Lack of relationship between 11β‐hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients*

Kerstens, Michael; Riemens, SC; Sluiter, Willem; Jj, Pratt; Wolthers, B.G.; Dullaart, Robin P. F.

doi:10.1046/j.1365-2265.2000.00975.x

Cited by 41 publications

(31 citation statements)

References 49 publications

(55 reference statements)

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“…Kerstens et al (15) reported an increase in urinary free cortisol and cortisone, as well as of urinary metabolites of cortisol, without any changes of plasma cortisol and cortisone, in healthy men submitted to a 24 h low-dose hyperinsulinaemic clamp. Interestingly, no change was observed in insulinresistant type 2 diabetic subjects.…”

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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“…[59,60,61]) and might explain the association of low birth weight and insulin resistance [62]. Alterations in cortisol excretion and HPA axis regulation have specifically been observed in diabetes mellitus [63,64,65,66,67]. A recent study involving moderately overweight Type 2 diabetic patients and control subjects matched for weight, height, BMI and blood pressure showed increased central and peripheral sensitivity to glucocorticoids in diabetic patients even if their metabolism was optimally controlled (HbA 1c 6.9±0.2% vs 6.0±0.1%) [68].…”

Section: β-Hsd1 and Insulin Resistancementioning

confidence: 99%

11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

2004

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Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11β-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11β-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11β-HSD1 activity.[Diabetologia (2004) by increased waist-to-hip ratio-rather than lowerbody (gynoid) obesity is associated with glucose intolerance and other features of the metabolic syndrome, and represents an important predictor for increased morbidity and mortality, not only from diabetes but also from coronary heart disease and certain cancers [4]. Although the WHR encompasses both intra-abdominal (visceral) and abdominal subcutaneous adipose depots, more detailed studies emphasize the importance of the visceral component for the development of metabolic disorders [4]. A causal relationship of visceral obesity for insulin resistance was recently demonstrated by surgical removal of visceral (epididymal and perinephric) fat pads of obese Sprague-Dawley rats that markedly improved hepatic insulin sensitivity and reduced hepatic glucose production [5].

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“…The conventional measure of 11HSD1 is the ratio of urinary cortisol to cortisone metabolites, which is inconsistently altered in obesity (11)(12)(13)(14)(15)(16) and diabetes (17)(18)(19). However, this ratio may be confounded by the activity of other enzymes (e.g., 11HSD type 2, 5␣-and 5␤-reductase) that differ in obesity, and is insensitive to the tissue-specific changes in 11HSD1 that have been observed in animals.…”

mentioning

confidence: 99%

Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

et al. 2005

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11␤-Hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates cortisol from cortisone within adipose tissue and liver. 11HSD1 inhibitors may enhance insulin sensitivity in type 2 diabetes and be most efficacious in obesity when 11HSD1 is increased in subcutaneous adipose biopsies. We examined the regeneration of cortisol in vivo in obesity, and the effects of the 11HSD1 inhibitor carbenoxolone. We compared six lean and six obese men and performed a randomized, placebo-controlled crossover study of carbenoxolone in obese men. 11␤-Hydroxysteroid dehydrogenase type 1 (11HSD1) is a microsomal enzyme expressed in many tissues, including liver and adipose tissue (1). It catalyzes the regeneration of the active glucocorticoid cortisol from its inactive 11-keto metabolite cortisone. This intracellular generation of cortisol plays a key role in amplifying glucocorticoid receptor activation independently of the level of cortisol in the circulating plasma. Its potential importance is illustrated in animal models. Transgenic mice that overexpress 11HSD1 by approximately threefold selectively in adipocytes under the AP2 promoter/enhancer (2,3) develop about a twofold increase in intraadipose glucocorticoid levels despite no change in plasma levels, which are controlled by a compensatory fall in ACTH secretion. This results in central obesity together with hyperinsulinemia, hyperglycemia, hyperlipidemia, and hypertension. Mice with similar overexpression of 11HSD1 in liver under the ApoE promoter develop insulin resistance, dyslipidemia, and hypertension without obesity (4). Conversely, 11HSD1 knockout mice on a high-fat diet are protected from obesity, hyperglycemia, and dyslipidemia and redistribute fat to peripheral rather than central fat depots (5-7). Moreover, inbred rodent models of obesity and diabetes show tissue-specific dysregulation of 11HSD1 (2,8,9); most commonly, 11HSD1 is reduced in liver but increased in adipose tissue. These findings substantiate the hypothesis that increased intra-adipose glucocorticoid regeneration by 11HSD1 contributes to obesity and its metabolic complications.Whether increased 11HSD1 levels have a similar importance in human obesity and associated type 2 diabetes is controversial (10). The conventional measure of 11HSD1 is the ratio of urinary cortisol to cortisone metabolites, which is inconsistently altered in obesity (11-16) and diabetes (17)(18)(19). However, this ratio may be confounded by the activity of other enzymes (e.g., 11HSD type 2, 5␣-and 5␤-reductase) that differ in obesity, and is insensitive to the tissue-specific changes in 11HSD1 that have been observed in animals. Hepatic 11HSD1 has been assessed in humans by measuring the conversion of an oral dose of cortisone into cortisol in peripheral plasma after "first pass" metabolism, and is consistently reduced in obesity

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Lack of relationship between 11β‐hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients*

Cited by 41 publications

References 49 publications

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

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

11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

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