Indomethacin and salicylate modulate effect of insulin on glucose kinetics in dogs

1985 ◽  
Vol 248 (6) ◽  
pp. E648-E655 ◽  
Author(s):  
J. D. Miller ◽  
S. Ganguli ◽  
M. A. Sperling
Keyword(s):  
Insulin Infusion ◽  
Sodium Salicylate ◽  
Specific Activity ◽  
Serum Insulin ◽  
Glucose Production ◽  
Saline Control ◽  
Base Line ◽  
Similar Extent ◽  
Modulate Effect ◽  
Experimental Animals

We studied insulin's effects on glucose production (Ra) and utilization (Rd) in trained, conscious dogs before and during treatment with indomethacin (Indo) and salicylate (S). Ra and Rd (mg X kg-1 X min-1) were calculated by isotope dilution using [3-3H]glucose. Animals were treated with either oral Indo or acetylsalicylic acid for 1 day before the respective studies. On the study day, experimental animals were given a continuous infusion of either saline (control), Indo (5 mg/kg bolus followed by 0.05 mg X kg-1 X min-1), or sodium salicylate (0.45 mg X kg-1 X min-1) for 330 min on separate days; each animal participated in all three protocols. After establishing steady-state specific activity, control (C) and experimental animals (n = 6/group) received insulin, 0.275 mU X kg-1 X min-1 for 150 min, raising serum insulin levels two- to threefold above basal. During insulin infusion in C, plasma glucose (G) fell from 99 +/- 2 to 82 +/- 6 ml/dl (P less than 0.01), associated with a transient fall in Ra from 2.5 +/- 0.3 to 1.9 +/- 0.2 (P less than 0.01) at 30 min, returning to base line at 45 min; Rd did not change. In the Indo and S groups, G also fell by a similar extent. In contrast to C, however, the fall in G was associated with a rise in Rd, commencing at 30 min in the Indo group (P less than 0.05) and at 45 min in the S group (P less than 0.01); Ra did not fall and actually rose above basal (P less than 0.05), although it did not match the rise in Rd.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin regulation of renal glucose metabolism in humans

1999 ◽  
Vol 276 (1) ◽  
pp. E78-E84 ◽  
Author(s):  
Eugenio Cersosimo ◽  
Peter Garlick ◽  
John Ferretti
Keyword(s):  
Glucose Metabolism ◽  
Insulin Infusion ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Saline Infusion ◽  
Saline Control ◽  
Control Group ◽  
Renal Gluconeogenesis ◽  
Endogenous Glucose

Eighteen healthy subjects had arterialized hand and renal veins catheterized after an overnight fast. Systemic and renal glucose and glycerol kinetics were measured with [6,6-2H2]glucose and [2-13C]glycerol before and after 180-min peripheral infusions of insulin at 0.125 (LO) or 0.25 (HI) mU ⋅ kg−1 ⋅ min−1with variable [6,6-2H2]dextrose or saline (control). Renal plasma flow was determined by plasma p-aminohippurate clearance. Arterial insulin increased from 37 ± 8 to 53 ± 5 (LO) and to 102 ± 10 pM (HI, P < 0.01) but not in control (35 ± 8 pM). Arterial glucose did not change and averaged 5.2 ± 0.1 (control), 4.7 ± 0.2 (LO), and 5.1 ± 0.2 (HI) μmol/ml; renal vein glucose decreased from 4.8 ± 0.2 to 4.5 ± 0.2 μmol/ml (LO) and from 5.3 ± 0.2 to 4.9 ± 0.1 μmol/ml (HI) with insulin but not saline infusion (5.3 ± 0.1 μmol/ml). Endogenous glucose production decreased from 9.9 ± 0.7 to 6.9 ± 0.5 (LO) and to 5.7 ± 0.5 (HI) μmol ⋅ kg−1 ⋅ min−1; renal glucose production decreased from 2.5 ± 0.6 to 1.5 ± 0.5 (LO) and to 1.2 ± 0.6 (HI) μmol ⋅ kg−1 ⋅ min−1, whereas renal glucose utilization increased from 1.5 ± 0.6 to 2.6 ± 0.7 (LO) and to 2.9 ± 0.7 (HI) μmol ⋅ kg−1 ⋅ min−1after insulin infusion (all P < 0.05 vs. baseline). Neither endogenous glucose production (10.0 ± 0.4), renal glucose production (1.1 ± 0.4), nor renal glucose utilization (0.8 ± 0.4) changed in the control group. During insulin infusion, systemic gluconeogenesis from glycerol decreased from 0.67 ± 0.05 to 0.18 ± 0.02 (LO) and from 0.60 ± 0.04 to 0.20 ± 0.02 (HI) μmol ⋅ kg−1 ⋅ min−1( P < 0.01), and renal gluconeogenesis from glycerol decreased from 0.10 ± 0.02 to 0.02 ± 0.02 (LO) and from 0.15 ± 0.03 to 0.09 ± 0.03 (HI) μmol ⋅ kg−1 ⋅ min−1( P < 0.05). In contrast, during saline infusion, systemic (0.66 ± 0.03 vs. 0.82 ± 0.05 μmol ⋅ kg−1 ⋅ min−1) and renal gluconeogenesis from glycerol (0.11 ± 0.02 vs. 0.41 ± 0.04 μmol ⋅ kg−1 ⋅ min−1) increased ( P < 0.05 vs. baseline). We conclude that glucose production and utilization by the kidney are important insulin-responsive components of glucose metabolism in humans.

Elevated postprandial insulin levels do not induce satiety in normal-weight humans

1984 ◽  
Vol 247 (4) ◽  
pp. R745-R749 ◽  
Author(s):  
R. Woo ◽  
H. R. Kissileff ◽  
F. X. Pi-Sunyer
Keyword(s):  
Food Intake ◽  
Test Meal ◽  
Plasma Insulin ◽  
Insulin Infusion ◽  
Serum Insulin ◽  
Insulin Level ◽  
Normal Weight ◽  
Base Line ◽  
Glucose Levels ◽  
Postprandial Insulin

To determine whether an elevated insulin level contributes to satiety, two experiments were conducted using a covert system of monitoring food intake. Normal-weight volunteers received intravenous infusion of either 0.15 M saline or a mixture of glucose and insulin during a single-course meal. In the first group, the glucose-insulin infusion (0.03 U insulin X kg-1 X h-1 and 0.25 g glucose X kg-1 X h-1) was begun 30 min before the start of the test meal and ended 15 min after subjects had voluntarily stopped eating. Plasma insulin was raised threefold, and glucose increased 20 mg/dl above preinfusion base line at time of eating. In the second group, the glucose-insulin mixture (insulin bolus of 12 mU/kg plus 0.03 U insulin X kg-1 X h-1 and 0.125 g glucose X kg-1 X h-1) was delivered 12 min after an appetizer was served and just as the test meal began. This infusion was stopped 12 min after the end of the meal. Serum insulin was fourfold higher than saline infusion levels at onset of eating, but glucose remained the same. The changes induced in these studies by the glucose-insulin infusions mimicked normal insulin and glucose levels seen shortly before satiation is complete in a meal. No effect on meal size or duration was observed. Therefore normal postprandial elevation of insulin is unlikely to signal satiety in humans.

Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects

1988 ◽  
Vol 118 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Ole Schmitz
Keyword(s):  
Insulin Resistance ◽  
Insulin Infusion ◽  
Serum Insulin ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Peripheral Tissues ◽  
Endogenous Glucose

Abstract. To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU·kg−1·min−1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU·kg−1·min−1 sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16,22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates ([3−3H]glucose) in uraemic patients compared with controls (P < 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 ± 1.0 versus 1.4 ± 0.3 (mean ± 1 sd), −0.3 ± 0.7 versus 0.7 ± 0.3, and −1.1 ± 0.7 versus 0.2 ± 0.6 mg·kg−1·min−1; P < 0.05, P < 0.01 and P < 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 ± 0.3 versus 2.2 ± 0.6 mg·kg−1·min−1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above ≈30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng·kg−1·min−1, respectively, for 210 min concomitant with somatostatin (125 μg/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 ± 0.8 versus 4.8 ± 1.0 mg·kg−1·min−1; P < 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.

Physiological insulin action is opposed by beta-adrenergic mechanisms in dogs

1988 ◽  
Vol 255 (1) ◽  
pp. E33-E40 ◽  
Author(s):  
G. A. Werther ◽  
S. Joffe ◽  
R. Artal ◽  
M. A. Sperling
Keyword(s):  
Insulin Infusion ◽  
Glucose Production ◽  
Beta Blockade ◽  
Base Line ◽  
Adrenergic Blockade ◽  
Hormonal Changes ◽  
Beta Adrenergic ◽  
Adrenergic Mechanisms ◽  
Alpha Blockade

To investigate the possible role of adrenergic mechanisms in modulating glucose homeostasis during physiological insulin changes, we studied the effects of alpha-, beta-, or combined alpha- and beta-adrenergic blockade on glucose production (Ra) and utilization (Rd) via isotope ([3-(3)H]glucose) dilution during nonstressful, nonhypoglycemic conditions in response to physiological insulin changes in conscious dogs. Without adrenergic blockade, infusion of insulin at 0.275 mU.kg-1.min-1 (control) caused glucose to fall from 92 +/- 4 to 82 +/- 4 mg/dl over 30 min, because of transient fall in Ra from 2.8 +/- 0.4 to 2.3 +/- 0.3 mg.kg-1.min-1, which recovered to base line by 30 min. There was a later rise in Rd to 3.9 +/- 0.4 mg.kg-1.min-1 at 45 min, but no counter-regulatory hormonal changes (glucagon, cortisol, epinephrine, and norepinephrine) to account for these findings in glucose kinetics. alpha-Blockade alone led to an initial rise in base-line insulin and consequent fall in glucose, associated with a transient fall in Ra but no change in Rd; infusion of insulin led to a further small fall in glucose, with no change in Ra, but with a rise at 30 min in Rd similar to controls. beta-Blockade alone led to an initial fall in insulin and modest rise in glucose; insulin infusion led to a greater rate of fall in glucose than in controls (from 112 +/- 6 to 78 +/- 7 mg/dl over 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of gluconeogenesis in sustaining glucose production during hypoglycemia caused by continuous insulin infusion in conscious dogs

Diabetes ◽  
1988 ◽  
Vol 37 (6) ◽  
pp. 749-759 ◽  
Author(s):  
R. T. Frizzell ◽  
G. K. Hendrick ◽  
D. W. Biggers ◽  
D. B. Lacy ◽  
D. P. Donahue ◽  
...  
Keyword(s):  
Insulin Infusion ◽  
Glucose Production ◽  
Conscious Dogs ◽  
Continuous Insulin Infusion

scholarly journals The Irs1 Branch of the Insulin Signaling Cascade Plays a Dominant Role in Hepatic Nutrient Homeostasis

2009 ◽  
Vol 29 (18) ◽  
pp. 5070-5083 ◽  
Author(s):  
Shaodong Guo ◽  
Kyle D. Copps ◽  
Xiaocheng Dong ◽  
Sunmin Park ◽  
Zhiyong Cheng ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
High Fat Diet ◽  
Insulin Infusion ◽  
Dominant Role ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
High Fat ◽  
Lipogenic Genes ◽  
Hepatic Glucose ◽  
Nutrient Homeostasis

ABSTRACT We used a Cre-loxP approach to generate mice with varied expression of hepatic Irs1 and Irs2 to establish the contribution of each protein to hepatic nutrient homeostasis. While nutrient-sensitive transcripts were expressed nearly normally in liver lacking Irs2 (LKO2 mice), these transcripts were significantly dysregulated in liver lacking Irs1 (LKO1 mice) or Irs1 and Irs2 together (DKO mice). Similarly, a set of key gluconeogenic and lipogenic genes was regulated nearly normally by feeding in liver retaining a single Irs1 allele without Irs2 (DKO/1 mice) but was poorly regulated in liver retaining one Irs2 allele without Irs1 (DKO/2 mice). DKO/2 mice, but not DKO/1 mice, also showed impaired glucose tolerance and insulin sensitivity—though both Irs1 and Irs2 were required to suppress hepatic glucose production during hyperinsulinemic-euglycemic clamp. In contrast, either hepatic Irs1 or Irs2 mediated suppression of HGP by intracerebroventricular insulin infusion. After 12 weeks on a high-fat diet, postprandial tyrosine phosphorylation of Irs1 increased in livers of control and LKO2 mice, whereas tyrosine phosphorylation of Irs2 decreased in control and LKO1 mice. Moreover, LKO1 mice—but not LKO2 mice—that were fed a high-fat diet developed postprandial hyperglycemia. We conclude that Irs1 is the principal mediator of hepatic insulin action that maintains glucose homeostasis.

Use of [3-3H]glucose and [6-14C]glucose to measure glucose turnover and glucose metabolism in humans

1992 ◽  
Vol 263 (1) ◽  
pp. E17-E22 ◽  
Author(s):  
H. Katz ◽  
M. Homan ◽  
P. Butler ◽  
R. Rizza
Keyword(s):  
Indirect Calorimetry ◽  
Glucose Oxidation ◽  
Insulin Infusion ◽  
Specific Activity ◽  
Glucose Turnover ◽  
Detectable Effect ◽  
High Dose ◽  
Turnover Rates ◽  
Extracellular Glucose ◽  
Total Glucose

[3-3H]glucose is frequently used to measure glucose turnover in humans. If fructose 6-phosphate-fructose 1,6-diphosphate cycling (Fpc) is negligible in both liver and muscle, then [3-3H]- and [6-14C]glucose (corrected for Cori cycle activity) should provide equivalent measures of glucose turnover. In addition, if glycogenolysis is fully suppressed, then [14C]lactate specific activity should equal that of [6-14C]glucose from which it was derived, and oxidation of [6-14C]glucose, as measured by rate of generation of 14CO2, should equal total glucose oxidation (i.e., that derived from intra- and extracellular pools) as measured by indirect calorimetry. To address these questions, glucose turnover was measured simultaneously with [3-3H]- and [6-14C]glucose in the basal state and in presence of low (approximately 200 pM) and high (approximately 750 pM) insulin concentrations. Glucose turnover rates measured with [3-3H]- and [6-14C]glucose were equivalent at all insulin concentrations, indicating that Fpc had no detectable effect on measurement of glucose appearance. [14C]lactate specific activity was lower (P less than 0.01) than that of [6-14C]glucose in the basal state but not during either low- or high-dose insulin infusion, implying that all lactate was derived from extracellular glucose. On the other hand, glucose oxidation as measured by rate of generation of 14CO2 was lower (P less than 0.05) than glucose oxidation as measured by indirect calorimetry during both insulin infusions, implying either that suppression of glycogenolysis was not complete in all tissues or that one or both of these techniques do not accurately measure glucose oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of the rate of appearance in the non-steady state with a two-compartment model

1992 ◽  
Vol 263 (2) ◽  
pp. E400-E415 ◽  
Author(s):  
A. Mari
Keyword(s):  
Steady State ◽  
Time Course ◽  
Specific Activity ◽  
Glucose Production ◽  
Compartment Model ◽  
New Method ◽  
Two Compartment Model ◽  
Glucose Clamp Technique ◽  
Glucose Output ◽  
The Relationship

A simple tracer-based method for calculating the rate of appearance of endogenous substances in the non-steady state, free from the inconsistencies of Steele's equation, is still lacking. This paper presents a method based on a two-compartment model by which the rate of appearance can be calculated with only a modest increase in complexity over Steele's approach. An equation is developed where the rate of appearance is expressed as a sum of three terms: a steady-state term, a term for the first compartment, and a term for the second compartment. The formula employs three parameters and makes the relationship between rate of appearance and specific activity changes explicit. An equation is also provided for estimating the error of the method in each individual run. The algorithm can be implemented with a spreadsheet on a personal computer. Simulated and experimental data obtained by the hyperinsulinemic euglycemic glucose clamp technique were used as a test. The accuracy with which the time course of glucose production could be reconstructed was clearly better than that using Steele's equation. Marked negative values for endogenous glucose output were calculated with Steele's equation but not with the new method. The characteristics of generality, simplicity, and accuracy and the availability of an error estimate make this new method suitable for routine application to non-steady-state tracer analysis.

Effect of a selective rise in hepatic artery insulin on hepatic glucose production in the conscious dog

1999 ◽  
Vol 276 (4) ◽  
pp. E806-E813
Author(s):  
Dana K. Sindelar ◽  
Kayano Igawa ◽  
Chang A. Chu ◽  
Jim H. Balcom ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Portal Vein ◽  
Hepatic Artery ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Insulin Level ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Selective Increase

In the present study we compared the hepatic effects of a selective increase in hepatic sinusoidal insulin brought about by insulin infusion into the hepatic artery with those resulting from insulin infusion into the portal vein. A pancreatic clamp was used to control the endocrine pancreas in conscious overnight-fasted dogs. In the control period, insulin was infused via peripheral vein and the portal vein. After the 40-min basal period, there was a 180-min test period during which the peripheral insulin infusion was stopped and an additional 1.2 pmol ⋅ kg−1⋅ min−1of insulin was infused into the hepatic artery (HART, n = 5) or the portal vein (PORT, n = 5, data published previously). In the HART group, the calculated hepatic sinusoidal insulin level increased from 99 ± 20 (basal) to 165 ± 21 pmol/l (last 30 min). The calculated hepatic artery insulin concentration rose from 50 ± 8 (basal) to 289 ± 19 pmol/l (last 30 min). However, the overall arterial (50 ± 8 pmol/l) and portal vein insulin levels (118 ± 24 pmol/l) did not change over the course of the experiment. In the PORT group, the calculated hepatic sinusoidal insulin level increased from 94 ± 30 (basal) to 156 ± 33 pmol/l (last 30 min). The portal insulin rose from 108 ± 42 (basal) to 192 ± 42 pmol/l (last 30 min), whereas the overall arterial insulin (54 ± 6 pmol/l) was unaltered during the study. In both groups hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. In the HART group, net hepatic glucose output (NHGO) was suppressed from 9.6 ± 2.1 μmol ⋅ kg−1⋅ min−1(basal) to 4.6 ± 1.0 μmol ⋅ kg−1⋅ min−1(15 min) and eventually fell to 3.5 ± 0.8 μmol ⋅ kg−1⋅ min−1(last 30 min, P < 0.05). In the PORT group, NHGO dropped quickly ( P < 0.05) from 10.0 ± 0.9 (basal) to 7.8 ± 1.6 (15 min) and eventually reached 3.1 ± 1.1 μmol ⋅ kg−1⋅ min−1(last 30 min). Thus NHGO decreases in response to a selective increase in hepatic sinusoidal insulin, regardless of whether it comes about because of hyperinsulinemia in the hepatic artery or portal vein.

Dissociation of Na-K-ATPase specific activity and net reabsorption of sodium

1975 ◽  
Vol 228 (6) ◽  
pp. 1745-1749 ◽  
Author(s):  
KA Fisher ◽  
LG Welt ◽  
JP Hayslett
Keyword(s):  
Enzyme Activity ◽  
Renal Cortex ◽  
Specific Activity ◽  
Specific Effect ◽  
Renal Tissue ◽  
Tubular Reabsorption ◽  
Sodium Absorption ◽  
Sodium Reabsorption ◽  
Base Line ◽  
Outer Medulla

Prevoius studies have suggested that the increase in specific activity of Na-K-ATPase in renal tissue during treatment with glucocorticoids occurred as a result of aconcurrent rise in net tubular reabsorption of sodium. Since recent data have indicated a specific effect of glucocortiocoids on epithelial cells, experiments were performed to determine whether enzyme activity and net sodium reabsorption could be dissociated.Evidence is provided demonstrating that base-line specific activity of Na-K-ATPase in rat renal cortex and outer medulla does not correlate directly with net sodium reabsorption since enzyme activity did not change after a chronic reduction in glomerularfiltration rate and the rate of sodium reabsorption. Further studies showed a markedrise in Na-K-ATPase after 4 days of treatment with methylprednisolone despite a fall in sodium absorption. These results suggest a direct effect of glucocorticoids onrenal Na-K-ATPase and illistrate the difficulty in assigning a transport role tothis enzyme from the correlation of specific activity with rates of net electrolyte transport.

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