Splanchnic Cortisol Production Occurs in Humans

Basu, Rita; Singh, Ravinder J.; Basu, Ananda; Chittilapilly, Elizabeth; Johnson, Christopher M.; Toffolo, Gianna; Cobelli, Claudio; Rizza, Robert A.

doi:10.2337/diabetes.53.8.2051

Cited by 103 publications

(101 citation statements)

References 44 publications

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“…15,16 This extra-adrenal source contributes to peripheral cortisol levels and potentially affects the selectivity index. Furthermore, a previous study showed that admixture of blood from the accessory hepatic veins into AVs lowers the selectivity index of cortisol.…”

Section: Discussionmentioning

confidence: 99%

Plasma Metanephrine for Assessing the Selectivity of Adrenal Venous Sampling

et al. 2013

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A drenal hypertension caused by primary aldosteronism comprises the most common curable form of secondary hypertension. In the analytic workup of patients with primary aldosteronism, adrenal venous sampling (AVS) is recommended for establishing the origins of excess production of hormones.1 AVS is a technically demanding procedure in which correct cannulation of the adrenal veins, especially the right, can pose significant difficulty. 2,3 Correct positioning of the catheter is verified by measurement of plasma cortisol concentrations. High cortisol concentrations in adrenal blood compared with peripheral blood ascertain correct catheter placement and thus selective sampling. Because cortisol has a long circulating halflife (100 minutes), increases in adrenal vein (AV) blood above levels of peripheral venous (PV) blood are relatively minor and subsequently subject to interpretative error. Furthermore, as a result of physiological corticotropin fluctuations, cortisol is secreted in a variable fashion so that fluctuating levels can interfere with the interpretation of AVS selectivity. [4][5][6] This problem can be overcome using cosyntropin stimulation. 7 Cosyntropin stimulation, however, adds to the complexity of the procedure and for this reason is not always used.With the above considerations in mind, there seems a need for more reliable parameters than cortisol in assessing the correct positioning of catheters during AVS.8 Plasma metanephrine, the O-methylated metabolite of epinephrine, represents one such alternative analyte. More than 90% of plasma metanephrine is produced within the adrenal medulla, with <10% produced from epinephrine after release from the adrenals. 7 Compared with cortisol, plasma metanephrine has a short circulating half-life of 3 to 6 minutes, resulting in close to 90-fold increases of AV compared with PV concentrations in situations where catheters are correctly positioned.7 Such large Abstract-Adrenal vein sampling is used to establish the origins of excess production of adrenal hormones in primary aldosteronism. Correct catheter positioning is confirmed using adrenal vein measurements of cortisol, but this parameter is not always reliable. Plasma metanephrine represents an alternative parameter. The objective of our study was to determine the use of plasma metanephrine concentrations to establish correct catheter positioning during adrenal vein sampling with and without cosyntropin stimulation. We included 52 cosyntropin-stimulated and 34 nonstimulated sequential procedures. Plasma cortisol and metanephrine concentrations were measured in adrenal and peripheral venous samples. Success rates of sampling, using an adrenal to peripheral cortisol selectivity index of 3.0, were compared with success rates of metanephrine using a selectivity index determined by receiver operating characteristic curve analysis. Among procedures assessed as selective using cortisol, the adrenal to peripheral vein ratio of metanephrine was 6-fold higher than that of cortisol (94.0 versus 15.5; P<0.0001). Ther...

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Section: Discussionmentioning

confidence: 99%

Plasma Metanephrine for Assessing the Selectivity of Adrenal Venous Sampling

et al. 2013

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“…At ϳ0900 h, H]glucose and a hormone cocktail containing somatostatin and replacement amounts of growth hormone and glucagon were started (time 0 min) and continued until the end of the study as part of a separate experiment (14). Insulin was infused at a rate of 0.78 mU ⅐ kg lean body wt Ϫ1 ⅐ min Ϫ1 from 0 to 180 min, then at 1.56 mU ⅐ kg lean body wt Ϫ1 ⅐ min Ϫ1 from 181 to 300 min, and then at 3.1 mU ⅐ kg lean body wt Ϫ1 ⅐ min Ϫ1 from 301 to 420 min.…”

Section: Methodsmentioning

confidence: 99%

Selective Downregulation of the High–Molecular Weight Form of Adiponectin in Hyperinsulinemia and in Type 2 Diabetes

et al. 2007

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OBJECTIVE-Adiponectin is an adipocyte-specific secretory protein found in circulation in several different forms and is present at significantly lower levels in the plasma of diabetic patients compared with that of insulin-sensitive individuals. We wanted to test whether insulin per se is a contributing factor toward lower plasma adiponectin concentrations and, if so, whether the splanchnic bed contributes to this phenomenon. RESEARCH DESIGN AND METHODS-We sampled femoral artery and hepatic venous samples and measured the highmolecular weight (HMW) and low-molecular weight (LMW) fractions of adiponectin in 11 type 2 diabetic and 7 nondiabetic subjects matched for age, sex, and BMI during basal conditions and during a hyperglycemic (ϳ9.5 mmol/l) hyperinsulinemic (ϳ700 pmol/l) clamp.RESULTS-Under these conditions, total arterial adiponectin, HMW, and the ratio of HMW to total adiponectin all were lower (P Ͻ 0.01) in the diabetic versus nondiabetic subjects, whereas the LMW form did not significantly differ. Under hyperinsulinemic conditions, total adiponectin levels dropped, primarily due to a reduction of the HMW form, whereas LMW forms were not significantly affected.CONCLUSIONS-HMW adiponectin and the ratio of HMW to total adiponectin are lower in individuals with diabetes than in nondiabetic subjects. We conclude that HMW adiponectin is downregulated in hyperinsulinemia and type 2 diabetes. Diabetes 56: [2174][2175][2176][2177] 2007 A diponectin is a secretory protein uniquely produced by adipocytes (1) and accepted as a marker for systemic insulin sensitivity, particularly as an indicator of hepatic insulin sensitivity and lipid content (2). Decreased levels correlate well with cardiovascular and atherosclerotic disease, and negative correlation with proinflammatory markers makes it one of the most promising biomarkers for the metabolic syndrome. Studies with recombinant protein and, more importantly, analysis of a number of mouse models with altered adiponectin levels have demonstrated potent hepatic insulin-sensitizing and anti-atherosclerotic activities (3,4).Several articles have clarified relevance of the observation that adiponectin circulates as a mixture of several different complexes. The sexual dimorphism causing higher levels of adiponectin in females is primarily due to higher levels of the high-molecular weight (HMW) form, a complex of at least 18 subunits of adiponectin (5). A number of studies have taken advantage of the potent predictive potential that measurement of the HMW offers and have further strengthened the strong correlations with the metabolic syndrome and insulin sensitivity previously revealed with measurements of total adiponectin (6,7).A small study in patients suggested that during hyperinsulinemic-euglycemic clamp, plasma adiponectin levels were significantly decreased (8). Patients carrying mutant insulin receptor genes that lead to functionally impaired receptors or subjects with anti-insulin receptor autoantibodies present with very high levels of adiponectin (9). This le...

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“…Previous attempts to measure adipose 11HSD1 in vivo using arteriovenous sampling across abdominal subcutaneous adipose tissue have been inconclusive, perhaps because of variability in measurement (26). Recently, we (27) and others (28) have validated a new approach using deuterated cortisol tracer infusion to measure the turnover of 11HSD activities in vivo. Here, we use this technique to quantify systemic regeneration of cortisol by 11HSD1.…”

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confidence: 99%

“…Here, we use this technique to quantify systemic regeneration of cortisol by 11HSD1. Recent studies using arteriovenous sampling have suggested that the splanchnic circulation (liver and intra-abdominal adipose tissue) accounts for most of the systemic regeneration of cortisol (28). To assess cortisol regeneration specifically in subcutaneous adipose tissue, we have developed a new technique using in vivo microdialysis.…”

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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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Splanchnic Cortisol Production Occurs in Humans

Cited by 103 publications

References 44 publications

Plasma Metanephrine for Assessing the Selectivity of Adrenal Venous Sampling

Plasma Metanephrine for Assessing the Selectivity of Adrenal Venous Sampling

Selective Downregulation of the High–Molecular Weight Form of Adiponectin in Hyperinsulinemia and in 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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