scholarly journals Co-administration of 5α-reductase Inhibitors Worsens the Adverse Metabolic Effects of Prescribed Glucocorticoids

2020 ◽  
Vol 105 (9) ◽  
pp. e3316-e3328 ◽  
Author(s):  
Nantia Othonos ◽  
Thomas Marjot ◽  
Conor Woods ◽  
Jonathan M Hazlehurst ◽  
Nikolaos Nikolaou ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Fatty Acids ◽  
Adverse Effects ◽  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Randomized Study ◽  
Metabolic Effects ◽  
Healthy Male ◽  
Nonesterified Fatty Acids ◽  
Reductase Inhibitors

Abstract Context Glucocorticoids (GCs) are commonly prescribed, but their use is associated with adverse metabolic effects. 5α-reductase inhibitors (5α-RI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs. Objective We hypothesized that 5α-RI may worsen the adverse effects of GCs. Design Prospective, randomized study. Patients A total of 19 healthy male volunteers (age 45 ± 2 years; body mass index 27.1 ± 0.7kg/m2). Interventions Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable isotopes, adipose tissue microdialysis, and biopsy. Participants were then randomized to either prednisolone (10 mg daily) or prednisolone (10 mg daily) plus a 5α-RI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated. Main Outcome Measures Ra glucose, glucose utilization (M-value), glucose oxidation, and nonesterified fatty acids (NEFA) levels. Results Co-administration of prednisolone with a 5α-RI increased circulating prednisolone levels (482 ± 96 vs 761 ± 57 nmol/L, P = 0.029). Prednisolone alone did not alter Ra glucose (2.55 ± 0.34 vs 2.62 ± 0.19 mg/kg/minute, P = 0.86), M-value (3.2 ± 0.5 vs 2.7 ± 0.7 mg/kg/minute, P = 0.37), or glucose oxidation (0.042 ± 0.007 vs 0.040 ± 0.004 mmol/hr/kg/minute, P = 0.79). However, co-administration with a 5α-RI increased Ra glucose (2.67 ± 0.16 vs 3.05 ± 0.18 mg/kg/minute, P < 0.05) and decreased M-value (4.0 ± 0.5 vs 2.6 ± 0.4 mg/kg/minute, P < 0.05), and oxidation (0.043 ± 0.003 vs 0.036 ± 0.002 mmol/hr/kg, P < 0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1 ± 28.9 vs 36.8 ± 14.3 μmol/L, P = 0.81), unless co-administered with a 5α-RI (49.8 ± 8.6 vs 88.5 ± 13.5 μmol/L, P < 0.01). Conclusions We have demonstrated that 5α-RIs exacerbate the adverse effects of prednisolone. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects.

scholarly journals Effects of peroral alanine administration in lactating ewes with decreased availability of glucose

1997 ◽  
Vol 78 (5) ◽  
pp. 805-813 ◽  
Author(s):  
Kjell Holtenius ◽  
Paul Holtenius
Keyword(s):  
Fatty Acids ◽  
Plasma Level ◽  
Free Fatty Acids ◽  
Skeletal Muscles ◽  
Plasma Insulin ◽  
Glucose Oxidation ◽  
Negative Energy ◽  
Crossover Design ◽  
Metabolic Effects ◽  
Significant Elevation

The metabolic effects of a phlorizin-induced drainage of glucose were studied in six lactating ewes with or without peroral alanine drenches in a study of crossover design. Phlorizin gave rise to a small, but significant, elevation of plasma β-hydroxybutyrate. The plasma level of alanine decreased by about 30 % due to the phlorizin injections and alanine was negatively correlated to β-hydroxybutyrate. The plasma level of free fatty acids increased due to phlorizin. Plasma insulin and glucose concentrations were not significantly affected by phlorizin while glucagon level showed a small but significant increase. Peroral alanine drenches to phlorizin-treated ewes gave rise to a transitory elevation of alanine in plasma. The plasma level of free fatty acids was about 40 % lower in phlorizin-treated ewes receiving alanine and β-hydroxybutyrate tended to be lower (P < 0.08). We suggest that β-hydroxybutyrate, apart from its function as an oxidative fuel, might play an important role by limiting glucose oxidation and protein degradation in skeletal muscles during periods of negative energy balance in ruminants. Furthermore, it is suggested that alanine supplementation decreases lipolysis and ketogenesis in lactating ewes.

Effects of fasting on blood plasma levels, metabolism and metabolic effects of epinephrine and norepinephrine in steers

1988 ◽  
Vol 118 (2) ◽  
pp. 254-259 ◽  
Author(s):  
Daniel Fröhli ◽  
Jürg W. Blum
Keyword(s):  
Fatty Acids ◽  
Blood Plasma ◽  
Plasma Levels ◽  
Food Restriction ◽  
Metabolic Effects ◽  
Immunoreactive Insulin ◽  
Metabolic Clearance ◽  
Clearance Rates ◽  
Nonesterified Fatty Acids ◽  
Before And After

Abstract. Experiments were designed to study effects of 3 days of fasting on blood plasma levels, metabolic clearance rates (MCR) and effects of norepinephrine (NE) and epinephrine (E) on levels of glucose, nonesterified fatty acids (NEFA) and immunoreactive insulin (IRI) in 12 steers. During fasting, levels of E, NE and protein did not change, whereas IRI, T3 and glucose decreased and NEFA, acetoacetate and β-hydroxybutyrate increased. Before and at the end of fasting, NE or E were iv infused for 120 min. NE and E were elevated after 15 min and to the end of the infusion. The increase in E, but not in NE, was significantly greater after 3 days of fasting than before fasting (P < 0.05). MCR for E was lower after fasting (299 ± 17 vs 204 ± 10 ml·kg−0.75·min−1; P < 0.001), whereas MCR for NE was not significantly different (455 ± 37 vs 400 ±27 ml·kg−0.75·min−1). MCR was higher for NE than for E, both before and after fasting (P < 0.05). After the infusions, E and NE decreased within minutes to pre-infusion concentrations. During E infusions, NEFA increased significantly more, whereas glucose increased less in fasted than in fed animals. During NE infusions, NEFA increased in fasted, but not in fed animals, and glucose increased less at the end than before fasting. IRI decreased during E infusions only in fed animals, and transiently increased after the infusion, except after NE infusion in fasted steers. Changes in plasma levels, clearance rates and sensitivity to effects of NE and E, together with alterations of insulin and T3 concentrations, may contribute to shifts in energy metabolism during food restriction.

Metabolic effects of treadmill exercise training on the diabetic heart

1992 ◽  
Vol 73 (1) ◽  
pp. 265-271 ◽  
Author(s):  
D. J. Paulson ◽  
R. Mathews ◽  
J. Bowman ◽  
J. Zhao
Keyword(s):  
Exercise Training ◽  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Plasma Lipids ◽  
High Energy ◽  
Diabetic Rats ◽  
Metabolic Effects ◽  
Sedentary Control ◽  
Oxidation Rates

This study determined whether exercise training in rats would prevent the accumulation of lipids and depressed glucose utilization found in hearts from diabetic rats. Diabetes was induced by intravenous streptozotocin (60 mg/kg). Trained diabetic rats were run on a treadmill for 60 min, 27 m/min, 10% grade, 6 days/wk for 10 wk. Training of diabetic rats had no effect on glycemic control but decreased plasma lipids. In vivo myocardial long-chain acylcarnitine, acyl-CoA, and high-energy phosphate levels were similar in sedentary control, sedentary diabetic, and trained diabetic groups. The levels of myocardial triacylglycerol were similar in sedentary control and diabetic rats but decreased in trained diabetic rats. Hearts were perfused with buffer containing diabetic concentrations of glucose (22 mM) and palmitate (1.2 mM). D-[U-14C] glucose oxidation rates (14CO2 production) were depressed in hearts from sedentary diabetic rats relative to sedentary control rats. Hearts from trained diabetic rats exhibited increased glucose oxidation relative to those of sedentary diabetic rats, but this improvement was below that of the sedentary control rats. [9,10(-3)H]palmitate oxidation rates (3H2O production) were identical in all three groups. These findings suggest that exercise training resulted in a partial normalization of myocardial glucose utilization in diabetic rats.

Effects of nonesterified fatty acids on glucose metabolism after glucose ingestion

Diabetes ◽  
1997 ◽  
Vol 46 (10) ◽  
pp. 1586-1593 ◽  
Author(s):  
Y. T. Kruszynska ◽  
M. I. Mulford ◽  
J. G. Yu ◽  
D. A. Armstrong ◽  
J. M. Olefsky
Keyword(s):  
Fatty Acids ◽  
Glucose Metabolism ◽  
Nonesterified Fatty Acids ◽  
Glucose Ingestion

scholarly journals Sirtuin 3 Restores Synthesis and Secretion of Very Low-Density Lipoproteins in Cow Hepatocytes Challenged with Nonesterified Fatty Acids In Vitro

2021 ◽  
Vol 8 (7) ◽  
pp. 121
Author(s):  
Dongmei Xing ◽  
Baogen Wang ◽  
Hong Lu ◽  
Tao Peng ◽  
Jianming Su ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Dairy Cows ◽  
Low Density Lipoproteins ◽  
Mrna Abundance ◽  
Low Density ◽  
Sirtuin 3 ◽  
Very Low Density Lipoproteins ◽  
Nonesterified Fatty Acids ◽  
Tag Accumulation

Fatty liver is closely associated with elevated concentrations of nonesterified fatty acids (NEFA) and a low level of very low-density lipoproteins (VLDL) in blood of dairy cows. High NEFA inhibit the VLDL synthesis and assembly, and cause hepatic triacylglycerol (TAG) deposition. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, antagonizes NEFA-induced TAG accumulation through modulating expressions of fatty acid synthesis and oxidation genes in cow hepatocytes. However, the role of SIRT3 in the VLDL synthesis and assembly was largely unknown. Here we aimed to test whether SIRT3 would recover the synthesis and assembly of VLDL in cow hepatocytes induced by high NEFA. Primary cow hepatocytes were isolated from 3 Holstein cows. Hepatocytes were infected with SIRT3 overexpression adenovirus (Ad-SIRT3), SIRT3-short interfering (si) RNA, or first infected with Ad-SIRT3 and then incubated with 1.0 mM NEFA (Ad-SIRT3 + NEFA). Expressions of key genes in VLDL synthesis and the VLDL contents in cell culture supernatants were measured. SIRT3 overexpression significantly increased the mRNA abundance of microsomal triglyceride transfer protein (MTP), apolipoprotein B100 (ApoB100) and ApoE (p < 0.01), and raised VLDL contents in the supernatants (p < 0.01). However, SIRT3 silencing displayed a reverse effect in comparison to SIRT3 overexpression. Compared with NEFA treatment alone, the Ad-SIRT3 + NEFA significantly upregulated the mRNA abundance of MTP, ApoB100 and ApoE (p < 0.01), and increased VLDL contents in the supernatants (p < 0.01). Our data demonstrated that SIRT3 restored the synthesis and assembly of VLDL in cow hepatocytes challenged with NEFA, providing an in vitro basis for further investigations testing its feasibility against hepatic TAG accumulation in dairy cows during the perinatal period.

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