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.

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.

Mechanism, temporal patterns, and magnitudes of the metabolic responses to the KATP channel agonist diazoxide

2005 ◽  
Vol 288 (1) ◽  
pp. E80-E85 ◽  
Author(s):  
Bharathi Raju ◽  
Philip E. Cryer
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Plasma Glucose ◽  
Plasma Insulin ◽  
Temporal Patterns ◽  
Metabolic Responses ◽  
Nonesterified Fatty Acid ◽  
Nonesterified Fatty Acids ◽  
C Peptide

To assess the mechanism, temporal patterns, and magnitudes of the metabolic responses to the ATP-dependent potassium channel agonist diazoxide, neuroendocrine and metabolic responses to intravenous diazoxide (saline, 1.0 and 2.0 mg/kg) and oral diazoxide (placebo, 4.0 and 6.0 mg/kg) were assessed in healthy young adults. Intravenous diazoxide produced rapid, but transient, decrements ( P = 0.0023) in plasma insulin (e.g., nadirs of 2.8 ± 0.5 and 1.8 ± 0.3 μU/ml compared with 7.0 ± 1.0 μU/ml after saline at 4.0–7.5 min) and C-peptide ( P = 0.0228) associated with dose-related increments in plasma glucose ( P = 0.0044) and serum nonesterified fatty acids ( P < 0.0001). After oral diazoxide, plasma insulin appeared to decline, as did C-peptide, again associated with dose-related increments in plasma glucose ( P < 0.0001) and serum nonesterified fatty acids ( P = 0.0141). Plasma glucagon, as well as cortisol and growth hormone, was not altered. Plasma epinephrine increased ( P = 0.0215) slightly only after intravenous diazoxide. There were dose-related increments in plasma norepinephrine ( P = 0.0038 and P = 0.0005, respectively), undoubtedly reflecting a compensatory sympathetic neural response to vasodilation produced by diazoxide, but these would not raise plasma glucose or serum nonesterified fatty acid levels. Thus selective suppression of insulin secretion, without stimulation of glucagon secretion, raised plasma glucose and serum nonesterified fatty acid concentrations. These findings define the temporal patterns and magnitudes of the metabolic responses to diazoxide and underscore the primacy of regulated insulin secretion in the physiological regulation of postabsorptive carbohydrate and lipid metabolism.

Forearm Glucose Uptake in Cirrhosis and Its Relationship to Glucose Tolerance

1980 ◽  
Vol 59 (3) ◽  
pp. 191-198 ◽  
Author(s):  
B. A. Leatherdale ◽  
R. A. Chase ◽  
J. Rogers ◽  
K. G. M. M. Alberti ◽  
P. Davies ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Serum Insulin ◽  
Oral Glucose ◽  
Glucose Load ◽  
Peripheral Tissues ◽  
Insulin Levels ◽  
Glucose Levels ◽  
Control Subjects ◽  
Cirrhotic Patients

1. Oral glucose-tolerance tests (100 g) were carried out in six patients with stable well-compensated cryptogenic cirrhosis and in 12 control subjects. 2. In confirmation of previous studies, patients with cirrhosis had high post-glucose serum insulin levels and were glucose intolerant (mean incremental glucose area 954 ± 186 compared with 482 ± 35 mmol 3 h−11−1 in controls; P<0.05) 3. Forearm arteriovenous differences of glucose and forearm blood flows were measured to estimate the proportion of the glucose load metabolized in peripheral tissues. Values in cirrhotic patients and control subjects (5614 ± 1630 compared with 5344 ± 672 μmol of glucose min−11−1 of forearm in 3 h) were similar despite higher glucose levels and sustained high insulin levels in the cirrhotic patients. 4. Peak lactate concentrations after glucose were of similar magnitude in the two groups (0.66 ± 0.12 compared with 0.62 ± 0.75 mmol/l) but in the patients with cirrhosis the peak occurred later and was more sustained. 5. The glucose intolerance of cirrhosis is primarily due to impaired hepatic retention of the glucose load. Insulin resistance in peripheral tissues-5-also be important since the higher insulin concentrations found in cirrhotic patients failed to enhance peripheral glucose uptake.

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 Fasting insulin reflects heterogeneous physiological processes: role of insulin clearance

2011 ◽  
Vol 301 (2) ◽  
pp. E402-E408 ◽  
Author(s):  
Mark O. Goodarzi ◽  
Jinrui Cui ◽  
Yii-Der I. Chen ◽  
Willa A. Hsueh ◽  
Xiuqing Guo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Waist Circumference ◽  
Mexican Americans ◽  
Fasting Glucose ◽  
Insulin Clearance ◽  
Oral Glucose ◽  
Metabolic Clearance ◽  
Insulinogenic Index ◽  
Fasting Insulin

Several processes contribute to variation in fasting insulin concentration, including fasting glucose, insulin resistance, insulin secretion, and insulin clearance. Our goal was to determine the relative contribution of each of these insulin-related traits, plus anthropometric parameters, to fasting insulin among 470 Mexican Americans. The euglycemic hyperinsulinemic clamp yielded insulin sensitivity (M value) and metabolic clearance rate of insulin (MCRI). Acute insulin secretion was estimated by the insulinogenic index (IGI30) from the oral glucose tolerance test. Regression (univariate) and generalized estimating equations (multivariate) were used to describe the relationship of insulin-related traits to fasting insulin. Univarate analyses were used to select which traits to include in the multivariate model. In multivariate analysis, MCRI, M, BMI, waist circumference, and fasting glucose were independently associated with fasting insulin. Decreasing M and MCRI were associated with increasing fasting insulin, whereas increasing BMI, waist circumference, and fasting glucose were associated with increasing fasting insulin. Standardized coefficients allowed determination of the relative strength of each trait's association with fasting insulin in the entire cohort (strongest to weakest): MCRI (−0.35, P < 0.0001), M (−0.24, P < 0.0001), BMI (0.20, P = 0.0011), waist circumference (0.16, P = 0.021), and fasting glucose (0.11, P = 0.014). Fasting insulin is a complex phenotype influenced by several independent processes, each of which might have its own environmental and genetic determinants. One of the most associated traits was insulin clearance, which has implications for studies that have used fasting insulin as a surrogate for insulin resistance.

scholarly journals Inhibition of Ghrelin Activity by Receptor Antagonist [d-Lys-3] GHRP-6 Attenuates Alcohol-Induced Hepatic Steatosis by Regulating Hepatic Lipid Metabolism

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 517 ◽  
Author(s):  
Karuna Rasineni ◽  
Jacy L. Kubik ◽  
Carol A. Casey ◽  
Kusum K. Kharbanda
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Receptor Antagonist ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Serum Insulin ◽  
Acid Uptake ◽  
Hepatic Lipid ◽  
Insulin Levels

Alcoholic steatosis, characterized by an accumulation of triglycerides in hepatocytes, is one of the earliest pathological changes in the progression of alcoholic liver disease. In our previous study, we showed that alcohol-induced increase in serum ghrelin levels impair insulin secretion from pancreatic β-cells. The consequent reduction in the circulating insulin levels promote adipose-derived fatty acid mobilization to ultimately contribute to hepatic steatosis. In this study, we determined whether inhibition of ghrelin activity in chronic alcohol-fed rats could improve hepatic lipid homeostasis at the pancreas–adipose–liver axis. Adult Wistar rats were fed Lieber-DeCarli control or an ethanol liquid diet for 7 weeks. At 6 weeks, a subset of rats in each group were injected with either saline or ghrelin receptor antagonist, [d-Lys-3] GHRP-6 (DLys; 9 mg/kg body weight) for 5 days and all rats were sacrificed 2 days later. DLys treatment of ethanol rats improved pancreatic insulin secretion, normalized serum insulin levels, and the adipose lipid metabolism, as evidenced by the decreased serum free fatty acids (FFA). DLys treatment of ethanol rats also significantly decreased the circulating FFA uptake, de novo hepatic fatty acid synthesis ultimately attenuating alcoholic steatosis. To summarize, inhibition of ghrelin activity reduced alcoholic steatosis by improving insulin secretion, normalizing serum insulin levels, inhibiting adipose lipolysis, and preventing fatty acid uptake and synthesis in the liver. Our studies provided new insights on the important role of ghrelin in modulating the pancreas–adipose–liver, and promoting adipocyte lipolysis and hepatic steatosis. The findings offer a therapeutic approach of not only preventing alcoholic liver injury but also treating it.

Role of gastric inhibitory polypeptide in postprandial hyperinsulinemia of obesity

1988 ◽  
Vol 254 (6) ◽  
pp. E767-E774 ◽  
Author(s):  
L. R. Roust ◽  
M. Stesin ◽  
V. L. Go ◽  
P. C. O'Brien ◽  
R. A. Rizza ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Kinetic Model ◽  
Healthy Subjects ◽  
Gastric Inhibitory Polypeptide ◽  
Volume Of Distribution ◽  
Insulin Clearance ◽  
C Peptide ◽  
Obese Subjects ◽  
Secretion Rates

To assess the contribution of gastric inhibitory polypeptide (GIP) to the postprandial hyperinsulinemia of obesity, secretion rates of GIP (generated from kinetic analyses from infusions of porcine GIP) and insulin (from C-peptide applied to a validated kinetic model) to meals of 3 sizes were determined in 10 obese (5 male and 5 female) and 10 lean, sex- and age-matched healthy subjects. Although the postprandial secretion rates of GIP were greater in obese subjects (P = 0.03), postprandial concentrations of GIP were not. The latter may be explained by the greater volume of distribution of GIP in obese subjects (P = 0.036). Secretion rates and volume of distribution of GIP were correlated (r = 0.652, P less than 0.01). Despite excessive integrated postprandial (P = 0.010) insulin concentrations, insulin secretion was not significantly different between obese and lean subjects. We conclude that 1) although postprandial plasma GIP concentrations are normal, GIP secretion is increased in obesity, 2) the postprandial hyperinsulinemia of obesity is not due to excessive insulin secretion but is likely secondary to altered insulin clearance, and 3) GIP cannot account for the hyperinsulinemia of obesity through its insulinotropic action.

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