Increase in lumbar spine but not distal radius bone mineral density in adults after pancreas kidney transplantation.

Osteoporosis occurs in every third individual after simultaneous pancreas kidney transplantation (SPKT). Currently used bone measures insufficiently predict their fracture risk. Lumbar spine Trabecular bone score (TBS) and distal radius areal and volumetric bone mineral density (BMD) were monitored for the first time in patients with type 1 diabetes and chronic renal failure after SPKT with steroid-sparing protocol. In 33 subjects (mean age 43.4 ± 9.8 years), dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were performed just after SPKT (baseline) and one and three years later. While TBS Z-scores increased (-1.1 ± 1.2 and -0.3 ± 1.0; p˂0.001, at baseline and year three, respectively), trabecular volumetric BMD Z-scores at distal radius metaphysis did not change during the study (-1.3 ± 1.3 and -1.3 ± 1.0; p = 0.38). Similarly, areal BMD Z-scores increased at lumbar spine, total hip and femoral neck (all p < 0.01), but not at the distal radius. SPKT induced bone measures' improvement at lumbar spine and hip but not at distal radius. Before suggesting changes in current clinical care, predictive value of individual bone measures or its combination for fracture risk assessment remains to be elucidated.

Retrospective Analysis of Bone Metabolism in Patients on Waiting List for Simultaneous Pancreas-Kidney Transplantation.

Posttransplant osteoporosis, which evolves from preexisting bone pathologies, represents a serious complication with deteriorating consequences. The aim of our study was to evaluate epidemiological data on bone mineral density (BMD) in subjects with type 1 diabetes (T1DM) in advanced stages of diabetic nephropathy indicated for simultaneous pancreas-kidney transplantation (SPK). We retrospectively compiled biochemical and densitometrical data from 177 patients with T1DM at CKD (chronic kidney disease) stages G4-G5 (115 men, 62 women, median age 40 yr, diabetes duration 23 yr) enrolled on waiting list for SPK for the first time between the years 2011 and 2016. Median Z-scores were as follows: lumbar spine (LS): -0.8 [interquartile range -1.75 to 0.1]; total hip (TH): -1.2 [-1.75 to -0.6]; femoral neck (FN): -1.2 [-1.9 to -0.7]; and distal radius (DR): -0.8 [-1.4 to -0.1]. We noted a gender difference in LS, with worse results for men (-1.1 vs. -0.3) even after adjusting for BMI (body mass index) and glomerular filtration (p < 0.001). Osteoporotic and osteopenic ranges (based on T-scores) for all major sites were 27.7% and 56.5%, respectively, with similar results across both genders. Women had a significantly higher proportion of normal BMD in LS than men (67.7 vs. 49.4%, p < 0.05). Patients with T1DM at CKD stages G4-G5 exhibited serious BMD impairment despite their young age. Men surprisingly displayed lower Z-scores and higher percentages of pathological BMD values in LS than women did. The introduction of adequate preventive measures during the advanced stages of diabetic nephropathy to prevent bone loss is recommended.

Osteoporosis Therapy With Denosumab in Organ Transplant Recipients.

OBJECTIVE: Osteoporosis and fragility fractures represent serious complications for the solid organ transplant population. The recommended osteoporosis therapy for organ recipients involves supplementation with calcium and vitamin D and bisphosphonate administration. However, these options can prove limited for patients with impaired renal function. An alternative therapy option is offered by denosumab, a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand. PATIENTS AND METHODS: We evaluated 63 patients with osteoporosis (23 males and 40 females, age 56.4 ± 13.1 years) following solid organ transplantation (15 diabetic patients after simultaneous transplantation of the kidney and pancreas, 34 patients after kidney transplantation, and 14 patients with liver grafts). Osteoporosis was diagnosed according to standard DEXA examination using the Lunar Prodigy apparatus. Transplanted patients with impaired renal function were treated for osteoporosis of the lumbar spine (L-spine) and/or proximal femur with calcium and vitamin D supplementation and 60 mg of denosumab every 6 months between the years 2012 and 2017. The mean duration of the therapy was 1.65 ± 0.7 years. RESULTS: After denosumab therapy, L-spine T-scores improved across the whole group, ranging from -2.7 ± 0.09 to -1.8 ± 1.0 (p < 0.001). T-score values for the proximal femur increased from -2.5 ± 0.8 to -2.0 ± 0.7 after the therapy (p < 0.01). We observed only a mild, statistically insignificant improvement in distal forearm T-scores. The mean increase in L-spine bone mineral density (BMD) was 11.5 ± 6.2% in subjects with osteoporosis at this site and 10.4 ± 6.1% in the case of all patients. BMD of the proximal femur increased by 10.4 ± 8.3% in patients with osteoporosis and by 7.5 ± 7.3% in all patients. Denosumab therapy decreased the prevalence of osteoporosis in the L-spine from 75 to 27% (p < 0.001) and proximal femur osteoporosis from 54 to 36% (p < 0.05). Denosumab therapy reduced elevated levels of osteocalcin and beta-crosslaps (ßCTX) in comparison with baseline levels (p < 0.001) across the whole group of graft recipients. CONCLUSION: Denosumab therapy was well-tolerated and improved bone density in our group of solid organ transplant recipients. The indications are that denosumab could be a viable therapeutic option for transplanted patients with osteoporosis, especially in those with renal function impairment or bisphosphonate intolerance.

Intramyocellular lipid content in subjects with impaired fasting glucose after telmisartan treatment, a randomised cross-over trial.

Ectopic lipid accumulation in skeletal muscle is associated with insulin resistance. Telmisartan improves metabolic parameters in type 2 diabetic patients. The aim of our study was to evaluate the in vivo effect of telmisartan on intramyocellular lipid content (IMCL) in subjects with impaired fasting glucose (IFG) by magnetic resonance spectroscopy (MRS). We enrolled 10 subjects with IFG in a cross-over, placebo-controlled, randomized, double-blind trial, treated with 3 weeks of telmisartan (160 mg daily) or placebo. After completing each treatment, a hyperinsulinaemic euglycaemic clamp (1 mU/kg per min; 5 mmol/l; 120 min) to assess insulin action (metabolic clearance rate of glucose, MCR) and (1)H MRS of the m. tibialis anterior using a MR Scanner Siemens Vision operating at 1.5 T to evaluate IMCL content, were performed. Plasma adipokine levels were determined simultaneously. Telmisartan treatment resulted in a lower fasting plasma glucose (FPG) (p < 0.05), but insulin action was comparable to after placebo. Telmisartan did not affect IMCL content. After placebo, IMCL correlated negatively with total cholesterol (p < 0.001), MCR (p < 0.05) and adiponectin (p < 0.05) and positively with FPG (p < 0.05). After telmisartan treatment there was only a positive correlation between IMCL and TNFα (p < 0.05). IMCL content is related to parameters of glucose metabolism and insulin action in sedentary IFG subjects. A short telmisartan treatment did not affect the IMCL content despite its positive effect on FPG. The improvement in FPG was probably mediated through interference with other metabolic pathways.

Effect of telmisartan on selected adipokines, insulin sensitivity, and substrate utilization during insulin-stimulated conditions in patients with metabolic syndrome and impaired fasting glucose.

OBJECTIVE: Telmisartan improves glucose and lipid metabolism in rodents. This study evaluated the effect of telmisartan on insulin sensitivity, substrate utilization, selected plasma adipokines and their expressions in subcutaneous adipose tissue (SAT) in metabolic syndrome. DESIGN AND METHODS: Twelve patients with impaired fasting glucose completed the double-blind, randomized, crossover trial. Patients received telmisartan (160 mg/day) or placebo for 3 weeks and vice versa with a 2-week washout period. At the end of each period, a hyperinsulinemic euglycemic clamp (HEC) combined with indirect calorimetry was performed. During HEC (0, 30, and 120 min), plasma levels of adipokines were measured and a needle biopsy (0 and 30 min) of SAT was performed. RESULTS: Fasting plasma glucose was lower after telmisartan compared with placebo (P<0.05). There were no differences in insulin sensitivity and substrate utilization. We found no differences in basal plasma adiponectin, resistin and tumour necrosis factor α (TNFα), but an increase was found in basal leptin, after telmisartan treatment. Insulin-stimulated plasma adiponectin (P<0.05), leptin and resistin (P<0.001) were increased, whereas TNFα was decreased (P<0.05) after telmisartan treatment. Expression of resistin, but not adiponectin, TNFα and leptin was increased after telmisartan treatment. CONCLUSIONS: Despite the decrease in fasting plasma glucose, telmisartan does not improve insulin sensitivity and substrate utilization. Telmisartan increases plasma leptin as well as insulin-stimulated plasma adiponectin, leptin and resistin, and decreases plasma TNFα during HEC. Changes in plasma adipokines cannot be explained by their expressions in SAT. The changes in plasma adipokines might be involved in the metabolic effects of telmisartan in metabolic syndrome.

Metabolic characteristics of soleus muscle in relation to insulin action in the offspring of hypertensive parents.

Insulin resistance affecting skeletal muscle metabolism is present in the prehypertensive state. The aim of our study was to test the hypothesis that blood pressure value is related to skeletal muscle composition, measured by (31)P magnetic resonance (MR) spectroscopy, and to insulin sensitivity in the offspring of hypertensive parents (OH) and healthy controls. Study groups consisted of 10 healthy young lean OH with normal glucose tolerance, confirmed with oral glucose tolerance test, and 13 controls matched for age, sex, and body mass index. Insulin action was estimated as glucose disposal (M), glucose metabolic clearance rate (MCR), and insulin sensitivity index (M/I) during a 10-hour hyperinsulinemic euglycemic clamp. The sum of immunoreactive insulin values from the oral glucose tolerance test was calculated. (31)P MR spectroscopy was performed on a whole-body MR scanner (Siemens Vision, Erlangen, Germany) operating at 1.5 T and equipped with actively shielded gradient coils. There were no differences in common metabolic and anthropometric parameters between OH and controls except for the blood pressure, which was in the range of normal to high-normal level in OH. Mean blood pressure was significantly higher in OH (95.73 +/- 4.39 vs 83.76 +/- 3.95 mm Hg; P < .001). Trend toward insulin resistance was registered in OH with significantly lower M/I (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg x kg(-1) x min(-1) x mIU(-1) x L(-1); P < .05). There were no significant differences in total serum magnesium (sMg) levels between OH and controls, although a positive correlation exists between sMg and insulin sensitivity expressed as M (r = 0.63, P < .01), MCR (r = 0.54, P < .01), and M/I (r = 0.51, P < .05). No differences in signal intensities of phosphocreatine (PCr), phosphomonoesters, phosphodiesters, inorganic phosphates (Pi), adenosine triphosphates (Patp and betaATP), and calculated concentrations of intracellular ionized magnesium (Mgi) and H(+) ions between the groups were detected. Systolic blood pressure correlates positively with PCr/Patp (r = 0.43, P < .05), Pi/Patp (r = 0.413, P < .05), and Pi/betaATP (r = 0.48, P < .05). Diastolic blood pressure correlates positively only with the ratio Pi/betaATP (r = 0.42, P < .05). The sum of immunoreactive insulin values correlates with PCr/betaATP (r = 0.53, P < .01) and with Pi/betaATP (r = 0.6, P < .01). In conclusion, increase in blood pressure and insulin resistance were confirmed in offspring of OH. Insulin sensitivity is related to sMg and the elevation of blood pressure is associated with the activation of energy metabolism in skeletal muscle. The relationship between muscle energetic characteristics and markers of insulin resistance suggests that the alteration of energy metabolism may be present in early stages of metabolic syndrome.

Intramyocellular lipid quantification from 1H long echo time spectra at 1.5 and 3 T by means of the LCModel technique.

PURPOSE: To introduce a method of independent determination of CH2 and CH3 components of intramyocellular lipids (IMCLs) by using long TE for spectra measurement and LCModel for spectra evaluation, to test this technique in controls and insulin-resistant subjects, and to compare results at 1.5 and 3 T. MATERIALS AND METHODS: Eight healthy volunteers and 11 patients with type 2 diabetes mellitus underwent measurement using a 1.5-T MR scanner; six healthy volunteers were measured using a 3-T MR scanner. Spectra from the tibialis anterior muscle were acquired by using a point resolved spectroscopy (PRESS) sequence with the following parameters: TR/TE/ACQ = 2000 msec/270 msec/256. Spectra were processed by LCModel 6.1 software with two types of adopted basis-set. RESULTS: Spectra with good separation of both CH2 and CH3 components of IMCL and extramyocellular lipids (EMCLs) were obtained and the LCModel routine was successfully applied. The reproducibility comparison (N= 7 at 1.5 T vs. N = 5 at 3 T) showed that better results can be obtained at higher B0 values. The comparison of the healthy and insulin-resistant subjects proved that both IMCL_CH2/Cr and IMCL_CH3/Cr ratios significantly differ. CONCLUSION: Long TE spectroscopy of the human muscle with IMCL quantification using the LCModel technique can detect changes in IMCL levels as well as help in the study of fatty acyl chain composition. Using a higher field strength increased the intra-individual reproducibility by approximately 150%.