GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve

2001 ◽  
Vol 281 (2) ◽  
pp. E242-E247 ◽  
Author(s):  
Andreas Brandt ◽  
Martin Katschinski ◽  
Rudolf Arnold ◽  
Kenneth S. Polonsky ◽  
Burkhard Göke ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Insulin Clearance ◽  
Constant Infusion ◽  
Independent Effect ◽  
High Dose ◽  
Β Cell ◽  
Normal Volunteers

The present study was undertaken to establish in normal volunteers the alterations in β-cell responsiveness to glucose associated with a constant infusion of glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min. A high-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels by use of a two-compartmental model that utilized mean kinetic parameters. During the saline study, from 5 to 15 mM glucose, the relationship between glucose and ISR was linear. Constant GLP-1 infusion (0.4 pmol · kg−1 · min−1) shifted the dose-response curve to the left, with an increase in the slope of this curve from 5 to 9 mM glucose from 71.0 ± 12.4 pmol · min−1 · mM−1during the saline study to 241.7 ± 36.6 pmol · min−1 · mM−1 during the constant GLP-1 infusion ( P < 0.0001). GLP-1 consistently stimulated a >200% increase in ISR at each 1 mM glucose interval, maintaining plasma glucose at <10 mM ( P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant priming of the β-cell response to glucose ( P = 0.2). Insulin clearance rates were similar in all three studies at corresponding insulin levels. These studies demonstrate that physiological levels of GLP-1 stimulate glucose-induced insulin secretion in a linear manner, with a consistent increase in ISR at each 1 mM glucose interval, and that they have no independent effect on insulin clearance and no priming effect on subsequent insulin secretory response to glucose.

Insulin secretion and clearance during low-dose graded glucose infusion

1995 ◽  
Vol 268 (1) ◽  
pp. E21-E27 ◽  
Author(s):  
M. M. Byrne ◽  
J. Sturis ◽  
K. S. Polonsky
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Dose Response ◽  
Response Curve ◽  
Low Dose ◽  
Compartment Model ◽  
Glucose Infusion ◽  
Dose Response Curve ◽  
Intravenous Glucose ◽  
Normal Volunteers

The present study was undertaken in normal volunteers to define the alterations in beta-cell responsiveness to glucose associated with different physiological states, including fasting and refeeding, and after prolonged intravenous glucose infusion. A low-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels using a two-compartment model utilizing individual kinetic parameters. From 5 to 9 mmol/l glucose, the relationship between glucose and ISR was linear. After a 42-h glucose infusion at a rate of 4 mg.kg-1.min-1, the ISR increased by 53% over the same glucose concentration range (P < 0.002), resulting in a shift of the dose-response curve to the left. Insulin clearance rates decreased 27% after the 42-h glucose infusion (P < 0.001). After a 72-h fast, ISR decreased by 32% from baseline over the 5-8 mmol/l glucose range (P = 0.056), resulting in a shift of the dose-response curve to the right. This shift was reversed by a 42-h period of refeeding, after which ISR was increased by 77% compared with the fasting study (P < 0.02). Refeeding enhanced the beta-cell responsiveness, and ISR increased by 31% after refeeding compared with the baseline study (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of islet neurotransmitter sensitivity following ventromedial hypothalamic lesion

1983 ◽  
Vol 244 (5) ◽  
pp. R635-R640 ◽  
Author(s):  
L. A. Campfield ◽  
F. J. Smith
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Dose Response ◽  
Response Curve ◽  
Pancreatic Beta Cell ◽  
Dose Response Curve ◽  
Norepinephrine Dose ◽  
Increased Sensitivity ◽  
The Right ◽  
Glucose Responsiveness

Recent studies suggest that alterations in autonomic neural activity may mediate the obese state observed following ventromedial hypothalamic (VMH) lesion. To assess the role of these alterations in the increased glucose responsiveness of the beta-cell observed in this state, we have determined the sensitivity of insulin secretion to norepinephrine or/and acetylcholine in statically incubated pancreatic islets from rats 30-40 days after VMH lesion. In islets from VMH-lesioned rats compared with islets from sham-operated and intact rats, the acetylcholine dose-response curve was shifted down and to the right, indicating a decreased sensitivity, whereas the norepinephrine dose-response curve was translated to the left, indicating an increased sensitivity. The interaction profile, which summarizes combined neurotransmitter exposure on insulin secretion, was shifted in the direction of net inhibition. Thus it was concluded that, following VMH lesion, autonomic neurotransmitter sensitivity of the pancreatic beta-cell was altered. It is suggested that these alterations play a role in the adaptation of the beta-cell to the experimentally induced obese state.

scholarly journals Excess-substrate inhibition in enzymology and high-dose inhibition in pharmacology: a reinterpretation

1994 ◽  
Vol 298 (1) ◽  
pp. 171-180 ◽  
Author(s):  
P W Kühl
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Substrate Inhibition ◽  
Recovery Process ◽  
Pulse Generation ◽  
Dose Response Curve ◽  
Hill Coefficient ◽  
High Dose ◽  
Recovery Model ◽  
Operation Cycle

A kinetic model, called the Recovery Model, which incorporates an obligatory recovery phase of fixed duration (tr) in the operation cycle of a macromolecule (enzyme, receptor) is proposed. Binding of a ligand (substrate, agonist) during tr disturbs the recovery process and causes inhibition (substrate inhibition, agonist autoinhibition). A quantitative stochastic analysis of a minimal version of the Recovery Model reveals that (1) plotting the response versus the logarithm of the ligand concentration never yields a strictly symmetrical bell-shaped dose-response curve, (2) the position and shape of the descent of the dose-response curve can vary greatly in dependence of the kinetic parameters of the system, and (3) a minimal steepness of the descent with a Hill coefficient of 1 exists provided that the response can be totally inhibited by high ligand concentrations. The Recovery Model is equally applicable to macromolecules that can bind single or multiple ligands, and suggests new ways to explain such diverse phenomena as partial agonism, pulse generation, desensitization, memory effects and ultrasensitivity. In addition, substrate inhibition and agonist autoinhibition are regarded as phenomena closely related to other kinds of non-Michaelian behaviour because of a common temporal mechanism, namely the temporal interference of arriving ligand molecules with timing-sensitive phases of the operation cycle.

Dose-response relationships in chemical carcinogenesis reflect differences in individual susceptibility. Consequences for cancer risk assessment, extrapolation, and prevention

1999 ◽  
Vol 18 (12) ◽  
pp. 707-712 ◽  
Author(s):  
W K Lutz
Keyword(s):  
Cancer Risk ◽  
Dose Response ◽  
Response Curve ◽  
Human Cancer ◽  
Tumor Formation ◽  
Dose Response Curve ◽  
Cancer Risk Assessment ◽  
High Dose ◽  
Exposure Level ◽  
Homogeneous Population

The shape of the dose-cancer incidence curve observed in an animal bioassay for carcinogenicity of a chemical is the result of a superposition of various mechanisms contributing to the process of carcinogenesis. For genotoxic carcinogens, for instance, a sublinear (convex; up-bent) shape could be the result of a saturation of DNA repair or of a higher rate of cell turnover associated with high-dose cytotoxicity and regenerative hyperplasia. In human cancer epidemiology, the situation is more complex. The human population is very heterogeneous with respect to both genetic and life-style factors that modulate the process of tumor formation. Therefore, individuals are expected to show widely variable susceptibility to carcinogenic factors, and the dose-response curve is in fact a reflection of the tolerance distribution. Each modulating factor divides the population up into sub populations of different susceptibility so that nonlinearities that could be present in a homogeneous population are flattened out. A linear extrapolation of a human cancer risk to low dose might therefore be appropriate under certain conditions even if the dose-response curve in animals has a strongly sigmoidal shape. For cancer prevention, the investigation of susceptibility factors is expected to be of great value. The elimination of concurrent risk factors in high-risk subpopulations or individuals might be more effective than a minor general reduction of a tolerable exposure level.

Dose-response in the treatment of breast cancer: a critical review.

1988 ◽  
Vol 6 (9) ◽  
pp. 1501-1515 ◽  
Author(s):  
I C Henderson ◽  
D F Hayes ◽  
R Gelman
Keyword(s):  
Breast Cancer ◽  
Dose Response ◽  
Response Curve ◽  
Drug Dose ◽  
Dose Response Curve ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Tumor Type ◽  
High Dose Therapy ◽  
Dose Therapy

In animal tumor models the dose-response curve for cytotoxic agents, especially cyclophosphamide, may be steep, but the slope and shape of this curve depends not only on the drug used but on the schedule of drug administration, the specific tumor type, tumor cell kinetics, and tumor mass. It might be anticipated from these studies that the human tumors most sensitive to dose effects would be leukemia, lymphoma, small-cell carcinoma of the lung, and testicular tumors rather than the low growth fraction, relatively less responsive tumors such as breast cancer. However, the clinical evidence for a steep dose-response curve in any tumor type is limited. For breast cancer such evidence is largely retrospective or derived from uncontrolled trials. The data available from randomized trials makes it seem unlikely that small, or even moderate, reductions in drug dose for nontrivial reasons will compromise the survival of patients with either early or metastatic disease. In spite of promising data from small trials, there is, as yet, inadequate evidence to justify the use of very-high-dose therapy and autologous marrow transplant outside the setting of a well-designed clinical trial. The value of high-dose therapy, intensive dose rate, and cumulative drug dose should each be studied in randomized controlled trials.

scholarly journals Assessing the maximum limit of SAR-OSL dating using quartz of different grain sizes

2018 ◽  
Vol 45 (1) ◽  
pp. 146-159 ◽  
Author(s):  
Valentina Anechitei-Deacu ◽  
Alida Timar-Gabor ◽  
Daniela Constantin ◽  
Oana Trandafir-Antohi ◽  
Laura Del Valle ◽  
...  
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Dose Range ◽  
Osl Dating ◽  
Dose Response Curve ◽  
High Dose ◽  
Response Curves ◽  
Grain Sizes ◽  
Coarse Grains ◽  
Dose Response Curves

Abstract SAR-OSL dating studies of Romanian, Serbian and Chinese loess using fine and coarse quartz have previously resulted in a series of controversial issues. We extend here the investigations using fine (4–11 μm) and different coarse quartz (>63 μm) grains extracted from aeolianites from a site on Eivissa Island (southwestern Mediterranean). Aeolianites were chosen since they contain quartz from a different geological context and have significantly lower environmental dose rates. The dose response curves of the OSL signals for fine and coarse quartz are similar to those for loess and are also represented by the sum of two saturating exponential functions. For doses up to ~200 Gy, the dose response curves of fine and coarse grains from aeolianites can be superimposed and the ages obtained for the different grain sizes are in agreement up to ~250 ka, increasing our confidence in the accuracy of the ages obtained for samples with such doses, irrespective of the magnitude of the environmental dose rate. Particularly for the fine quartz fraction, a mismatch between the SAR dose response curve and the dose response curve obtained when doses are added to the natural is reported, indicating that the application of the SAR protocol in the high dose range is problematic. This dose dependent deviation is much less pronounced for coarse grains. Thus, it seems reasonable to infer that the dose response curves for the coarse grains, although saturating earlier can be regarded as more reliable for equivalent dose calculation than those for the fine grains.

OVARIAN ASCORBIC ACID DEPLETION TEST FOR LUTEINIZING HORMONE

1967 ◽  
Vol 56 (4) ◽  
pp. 619-625 ◽  
Author(s):  
Hans Jacob Koed ◽  
Christian Hamburger
Keyword(s):  
Ascorbic Acid ◽  
Luteinizing Hormone ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Human Origin ◽  
Response Curves ◽  
Significant Difference ◽  
The Mean ◽  
Different Levels

ABSTRACT Comparison of the dose-response curves for LH of ovine origin (NIH-LH-S8) and of human origin (IRP-HMG-2) using the OAAD test showed a small, though statistically significant difference, the dose-response curve for LH of human origin being a little flatter. Two standard curves for ovine LH obtained with 14 months' interval, were parallel but at different levels of ovarian ascorbic acid. When the mean ascorbic acid depletions were calculated as percentages of the control levels, the two curves for NIH-LH-S8 were identical. The use of standards of human origin in the OAAD test for LH activity of human preparations is recommended.

HYPERTROPHIC ADRENALS AND THEIR RESPONSE TO STRESS AFTER LESIONS IN THE MEDIAN EMINENCE OF TOTALLY HYPOPHYSECTOMIZED PIGEONS

1961 ◽  
Vol 37 (4) ◽  
pp. 565-576 ◽  
Author(s):  
Richard A. Miller
Keyword(s):  
Dose Response ◽  
Median Eminence ◽  
Response Curve ◽  
Liver Parenchyma ◽  
Dose Response Curve ◽  
Pars Distalis ◽  
Adrenal Enlargement ◽  
Response To Stress ◽  
Lethal Doses ◽  
Chromaffin Tissue

ABSTRACT Four per cent formaldehyde, insulin, or epinephrine in oil was injected for 5 days into pigeons subjected to varying degrees of hypophysectomy alone or together with large lesions in the median eminence and hypothalamus. Adrenals atrophied after the removal of the pars distalis alone or together with the neurohypophysis in untreated pigeons but showed markedly hypertrophic interrenal tissue (cortex in mammals) after treatment with formaldehyde or insulin. The slope of the dose-response curve was similar in operated and unoperated pigeons. The accumulation of bile in the liver parenchyma, which may occur after removal of the pars distalis, is an endogenous stress which was associated regularly with adrenal hypertrophy. After very large lesions of the median eminence and ventral hypothalamus in addition to total hypophysectomy, adrenals hypertrophied rather than atrophied, and the response to formaldehyde paralleled that in intact and »hypohysectomized« pigeons. Interrenal tissue was stimulated regularly; chromaffin tissue was partially degranulated, sometimes showed hyperplasia with colchicine, but only occasionally appeared hypertrophied. Epinephrine in nearly lethal doses caused only minimal adrenal enlargement. After adrenal denervation followed by hypophysectomy, the adrenals were still stimulated by formaldehyde. It appears that the interrenal tissue of the pigeon responds to a humoral stimulus not of hypophyseal origin in the absence of the hypophyseal-hypothalamic system.

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