Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose

This is the final version of the article. Available from the publisher via the DOI in this record.OBJECTIVE: Matricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS: Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 +/- 3.7 kg). Another six lean subjects underwent fast-food-based hyperalimentation for 4 weeks (weight gain: 7.2 +/- 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses. RESULTS: SPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment-insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein. CONCLUSIONS: Our data suggest that SPARC expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity.This work was supported by Diabetes UK, Swedish Research Council (11285), University Hospital of Linkoping Research Funds; Diabetes Research Centre of Linkoping University; and the Gamla Tjaenarinnor Foundation. No potential conflicts of interest relevant to this article were reported. Parts of this study were presented in abstract form at the 69th Scientific Sessions of the American Diabetes Association, New Orleans, Louisiana, 5–9 June 2009

Effect of Contemporary Bariatric Surgical Procedures on Type 2 Diabetes Remission. A Population-Based Matched Cohort Study.

OBJECTIVE: The objective of the study is to evaluate the effect of gastric banding, gastric bypass and sleeve gastrectomy on medium to long-term diabetes control in obese participants with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Matched cohort study using primary care electronic health records from the UK Clinical Practice Research Datalink. Obese participants with type 2 diabetes who received bariatric surgery from 2002 to 2014 were compared with matched control participants who did not receive BS. Remission was defined for each year of follow-up as HbA1c <6.5 % and no antidiabetic drugs prescribed. RESULTS: There were 826 obese participants with T2DM who received bariatric surgery including adjustable gastric banding (LAGB) 220; gastric bypass (GBP) 449; or sleeve gastrectomy (SG) 153; with four procedures undefined. Mean HbA1c declined from 8.0 % before BS to 6.5 % in the second postoperative year; proportion with HbA1c <6.5 % (<48 mmol/mol) increased from 17 to 47 %. The proportion of patients in remission was 30 % in the second year, being 20 % for LAGB, 34 % for GBP and 38 % for SG. The adjusted relative rate of remission over the first six postoperative years was 5.97 (4.86 to 7.33, P < 0.001) overall; for LAGB 3.32 (2.27 to 4.86); GBP 7.16 (5.64 to 9.08); and SG 6.82 (5.05 to 9.19). Rates of remission were maintained into the sixth year of follow-up. CONCLUSIONS: Remission of diabetes may continue for up to 6 years after bariatric surgical procedures. Diabetes outcomes are generally more favourable after gastric bypass or sleeve gastrectomy than LAGB

Increased expression of vascular endothelial growth factor-a in seasonal allergic rhinitis

Increased vascular dilatation and permeability characterize allergic rhinitis. In this study oligonucleotide microarrays (Affymetrix HuGe95A) were used to identify differentially expressed vasoactive genes in nasal biopsies from 23 patients with symptomatic seasonal allergic rhinitis (SAR) and 12 healthy controls. RNA was extracted from the biopsies and pooled in three patient and three control pools. Out of 12 626 analysed transcripts, 39 were higher and 81 lower in the patients. Of these transcripts two have vasoactive effects: Vascular Endothelial Growth Factor-A (VEGF-A) and the Beta-1-Adrenergic Receptor. Both were higher in patients than in controls. The mean +/- SEM expression levels in arbitrary units of VEGF-A were 130 123 in the patients and 59 53 in the controls. The fold ratio in expression levels between patients/ controls was 2.2. The corresponding values for the beta-1-adrenergic receptor were 129 +/-123 in the patients and 40 +/- 31 in the controls. The fold ratio between patient/controls was 3.2. The role of VEGF-A was assessed by determining VEGF-A concentrations in nasal fluids from another 30 patients with SAR before and after allergen provocation. VEGF-A increased from 1243 +/- 30.2 to 163.2 +/- 37.8 pg/ml after challenge, P<0.05. In summary, oligonucleotide microarray analysis of nasal biopsies and protein analyses of nasal fluids indicate that VEGF-A may be an important mediator in SAR. (C) 2003 Elsevier Science Ltd. All rights reserved

DNA microarray analysis of chromosomal susceptibility regions to identify candidate genes for allergic disease: A pilot study

Objective-To examine whether DNA microarray analysis of chromosomal susceptibility regions for allergy can help to identify candidate genes. Material and Methods-Nasal biopsies were obtained from 23 patients with allergic rhinitis and 12 healthy controls. RNA was extracted from the biopsies and pooled into three patient and three control pools. These were then analysed in duplicate with DNA microarrays containing 12626 genes. Candidate genes were further examined in nasal biopsies (real-time polymerase chain reaction) and blood samples (single nucleotide polymorphisms) from other patients with allergic rhinitis and from controls. Results-A total of 37 differentially expressed genes were identified according to criteria involving both the size and consistency of the gene expression levels. The chromosomal location of these genes was compared with the chromosomal susceptibility regions for allergic disease. Using a statistical method, five genes were identified in these regions, including serine protease inhibitor, Kazal type, 5 (SPINK5) and HLA-DRB2. The relevance of these genes was examined in other patients with allergic rhinitis and in controls; none of the genes were differentially expressed in nasal biopsies. Moreover, no association between allergic rhinitis and SPINK5 polymorphisms was found, at either the genotype or haplotype level. Conclusions-DNA microarray analysis of chromosomal susceptibility regions did not lead to identification of candidate genes that could be validated in a new material. However, because gene polymorphisms may cause differential gene expression, further studies, including validation data, are needed to examine this approach

Health Care Use During 20 Years Following Bariatric Surgery.

Context Bariatric surgery results in sustained weight loss; reduced incidence of diabetes, cardiovascular events, and cancer; and improved survival. The long-term effect on health care use is unknown.Objective To assess health care use over 20 years by obese patients treated conventionally or with bariatric surgery.Design, Setting, and Participants The Swedish Obese Subjects study is an ongoing, prospective, nonrandomized, controlled intervention study conducted in the Swedish health care system that included 2010 adults who underwent bariatric surgery and 2037 contemporaneously matched controls recruited between 1987 and 2001. Inclusion criteria were age 37 years to 60 years and body mass index of 34 or higher in men and 38 or higher in women. Exclusion criteria were identical in both groups.Interventions Of the surgery patients, 13% underwent gastric bypass, 19% gastric banding, and 68% vertical-banded gastroplasty. Controls received conventional obesity treatment.Main Outcome Measures Annual hospital days (follow-up years 1 to 20; data capture 1987-2009; median follow-up 15 years) and nonprimary care outpatient visits (years 2-20; data capture 2001-2009; median follow-up 9 years) were retrieved from the National Patient Register, and drug costs from the Prescribed Drug Register (years 7-20; data capture 2005-2011; median follow-up 6 years). Registry linkage was complete for more than 99% of patients (4044 of 4047). Mean differences were adjusted for baseline age, sex, smoking, diabetes status, body mass index, inclusion period, and (for the inpatient care analysis) hospital days the year before the index date.Results In the 20 years following their bariatric procedure, surgery patients used a total of 54 mean cumulative hospital days compared with 40 used by those in the control group (adjusted difference, 15; 95% CI, 2-27; P = .03). During the years 2 through 6, surgery patients had an accumulated annual mean of 1.7 hospital days vs 1.2 days among control patients (adjusted difference, 0.5; 95% CI, 0.2 to 0.7; P &lt; .001). From year 7 to 20, both groups had a mean annual 1.8 hospital days (adjusted difference, 0.0; 95% CI, &minus;0.3 to 0.3; P = .95). Surgery patients had a mean annual 1.3 nonprimary care outpatient visits during the years 2 through 6 vs 1.1 among the controls (adjusted difference, 0.3; 95% CI, 0.1 to 0.4; P = .003), but from year 7, the 2 groups did not differ (1.8 vs 1.9 mean annual visits; adjusted difference, &minus;0.2; 95% CI, &minus;0.4 to 0.1; P = .12). From year 7 to 20, the surgery group incurred a mean annual drug cost of US $930; the control patients,$1123 (adjusted difference, &minus;$228; 95$335 to &minus;$121; P &lt; .001).Conclusions Compared with controls, surgically treated patients used more inpatient and nonprimary outpatient care during the first 6-year period after undergoing bariatric surgery but not thereafter. Drug costs from years 7 through 20 were lower for surgery patients than for control patients

Health-care costs over 15 years after bariatric surgery for patients with different baseline glucose status: results from the Swedish Obese Subjects study

BACKGROUND: Bariatric surgery prevents and induces remission of type 2 diabetes in many patients. The effect of preoperative glucose status on long-term health-care costs is unknown. We aimed to assess health-care costs over 15 years for patients with obesity treated conventionally or with bariatric surgery and who had either euglycaemia, prediabetes, or type 2 diabetes before intervention. METHODS: The Swedish Obese Subjects (SOS) study is a prospective study of adults who had bariatric surgery and contemporaneously matched controls who were treated conventionally (age 37-60 years; BMI of &ge;34 in men and &ge;38 in women) recruited from 25 Swedish surgical departments and 480 primary health-care centres. Exclusion criteria were identical for both study groups, and were previous gastric or bariatric surgery, recent malignancy or myocardial infarction, selected psychiatric disorders, and other contraindicating disorders to bariatric surgery. Conventional treatment ranged from no treatment to lifestyle intervention and behaviour modification. In this study, we retrieved prescription drug costs for the patients in the SOS study via questionnaires and the nationwide Swedish Prescribed Drug Register. We retrieved data for inpatient and outpatient visits from the Swedish National Patient Register. We followed up the sample linked to register data for up to 15 years. We adjusted mean differences for baseline characteristics. Analyses were by intention to treat. The SOS study is registered with ClinicalTrials.gov, number NCT01479452. FINDINGS: Between Sept 1, 1987, and Jan 31, 2001, 2010 adults who had bariatric surgery and 2037 who were treated conventionally were enrolled into the SOS study. In this study, we followed up 4030 patients (2836 who were euglycaemic; 591 who had prediabetes; 603 who had diabetes). Drug costs did not differ between the surgery and conventional treatment groups in the euglycaemic subgroup (surgery US$10,511 vs conventional treatment$10,680; adjusted mean difference -$225 [95$10,194 vs $13,186; -$3329 [-5722 to -937]; p=0&middot;007) and diabetes ($14,346 vs$19,511; -5487 [-7925 to -3049]; p<0·0001) subgroups than in the conventional treatment group. Compared with the conventional treatment group, we noted greater inpatient costs in the surgery group for the euglycaemic (51,225 vs $25,313;$22,931 [19,001-26,861]; p&lt;0&middot;0001), prediabetes ($58,699 vs$32,861; 27,152 [18,736-35,568]; p<0·0001), and diabetes (61,569 vs 47,569; 18,697 [9992-27,402]; p<0·0001) subgroups. We noted no differences in outpatient costs. Total health-care costs were higher in the surgery group in the euglycaemic (71,059 vs $45,542;$22,390 [17,358-27,423]; p&lt;0&middot;0001) and prediabetes ($78,151 vs$54,864; 26,292 [16,738-35,845]; p<0·0001) subgroups than in the conventional treatment group, whereas we detected no difference between treatment groups in patients with diabetes (88,572 vs $79,967;$9081 [-1419 to 19,581]; p=0&middot;090). INTERPRETATION: Total health-care costs were higher for patients with euglycaemia or prediabetes in the surgery group than in the conventional treatment group, but we detected no difference between the surgery and conventional treatment groups for patients with diabetes. Long-term health-care cost results support prioritisation of patients with obesity and type 2 diabetes for bariatric surgery. FUNDING: AFA F&ouml;rs&auml;kring and Swedish Scientific Research Council