Critical illness-induced bone loss is related to deficient autophagy and histone hypomethylation

BACKGROUND Survivors of critical illness are at increased risk of fractures. This may be due to increased osteoclast formation during critical illness, leading to trabecular bone loss. Such bone loss has also been observed in Paget's disease, and has been related to deficient autophagy. Deficient autophagy has also been documented in vital organs and skeletal muscle of critically ill patients. The objective of this study was to investigate whether deficient autophagy can be linked to critical illness-induced bone loss. METHODS Osteoclasts grown in vitro and their precursor cells isolated from peripheral blood of critically ill patients and from matched healthy volunteers were analysed for the expression of autophagy genes (SQSTM1, Atg3 and Atg7), and proteins (p62, Atg-5, and microtubule-associated protein light chain 3-II (LC3-II)) and for autophagy and epigenetic signalling factors via PCR arrays and were treated with the autophagy inducer rapamycin. The effect of rapamycin was also investigated at the tissue level in an in vivo rabbit model of critical illness. RESULTS Many more osteoclasts formed in vitro from the blood precursor cells isolated from critically ill patients, which accumulated p62, and displayed reduced expression of Atg5, Atg7, and LC3-II compared to healthy controls, suggesting deficient autophagy, whilst addition of rapamycin reduced osteoclast formation. PCR arrays revealed a down-regulation of histone methyltransferases coupled with an up-regulation of negative regulators of autophagy. Critically ill rabbits displayed a reduction in trabecular and cortical bone, which was rescued with rapamycin. CONCLUSIONS Deficient autophagy in osteoclasts and their blood precursor cells at least partially explained aberrant osteoclast formation during critical illness and was linked to global histone hypomethylation. Treatment with the autophagy activator Rapamycin reduced patient osteoclast formation in vitro and reduced the amount of bone loss in critically ill rabbits in vivo. These findings may help to develop novel therapeutic targets to prevent critical illness-induced bone loss

Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients

Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T(3) and high rT(3) levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment. Serum thyroid parameters and the expression of tissue D1-D3 were determined. Serum TSH, T(4), T(3), and the T(3)/rT(3) ratio were lower, whereas serum rT(3) was higher than in normal subjects (P < 0.0001). Liver D1 activity was down-regulated and D3 activity was induced in liver and skeletal muscle. Serum T(3)/rT(3) ratio correlated positively with liver D1 activity (P < 0.001) and negatively with liver D3 activity (ns). These parameters were independent of the type of insulin treatment. Liver D1 and serum T(3)/rT(3) were highest in patients who died from severe brain damage, intermediate in those who died from sepsis or excessive inflammation

Effects of an educational program and a standardized insulin order form on glycemic outcomes in non-critically ill hospitalized patients

BACKGROUND: The optimal approach to managing hyperglycemia in noncritically ill hospital patients is unclear. OBJECTIVE: To investigate the effects of targeted quality improvement interventions on insulin prescribing and glycemic control. DESIGN: A cohort study comparing an intervention group (IG) to a concurrent control group (CCG) and an historic control group (HCG). SETTING: University of Michigan Hospital. PATIENTS: Hyperglycemic, noncritically ill hospital patients treated with insulin. INTERVENTION: Physician and nurse education and a standardized insulin order form based on the principles of physiologic insulin use. MEASUREMENTS: Glycemic control and insulin prescribing patterns. RESULTS: Patients in the IG were more likely to be treated with a combination of scheduled basal and nutritional insulin than in the other groups. In the final adjusted regression model, patients in the IG were more likely to be in the target glucose range (odds ratio [OR], 1.72; P = 0.01) and less likely to be severely hyperglycemic (OR, 0.65; P < 0.01) when compared to those in the CCG. Patients in the IG were also less likely to experience hypoglycemia than those in the CCG ( P = 0.06) or the HCG ( P = 0.01). Over 80% of all patient-days for all groups contained glucose readings outside of the target range. CONCLUSIONS: Standardized interventions encouraging the physiologic use of subcutaneous insulin can lead to significant improvements in glycemic control and patient safety in hospitalized patients. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. Additional research is needed to determine the best strategy for safely achieving metabolic control in these patients. Journal of Hospital Medicine 2010. © 2010 Society of Hospital Medicine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78247/1/780_ftp.pd