Comparison of regional fat measurements by dual-energy X-ray absorptiometry and conventional anthropometry and their association with markers of diabetes and cardiovascular disease risk.

BACKGROUND/OBJECTIVES: Fat distribution is a strong and independent predictor of type 2 diabetes (T2D) and cardiovascular disease (CVD) and is usually determined using conventional anthropometry in epidemiological studies. Dual-energy X-ray absorptiometry (DXA) can measure total and regional adiposity more accurately. Nonetheless, whether DXA provides more precise estimates of cardiovascular risk in relation to total and regional adiposity is not known. We determined the strength of the associations between DXA- and conventional anthropometry determined fat distribution and T2D and CVD risk markers. SUBJECTS/METHODS: Waist (WC) and hip circumference (HC) and DXA was used to measure total and regional adiposity in 4950 (2119 men) participants aged 29-55 years from the Oxford Biobank without pre-existing T2D or CVD. Cross-sectional associations were compared between WC and HC vs. DXA-determined regional adiposity (all z-score normalised) with impaired fasting glucose, hypertriglyceridemia, hypertension and insulin resistance (IR). RESULTS: Following adjustment for total adiposity, upper body adiposity measurements showed consistently increased risk of T2D and CVD risk markers except for abdominal subcutaneous fat in both sexes, and arm fat in men, which showed protective associations. Among upper adiposity depots, visceral fat mass showed stronger odds ratios (OR) ranging from 1.69 to 3.64 compared with WC 1.07-1.83. Among lower adiposity depots, HC showed modest protection for IR in both sexes (men: OR 0.80 (95% confidence interval 0.67, 0.96); women: 0.69 (0.56, 0.86)), whereas gynoid fat and in particular leg fat showed consistent and strong protective effects for all outcomes in both men and women. The differential effect of body fat distribution on CVD and T2D were more pronounced at higher levels of total adiposity. CONCLUSIONS: Compared with DXA, conventional anthropometry underestimates the associations of regional adiposity with T2D and CVD risk markers. After correcting for overall adiposity, greater subcutaneous fat mass in particular in the lower body is protective relative to greater android or visceral adipose tissue mass.

Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity.

AIM: The Wnt/ß-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo. METHODS: We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the involvement of SFRP1. RESULTS: SFRP1 is expressed in both murine and human mature adipocytes. The expression of SFRP1 is induced during in vitro adipogenesis, and SFRP1 is preferentially expressed in mature adipocytes in human adipose tissue. Constitutive ectopic expression of SFRP1 is proadipogenic and inhibits the Wnt/ß-catenin signaling pathway. In vivo endogenous levels of adipose SFRP1 are regulated in line with proadipogenic states. However, in longitudinal studies of high-fat-diet-fed mice, we observed a dynamic temporal but biphasic regulation of endogenous SFRP1. In agreement with this profile, we observed that SFRP1 expression in human tissues peaks in patients with mild obesity and gradually falls in morbidly obese subjects. CONCLUSIONS: Our results suggest that SFRP1 is an endogenous modulator of Wnt/ß-catenin signaling and participates in the paracrine regulation of human adipogenesis. The reduced adipose expression of SFRP1 in morbid obesity and its knock-on effect to prevent further adipose tissue expansion may contribute to the development of metabolic complications in these individuals.

Intra-renal localization of b2-microglobulin (b2-m) in renal transplant material. An immunohistochemical study.

The distribution of b2-m immunoreactivity in biopsy material (paraffin sections) of 34 patients with renal transplantation was examined. b2-m was present along the glomerular capillary walls and in cytoplasm of the epithelial cells of convoluted tubules and mainly towards their basement membranes in 15 out of 17 with acute rejection, in 5 out of 8 with chronic rejection and only one case of normal donor. The more frequent detection and the more intense staining of b2-m in acute kidney rejection are discussed.

Wnt signaling in cardiovascular physiology.

Wnt signaling pathways play a key role in cardiac development, angiogenesis, and cardiac hypertrophy; emerging evidence suggests that they are also involved in the pathophysiology of atherosclerosis. Specifically, an important role for Wnts has been described in the regulation of endothelial inflammation, vascular calcification, and mesenchymal stem cell differentiation. Wnt signaling also induces monocyte adhesion to endothelial cells and is crucial for the regulation of vascular smooth-muscle cell (VSMC) behavior. We discuss how the Wnt pathways are implicated in vascular biology and outline the role of Wnt signaling in atherosclerosis. Dissecting Wnt pathways involved in atherogenesis and cardiovascular disease may provide crucial insights into novel mechanisms with therapeutic potential for atherosclerosis.

WNT10B mutations in human obesity.

AIMS/HYPOTHESIS: Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene. SUBJECTS AND METHODS: We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin. RESULTS: One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties. CONCLUSIONS/INTERPRETATION: These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.

In-patient management of diabetes mellitus and patient satisfaction.

AIMS: To devise a system for assessing in-patient glycaemic control and care satisfaction in diabetic patients admitted to hospital for reasons other than their diabetes. METHODS: Consecutive January to March 2001 case-notes were reviewed. Admissions with acute metabolic complications, acute myocardial infarction and pregestational or gestational diabetes were excluded. Glycaemic control, frequency of blood monitoring and management of hyperglycaemia were recorded. The diabetes treatment satisfaction questionnaire was used to assess preadmission satisfaction with care. Post-admission a 12-stem questionnaire was used to assess satisfaction with in-patient diabetes management. RESULTS: Hypoglycaemia was common. Although none developed a hyperglycaemic emergency, high blood glucose was prevalent and, frequently, persistent hyperglycaemia or recurrent hypoglycaemia was not acted on appropriately. The overall score for in-patient satisfaction with treatment was fair (4.1 +/- 1.8 on a six-point scale; 6 = very satisfied and 1 = very dissatisfied). Scores were higher among patients on surgical wards than on medical wards (P = 0.008), but satisfaction did not vary when patients were stratified according to sex, age and mode of treatment. CONCLUSION: Current systems are not achieving satisfactory in-patient glycaemic control and there is poor satisfaction with medical in-patient diabetes care. Following changes intended to produce improvements, this assessment system can be used recurrently to monitor in-patient care and satisfaction.

Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects.

Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) is an accessory protein which can potentiate the transcriptional activation function of many nuclear hormone receptors. Its tissue distribution and physiological studies suggest that its principal in vivo roles are to promote cold-induced thermogenesis, mitochondrial biogenesis, hepatic gluconeogenesis, and fatty acid beta-oxidation. It is expressed in the white adipose tissue of both humans and rodents, and in rodents it has been suggested to mediate in part the leptin-induced conversion of white adipocytes from fat storing to fat oxidising cells. In this study, quantitative real-time PCR has been used in human tissue to demonstrate that (1) PGC1alpha mRNA levels in subcutaneous fat are three-fold lower in morbidly obese than in slim subjects; (2) there are no differences in PGC1alpha mRNA between omental and subcutaneous mature adipocytes; (3) there is a robust induction of PGC1alpha expression during subcutaneous human preadipocyte differentiation ex vivo. Whether low PGC1alpha expression is a prelude to the development of obesity, or a consequence of that obesity, attempts to upregulate endogenous white adipose tissue expression may prove a valuable new avenue to explore in obesity therapy.

Monoclonal gammopathy in chronic myeloproliferative disorders.

The incidence of monoclonal gammopathy in 61 patients with chronic myeloproliferative disorders (CMPD) was studied. The distribution of patients among the CMPD subgroups was: chronic myelocytic leukemia, 24 patients; myelofibrosis, 11; polycythemia vera, 15; essential thrombocythemia, 7; unclassified MPD, 4 patients. Monoclonal gammopathy was found in 5 patients (8.2%). Two of these patients (1 IgA/k and 1 IgM/k) had myelofibrosis and 3 (2 IgG/k and 1 IgG/lambda) polycythemia vera. The presence of monoclonal gammopathy indicates an involvement of the lymphoplasmatic system in CMPD.