Metabolic Effects of Exogenous Glucocorticoids in Fasted Man

Owen, Oliver E.; Cahill, George F.

doi:10.1172/jci107452

Cited by 91 publications

(32 citation statements)

References 43 publications

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“…This difference must be made up by sodium since potassium excretion rises vey little, if at all. A similar quantitative lag in the increase of ammonium excretion relative to keto acid (i.e., organic acid) excretion during the first 5-7 days of fasting is evident in the data of Owen and Cahill (27). Conversion of the ammonium excretion data in their Fig.…”

Section: Discussionsupporting

confidence: 64%

The mechanism of the natriuresis of fasting.

Sigler¹

1975

J. Clin. Invest.

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A B S T R A C T This study tests the hypothesis that obligatory cation coverage of metabolically generated anions is the mechanism for the sodium diuresis of fasting. Nine obese female subjects were equilibrated on a constant sodium and caloric intake and then fasted while sodium intake was maintained. Particular attention was paid to maintaining the same upright activity schedule during fasting as during control. Consecutive 3-h increases in urinary sodium, ammonium, and potassium excretion during fasting were matched against simultaneously determined increases in organic acid anions (OAS) and H2PO4-, which would exist in combination with the cations. The changes were significantly correlated (r = 0.891, P < 0.001) in the relationship y = 0.73x + 19 where y equals increases in organic acid salts + H2PO4-and x equals increases in cations. As ammonium excretion rose, sodium conservation occurred with ammonium replacing sodium at the major urinary cation. Corollaries to the hypothesis were also found to be true. They were: (a) Increases in ammonium excretion lagged considerably behind increases in OAS + H2PO4c during the diuretic phase making sodium coverage necessary. (b) Sodium loss was much greater than chloride although chloride balance was minimally negative. (c) After refeeding with glucose, sodium excretion promptly decreased and appeared best correlated with simultaneous decreases in OAS. Ammonium excretion also fell but much less than sodium. The data support the hypothesis that obligatory cation coverage of metabolically generated anions is a major mechanism responsible for the sodium diuresis of fasting. INTRODUCTIONLarge quantities of electrolyte and water are lost in the urine during the 1st wk of fasting. The principal

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Section: Discussionsupporting

confidence: 64%

The mechanism of the natriuresis of fasting.

Sigler¹

1975

J. Clin. Invest.

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“…Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone-induced insulin resistance in glucose transport activity (rather than the inhibition of phosphatidylinositol 3-kinase activation resulting from a decreased IRS-1 content) is likely to underlie impaired glucose transporter regulation. Diabetes 49:1700-1708, 2000 R esearch has shown that glucocorticoids are hormones that induce insulin resistance and that their clinical use often exacerbates diabetes (1)(2)(3). This glucocorticoid-induced insulin resistance has been demonstrated not only in clinical cases but also in animal experiments (4,5) and in vitro experiments using isolated or cultured cells (6)(7)(8).…”

mentioning

confidence: 99%

Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction.

et al. 2000

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Glucocorticoids reportedly induce insulin resistance. In this study, we investigated the mechanism of glucocorticoid-induced insulin resistance using 3T3-L1 adipocytes in which treatment with dexamethasone has been shown to impair the insulin-induced increase in glucose uptake. In 3T3-L1 adipocytes treated with dexamethasone, the GLUT1 protein expression level was decreased by 30%, which possibly caused decreased basal glucose uptake. On the other hand, dexamethasone treatment did not alter the amount of GLUT4 protein in total cell lysates but decreased the insulin-stimulated GLUT4 translocation to the plasma membrane, which possibly caused decreased insulin-stimulated glucose uptake. Dexamethasone did not alter tyrosine phosphorylation of insulin receptors, and it significantly decreased protein expression and tyrosine phosphorylation of insulin receptor substrate (IRS)-1. Interestingly, however, protein expression and tyrosine phosphorylation of IRS-2 were increased. To investigate whether the reduced IRS-1 content is involved in insulin resistance, IRS-1 was overexpressed in dexamethasone-treated 3T3-L1 adipocytes using an adenovirus transfection system. Despite protein expression and phosphorylation levels of IRS-1 being normalized, insulin-induced 2-deoxy-D-[ 3 H]glucose uptake impaired by dexamethasone showed no significant improvement. Subsequently, we examined the effect of dexamethasone on the glucose uptake increase induced by overexpression of GLUT2-tagged p110␣, constitutively active Akt (myristoylated Akt), oxidative stress (30 mU glucose oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carboxamide ribonucleoside for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). Dexamethasone treatment clearly inhibited the increases in glucose uptake produced by these agents. Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone-induced insulin resistance in glucose transport activity (rather than the inhibition of phosphatidylinositol 3-kinase activation resulting from a decreased IRS-1 content) is likely to underlie impaired glucose transporter regulation.

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“…The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40±8 yr (10 INTRODUCTION Like other glucocorticoids (1)(2)(3)(4), prednisone increases blood glucose in man (5). This effect is accompanied by hyperinsulinemia (insulin resistance) (6) that may be attributable to either reduced peripheral insulin sensitivity or increased hepatic glucose production (6).…”

mentioning

confidence: 99%

An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects.

Pagano¹,

Cavallo‐Perin²,

Cassader³

et al. 1983

J. Clin. Invest.

249

147

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A B S T R A C T Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 ,uCi/ min) was performed for 120 min before and during a euglycemic clamp repeated at 100, -1,000, and -10,000 MU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35±7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5±2.1 vs. 83.7± 1.9 mg/dl) and mean fasting plasma insulin values (17.8±1.2 vs. 14.3±0.8 AU/ml) were significantly higher (P < 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P < 0.001) after prednisone at all three steady state plasma insulin levels: 2.8±0.3 vs. 7.4±1.1 at '100 MU/ml; 6.0±0.5 vs. 12.2±1.1 at -1,000 psU/ml; 7.4±0.6 vs. 14.4±0.5 at -10,000 ,uU/ml. Fasting glucose production (in mg/ kg per min) was significantly higher after prednisone: 3.7±0.2 vs. 2.9±0.2, P < 0.001. Suppression of glucose production at steady state plasma insulin level of -100 IAU/ml was less after prednisone (1.01±0.35 vs. 0.14±0.13, NS), and total at -1,000 and -10,000 1uU/ ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40±8 yr (10

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Metabolic Effects of Exogenous Glucocorticoids in Fasted Man

Cited by 91 publications

References 43 publications

The mechanism of the natriuresis of fasting.

The mechanism of the natriuresis of fasting.

Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction.

An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects.

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