Brenda L. Mangelsdorf

Effects of Low-Dose Prednisolone on Hepatic and Peripheral Insulin Sensitivity, Insulin Secretion, and Abdominal Adiposity in Patients With Inflammatory Rheumatologic Disease

OBJECTIVE The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations. RESEARCH DESIGN AND METHODS Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-2H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography. RESULTS Prednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different. CONCLUSIONS Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.

Acute effect of calcium citrate on serum calcium and cardiovascular function.

Calcium supplements have been associated with an increased risk of cardiovascular events. However, the validity of these findings has been questioned. A major concern is that the mechanism underlying an increase in cardiovascular events has not been demonstrated. Calcium initiates cardiac and vascular contraction following influx of calcium into cardiac and smooth muscle from extracellular fluid. We have investigated whether the acute rise in serum calcium following calcium supplement administration is associated with adverse changes in cardiovascular function. In an open interventional study, we recruited 25 volunteers (16 female, age 60.3 ± 6.5 years, body mass index 25.7 ± 2.7 kg/m2) from the community who were not taking calcium supplements. Participants were studied before and 3 hours after a single oral dose of 1000 mg calcium citrate. We assessed well‐validated markers of arterial stiffness (pulse wave velocity [PWV]), arterial wave reflection (augmentation index [AIx]), and myocardial perfusion (subendocardial viability ratio [SEVR]) by pulse wave analysis and endothelial function (reactive hyperemia index [RHI]) by peripheral arterial tonometry. Total and ionized serum calcium were acutely increased by 0.10 ± 0.07 and 0.06 ± 0.03 mmol/L, respectively, 3 hours after calcium citrate administration (p < 0.0001 for both comparisons). Following administration of calcium citrate there was a fall in AIx from a median of 29.7% (23.8% to 34.0%) to 26.4% (22.7% to 34.0%, p = 0.03) and an increase in SEVR from 163% (148% to 174%) to 170% (149% to 185%, p = 0.007). PWV and RHI were not significantly altered. The change in total calcium was negatively correlated with the change in AIx (r = –0.48, p = 0.02). In summary, the acute increase in serum calcium following calcium supplement administration is associated with reduced arterial wave reflection and a marker of increased myocardial perfusion. If maintained long‐term, these changes would be expected to reduce cardiovascular risk. Acute serum calcium–mediated changes in these parameters of cardiovascular function are unlikely to underlie an association between calcium supplementation and cardiovascular events.

Acute Effect of Increasing Glucocorticoid Replacement Dose on Cardiovascular Risk and Insulin Sensitivity in Patients With Adrenocorticotrophin Deficiency

CONTEXT Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined. OBJECTIVE The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulins hemodynamic effects was responsible for this effect. DESIGN We conducted an open interventional study between 2011 and 2013. SETTING The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia. PATIENTS Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied. INTERVENTION Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d. MAIN OUTCOME MEASURE The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load. RESULTS Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose. CONCLUSIONS Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.

Free and Total Plasma Cortisol Measured by Immunoassay and Mass Spectrometry Following ACTH1–24 Stimulation in the Assessment of Pituitary Patients

CONTEXT Measurement of plasma cortisol by immunoassay after ACTH₁₋₂₄ stimulation is used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Liquid chromatography-tandem mass spectrometry (LCMS) has greater analytical specificity than immunoassay and equilibrium dialysis allows measurement of free plasma cortisol. OBJECTIVE We investigated the use of measuring total and free plasma cortisol by LCMS and total cortisol by immunoassay during an ACTH₁₋₂₄ stimulation test to define HPA status in pituitary patients. DESIGN AND SETTING This was a case control study conducted in a clinical research facility. PARTICIPANTS We studied 60 controls and 21 patients with pituitary disease in whom HPA sufficiency (n = 8) or deficiency (n = 13) had been previously defined. INTERVENTION Participants underwent 1 μg ACTH(1-24) intravenous and 250 μg ACTH₁₋₂₄ intramuscular ACTH₁₋₂₄ stimulation tests. MAIN OUTCOME MEASURES Concordance of ACTH₁₋₂₄-stimulated total and free plasma cortisol with previous HPA assessment. RESULTS Total cortisol was 12% lower when measured by immunoassay than by LCMS. Female sex and older age were positively correlated with ACTH₁₋₂₄-stimulated total and free cortisol, respectively. Measurements of total cortisol by immunoassay and LCMS and free cortisol 30 minutes after 1 μg and 30 and 60 minutes after 250 μg ACTH₁₋₂₄ were concordant with previous HPA axis assessment in most pituitary patients. However, free cortisol had greater separation from the diagnostic cutoff than total cortisol. CONCLUSIONS Categorization of HPA status by immunoassay and LCMS after ACTH₁₋₂₄ stimulation was concordant with previous assessment in most pituitary patients. Free cortisol may have greater clinical use in patients near the diagnostic threshold.

Effect of acute and chronic glucocorticoid therapy on insulin sensitivity and postprandial vascular function.

Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low‐dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis.

Effects of prednisolone on energy and fat metabolism in patients with rheumatoid arthritis: tissue-specific insulin resistance with commonly used prednisolone doses

Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low‐dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism.

Treatment of prednisolone-induced hyperglycaemia in hospitalized patients: Insights from a randomized-controlled study.

Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine‐based basal‐bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane‐based insulin regimen is safer and more effective than a glargine‐based regimen in hospitalized patients.

Relationship between Vitamin D Status and Autonomic Nervous System Activity

Vitamin D deficiency is associated with increased arterial stiffness. However, the mechanisms underlying this association have not been clarified. The aim was to investigate whether changes in autonomic nervous system activity could underlie an association between 25 hydroxy vitamin D and arterial stiffness. A total of 49 subjects (age = 60 ± 8 years, body mass index = 26.7 ± 4.6 kg/m2, 25 hydroxy vitamin D = 69 ± 22 nmol/L) underwent measurements of pulse wave velocity (PWV) and augmentation index (AIx), spontaneous baroreflex sensitivity, plasma metanephrines and 25 hydroxy vitamin D. Subjects with 25 hydroxy vitamin D ≤ 50 nmol/L were restudied after 200,000 International Units 25 hydroxy vitamin D. Plasma metanephrine was positively associated with AIx (p = 0.02) independent of age, sex, smoking and cholesterol and negatively associated with 25 hydroxy vitamin D (p = 0.002) independent of age, sex and season. In contrast, there was no association between baroreflex sensitivity and 25 hydroxy vitamin D (p = 0.54). Treatment with vitamin D increased 25 hydroxy vitamin D from 43 ± 5 to 96 ± 24 nmol/L (p < 0.0001) but there was no significant change in plasma metanephrine (115 ± 25 vs. 99 ± 39 pmol/L, p = 0.12). We conclude that as plasma metanephrine was negatively associated with 25 hydroxy vitamin D and positively with AIx, it could mediate an association between these two variables. This hypothesis should be tested in larger interventional studies.

Thrombospondin-1 is a glucocorticoid responsive protein in humans

OBJECTIVE Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. DESIGN AND METHODS Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushings syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. RESULTS In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P<0.0001) and plasma TSP1 concentrations (P<0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushings, 638 (535-756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P<0.0001). Plasma TSP1 >400 ng/ml diagnosed Cushings syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P<0.01) in patients with secondary adrenal insufficiency. CONCLUSIONS TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.