Sex-specific action of insulin to acutely increase the metabolic clearance rate of dehydroepiandrosterone in humans.

Nestler, John E.; Kahwash, Ziad

doi:10.1172/jci117487

Cited by 45 publications

(39 citation statements)

References 62 publications

(49 reference statements)

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“…In this study, androgens and the interaction between insulin and ACTH stimulation were not assessed. Furthermore, Nestler & Kahwash (16) reported that the metabolic clearance of DHEA increased during insulin infusion in men, but not in healthy women. To the best of our knowledge, these are the only previous studies that have assessed the effects of insulin infusion on urinary excretion of adrenal steroid metabolites.…”

Section: Discussionmentioning

confidence: 99%

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Tosi

Negri²,

Brun³

et al. 2011

European Journal of Endocrinology

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Objective: In hyperandrogenic women, hyperinsulinaemia amplifies 17a-hydroxycorticosteroid intermediate response to ACTH, without alterations in serum cortisol or androgen response to stimulation. The aim of the study is to assess whether acute hyperinsulinaemia determines absolute changes in either basal or ACTH-stimulated adrenal steroidogenesis in these subjects. Design and methods: Twelve young hyperandrogenic women were submitted in two separate days to an 8 h hyperinsulinaemic (80 mU/m 2 !min) euglycaemic clamp, and to an 8 h saline infusion. In the second half of both the protocols, a 4 h ACTH infusion (62.5 mg/h) was carried out. Serum cortisol, progesterone, 17a-hydroxyprogesterone (17-OHP), 17a-hydroxypregnenolone (17-OHPREG), DHEA and androstenedione were measured at basal level and during the protocols. Absolute adrenal hormone secretion was quantified by measuring C19 and C21 steroid metabolites in urine collected after the first 4 h of insulin or saline infusion, and subsequently after 4 h of concurrent ACTH infusion. Results: During insulin infusion, ACTH-stimulated 17-OHPREG and 17-OHP were significantly higher than during saline infusion. No significant differences in cortisol and androgens response to ACTH were found between the protocols. Nevertheless, urinary excretion of ACTH-stimulated C19 and C21 steroid metabolites was significantly higher during hyperinsulinaemia than at basal insulin levels (both P!0.005). Changes in steroid metabolites molar ratios suggested stimulation by insulin of 5a-reductase activity. Conclusions: These in vivo data support the hypothesis that insulin acutely enhances ACTH effects on both the androgen and glucocorticoid pathways.

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Section: Discussionmentioning

confidence: 99%

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Tosi

Negri²,

Brun³

et al. 2011

European Journal of Endocrinology

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“…In this regard, it has been proposed that reduced DHEA may mediate the relationship with an increased risk of cardiovascular disease through a diminished inhibition of fibroblast growth and differentiation, alterations in the plasma lipid profile and through a diminished inhibition of platelet aggregation (88). It has also been shown that insulin may increase the metabolic clearance of DHEA (89), and studies by our group have demonstrated that hyperinsulinemia induced during DHEA infusion stimulated DHEA fatty acid esterification through the action of plasma lecithin: cholesterol acyltrasferase (90). On the other hand, DHEA-S may have direct effects on insulin sensitivity by increasing insulin binding to its own receptor (91).…”

Section: Insulin Resistance and Hyperinsulinemiamentioning

confidence: 99%

Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies

Tchernof

Labrie

2004

European Journal of Endocrinology

153

100

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The age-related decline in serum dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) has suggested that a relative deficiency of these steroids may be causally related to the development of chronic diseases generally associated with aging, including insulin resistance, obesity, cardiovascular disease, cancer, reductions of the immune defense, depression and a general deterioration in the sensation of well-being. The numerous studies which have focused on the link between DHEA and cardiovascular disease have generally been inconsistent, generating much debate and controversy on this issue. The present article is an analysis of studies on the relationship between endogenous DHEA or DHEA-S, obesity and cardiovascular disease risk, as well as DHEA treatment studies. Elevated plasma levels of free DHEA are associated with reduced obesity in both men and women, and with smaller abdominal body fat accumulations in men. However, contradictory results have been reported regarding the relationships between the sulfate ester DHEA-S and adiposity. Age differences in the populations studied may have been a confounding factor in these associations. On the other hand, DHEA-S level is not a predictor of cardiovascular disease endpoints in women, and appears to be a relatively weak one in men. DHEA intervention studies suggest that the effects of DHEA on serum lipids are, at best, modest or non-significant. The uncertainty as to whether endogenous and exogenous DHEA should be considered cardioprotective is related to discrepancies in the literature on this topic. Several studies may have been plagued by methodological problems such as low power, unreliable analytical methods, confounding factors or other differences in the populations studied. As a consequence, the original reports demonstrating dramatic effects of either endogenous or exogenous DHEA on cardiovascular disease risk have never been replicated. We propose that the effects of DHEA on cardiovascular disease risk (either favorable or unfavorable) should be considered to be much more modest than previously believed.

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“…Nestler et al also reported a suppression of serum DHEAS levels by insulin infusion in men [26]. An inhibition of adrenal 17,20-lyase activity and an increase in the metabolic clearance rate of DHEA were considered as the mechanisms for the fall in serum DHEAS levels [27,28].…”

Section: Discussionmentioning

confidence: 99%

A Close Association between Insulin Resistance and Dehydroepiandrosterone Sulfate in Subjects with Essential Hypertension.

Suzuki¹,

Kanazawa²,

Hasegawa³

et al. 1999

Endocr J

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Abstract.To examine the serum levels of dehydroepiandrosterone sulfate (DHEAS) and its relation with insulin resistance and the other risk factors in essential hypertension, serum DHEAS and insulin sensitivity were assessed in 35 male hypertensive and 17 male healthy control subjects aged 50-59 years. Fasting plasma insulin and the area under curve of plasma insulin were determined during a 75 g oral glucose tolerance test. Insulin sensitivity was measured by the steady state plasma glucose method. Fasting plasma insulin and the area under curve of plasma insulin were significantly higher in the hypetensive group than in control group. Steady state plasma glucose was significantly higher in hypertensive subjects indicating insulin resistance compared with control subjects.On the other hand, fasting serum DHEAS levels were significantly lower in the hypertensive group than in the control group. Fasting serum DHEAS levels were inversely correlated with steady state plasma glucose significantly (p=0.0008), indicating a close association between DHEAS levels and insulin resistance.Fasting serum DHEAS was inversely correlated with systolic blood pressure and fasting plasma insulin. In multiple regression analysis of hypertensive subjects, steady state plasma glucose was the strongest determinant of the fasting serum level of DHEAS, followed by systolic blood pressure and fasting plasma insulin. These 3 factors accounted for 51.6% of the variation in DHEAS.In nonobese and nondiabetic essential hypertension, serum DHEAS was lower and insulin resistance was the most significant independent determinant of reduced serum DHEAS, followed by systolic blood pressure and fasting plasma insulin. [7, 8] were found to be associated with insulin resistance. In non-diabetic men, decreased serum DHEAS levels were related to higher insulin concentrations, suggesting insulin resistance [9]. Nevertheless, no study has investigated direct relationship between DHEAS and insulin resistance measured by a precise method in hypertensive subjects.The purpose of this study was primarily to determine if serum DHEAS levels are changed in subjects with essential hypertension compared with healthy controls, and secondarily to evaluate the relationship

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Sex-specific action of insulin to acutely increase the metabolic clearance rate of dehydroepiandrosterone in humans.

Cited by 45 publications

References 62 publications

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies

A Close Association between Insulin Resistance and Dehydroepiandrosterone Sulfate in Subjects with Essential Hypertension.

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