in normal subjects

Fugleberg, Steen; Kølendorf, K; Thorsteinsson, Birger; Bliddal, Henning; Lund, B; Bojsen, F

doi:10.1007/bf00282586

Cited by 18 publications

(10 citation statements)

References 8 publications

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“…This approach assumes an approximately linear relationship between insulin concentration and removal rate over the insulin concentration range studied. This assumption has been previously verified by us and others: the MCR for insulin is constant below 150 fiU/ml (10)(11)(12)(13)(14). The plasma glucose level was monitored and maintained between 80 and 90 mg/dl throughout the study period by infusing 20% dextrose at a variable rate adjusted according to glucose measurements made every 5 min.…”

Section: Materials Regular Human Insulin Was Supplied By Lilly (Indimentioning

confidence: 69%

Hyperinsulinemia Does Not Compensate for Peripheral Insulin Resistance in Obesity

Prager¹,

Wallace²,

Olefsky³

1987

Diabetes

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Based on previous steady-state measures of the biologic activity of insulin, it was thought that postprandial hyperinsulinemia in obesity compensated for insulin resistance. However, we recently demonstrated kinetic defects in insulin action in insulin-resistant nondiabetic obese subjects: activation of insulin-stimulated glucose disposal was slower and deactivation was faster in obese than in normal subjects. In view of these kinetic defects in peripheral insulin action and of the fact that insulin is normally secreted in a phasic manner after meals, we postulated that the hyperinsulinemia of obesity does not compensate for insulin resistance and that the abnormal kinetics of insulin action in obesity are functionally important. To test this hypothesis, oral glucose tolerance tests (OGTTs) were performed in five control (mean age, 33 +/- 2 yr) and five obese (mean age, 41 +/- 5 yr) subjects. All controls had normal glucose tolerance; two obese subjects had normal and three had impaired glucose tolerance. After the results of the OGTTs were available, euglycemic clamp studies were performed in which insulin was infused in a phasic stepped fashion to mimic the rise and fall of mean peripheral insulin levels during the OGTTs. Each subject was clamped at both the "normal" and "obese" OGTT insulin profiles. During the OGTT, glucose and insulin levels were significantly elevated in the obese subjects compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Materials Regular Human Insulin Was Supplied By Lilly (Indimentioning

confidence: 69%

Hyperinsulinemia Does Not Compensate for Peripheral Insulin Resistance in Obesity

Prager¹,

Wallace²,

Olefsky³

1987

Diabetes

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“…Since this process is known to be capacity-limited, the overall elimination kinetics of insulin show non-linear characteristics. Although Fugleberg et al (1982) and Morishima et al (1985) demonstrated that the kidney was not responsible for saturable insulin degradation, there is no data for non-saturable clearance of human insulin in rats. Therefore, we analysed the pharmacokinetics of insulin in rats using a conventional saturable elimination kinetics.…”

Section: Non-linear Pharmacokinetics Of Insulinmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modelling of human insulin: validity of pharmacological availability as a substitute for extent of bioavailability

Miyazaki

Mukai

Iwanaga

et al. 2001

Journal of Pharmacy and Pharmacology

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A method for assessing the extent of bioavailability (EBA) of human insulin from pharmacological data was determined. The time course governing increases in the plasma concentration of immuno-reactive insulin (IRI), as well as its pharmacological effects (glucodynamics), was determined after the intravascular administration of varying doses of human insulin. Pharmacokinetic (PK), pharmacodynamic (PD), and link models were constructed to elucidate the quantitative relationship between plasma IRI levels and pharmacological effects. After extravascular administration of the test formulation, only the time course governing the observed pharmacological effects was determined. The pharmacological data was translated into theoretical plasma concentration data, using the PK-PD model. Following this, the area under the theoretical plasma concentration-time curve (AUC) of the test formulation was calculated. The EBA was then estimated against a reference (intravascular) formulation, using a conventional equation. Since the pharmacological effects of insulin were observed to be highly dosing-rate-dependent, the PD model used in this study was modified to apply over a wide range of infusion rates. The results of the PK-PD analysis indicate that the doses administered can be accurately predicted from pharmacological data. To validate this method, the EBAs of controlled release formulations (the Osmotic Mini Pumps) of insulin, subcutaneously administered to the rat, were estimated. The EBA values obtained (92-96%) fell within a reasonable range. The area under the effect-time curves (AUE) obtained following subcutaneous applications of the Osmotic Mini Pump were calculated in a model-independent manner, in addition to pharmacological availabilities (PA), which were estimated against the reference (intravascular) formulations. The estimated PA values varied from 312% to 78%, in accordance with the intravascular input rates of the reference formulations. This indicates that PA should not be used as a substitute for EBA, unless data involving similar intravascular dosing rates to that of the reference formulations is available.

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“…Flakoll PJ, Wentzel LS, Rice DE, Hill JO and Abumrad NN [42] quantify the insulin-dependent whole body glucose uptake corresponding to c 1 ≈ 0.06 (pM min) −1 . Information about insulin clearance is given by [43] resulting in c 2 ≈ 1.4 min −1 . This yields the fixed parameter values c = ( c 1, c 2 ) = (0.06, 1.4) ⊤ .…”

Section: Methodsmentioning

confidence: 99%

Linking neuronal brain activity to the glucose metabolism

Göbel

Oltmanns

Chung

2013

Theor Biol Med Model

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BackgroundEnergy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis.MethodsFirst, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism.ResultsOur examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis.ConclusionsThe hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.

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The relationship between plasma concentration and plasma disappearance rate of immunoreactive insulin in normal subjects

Cited by 18 publications

References 8 publications

Hyperinsulinemia Does Not Compensate for Peripheral Insulin Resistance in Obesity

Hyperinsulinemia Does Not Compensate for Peripheral Insulin Resistance in Obesity

Pharmacokinetic-pharmacodynamic modelling of human insulin: validity of pharmacological availability as a substitute for extent of bioavailability

Linking neuronal brain activity to the glucose metabolism

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