Impact of acute and chronic low-dose glucocorticoids on protein metabolism

CONTEXT: High-dose glucocorticoids cause acute protein loss by increasing protein breakdown and oxidation. Whether lower glucocorticoid doses, typical of therapeutic use, induce sustained catabolism has not been studied. OBJECTIVE: Our objective was to assess the effect of acute and chronic therapeutic glucocorticoid doses on protein metabolism. DESIGN AND SETTING: We conducted an open longitudinal and a cross-sectional study at a clinical research facility. PATIENTS AND INTERVENTION: Ten healthy subjects were studied before and after a short course of prednisolone (5 and 10 mg/d sequentially for 7 d each). Twelve subjects with inactive polymyalgia rheumatica receiving chronic (>12 months) prednisone (mean = 5.0 +/- 0.8 mg/d) were compared with 12 age- and gender-matched normal subjects. MAIN OUTCOME MEASURE: Whole-body protein metabolism was assessed using a 3-h primed constant infusion of 1-[(13)C]leucine, from which rates of leucine appearance (leucine Ra, an index of protein breakdown), leucine oxidation (Lox, index of protein oxidation) and leucine incorporation into protein (LIP, index of protein synthesis) were estimated. RESULTS: Prednisolone induced an acute significant increase in Lox (P = 0.008) and a fall in LIP (P = 0.08) but did not affect leucine Ra. There was no significant difference between the effects of the 5- and 10-mg prednisolone doses on leucine metabolism. In subjects receiving chronic prednisone therapy, leucine Ra, Lox, and LIP were not significantly different from normal subjects. CONCLUSION: Glucocorticoids stimulate protein oxidation after acute but not chronic administration. This time-related change suggests that glucocorticoid-induced stimulation of protein oxidation does not persist but that a metabolic adaptation occurs to limit protein loss.     

Cephalic phase metabolic responses in normal weight adults

The presence and physiologic importance of cephalic phase insulin release in humans remains controversial. The aim of these studies was to determine whether cephalic phase insulin release could be demonstrated in normal weight subjects and whether it would be associated with changes in blood glucose, free fatty acid, and pancreatic polypeptide levels. The studies were followed by a hyperglycemic clamp to determine whether cephalic responses would alter overall glucose disposal or glucose-stimulated insulin secretion. In all, 17 subjects were studied on two occasions with and without (control study) presentation of food stimuli. Tease-feeding alone (n = 6), or the administration of a sweet taste alone (aspartame, n = 5) failed to stimulate cephalic responses. However, the presentation of the combined stimuli (tease meals plus sweet taste, n = 7) resulted in a significant fall (P less than .005) in blood glucose levels and a variable rise in serum insulin (% insulin rise 38 +/- 15%, P less than .05) and C-peptide levels (7 +/- 6%, NS) within five minutes of the food presentation when compared with control studies, with no change seen in free fatty acid or pancreatic polypeptide levels. The blood glucose fall correlated strongly (r = .90, P less than .01) with a score of the subjective response to the food and taste.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the enteroinsular axis in two strains of obese rat, the fatty Zucker and the JCR:LA-corpulent

The 'fatty' Zucker and more recently the JCR:LA-cp 'corpulent' have been studied extensively as genetic models of the hyperinsulinemia, insulin resistance and abnormal fat metabolism of obesity. It has been hypothesized that an abnormal enteroinsular axis leading to hypersecretion of the insulin releasing hormone gastric inhibitory polypeptide (GIP) could contribute to the hyperinsulinemia of obesity, although this has been controversial. The present study was undertaken to compare the enteroinsular axis in fatty Zucker and JCR:LA-cp rats. The in vivo GIP and insulin responses to an oral glucose challenge, as well as glucose tolerance, were compared in lean and obese phenotypes of both strains as well as the sensitivity of the perfused pancreas to the secretagogues glucose, arginine and GIP. In addition, the effect of perfusate glucose concentration on the beta cell response to GIP was assessed in both strains. Tissue samples from the pancreas were taken for immunocytochemical analysis of comparative size and composition of pancreatic islets. Our results indicate that corpulent rats are hyperGIPemic when compared to fatty Zuckers and that hyperinsulinemia (both in vivo and in vitro) is more severe in the JCR:LA-cp than in the fatty Zucker, as is the degree of insulin resistance (as evidenced by glucose intolerance). Islets of corpulent rats were found to be larger than those of fa/fa rats as well as having a larger area occupied by beta cells. It was concluded that GIP may contribute to fasting hyperinsulinemia in the Zucker rat (as a result of a defective glucose threshold for the insulinotropic action of GIP), whereas the hyperGIPemia of the JCR:LA-cp rat may contribute to the massive nutrient-stimulated hyperinsulinemia observed in the male phenotype of this strain.     

Effect of Ranolazine on A1C and Glucose Levels in Hyperglycemic Patients With Non-ST Elevation Acute Coronary Syndrome

OBJECTIVE

We determined the relationships between glycemia at randomization, concurrent antidiabetic therapy, and change in A1C and fasting plasma glucose (FPG) in patients with diabetes receiving standard treatment for diabetes and randomized to ranolazine or placebo within the MERLIN-TIMI-36 (MERLIN) study. Ranolazine is a novel first-in-class drug approved for treating angina pectoris.

RESEARCH DESIGN AND METHODS

Randomization and 4-month glycemic and antidiabetes drug usage data from MERLIN were analyzed using Spotfire and SAS version 9.1 software.

RESULTS

In patients with diabetes and A1C of ≥8–10% at randomization (n = 171), there was an absolute A1C reduction in the ranolazine group of 1.2% (95% CI −1.4 to −1.0), and the placebo-adjusted (n = 182) decrease in A1C by ranolazine was 0.59% (95% CI −0.99 to −0.20, P < 0.001). In patients with FPG of 150–400 mg/dl at randomization, ranolazine (n = 131) compared with placebo (n = 147) reduced FPG by 25.7 mg/dl (95% CI −43.3 to −8.1, P = 0.001). When changes in either A1C or FPG were correlated to A1C or FPG at randomization, the slopes were significantly steeper for ranolazine than placebo (A1C, P = 0.046; FPG, P < 0.001), indicating that lowering of A1C and FPG by ranolazine is related to hyperglycemia at randomization. Ranolazine, compared with placebo, was not associated with serious hypoglycemic events, associated with significant changes in concurrent antidiabetic therapy, or dependent on a history of angina.

CONCLUSIONS

Ranolazine, when added to concurrent antidiabetes treatment, lowers FPG and A1C in patients with cardiovascular disease and poorly controlled diabetes.Diabetes is an established risk factor for cardiovascular disease, and the risk of cardiovascular disease increases with worsening hyperglycemia (1–3). Furthermore, coronary artery disease is the most common cause of death in patients with diabetes (4). Patients with coronary artery disease and a recent myocardial infarction or acute coronary syndrome (ACS) have an increased incidence of impaired fasting plasma glucose (FPG) and new-onset diabetes (5–7). Management of diabetes in patients with cardiovascular disease is complicated by the fact that the cardiovascular safety of some oral glucose–lowering agents has been questioned, and outcome data are lacking (8).Ranolazine is a first-in-class anti-anginal drug with cardioprotective properties without effects on heart rate or blood pressure (9). The drug inhibits the cardiac late sodium current (10,11). The late sodium current is enhanced during ischemia and in the failing heart and contributes to the Na+-dependent cellular calcium overload associated with these pathological conditions (10,11). Ranolazine has been shown effective in treating chronic angina both as a monotherapy (MARISA trial) and in combination with commonly prescribed cardiovascular drugs (CARISA and ERICA trials) (12–14), with no increase in mortality in patients with established coronary artery disease, including those with diabetes (15,16).Post hoc analysis of data from the CARISA study demonstrated that ranolazine lowered A1C, a long-term biomarker of glucose control, in patients with chronic angina and diabetes, in a dose-dependent manner (17). While the mechanism of glycemic improvement remains incompletely understood, preliminary studies using isolated rat and human pancreatic islets suggest ranolazine may promote glucose-stimulated insulin secretion (18).In the MERLIN-TIMI-36 (MERLIN) study, the effects of ranolazine to lower A1C and glucose were confirmed using prespecified glycemic end points (16). In this study, patients with diabetes were receiving standard of care treatment for diabetes with mean A1C levels of 7.5% at randomization. Despite the relatively low mean A1C at randomization, ranolazine was found to significantly reduce A1C in patients with diabetes and to reduce the incidence of newly elevated A1C in initially normoglycemic patients (16). The mean placebo-corrected reductions in A1C with ranolazine treatment at 4 months were 0.42% (P < 0.001) and 0.18% (P < 0.001) for patients with and without diabetes, respectively. There were no differences in the reported incidence of hypoglycemia between placebo and ranolazine.The glucose-lowering response to multiple antidiabetic therapies is greater in patients with higher baseline A1C and glucose values (19). Therefore, the current analysis of the MERLIN data was undertaken to evaluate the effects of ranolazine on FPG and A1C in diabetic patients with moderate or severe hyperglycemia, defined as an A1C of 6 to <8% or ≥8–10%, or FPG <150 or ≥150–400 mg/dl, respectively, at randomization. Additionally, MERLIN data were assessed as to whether effects of ranolazine on glycemia were influenced by concurrent antidiabetic therapy.     

X-ray requesting patterns before and after introduction of the Ottawa Knee Rules in a UK emergency department.

OBJECTIVES: To compare knee radiology requesting rates among junior doctors before and after the formal introduction of the Ottawa Knee Rules (OKR) in a UK emergency department (ED), and to test the validity of the OKR for decisions on the use of radiography for acute, isolated knee injuries. METHODS: All junior doctors in a district general hospital ED seeing adult patients with isolated knee injuries completed a questionnaire before and after the introduction of the OKR. All patients were followed up to obtain a final diagnosis. The outcome measures were: adherence to the OKR, the presence of a fracture and whether a radiograph had been requested. The results were analysed to determine the sensitivity, specificity, positive and negative predictive values of the OKR. Comparisons between the request rate for knee radiography before and after the introduction of the OKR were made. RESULTS: A total of 130 patients were enrolled and followed up over a 3-month period; 58 before and 72 after OKR introduction. The OKR had a sensitivity of 100% (71.8-100%), a specificity of 55.1% (46.1-64.1%), a positive predictive value of 18.5% (9.03-27.9%) and a negative predictive value of 100% (87.8-100%) for the detection of bony injury. The introduction of the OKR did not result in a significant reduction in the number of radiographs performed (58.6-55.6%; P= 0.726). DISCUSSION: This study shows the OKR to be a highly sensitive clinical guide with a high negative predictive value in the setting of a UK ED. It suggests that the reduction in radiograph requests seen elsewhere may not be as apparent in this setting.     

Impact of growth hormone and dehydroepiandrosterone on protein metabolism in glucocorticoid-treated patients

CONTEXT: Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. OBJECTIVE: Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. DESIGN: This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). SETTING: The studies were performed at a clinical research facility. PATIENTS AND INTERVENTION: In study 1, six subjects (age 69+/-4 yr) treated with long-term (>6 months) GCs (prednisone dose 8.3+/-0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71+/-3 yr) treated with long-term GCs (prednisone dose 5.4+/-0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). MAIN OUTCOME MEASURE: Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. RESULTS: In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P=0.03) and 31% (P=0.02), and increased leucine incorporation into protein by 10% (P=0.13) and 19% (P=0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. CONCLUSION: GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.     

Predicting adherence to immunosuppressant therapy: a prospective analysis of the theory of planned behaviour.

BACKGROUND: The objective of this study was to increase the ability to predict renal transplant patients (RTPs) who are most likely to be non-adherent to their immunosuppressant therapy (IST). METHODS: One hundred and fifty-eight RTPs completed questionnaires assessing Theory of Planned Behaviour (TPB) variables (attitudes, subjective norms and perceived behavioural control) relevant to intentions to adhere to their IST, with the addition of a general measure of past adherence to medical advice. In the full sample, intentions to adhere to IST was the outcome variable. In a subsample of 70 RTPs, the primary outcome was IST adherence. RESULTS: TPB variables (attitudes, beta = 0.32, P < 0.01; perceived behavioural control, beta = 0.37, P < 0.01; but not subjective norms, beta = -0.001, ns) explained 41% of the variance in intentions to adhere to IST (P < 0.001). Past behaviour predicted perceived behavioural control (beta = 0.67, P < 0.001). Subsample analyses explained 33% (P < 0.001) of the variance in adherence, with intentions and past behaviour being the primary factors (P < 0.05). CONCLUSIONS: RTPs particularly at risk may be those who have a history of non-adherence to medical advice, especially when they have negative attitudes about IST adherence and feel they have little control over their medication-taking behaviour. Interventions to improve attitudes about IST adherence and control of adherence behaviour are needed.     

Negative regulation of Caenorhabditis elegans epidermal damage responses by death-associated protein kinase

Wounding of epidermal layers triggers multiple coordinated responses to damage. We show here that the Caenorhabditis elegans ortholog of the tumor suppressor death-associated protein kinase, dapk-1, acts as a previously undescribed negative regulator of barrier repair and innate immune responses to wounding. Loss of DAPK-1 function results in constitutive formation of scar-like structures in the cuticle, and up-regulation of innate immune responses to damage. Overexpression of DAPK-1 represses innate immune responses to needle wounding. Up-regulation of innate immune responses in dapk-1 requires the TIR-1/p38 signal transduction pathway; loss of function in this pathway synergizes with dapk-1 to drastically reduce adult lifespan. Our results reveal a previously undescribed function for the DAPK tumor suppressor family in regulation of epithelial damage responses.