Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans

1988 ◽  
Vol 254 (3) ◽  
pp. E349-E357 ◽  
Author(s):  
H. Tillil ◽  
E. T. Shapiro ◽  
M. A. Miller ◽  
T. Karrison ◽  
B. H. Frank ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Compartmental Analysis ◽  
Normal Subjects ◽  
Insulin Clearance ◽  
Base Line ◽  
Metabolic Clearance ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Endogenous Insulin ◽  
Normal Humans

Insulin secretion and clearance were studied in 2 groups of 7 normal subjects who each received 25, 50, and 100 g of glucose either orally or intravenously (iv) on separate occasions. Insulin secretion rates were calculated during a 1-h base line and for 5 h after glucose administration from a two-compartmental analysis of peripheral C-peptide concentrations using individual kinetic parameters derived after iv bolus injections of biosynthetic human C-peptide. Incremental glucose areas after oral or iv glucose increased as a function of the glucose dose (P = 0.0001). Incremental insulin secretion increased with increasing doses of both oral and iv glucose (P = 0.0001). The metabolic clearance rate (MCR) of endogenous insulin was calculated as the ratio of the total area under the insulin secretion rate curve and the simultaneous peripheral insulin concentration curve. The basal MCR was 1,879.5 +/- 110.5 ml/min (mean +/- SE). The poststimulatory MCR decreased with increasing doses of both oral and iv glucose concomitant with the greater insulin secretory response (P = 0.0014). This decrease in insulin clearance was not significantly different between oral and iv administration of glucose (P = 0.495). In conclusion diminished insulin clearance may be seen after marked stimulation of insulin secretion with larger doses of oral and iv glucose.

Feedback inhibition by biosynthetic human insulin of insulin release in healthy human subjects

1982 ◽  
Vol 243 (6) ◽  
pp. E476-E482 ◽  
Author(s):  
W. K. Waldhausl ◽  
S. Gasic ◽  
P. Bratusch-Marrain ◽  
A. Korn ◽  
P. Nowotny
Keyword(s):  
Insulin Release ◽  
Human Insulin ◽  
Clearance Rate ◽  
Feedback Inhibition ◽  
Insulin Clearance ◽  
Metabolic Clearance ◽  
C Peptide ◽  
Endogenous Insulin ◽  
Hepatic Insulin Clearance ◽  
Biosynthetic Human Insulin

To determine the impact of biosynthetic human insulin (BHI) on endogenous insulin release, splanchnic output and arterial concentrations of C-peptide were measured in eight healthy men after intravenous administration of 0, 0.5, 1.25, U BHI . m-2 . h-1 for 70 min each. Euglycemia was maintained by a variable glucose infusion. Arterial levels of serum insulin were 48 +/- 6 pmol/liter before and 135 +/- 12, 265 +/- 18, and 593 +/- 47 pmol/liter after BHI infusion. Splanchnic C-peptide output was reduced by BHI infusion from 88 +/- 10 pmol/min before to 50 +/- 9, 28 +/- 10, and 18 +/- 16 pmol/min (P less than 0.0025). Simultaneously, arterial concentrations of C-peptide fell from 539 +/- 54 pmol/liter by 29 and 43% when 1.25 and 2.5 U . m-2 . h-1 of BHI were administered. Hepatic insulin uptake was directly related with BHI infusion rate (r = 0.88) and rose during BHI administration from a basal value of 58 +/- 7 to an uptake of 265 +/- 31 pmol/min when 2.5 U . m-2 . h-1 were infused (P less than 0.0005). Basal hepatic insulin clearance was 4.75 +/- 0.60 ml . kg-1 . min-1 and remained unchanged after BHI infusion as did hepatic fractional extraction of insulin, which was 61 +/- 4% in the basal state. Metabolic clearance rate of immunoreactive insulin (MCRi) was dose-dependently reduced by BHI infusion, whereas the relative share of hepatic insulin clearance in total MCRi rose simultaneously (P less than 0.01). We conclude that feedback inhibition of endogenous insulin release may play an important role in vivo. Furthermore, it appears that nonhepatic insulin degradation is a saturable phenomenon as total MCRi fell in the presence of its unchanged hepatic clearance rate after the infusion of large amounts of BHI.

Twenty-four hour C-peptide and insulin secretion rates and diurnal profiles of glucose, lipids and intermediary metabolites in cirrhosis

1992 ◽  
Vol 83 (5) ◽  
pp. 597-605 ◽  
Author(s):  
Yolanta T. Kruszynska ◽  
Janet Munro ◽  
Philip D. Home ◽  
Neil McIntyre
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Serum Insulin ◽  
Insulin Clearance ◽  
Metabolic Clearance ◽  
Intermediary Metabolites ◽  
C Peptide ◽  
Control Subjects ◽  
Glucose Profiles ◽  
Cirrhotic Patients

1. To examine the contributions of hypersecretion and decreased insulin clearance to the hyperinsulinaemia of cirrhosis, insulin secretion was calculated over the day from serum C-peptide concentrations and C-peptide metabolic clearance rate. The latter was measured during infusions of recombinant human C-peptide. In cirrhotic patients (n = 9) insulin secretion rate was twice that of normal control subjects (n = 10), both in the basal state [02.00–07.00 hours, 15.7 ± 2.1 (mean ± sem) nmol/h (2.6 ± 0.4 units/h) versus 7.0 ± 0.9 nmol/h (1.2 ± 0.2 units/h), P<0.002] and over 24 h [787 ± 93 nmol (132 ± 16 units) versus 346 ± 34 nmol (58 ± 6 units), P<0.001]. However, the area under the serum insulin concentration curve was approximately six times greater in the cirrhotic patients (24 h basal, 6.3 ± 1.0 versus 1.1 ± 0.31 nmol l−1 h, P<0.001; 24 h total, 21.7 ± 3.2 versus 3.7 ± 0.7 nmol l−1 h, P<0.001). Thus, despite impairment of insulin clearance there is continuing hyper-section of insulin in cirrhosis. 2. The relationship of carbohydrate and lipid metabolism with insulin secretion was assessed. In cirrhotic patients, 24 h blood glucose profiles showed a worsening of glucose tolerance over breakfast, despite greater insulin secretion compared with other meals, suggesting that the insulin insensitivity of cirrhosis is worse at this time. 3. Cirrhotic patients showed impaired suppression of blood glycerol levels after meals but normal suppression of serum non-esterified fatty acid concentrations. The greatest differences in the profiles of serum lipids and lipid-related metabolites in cirrhotic patients and control subjects occurred at night. Whereas in control subjects, serum non-esterified fatty acid, blood glycerol and blood 3-hydroxybutyrate concentrations peaked between 01.00 and 03.00 hours, falling gradually thereafter until 08.00 hours, in cirrhotic patients serum non-esterified fatty acid and blood glycerol levels showed a gradual increase during the night to reach maximal levels at 08.00 hours when they were twice those of control subjects (P<0.001). 4. The blood 3-hydroxybutyrate and serum triacyl-glycerol profiles suggested that in cirrhotic patients there was preferential utilization of non-esterified fatty acids for ketogenesis and reduced re-esterification to triacylglycerol.

Sensitivity of insulin secretion to feedback inhibition by hyperinsulinaemia

1981 ◽  
Vol 98 (1) ◽  
pp. 81-86 ◽  
Author(s):  
Ralph A. DeFronzo ◽  
Christian Binder ◽  
John Wahren ◽  
Philip Felig ◽  
Eleuterio Ferrannini ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Plasma Glucose ◽  
Plasma Insulin ◽  
Feedback Inhibition ◽  
Normal Subjects ◽  
Insulin Concentration ◽  
Plasma Insulin Concentration ◽  
C Peptide ◽  
Endogenous Insulin ◽  
Arterial Plasma

Abstract. The ability of insulin to inhibit its own secretion was examined in 15 normal subjects given an intravenous infusion of insulin in a dose of 0.25, 0.50, 1.0, 5.0 or 10.0 mU/kg/min for two hours. Arterial plasma insulin concentration achieved during the infusion segregated into three levels of hyperinsulinaemia: 35 ± 1 (mean ± sem), 87 ± 15 and 828 ± 210 μU/ml. Plasma glucose concentration was kept constant at the basal level by a variable glucose infusion. Fasting C-peptide (0.29 ± 0.02 pmol/ml) fell significantly in all subjects during hyperinsulinaemia and reached a concentration of 0.19 ± 0.03 pmol/ml at 60 min and 0.14 ± 0.03 at 120 min after the start of the insulin infusion. The C-peptide response was not related to the infusion dose nor to the steady state plasma insulin concentration. It is concluded that (a) basal insulin secretion as evaluated from C-peptide measurements is inhibited by small (24 ± 3 μU/ml) physiological elevations in plasma insulin concentration independent of changes in plasma glucose, and (b) supraphysiological or even pharmacological elevations in plasma insulin do not result in a further decrease in endogenous insulin secretion above that achieved with mild hyperinsulinaemia.

scholarly journals Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors

2018 ◽  
Vol 314 (5) ◽  
pp. R639-R646 ◽  
Author(s):  
Andrea Tura ◽  
Roberto Bizzotto ◽  
Yuchiro Yamada ◽  
Yutaka Seino ◽  
Giovanni Pacini ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Clearance ◽  
Second Phase ◽  
Incretin Hormones ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Double Deletion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
First Phase Insulin Secretion

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10−3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10−3 l/min in DIRKO mice vs. 0.54 ± 0.03 10−3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

scholarly journals Variability in Estimated Modelled Insulin Secretion

2021 ◽  
pp. 193229682199112
Author(s):  
Jennifer J. Ormsbee ◽  
Hannah J. Burden ◽  
Jennifer L. Knopp ◽  
J. Geoffrey Chase ◽  
Rinki Murphy ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Kinetic Parameters ◽  
Pancreatic Beta Cells ◽  
Compartment Model ◽  
Interquartile Range ◽  
Cumulative Distribution ◽  
Model Framework ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Model Based

Background: The ability to measure insulin secretion from pancreatic beta cells and monitor glucose-insulin physiology is vital to current health needs. C-peptide has been used successfully as a surrogate for plasma insulin concentration. Quantifying the expected variability of modelled insulin secretion will improve confidence in model estimates. Methods: Forty-three healthy adult males of Māori or Pacific peoples ancestry living in New Zealand participated in an frequently sampled, intravenous glucose tolerance test (FS-IVGTT) with an average age of 29 years and a BMI of 33 kg/m2. A 2-compartment model framework and standardized kinetic parameters were used to estimate endogenous pancreatic insulin secretion from plasma C-peptide measurements. Monte Carlo analysis (N = 10 000) was then used to independently vary parameters within ±2 standard deviations of the mean of each variable and the 5th and 95th percentiles determined the bounds of the expected range of insulin secretion. Cumulative distribution functions (CDFs) were calculated for each subject for area under the curve (AUC) total, AUC Phase 1, and AUC Phase 2. Normalizing each AUC by the participant’s median value over all N = 10 000 iterations quantifies the expected model-based variability in AUC. Results: Larger variation is found in subjects with a BMI > 30 kg/m2, where the interquartile range is 34.3% compared to subjects with a BMI ≤ 30 kg/m2 where the interquartile range is 24.7%. Conclusions: Use of C-peptide measurements using a 2-compartment model and standardized kinetic parameters, one can expect ~±15% variation in modelled insulin secretion estimates. The variation should be considered when applying this insulin secretion estimation method to clinical diagnostic thresholds and interpretation of model-based analyses such as insulin sensitivity.

Development of hyperinsulinemia and insulin resistance during the early stage of weight gain

2008 ◽  
Vol 294 (3) ◽  
pp. E568-E575 ◽  
Author(s):  
Johannes Erdmann ◽  
Bianca Kallabis ◽  
Ulrich Oppel ◽  
Oleg Sypchenko ◽  
Stefan Wagenpfeil ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Weight Gain ◽  
Early Stage ◽  
Normal Range ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Glucose Levels ◽  
Hyperglycemic Clamp ◽  
First Time

Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m2 BMI within 41/2 mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher post-weight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively.

C-Peptide Clearance: Potential Marker of Endogenous Insulin Secretion for Pkpd Studies of Insulin In Neonates

2015 ◽  
Vol 37 (8) ◽  
pp. e59
Author(s):  
E.R. Salis ◽  
M.K. Soelbeck ◽  
D.M. Reith ◽  
B.J. Wheeler ◽  
R.S. Broadbent ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
C Peptide ◽  
Endogenous Insulin Secretion ◽  
Endogenous Insulin ◽  
Potential Marker
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