Inhibition by proinsulin of endogenous C-peptide release in healthy man

To determine the role of proinsulin on endogenous insulin release, splanchnic output and arterial concentrations of C-peptide were measured in healthy subjects before and during infusion of human (HPI) and porcine (PPI) proinsulin at increasing rates for 70 min each (HPI, 328 and 656 micrograms X m-2 X h-1; PPI, 54, 134, and 268 micrograms/m-2 X h-1), while euglycemia was maintained by variable glucose infusion. By using this approach splanchnic C-peptide output was reduced by human proinsulin infusion from 143 +/- 16 (mean +/- SE) pmol/min to 111 +/- 18 and 75 +/- 11 pmol/min (P = 0.01). Simultaneously, arterial concentrations of C-peptide decreased from 716 +/- 40 pmol/l by 23 and 32%. Similar inhibition was induced by porcine PPI of splanchnic C-peptide output at an infusion rate of 268 micrograms X m-2 X h-1. Mean metabolic clearance rate was 2.7 and 3.7 ml X kg-1 X min-1 for HPI and PPI, respectively. Splanchnic glucose output was almost completely suppressed by human and porcine proinsulin at maximal infusion rates. This effect preceded both inhibition by proinsulin of splanchnic C-peptide output and stimulation of peripheral glucose utilization. We conclude that human and porcine proinsulin suppress endogenous insulin secretion at pharmacological concentrations. The observed constancy of the metabolic clearance rate of HPI demonstrates that its clearance remains a nonsaturable process up to supraphysiological HPI concentrations, while clearance of PPI appears to be subject to saturation. Furthermore, it appears that splanchnic glucose output responds earlier to proinsulin exposure than suppression of C-peptide release or stimulation of peripheral glucose utilization.

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Glucoregulation during rest and exercise in depancreatized dogs: role of the acute presence of insulin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.262.5.e574 ◽

1992 ◽

Vol 262 (5) ◽

pp. E574-E582 ◽

Cited By ~ 2

Author(s):

D. H. Wasserman ◽

J. L. Bupp ◽

J. L. Johnson ◽

D. Bracy ◽

D. B. Lacy

Keyword(s):

Insulin Sensitivity ◽

Plasma Glucose ◽

Clearance Rate ◽

Glucose Utilization ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

Rest And Exercise

To determine the effects of the presence of insulin in poorly controlled diabetes, depancreatized (PX) dogs (n = 5) were studied during rest and 150 min of exercise in paired experiments in which saline alone was infused (IDEF) and in which insulin was replaced intraportally (200 microU.kg-1.min-1) with glucose clamped at the levels in IDEF (IR+G). PX dogs (n = 4) were also studied with insulin, but glucose was allowed to fall (IR). Insulin was not detectable, 6 +/- 1 and 6 +/- 2 microU/ml in IDEF, IR+G, and IR. Plasma glucose was 470 +/- 47, 480 +/- 48, and 372 +/- 35 mg/dl at rest in IDEF, IR+G, and IR, respectively. Levels were unchanged with exercise in IDEF and IR+G, but fell by 139 +/- 13 mg/dl in IR. Basal glucose rate of appearance (Ra) was 7.0 +/- 0.9, 1.3 +/- 1.1, and 6.0 +/- 0.7 mg.kg-1.min-1 in IDEF, IR+G, and IR, respectively. Exercise elicited a rise in Ra in only IDEF. The rises in Rd and metabolic clearance rate in IDEF were reduced (delta 2.6 +/- 0.7 and delta 0.8 +/- 0.3 ml.kg-1.min-1 at 150 min) compared with IR+G (delta 5.3 +/- 1.9 and delta 1.7 +/- 0.2 ml.kg-1.min-1 at 150 min) and IR (delta 3.7 +/- 1.2 and delta 2.4 +/- 0.8 ml.kg-1.min-1). The insulin sensitivity of glucose utilization (Rd) was elevated by approximately 75% at 150 min. Basal glycerol was similar in IDEF and IR but was reduced by approximately 70% in IR+G. Glycerol rose similarly with exercise in IDEF and IR.(ABSTRACT TRUNCATED AT 250 WORDS)

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1982.243.6.e476 ◽

1982 ◽

Vol 243 (6) ◽

pp. E476-E482 ◽

Cited By ~ 2

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.

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Ingestion of a Mixed Meal Does Not Affect the Metabolic Clearance Rate of Biosynthetic Human C-Peptide*

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem-63-2-401 ◽

1986 ◽

Vol 63 (2) ◽

pp. 401-403 ◽

Cited By ~ 32

Author(s):

J. LICINIO-PAIXAO ◽

K. S. POLONSKY ◽

B. D. GIVEN ◽

W. PUGH ◽

D. OSTREGA ◽

...

Keyword(s):

Clearance Rate ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

Mixed Meal ◽

C Peptide

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SECRETION RATE AND METABOLIC CLEARANCE RATE OF PROLACTIN IN THE RAT DURING MID- AND LATE LACTATION

Journal of Endocrinology ◽

10.1677/joe.0.0820409 ◽

1979 ◽

Vol 82 (3) ◽

pp. 409-415 ◽

Cited By ~ 9

Author(s):

C. E. GROSVENOR ◽

N. S. WHITWORTH

Keyword(s):

Plasma Concentration ◽

Clearance Rate ◽

Secretion Rate ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

Urethane Anaesthesia ◽

Plateau Level ◽

Stimulation Of

The prolactin concentration in the plasma of lactating rats rose less rapidly and attained a significantly lower plateau level in response to suckling on day 20–21 of lactation than it did on day 13–14 of lactation. Neither differences in suckling stimulation of the older pups nor a higher metabolic clearance rate (MCR) of prolactin were implicated in the reduced prolactin concentration seen in the late-lactating rats. The MCR was, in fact, slightly reduced in both conscious and late-lactating rats anaesthetized with urethane when compared with those in mid-lactation. The MCR of prolactin was not significantly altered by urethane anaesthesia in rats on either day of lactation. However, the secretion rate of prolactin, computed from the MCR multiplied by the equilibrum concentration of prolactin during suckling, was considerably reduced (665 to 392 ng/min) from mid- to late lactation. We conclude from these data that the reduced plasma concentration of prolactin in response to suckling in late lactation is the result of an impairment within the prolactin secretory mechanism.

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Fish-oil supplementation reduces stimulation of plasma glucose fluxes during exercise in untrained males

British Journal Of Nutrition ◽

10.1079/bjn2003964 ◽

2003 ◽

Vol 90 (4) ◽

pp. 777-786 ◽

Cited By ~ 20

Author(s):

Jacques Delarue ◽

Francois Labarthe ◽

Richard Cohen

Keyword(s):

Fish Oil ◽

Lipid Oxidation ◽

Olive Oil ◽

Plasma Glucose ◽

Clearance Rate ◽

Carbohydrate Oxidation ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

Fish Oil Supplementation ◽

Stimulation Of

The present study examined the effects of a 3-week fish-oil supplementation (6 g/d) on the rate of plasma glucose disappearance (Rd glucose), hepatic glucose production (HGP), carbohydrate oxidation and lipid oxidation during exercise. Six untrained males (23±1 years; 67·6±2·7kg) performed two 90min cycling exercise sessions at 60% of maximal O2 output separated by 20 d. During the 20 d before the first test, they ingested 6g olive oil/d, then 6g fish oil/d during the 20 d before the second test. Plasma glucose fluxes and lipolysis were traced using 6,6-[2H2]glucose and 1,1,2,3,3-[2H5]glycerol respectively. Substrates oxidation was obtained from indirect calorimetry. At rest HGP and the Rd glucose were similar after olive oil and fish oil (1.83 (se 0·05) v. 1·67 (se 0·11) mg/kg per min). During exercise, fish oil reduced the stimulation of both the Rd glucose (5·06 (se 0·23) v. 6·37 (se 0·12) mg/kg per min; P<0·05) and HGP (4·88 (se 0·24) v. 5·91 (se 0·21) mg/kg per min; P<0·05). Fish oil also reduced glucose metabolic clearance rate (6·93 (se 0·29) v. 8·30 (se 0·57) ml/min). Carbohydrate oxidation tended to be less stimulated by exercise after fish oil than after olive oil (12·09 (se 0·60) v. 13·86 (se 1·11) mg/kg per min; NS). Lipid oxidation tended to be more stimulated by exercise after fish oil (7·34 (se 0·45) v. 6·85 (se 0·17) mg/kg per min; NS). Glycaemia, lactataemia, insulinaemia and glucagonaemia were similarly affected by exercise after fish oil and olive oil. Lipolysis at rest was similar after fish oil and olive oil (2·92 (se 0·42) v. 2·94 (se 0·28) μmol/kg per min) and similarly stimulated by exercise (6·42 (se 0·75) v. 6·77 (se 0·72) μmol/kg per min). It is concluded that fish oil reduced the Rd glucose by 26% by reducing glucose metabolic clearance rate, possibly by facilitating fat oxidation, and reduced HGP by 21%, possibly by a feedback mechanism.

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Ketone body turnover during and after exercise in overnight-fasted and starved humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1983.245.4.e318 ◽

1983 ◽

Vol 245 (4) ◽

pp. E318-E325 ◽

Cited By ~ 7

Author(s):

F. Fery ◽

E. O. Balasse

Keyword(s):

Clearance Rate ◽

Ketone Body ◽

Turnover Rate ◽

Ketone Bodies ◽

Sharp Contrast ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

Initial Degree ◽

Stimulation Of ◽

Marked Drop

The concentration of ketone bodies and their rate of transport (estimated with an infusion of beta-[14C]-hydroxybutyrate) were determined before, during, and after exercise in overnight-fasted and 3- to 5-day-fasted subjects who walked on a treadmill for 2 h at approximately 50% of their VO2max. In overnight-fasted subjects, exercise increased the rate of turnover (+125% after 2 h) and the metabolic clearance rate of ketone bodies whose concentration rose from 0.20 to 0.39 mM. Discontinuation of exercise was associated with a marked increase in ketone levels (+0.73 mM after 30 min of recovery) that was related to a further stimulation of ketogenesis (+19%) and to a marked drop of the metabolic clearance rate to below preexercise values. In sharp contrast with overnight-fasted subjects, starved subjects (with a resting ketone level averaging 5.7 mM) responded to work by a decrease in the turnover rate and in the concentration of ketones, their metabolic clearance rate remaining unchanged. Thus, the response of ketogenesis and muscular ketone uptake to exercise are both markedly influenced by the initial degree of fasting ketosis.

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Hepatic glycerol flux after E. coli endotoxin administration

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1984.247.4.r687 ◽

1984 ◽

Vol 247 (4) ◽

pp. R687-R692 ◽

Cited By ~ 1

Author(s):

O. P. McGuinness ◽

J. J. Spitzer

Keyword(s):

Blood Flow ◽

Clearance Rate ◽

Arterial Blood Flow ◽

Metabolic Clearance ◽

Hepatic Glucose Output ◽

Metabolic Clearance Rate ◽

Endotoxin Administration ◽

Arterial Blood ◽

Hepatic Glucose ◽

Glucose Output

Hepatic glycerol flux was examined in dogs after the administration of Escherichia coli endotoxin (0.4 mg/kg) to determine the contribution of the liver to the previously observed decline in the metabolic clearance rate of glycerol. Hepatic glycerol flux was estimated by determining hepatic arterial and portal venous blood flows with electromagnetic flow probes and by measuring arteriovenous difference of glycerol across the liver. Administration of endotoxin significantly decreased total hepatic blood flow (by approximately 20%) but did not alter hepatic arterial blood flow. Hepatic glycerol clearance decreased by 25–30% after endotoxin administration. Hepatic glycerol extraction also decreased. Under control conditions, 60% of the metabolic clearance rate of glycerol was attributable to the liver, whereas in the postendotoxin state approximately 72% of the glycerol clearance could be accounted for by hepatic clearance. Thus changes in transhepatic glycerol flux are only partially responsible for the previously observed alterations in glycerol clearance after endotoxin administration. Although hepatic glycerol clearance decreased, net hepatic glycerol, as well as lactate and alanine, uptake did not decrease, indicating that gluconeogenic precursor availability to the hepatocytes was not diminished. Hepatic glucose output was elevated after endotoxin administration. Changes in hepatic glucose output and gluconeogenic precursor uptake help explain the endotoxin-induced alternations in the fluxes of these metabolites.

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Splanchnic Glucose Production and its Regulation in Healthy Monozygotic Twins of Diabetics

Clinical Science ◽

10.1042/cs0440493 ◽

1973 ◽

Vol 44 (5) ◽

pp. 493-504 ◽

Cited By ~ 6

Author(s):

J. Wahren ◽

P. Felig ◽

E. Cerasi ◽

R. Luft ◽

Rosa Hendler

Keyword(s):

Glucose Utilization ◽

Monozygotic Twins ◽

Glucose Production ◽

Endogenous Insulin ◽

Site Of Action ◽

Insulin Dependent ◽

The Mean ◽

Small Increments ◽

Glucose Output ◽

Stimulation Of

1. Splanchnic exchange of glucose, lactate, pyruvate, glycerol and individual plasma amino acids was determined in five clinically unaffected monozygotic twins of insulin-dependent diabetics and in a group of five age- and sex-matched controls. The studies were performed in the postabsorptive state and after stimulation of endogenous insulin secretion by the intravenous infusion of glucose at a rate of 2 mg/min per kg for 45 min. 2. In the basal state the mean splanchnic glucose output was 25% lower for the twins than for the controls while splanchnic uptake of glucose precursors was similar in the two groups. The concentration of circulating insulin (which rose by no more than 10–15 μunits/ml in either group) was lower during the infusion in the twins than in the controls. Despite the lower insulin concentrations, infusion of glucose resulted in a complete shut off of splanchnic glucose production in the twins, while in the controls only a 50% inhibition of basal glucose output was observed. In both the twins and controls estimated peripheral glucose utilization was unchanged during the glucose infusion. 3. It is concluded that: (a) in clinically unaffected identical twins of known diabetics basal splanchnic glucose production is reduced while uptake of glucose precursors is unchanged, suggesting a diminished contribution to basal glucose output from hepatic glycogenolytic processes; (b) in the twins as well as in controls, the liver is the primary site of action of small increments in endogenous insulin; (c) hepatic sensitivity to endogenous insulin is augmented in twins as compared with controls.

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