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Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11β-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11β-HSD1 expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11β-HSD1-deficient mice and C57Bl/6 mice with sodium salicylate for 4 weeks. Glucose tolerance was assessed in vivo. Tissue transcript levels were assessed by quantitative PCR and enzyme activity by incubation with (3)H-steroid. Two weeks' administration of salsalate was also investigated in a randomized double-blind placebo-controlled crossover study in 16 men, with measurement of liver 11β-HSD1 activity in vivo and adipose tissue 11β-HSD1 transcript levels ex vivo. In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1-deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11β-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates. [ABSTRACT FROM AUTHOR]

Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 on insulin secretion, we generated β-cell-specific, 11β-HSD1-overexpressing (MIP-HSD1) mice on a strain background prone to β-cell failure. Unexpectedly, MIP-HSD1(tg/+) mice exhibited a reversal of high fat-induced β-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal-related kinase and p21 signaling pathways. 11β-HSD1(-/-) mice showed mild β-cell impairment that was offset by improved glucose tolerance. The benefit of higher β-cell 11β-HSD1 exhibited a threshold because homozygous MIP-HSD1(tg/tg) mice and diabetic Lep(db/db) mice with markedly elevated β-cell 11β-HSD1 levels had impaired basal β-cell function. Optimal elevation of β-cell 11β-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11β-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11β-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11β-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11β-HSD1 activity in obese type 2 diabetic subjects.Research Design and Methods: Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[(2)H](4)cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11β-HSD1 activity using tracer dilution.Results: In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[(2)H](3)cortisol in arterialized blood was increased (35 ± 2 vs. 29 ± 1 nmol/min, P < 0.05), splanchnic 9,12,12-[(2)H](3)cortisol production was not reduced (29 ± 6 vs. 29 ± 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged.Conclusions: Whole-body 11β-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese type 2 diabetic subjects. [ABSTRACT FROM AUTHOR]

Objective: People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.Research Design and Methods: This was a cross-sectional study of 1,066 men and women aged 60-75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.Results: In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).Conclusions: High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to characterize differences in the acute insulin response to glucose (AIR(g)) relative to insulin sensitivity (S(I)) in black and white premenopausal normoglycemic South African women matched for body fatness.Research Design and Methods: Cross-sectional analysis including 57 black and white South African women matched for BMI, S(I), AIR(g), and the disposition index (AIR(g) x S(I)) were performed using a frequently sampled intravenous glucose tolerance test with minimal model analysis, and similar measures were analyzed using an oral glucose tolerance test (OGTT). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography.Results: S(I) was significantly lower (4.4 +/- 0.8 vs. 9.4 +/- 0.8 and 2.9 +/- 0.8 vs. 6.0 +/- 0. 8 x 10(-5) min(-1)/[pmol/l], P < 0.001) and AIR(g) was significantly higher (1,028 +/- 255 vs. 352 +/- 246 and 1,968 +/- 229 vs. 469 +/- 246 pmol/l, P < 0.001), despite similar body fatness (30.9 +/- 1.4 vs. 29.7 +/- 1.3 and 46.8 +/- 1.2 vs. 44.4 +/- 1.3%) in the normal-weight and obese black women compared with their white counterparts, respectively. Disposition index, a marker of beta-cell function, was not different between ethnic groups (3,811 +/- 538 vs. 2,966 +/- 518 and 3,646 +/- 485 vs. 2,353 +/- 518 x 10(-5) min, P = 0.10). Similar results were obtained for the OGTT-derived measures.Conclusions: Black South African women are more insulin resistant than their white counterparts but compensate by increasing their insulin response to maintain normal glucose levels, suggesting an appropriate beta-cell response for the level of insulin sensitivity. [ABSTRACT FROM AUTHOR]

Objective: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates cortisol from cortisone. 11beta-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11beta-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11beta-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo.Research Design and Methods: Six healthy men underwent 9,11,12,12-[(2)H](4)-cortisol infusions with simultaneous sampling of arterialized and superficial epigastric vein blood sampling. Four men with stable chronic liver disease and a transjugular intrahepatic porto-systemic shunt in situ underwent tracer infusion with simultaneous sampling from the portal vein, hepatic vein, and an arterialized peripheral vein.Results: Significant cortisol and 9,12,12-[(2)H](3)-cortisol release were observed from subcutaneous adipose tissue (15.0 [95% CI 0.4-29.5] and 8.7 [0.2-17.2] pmol . min(-1) . 100 g(-1) adipose tissue, respectively). Splanchnic release of cortisol and 9,12,12-[(2)H](3)-cortisol (13.5 [3.6-23.5] and 8.0 [2.6-13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected.Conclusions: Cortisol is released from subcutaneous adipose tissue by 11beta-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, visceral adipose 11beta-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. DESIGN AND SETTING: Nested case-control study within a cohort of patients (> or = 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. PATIENTS: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430-436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. MAIN OUTCOME MEASURE: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. RESULTS: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose-response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). CONCLUSIONS: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes. [ABSTRACT FROM AUTHOR]