Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation

2003 ◽  
Vol 285 (1) ◽  
pp. E106-E115 ◽  
Author(s):  
Byoung Moon ◽  
Jamie Jun-Mae Kwan ◽  
Noreen Duddy ◽  
Gary Sweeney ◽  
Najma Begum
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Muscle Metabolism ◽  
Inhibitory Effect ◽  
Intrinsic Activity ◽  
Glut4 Translocation ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition

Elevated levels of resistin have been proposed to cause insulin resistance and therefore may serve as a link between obesity and type 2 diabetes. However, its role in skeletal muscle metabolism is unknown. In this study, we examined the effect of resistin on insulin-stimulated glucose uptake and the upstream insulin-signaling components in L6 rat skeletal muscle cells that were either incubated with recombinant resistin or stably transfected with a vector containing the myc-tagged mouse resistin gene. Transfected clones expressed intracellular resistin, which was released in the medium. Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. Furthermore, resistin did not alter the insulin receptor (IR) content and its phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic activity. Insulin-stimulated phosphorylation of Akt/protein kinase B-α, one of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also not affected by resistin. Expression of resistin also inhibited insulin-stimulated 2-DG uptake when compared with cells expressing the empty vector (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3-kinase signaling. We conclude that resistin does not alter IR signaling but does affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic activity of cell surface glucose transporters.

Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle

1997 ◽  
Vol 273 (3) ◽  
pp. C1082-C1087 ◽  
Author(s):  
A. D. Lee ◽  
P. A. Hansen ◽  
J. Schluter ◽  
E. A. Gulve ◽  
J. Gao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Inhibitory Effect ◽  
Phosphate Concentration ◽  
Intrinsic Activity ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Glut 4

beta-Adrenergic stimulation has been reported to inhibit insulin-stimulated glucose transport in adipocytes. This effect has been attributed to a decrease in the intrinsic activity of the GLUT-4 isoform of the glucose transporter that is mediated by phosphorylation of GLUT-4. Early studies showed no inhibition of insulin-stimulated glucose transport by epinephrine in skeletal muscle. The purpose of this study was to determine the effect of epinephrine on GLUT-4 phosphorylation, and reevaluate the effect of beta-adrenergic stimulation on insulin-activated glucose transport, in skeletal muscle. We found that 1 microM epinephrine, which raised adenosine 3',5'-cyclic monophosphate approximately ninefold, resulted in GLUT-4 phosphorylation in rat skeletal muscle but had no inhibitory effect on insulin-stimulated 3-O-methyl-D-glucose (3-MG) transport. In contrast to 3-MG transport, the uptakes of 2-deoxyglucose and glucose were markedly inhibited by epinephrine treatment. This inhibitory effect was presumably mediated by stimulation of glycogenolysis, which resulted in an increase in glucose 6-phosphate concentration to levels known to severely inhibit hexokinase. We conclude that 1) beta-adrenergic stimulation decreases glucose uptake by raising glucose 6-phosphate concentration, thus inhibiting hexokinase, but does not inhibit insulin-stimulated glucose transport and 2) phosphorylation of GLUT-4 has no effect on glucose transport in skeletal muscle.

Gliclazide increases insulin receptor tyrosine phosphorylation but not p38 phosphorylation in insulin-resistant skeletal muscle cells

2002 ◽  
Vol 205 (23) ◽  
pp. 3739-3746 ◽  
Author(s):  
Naresh Kumar ◽  
Chinmoy S. Dey
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Mapk Pathway ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Insulin Resistant ◽  
Resistant Cells

SUMMARY Sulfonylurea drugs are used in the treatment of type 2 diabetes. The mechanism of action of sulfonylureas is to release insulin from pancreatic cells and they have been proposed to act on insulin-sensitive tissues to enhance glucose uptake. The goal of the present study was to test the hypothesis that gliclazide, a second-generation sulfonylurea, could enhance insulin signaling in insulin-resistant skeletal muscle cells. We demonstrated that gliclazide enhanced insulin-stimulated insulin receptor tyrosine phosphorylation in insulin-resistant skeletal muscle cells. Although insulin receptor substrate-1 tyrosine phosphorylation was unaffected by gliclazide treatment, phosphatidylinositol 3-kinase activity was partially restored by treatment with gliclazide. No increase in 2-deoxyglucose uptake in insulin-resistant cells by treatment with gliclazide was observed. Further investigations into the mitogen-activated protein kinase (MAPK) pathway revealed that insulin-stimulated p38 phosphorylation was impaired, as compared with extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase(JNK), which were phosphorylated normally in insulin-resistant cells. Treatment with gliclazide could not restore p38 phosphorylation in insulin-resistant cells. We propose that gliclazide can regulate part of the insulin signaling in insulin-resistant skeletal muscle, and p38 could be a potential therapeutic target for glucose uptake to treat insulin resistance.

Changes in dietary sodium consumption modulate GLUT4 gene expression and early steps of insulin signaling

2004 ◽  
Vol 286 (4) ◽  
pp. R779-R785 ◽  
Author(s):  
Maristela Mitiko Okamoto ◽  
Dóris Hissako Sumida ◽  
Carla Roberta Oliveira Carvalho ◽  
Alessandra Martins Vargas ◽  
Joel Cláudio Heimann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Dietary Sodium ◽  
Glut4 Translocation ◽  
Glut4 Gene Expression

Previous studies have shown that chronic salt overload increases insulin sensitivity, while chronic salt restriction decreases it. In the present study we investigated the influence of dietary sodium on 1) GLUT4 gene expression, by Northern and Western blotting analysis; 2) in vivo GLUT4 protein translocation, by measuring the GLUT4 protein in plasma membrane and microsome, before and after insulin injection; and 3) insulin signaling, by analyzing basal and insulin-stimulated tyrosine phosphorylation of insulin receptor (IR)-β, insulin receptor substrate (IRS)-1, and IRS-2. Wistar rats were fed normal-sodium (NS-0.5%), low-sodium (LS-0.06%), or high-sodium diets (HS-3.12%) for 9 wk and were killed under pentobarbital anesthesia. Compared with NS rats, HS rats increased ( P < 0.05) the GLUT4 protein in adipose tissue and skeletal muscle, whereas GLUT4 mRNA was increased only in adipose tissue. GLUT4 expression was unchanged in LS rats compared with NS rats. The GLUT4 translocation in HS rats was higher ( P < 0.05) both in basal and insulin-stimulated conditions. On the other hand, LS rats did not increase the GLUT4 translocation after insulin stimulus. Compared with NS rats, LS rats showed reduced ( P < 0.01) basal and insulin-stimulated tyrosine phosphorylation of IRS-1 in skeletal muscle and IRS-2 in liver, whereas HS rats showed enhanced basal tyrosine phosphorylation of IRS-1 in skeletal muscle ( P < 0.05) and of IRS-2 in liver. In summary, increased insulin sensitivity in HS rats is related to increased GLUT4 gene expression, enhanced insulin signaling, and GLUT4 translocation, whereas decreased insulin sensitivity of LS rats does not involve changes in GLUT4 gene expression but is related to impaired insulin signaling.

scholarly journals Bradykinin potentiates insulin-stimulated glucose uptake and enhances insulin signal through the bradykinin B2 receptor in dog skeletal muscle and rat L6 myoblasts

1998 ◽  
pp. 344-352 ◽  
Author(s):  
T Miyata ◽  
T Taguchi ◽  
M Uehara ◽  
S Isami ◽  
H Kishikawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Dependent Manner ◽  
Glut4 Translocation ◽  
Binding Studies ◽  
Insulin Receptor Tyrosine Kinase ◽  
Peripheral Tissues ◽  
Bradykinin B2 Receptor ◽  
Increase Glucose Uptake

Previously we demonstrated that bradykinin infusion could increase glucose uptake into dog peripheral tissues, and that bradykinin could potentiate insulin-induced glucose uptake through glucose transporter 4 (GLUT4) translocation in dog adipocytes. However, skeletal muscle is the predominant tissue for insulin-mediated glucose disposal. The aim of this study was to determine how bradykinin affected insulin-stimulated glucose uptake in dog skeletal muscle and myotubes transformed from rat L6 myoblasts. The bradykinin receptor binding studies revealed that dog skeletal muscle and rat L6 myoblasts possessed significant numbers of bradykinin receptors (Kd = 88 and 76 pmol/l, Bmax = 82.5 and 20 fmol/mg protein respectively). An RT-PCR (reverse transcriptase-polymerase chain reaction) amplification showed mRNA specific for bradykinin B2 receptor in both cells. Bradykinin significantly increased 2-deoxyglucose uptake in isolated muscle and L6 myoblasts in the presence of insulin (10(-7) mol/l) in a dose-dependent manner, but not in the absence of insulin. Bradykinin also enhanced insulin-stimulated GLUT4 translocation, and insulin-induced phosphorylation of insulin receptor beta subunit and insulin receptor substrate-1 (IRS-1) without affecting the binding affinities or numbers of cell surface insulin receptors in both cells. It is concluded that bradykinin could potentiate the insulin-induced glucose uptake through GLUT4 translocation in dog skeletal muscle and rat L6 myoblasts. This effect could be explained by the potency of bradykinin to upregulate the insulin receptor tyrosine kinase activity which stimulates phosphorylation of IRS-1, followed by an increase in GLUT4 translocation.

Cellular depletion of atypical PKCλ is associated with enhanced insulin sensitivity and glucose uptake in L6 rat skeletal muscle cells

2010 ◽  
Vol 299 (3) ◽  
pp. E402-E412 ◽  
Author(s):  
Clare Stretton ◽  
Ashleigh Evans ◽  
Harinder S. Hundal
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Dominant Negative Mutant

Atypical protein kinase C (aPKC) isoforms (λ and ζ) have been implicated in the control of insulin-stimulated glucose uptake in adipose and skeletal muscle, but their precise role in this process remains unclear, especially in light of accumulating evidence showing that, in response to numerous stimuli, including insulin and lipids such as ceramide, activation of aPKCs acts to negatively regulate key insulin-signaling molecules, such as insulin receptor substrate-1 (IRS-1) and protein kinase B (PKB)/cAMP-dependent PKC (Akt). In this study, we have depleted PKCλ in L6 skeletal muscle cells using RNA interference and assessed the effect this has upon insulin action. Muscle cells did not express detectable amounts of PKCζ. Depletion of PKCλ (>95%) had no significant effect on the expression of proteins participating in insulin signaling [i.e., insulin receptor, IRS-1, phosphatidylinositol 3-kinase (PI 3-kinase), PKB, or phosphate and tensin homolog deleted on chromosome 10] or those involved in glucose transport [Akt substrate of 160 kDa, glucose transporter (GLUT)1, or GLUT4]. However, PKCλ-depleted muscle cells exhibited greater activation of PKB/Akt and phosphorylation of its downstream target glycogen synthase kinase 3, in the basal state and displayed greater responsiveness to submaximal doses of insulin with respect to p85-PI 3-kinase/IRS-1 association and PKB activation. The increase in basal and insulin-induced signaling resulted in an associated enhancement of basal and insulin-stimulated glucose transport, both of which were inhibited by the PI 3-kinase inhibitor wortmannin. Additionally, like RNAi-mediated depletion of PKCλ, overexpression of a dominant-negative mutant of PKCζ induced a similar insulin-sensitizing effect on PKB activation. Our findings indicate that aPKCs are likely to play an important role in restraining proximal insulin signaling events but appear dispensable with respect to insulin-stimulated glucose uptake in cultured L6 muscle cells.

Oligomeric resistin impairs insulin and AICAR-stimulated glucose uptake in mouse skeletal muscle by inhibiting GLUT4 translocation

2009 ◽  
Vol 297 (1) ◽  
pp. E57-E66 ◽  
Author(s):  
Sebastian Beck Jørgensen ◽  
Jane Honeyman ◽  
Jonathan S. Oakhill ◽  
Daniel Fazakerley ◽  
Jacqueline Stöckli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Cytokine Signaling ◽  
Glut4 Translocation ◽  
Ampk Signaling ◽  
Akt Phosphorylation ◽  
L6 Myotubes ◽  
Edl Muscle

The hormone resistin is elevated in obesity and impairs glucose homeostasis. Here, we examined the effect of oligomerized human resistin on insulin signaling and glucose metabolism in skeletal muscle and myotubes. This was investigated by incubating mouse extensor digitorum longus (EDL) and soleus muscles and L6 myotubes with physiological concentrations of resistin and assessing insulin-stimulated glucose uptake, cellular signaling, suppressor of cytokine signaling 3 (SOCS-3) mRNA, and GLUT4 translocation. We found that resistin at a concentration of 30 ng/ml decreased insulin-stimulated glucose uptake by 30–40% in soleus muscle and myotubes, whereas in EDL muscle insulin-stimulated glucose uptake was impaired at a resistin concentration of 100 ng/ml. Impaired insulin-stimulated glucose uptake was not associated with reduced Akt phosphorylation or IRS-1 protein or increased SOCS-3 mRNA expression. To further investigate the site(s) at which resistin impairs glucose uptake we treated myotubes and skeletal muscle with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and found that, although resistin did not impair AMPK activation, it reduced AICAR-stimulated glucose uptake. These data suggested that resistin impairs glucose uptake at a point common to insulin and AMPK signaling pathways, and we thus measured AS160/TBC1D4 Thr642 phosphorylation and GLUT4 translocation in myotubes. Resistin did not impair TBC1D4 phosphorylation but did reduce both insulin and AICAR-stimulated GLUT4 plasma membrane translocation. We conclude that resistin impairs insulin-stimulated glucose uptake by mechanisms involving reduced plasma membrane GLUT4 translocation but independent of the proximal insulin-signaling cascade, AMPK, and SOCS-3.

Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

2002 ◽  
Vol 283 (2) ◽  
pp. E233-E240 ◽  
Author(s):  
Cheol S. Choi ◽  
Young-Bum Kim ◽  
Felix N. Lee ◽  
Janice M. Zabolotny ◽  
Barbara B. Kahn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Plasma Lactate ◽  
Peripheral Insulin Resistance ◽  
Lactate Levels ◽  
Lactate Infusion

Elevation of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding insulin resistance and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 μmol · kg−1 · min−1) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport decreased 25–30% ( P < 0.05) in soleus but not in epitrochlearis muscles of lactate-infused rats. Lactate infusion did not alter insulin's ability to phosphorylate the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively ( P < 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle.

scholarly journals β-Sitosterol-D-Glucopyranoside Mimics Estrogenic Properties and Stimulates Glucose Utilization in Skeletal Muscle Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3129
Author(s):  
Jyotsana Pandey ◽  
Kapil Dev ◽  
Sourav Chattopadhyay ◽  
Sleman Kadan ◽  
Tanuj Sharma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Utilization ◽  
Diabetes Management ◽  
Expression System ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Cell Periphery ◽  
Glut4 Translocation ◽  
In Silico Docking

Estrogenic molecules have been reported to regulate glucose homeostasis and may be beneficial for diabetes management. Here, we investigated the estrogenic effect of β-sitosterol-3-O-D-glucopyranoside (BSD), isolated from the fruits of Cupressus sempervirens and monitored its ability to regulate glucose utilization in skeletal muscle cells. BSD stimulated ERE-mediated luciferase activity in both ERα and ERβ-ERE luc expression system with greater response through ERβ in HEK-293T cells, and induced the expression of estrogen-regulated genes in estrogen responsive MCF-7 cells. In silico docking and molecular interaction studies revealed the affinity and interaction of BSD with ERβ through hydrophobic interaction and hydrogen bond pairing. Furthermore, prolonged exposure of L6-GLUT4myc myotubes to BSD raised the glucose uptake under basal conditions without affecting the insulin-stimulated glucose uptake, the effect associated with enhanced translocation of GLUT4 to the cell periphery. The BSD-mediated biological response to increase GLUT4 translocation was obliterated by PI-3-K inhibitor wortmannin, and BSD significantly increased the phosphorylation of AKT (Ser-473). Moreover, BSD-induced GLUT4 translocation was prevented in the presence of fulvestrant. Our findings reveal the estrogenic activity of BSD to stimulate glucose utilization in skeletal muscle cells via PI-3K/AKT-dependent mechanism.

Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells?

2008 ◽  
Vol 294 (1) ◽  
pp. E97-E102 ◽  
Author(s):  
Audrey E. Brown ◽  
Matthias Elstner ◽  
Stephen J. Yeaman ◽  
Douglass M. Turnbull ◽  
Mark Walker
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Mitochondrial Respiration ◽  
Respiratory Function ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Human Skeletal Muscle Cells ◽  
Basal Glucose Uptake

Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 μM azide resulted in 48 ± 3% and 56 ± 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 ± 39 pmol/min/mg (mean ± SE) in untreated cells. This increased to 669 ± 69 and 823 ± 83 pmol/min/mg in cells treated with 50 and 75 μM azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.

Human kidney 11β-hydroxysteroid dehydrogenase: regulation by adrenocorticotropin?

1996 ◽  
Vol 134 (3) ◽  
pp. 301-307 ◽  
Author(s):  
S Diederich ◽  
M Quinkler ◽  
K Miller ◽  
P Heilmann ◽  
M Schöneshöfer ◽  
...  
Keyword(s):  
Human Kidney ◽  
Kinetic Studies ◽  
Hydroxysteroid Dehydrogenase ◽  
Inhibitory Effect ◽  
Benjamin Franklin ◽  
Dependent Inhibition ◽  
Direct Inhibitory Effect ◽  
Dose Dependent Inhibition ◽  
Endogenous Substrates ◽  
Radioactive Detection

Diederich S, Quinkler M, Miller K, Heilmann P, Schöneshöfer M, Oelkers W. Human kidney 11βhydroxysteroid dehydrogenase: regulation by adrenocorticotropin? Eur J Endocrinol 1996;134:301–7. ISSN 0804–4643 In ectopic adrenocorticotropin (ACTH) syndrome (EAS) with higher ACTH levels than in pituitary Cushing's syndrome and during ACTH infusion, the ratio of cortisol to cortisone in plasma and urine is increased, suggesting inhibition of renal 11β-hydroxysteroid dehydrogenase (11β-HSD) by ACTH or by ACTH-dependent steroids. Measuring the conversion of cortisol to cortisone by human kidney slices under different conditions, we tested the possibility of 11β-HSD regulation by ACTH and corticosteroids. Slices prepared from unaffected parts of kidneys removed because of renal cell carcinoma were incubated with unlabeled or labeled cortisol, and cortisol and cortisone were quantitated after HPLC separation by UV or radioactive detection. The 11β-HSD activity was not influenced by incubation with increasing concentrations (10−12–10−9 mol/l) of ACTH (1–24 or 1–39) for 1 h. Among 12 ACTH-dependent steroids tested (10−9–10−6 mol/l), only corticosterone (IC50 = 2 × 10−7 mol/l), 18-OH-corticosterone and 11βOH-androstenedione showed a significant dose-dependent inhibition of 11β-HSD activity. The percentage conversion rate of cortisol to cortisone was concentration dependent over the whole range of cortisol concentrations tested (10−8–10−5 mol/l). A direct inhibitory effect of ACTH on 11β-HSD is, therefore, unlikely. The only steroids inhibiting the conversion of cortisol to cortisone are natural substrates for 11β-HSD Kinetic studies show a saturation of the enzyme at high cortisol concentrations. Thus, the reduced percentage renal cortisol inactivation in EAS seems to be due mainly to overload of the enzyme with endogenous substrates (cortisol, corticosterone and others) rather than to direct inhibition of 11β-HSD by ACTH or ACTHdependent steroids, not being substrates of 11β-HSD. S Diederich, Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany

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