David P. Macfarlane

Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome

Glucocorticoid hormones constitute an integral component of the response to stress, and many of the manifestations of glucocorticoid excess (Cushings syndrome) are predictable on the basis of their acute effects to raise blood pressure, induce insulin resistance, increase protein catabolism and elevate plasma glucose. However, it appears to be a paradox that the acute lipolytic effect of glucocorticoids is not manifest in long-term weight loss in humans. The effects of glucocorticoids on glucose metabolism are well characterised, involving impaired peripheral glucose uptake and hepatic insulin resistance, and there is mounting evidence that subtle abnormalities in glucocorticoid concentrations in the plasma and/or in tissue sensitivity to glucocorticoids are important in metabolic syndrome. The effects of glucocorticoids on fatty acid metabolism are less well understood than their influence on glucose metabolism. In this article, we review the literature describing the effects of glucocorticoids on fatty acid metabolism, with particular reference to in vivo human studies. We consider the implications for contrasting acute versus chronic effects of glucocorticoids on fat accumulation, effects in different adipose depots and the potential role of glucocorticoid signalling in the pathogenesis and therapy of metabolic syndrome.

Bile acids modulate glucocorticoid metabolism and the hypothalamic–pituitary–adrenal axis in obstructive jaundice ☆

Background & Aims Suppression of the hypothalamic–pituitary–adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5β-reductase. Methods The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5β-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. Results In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5β-reductase (Ki 9.19 ± 0.40 μM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5β-reductase activity, reduced urinary excretion of 3α,5β-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5β-reductase activity, supplementation of the fat-free diet with CDCA reduced 5β-reductase activity, and urinary 3α,5β-reduced corticosterone. Cholestasis in rats suppressed hepatic 5β-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3α,5β-tetrahydrocortisol was significantly lower than in healthy controls. Conclusion These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic–pituitary–adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease.

5α-Reductase Type 1 Modulates Insulin Sensitivity in Men

Context: 5α-Reductase (5αR) types 1 and 2 catalyze the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone in benign prostatic hyperplasia; finasteride inhibits 5αR2, and dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver. Objective: Our objective was to test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans. Design, Setting, and Participants: This double-blind randomized controlled parallel group study at a clinical research facility included 46 men (20–85 years) studied before and after intervention. Intervention: Oral dutasteride (0.5 mg daily; n = 16), finasteride (5 mg daily; n = 16), or control (tamsulosin; 0.4 mg daily; n = 14) was administered for 3 months. Main Outcome Measure: Glucose disposal was measured during a stepwise hyperinsulinemic-euglycemic clamp. Data are mean (SEM). Results: Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites and reduced circulating DHT but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high-dose insulin (dutasteride by −5.7 [3.2] μmol/kg fat-free mass/min, versus finasteride +7.2 [3.0], and tamsulosin +7.0 [2.0]). Dutasteride also reduced suppression of nonesterified fatty acids by insulin and increased body fat (by 1.6% [0.6%]). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose tissue. Conclusion: Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.

5α-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis and liver fibrosis in rodents

5α-Reductase type 1 (5αR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5αR1 allele (5αR1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCl4]) challenge. The effect of the 5α-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5αR1-KO mice demonstrated greater mean weight gain (21.6 ± 1.4 vs 16.2 ± 2.4 g), hyperinsulinemia (insulin area under the curve during glucose tolerance test 609 ± 103 vs. 313 ± 66 ng ⋅ mL−1 ⋅ min), and hepatic steatosis (liver triglycerides 136.1 ± 17.0 vs. 89.3 ± 12.1 μmol ⋅ g−1). mRNA transcript profiles in liver were consistent with decreased fatty acid β-oxidation and increased triglyceride storage. 5αR1-KO male mice were more susceptible to fibrosis after CCl4 administration (37% increase in collagen staining). The nonselective 5α-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 ± 1.2 vs. 7.0 ± 1.0 μmol ⋅ g−1) in obese male Zucker rats, both intact and castrated. 5αR1 deficiency induces insulin resistance and hepatic steatosis, consistent with the intrahepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5αR1 activity in obesity and with nonselective 5α-reductase inhibition in men with prostate disease may have important consequences for the onset and progression of metabolic liver disease.

Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis

The pathological mechanisms that distinguish simple steatosis from steatohepatitis (or NASH, with consequent risk of cirrhosis and hepatocellular cancer) remain incompletely defined. Whereas both a methionine- and choline-deficient diet (MCDD) and a choline-deficient diet (CDD) lead to hepatic triglyceride accumulation, MCDD alone is associated with hepatic insulin resistance and inflammation (steatohepatitis). We used metabolic tracer techniques, including stable isotope ([13C4]palmitate) dilution and mass isotopomer distribution analysis (MIDA) of [13C2]acetate, to define differences in intrahepatic fatty acid metabolism that could explain the contrasting effect of MCDD and CDD on NASH in C57Bl6 mice. Compared with control-supplemented (CS) diet, liver triglyceride pool sizes were similarly elevated in CDD and MCDD groups (24.37 ± 2.4, 45.94 ± 3.9, and 43.30 ± 3.5 μmol/liver for CS, CDD, and MCDD, respectively), but intrahepatic neutrophil infiltration and plasma alanine aminotransferase (31 ± 3, 48 ± 4, 231 ± 79 U/l, P < 0.05) were elevated only in MCDD mice. However, despite loss of peripheral fat in MCDD mice, neither the rate of appearance of palmitate (27.2 ± 3.5, 26.3 ± 2.3, and 28.3 ± 3.5 μmol·kg−1·min−1) nor the contribution of circulating fatty acids to the liver triglyceride pool differed between groups. Unlike CDD, MCDD had a defect in hepatic triglyceride export that was confirmed using intravenous tyloxapol (142 ± 21, 122 ± 15, and 80 ± 7 mg·kg−1·h−1, P < 0.05). Moreover, hepatic de novo lipogenesis was significantly elevated in the MCDD group only (1.4 ± 0.3, 2.3 ± 0.4, and 3.4 ± 0.4 μmol/day, P < 0.01). These findings suggest that important alterations in hepatic fatty acid metabolism may promote the development of steatohepatitis. Similar mechanisms may predispose to hepatocyte damage in human NASH.

Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver

To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m −2·min−1) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.

Should ‘Mild Primary Hyperparathyroidism’ be reclassified as ‘insidious’: is it time to reconsider?

Primary hyperparathyroidism (PHPT) is a common incidental finding on routine biochemical testing, affecting around 1% of the population. The majority of individuals will be asymptomatic at diagnosis, with no evidence of end organ damage, and unless individuals aged <50 years at diagnosis, they are often considered to have ‘mild’ PHPT, as they do not meet published criteria for parathyroidectomy (PTX). However, there is increasing evidence that ‘mild’ PHPT is associated with adverse health outcomes. Long‐term observational studies describing the natural history of ‘mild’ PHPT suggest that even though biochemistry may be relatively stable in the majority, bone mineral density (BMD) does decline after approximately 10 years of observation, whereas significant improvements in BMD are seen following PTX. Recent large European record linkage studies of ‘mild PHPT’ demonstrate significantly increased all‐cause and cardiovascular mortality, similar to rates published for patients with PHPT who meet the NIH surgical criteria. ‘Mild’ PHPT was also associated with increased admissions for nonfatal cardiovascular disease, renal failure, renal stones, fractures, hypertension, psychiatric disease, cancer and diabetes, suggesting that ‘insidious’ PHPT may be a more appropriate description, or at least that the term ‘mild’ should be abandoned. Randomized controlled trials (RCTs) have begun to explore the benefits of PTX in this condition, demonstrating improvements in BMD and some psychiatric outcomes at approximately 2 years of follow‐up. However, larger, adequately powered, long‐term, RCTs will be required to determine whether PTX improves potential long‐term morbidity and mortality in patients with PHPT who do not meet standard surgical criteria.

Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct

The effects of glucocorticoids on fuel metabolism are complex. Acute glucocorticoid excess promotes lipolysis but chronic glucocorticoid excess causes visceral fat accumulation. We hypothesized that interactions between cortisol and insulin and adrenaline account for these conflicting results. We tested the effect of cortisol on lipolysis and glucose production with and without insulin and adrenaline in humans both in vivo and in vitro.

The authors' reply: Nonsustained hypercalcaemia and primary hyperparathyroidism in the PEARS cohort.

The Parathyroid Epidemiology and Audit Research Study (PEARS) has reported data on several aspects of primary hyperparathyroidism (PHPT), including the incidence and prevalence (R1 in Data S1), associations with morbidity and mortality (R2, R3 in Data S1), the natural history, and most recently, predictors of adverse outcomes. An intriguing feature of PEARS is the temporal change in serum calcium. In 904 patients with mild, untreated PHPT, the median albumin-adjusted serum calcium was 2 62 mM at baseline, but subsequently decreased to lie within the reference range. At 1, 2, 5 and 10 year, the median serum calcium levels were 2 53, 2 51, 2 47 and 2 42 mM, respectively. In contrast, prospective data from other cohort studies of PHPT have suggested that serum calcium levels remain stable over time. In 60 patients followed for up to 10 year without surgery, mean serum calcium levels at baseline, 5 year and 10 year were 2 63, 2 65 and 2.58 mM, respectively. In 80 patients managed conservatively and followed for a mean of 46 months, mean albumin-adjusted serum calcium levels were 2 77 mM at the baseline and final visit. We followed 23 women with mild asymptomatic PHPT for up to 10 year, and while ionized calcium remained elevated and stable, mean albuminadjusted serum calcium increased from 2 49 mM at baseline to 2 70 mM at the final visit. Likewise, in reviews of patients followed in clinical practice, mean calcium levels were persistently elevated in 122 patients followed for ~6 year (R4 in Data S1), and in 68 patients followed for 4 5 year (R5 in Data S1). Thus, serum or ionized calcium in other cohort studies of PHPT remains elevated and stable, in contrast to the results from PEARS. The PEARS cohort was largely assembled from an algorithm based on biochemical test results, although there was a very high level of agreement between this algorithm and patient notes (R1 in Data S1). Resolution of hypercalcaemia has previously been reported in individuals identified by biochemical screening (R6 in Data S1), especially when the baseline level was only slightly elevated (R7 in Data S1). Because the majority of individuals with mild untreated PHPT in PEARS were normocalcaemic within 1 year of inclusion in the cohort and thereafter had sustained normocalcaemia, we question whether they can be considered to have PHPT and whether the conclusions drawn from (R1–R3 in Data S1) PEARS apply to individuals with PHPT and sustained hypercalcaemia.

Mild primary hyperparathyroidism: a misnomer?

In primary hyperparathyroidism (PHPT) treatment is traditionally offered to symptomatic patients, including those with proven end-organ damage (osteoporosis, renal failure or renal stones), individuals with severe hypercalcemia (serum calcium >2.85 mmol/l), and/or patients under 50 years of age, who in essence are considered to be at high risk of developing compli cations. The vast majority of patients (>80% [1]) do not fit these criteria, often being referred to as having ‘mild’ PHPT, and as such are simply monitored for the development of complications, while receiving no specific treatment.