Albuminuria in Patients with Morbid Obesity and the Effect of Weight Loss Following Bariatric Surgery.

BACKGROUND AND OBJECTIVES: Patients with morbid obesity are at an increased risk for cardiovascular and renal complications, which are not only linked to traditional cardiovascular risk factors. Thus, we evaluated (a) the prevalence of albuminuria in non-diabetic and diabetic morbidly obese patients and (b) the effect of weight loss following bariatric surgery. MATERIAL AND METHODS: We included 1307 patients (77% women, mean age 40 ± 12 years, BMI 45.6 ± 6.6 kg/m2) in a cross-sectional study. A subgroup (n = 318) was followed up for 2 years after bariatric surgery. Weight, cardiovascular risk markers and a 75-g glucose tolerance test were determined. Albuminuria was assessed by collecting 24-h urine on three consecutive days. RESULTS: In the cross-sectional study, the prevalence of microalbuminuria was 16.0% (n = 209), of macroalbuminuria 3.1% (n = 41). The chi-square for the association of albuminuria and diabetes was 31.937 (p < 0.001). Of all patients with albuminuria, 42.0% exhibited normal glucose tolerance. In a multivariate regression analysis, systolic blood pressure (beta = 0.236; p < 0.001), log fasting insulin (beta = 0.309; p < 0.001) and log 2-h postprandial insulin (beta = - 0.173; p = 0.033) were predictive risk factors for albuminuria. Longitudinally, albumin excretion decreased significantly from 11.1 (6.4, 18.4 mg/24 h) to 7.8 mg/24 h (4.9, 13.0 mg/24 h; p < 0.001). In the group with albuminuria preoperatively, albumin excretion decreased from 65.7 (38.2, 147.1 mg/24 h) to 13.5 mg/24 h (8.4, 36.8 mg/24 h; p < 0.001). After adjusting for age, sex and baseline albuminuria, patients with lower creatinine clearance showed a smaller decrease of albuminuria (beta = 0.117; p = 0.021). CONCLUSION: A substantial portion of patients with morbid obesity exhibits microalbuminuria, nearly half of those present with normal glucose tolerance. After weight loss, we found a significant decrease of albuminuria, potentially indicating or even contributing to the known reduction of cardiovascular mortality after bariatric surgery.

Frequency of Hypoglycaemia after Different Bariatric Surgical Procedures.

OBJECTIVES: The frequency of postprandial hypoglycaemia after different operative procedures of bariatric surgery (BS) is unknown, although this complication is potentially dangerous. Predictors and severity of hypoglycaemia after Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy, and gastric banding were investigated in a large prospective study. METHODS: This study was performed at an excellence centre for BS at a tertiary care institution. Data of 333 patients (mean BMI: 44.9 ± 9.6 kg/m2; mean age: 40 ± 10 years; 80.7% women) were analysed in a prospective study with a 2-year observation period after BS. All patients underwent a 2-hour oral glucose tolerance test (OGTT) with measurements of blood glucose (BG) and insulin. For the purpose of this study, hypoglycaemia was defined as a post-challenge BG <2.8 mmol/L during the OGTT. RESULTS: 72 (25.6%) of 281 patients showed post-challenge hypoglycaemia after surgery. Hypoglycaemia was different after various procedures: 32.6% of patients after RYGB, 22.6% after sleeve gastrectomy, but only 2.3% after gastric banding had hypoglycaemia. In the whole group, patients with hypoglycaemia had lost more weight (p = 0.013), had a slightly greater decrease in BMI (p = 0.037), a greater change in 2-hour post-challenge BG (p = 0.001), and a smaller change in 1-hour post-challenge insulin (p = 0.004) compared to patients without hypoglycaemia. CONCLUSION: This prospective study shows a higher prevalence of severe hypoglycaemia (25.6%) after BS than anticipated from retrospective registers. A systematic evaluation of glucose and insulin levels by OGTT 2 years post-surgery may help to identify patients at increased risk for symptomatic and asymptomatic hypoglycaemia.

Prevalence of Micronutrient Deficiency in Patients with Morbid Obesity Before Bariatric Surgery.

BACKGROUND: Postoperative micronutrient deficiency is a known side effect of bariatric surgery. In this study, we examined the prevalence of micronutrient deficiency in patients with morbid obesity (MO) preoperatively. METHODS: A total of 1732 patients with MO wishing to undergo bariatric surgery (age: 40 ± 12 years, mean BMI: 44 ± 9 kg/m2, means ± SD, 77.3% female) were analyzed in this cross-sectional examination. Iron state, vitamin B12, folic acid, 25hydroxy(OH)-vitamin D, PTH, vitamin A, and vitamin E levels were determined. Subsequently, patients underwent nutritional counseling and were substituted accordingly. RESULTS: A total of 63.2% (n = 1094) of the patients had a deficit in folic acid (< 5.3 ng/ml), 97.5% (n = 1689) in 25OHvitamin D (< 75 nmol/l), and 30.2% (n = 523) had a PTH elevation (> 56.9 pg/ml). A total of 5.1% (n = 88) of the patients presented with a deficit in vitamin B12 (< 188 pg/ml) and 6.2% (n = 107) in vitamin A (< 1.05 µmol/l). A total of 9.6% (n = 166) exhibited iron deficiency (ferritin < 15 µg/l). None of the patients had a deficit in vitamin E. There were no gender differences except for ferritin deficiency (women 11.8% vs. men 1.5%, p < 0.001). Patients in the highest BMI tertile had significantly more often a deficit in vitamin D (p = 0.033) and folic acid (p < 0.001). Patients in the lowest age tertile had significantly more often a deficit in folic acid (p < 0.001). CONCLUSIONS: Our data show a high prevalence of micronutrient deficiency in patients with morbid obesity preoperatively and emphasize the importance of exact preoperative evaluation and adequate substitution as well as postoperative surveillance.

Elevated Fetuin-A concentrations in morbid obesity decrease after dramatic weight loss.

CONTEXT: Morbid obesity (MO) is a risk factor for cardiovascular morbidity, mortality, and diabetes, which can be effectively reduced by bariatric surgery. The liver-secreted protein Fetuin-A is elevated in insulin resistance, is an independent predictor of type 2 diabetes and is associated with atherosclerosis. OBJECTIVE: We studied Fetuin-A concentrations in patients with MO before and after weight loss induced by gastric bypass. DESIGN: We conducted a cross-sectional study and a 16-month longitudinal study. SETTING: This study was performed in secondary care. PATIENTS, SUBJECTS, AND INTERVENTION: We included 75 MO patients [65 women, body mass index (BMI) 45.6 ± 8.1 kg/m(2)] and 38 healthy controls (21 women, BMI 26.0 ± 5.5 kg/m(2)) in a cross-sectional study and investigated them before and about 16 months after gastric bypass surgery. MAIN OUTCOME MEASURES: Apart from measurements of blood pressure and routine laboratory parameters, a 75-g oral glucose tolerance test was performed. Insulin resistance was calculated by using homeostatic model assessment (HOMA). RESULTS: Fetuin-A levels were significantly higher in MO (877 ± 318 µg/ml) than in controls (295 ± 61 µg/ml; P < 0.001). After surgery-induced weight loss (BMI 31.6 ± 6.8 vs. 45.6 ± 8.1 kg/m(2); P < 0.001), HOMA (2.0 ± 1.2 vs. 6.6 ± 6.3; P < 0.001) and Fetuin-A (710 ± 350 vs. 877 ± 318 µg/ml; P < 0.001) decreased. Delta (Δ) Fetuin-A concentrations correlated with Δfasting insulin (r = 0.710; P = 0.001), Δ2-h insulin (r = 0.693; P = 0.005), and HOMA-insulin resistance (r = 0.684; P = 0.001). CONCLUSIONS: Fetuin-A is markedly increased in patients with MO. The reduction of Fetuin-A after weight loss could play an important role in the beneficial effects of gastric bypass surgery.

YKL-40 is elevated in morbidly obese patients and declines after weight loss.

BACKGROUND: Patients suffering from morbid obesity (MO) have an increased cardiovascular morbidity and mortality. This increased cardiovascular burden is believed to be caused by a sub-inflammatory state through an increased secretion of monocyte chemoattractant protein-1 (MCP-1) by the adipose tissue, resulting in insulin resistance (IR) and type 2 diabetes mellitus (T2DM). YKL-40, which is elevated in inflammatory processes in T2DM and IR and in ruptured plaques, might as well be involved in the increased cardiovascular burden of MO patients. The present study aims to study the level of YKL-40 in MO patients before and after weight loss as well as to investigate the relationship between YKL-40, IR, MCP-1, and obesity. METHODS: We investigated YKL-40 levels in serum samples of both 17 morbidly obese patients before and after bariatric surgery and 17 healthy controls. YKL-40 levels were determined in serum samples by enzyme-linked immunosorbent assay. RESULTS: After a mean follow-up of 17.4 months and a mean weight loss of 40 kg through bariatric surgery, YKL-40 levels declined by 30.5% (p = 0.027). Multiple linear regression analysis revealed that only preoperative MCP-1 values remained independently and significantly (p = 0.001) associated with preoperative YKL-40 levels. Moreover, delta (change) homeostasis model assessment of insulin resistance (HOMA-IR) values remained independently and significantly (p = 0.002) associated with delta YKL-40 levels. CONCLUSIONS: We show for the first time that elevated levels of YKL-40 in MO patients decreased after massive weight loss via bariatric surgery. YKL-40 was correlated with HOMA-IR and fasting insulin levels, indicating a role in developing processes of IR and T2DM. The tight association of MCP-1 (plaque development) and YKL-40 (plaque rupture) points to a central role of both proteins, contributing to the increased cardiovascular mortality in MO patients.

Ghrelin and obestatin levels in severely obese women before and after weight loss after Roux-en-Y gastric bypass surgery.

BACKGROUND: Ghrelin and obestatin are derived from the same gene but have different effects: Ghrelin stimulates appetite, and previous-albeit inconsistent-data show that obestatin may be involved in satiety. The present study was designed to test the hypothesis that Roux-en-Y gastric bypass (RYGB) surgery and/or the weight loss that reliably results from this procedure would alter levels of ghrelin and obestatin and ghrelin/obestatin ratios in a cohort of morbidly obese women. METHODS: This is a longitudinal follow-up study in 18 morbidly obese women (mean weight 131.2 kg, mean body mass index [BMI] 47.4). Clinical parameters and fasting serum concentrations of ghrelin, obestatin, triglycerides, low-density lipoprotein cholesterol, glucose, and insulin were measured before and 2 years after RYGB surgery, which was associated with body weight reductions of 41.5 +/- 11.6 kg (mean 62.5% excess weight loss). RESULTS: Ghrelin concentrations (-12%, p = 0.022) and ghrelin/obestatin ratios (-14%, p = 0.017) were lower after surgery than before, while obestatin levels did not change. Changes in ghrelin concentrations correlated with changes in insulin levels (r = 0.45, p = 0.011). Most cardiovascular risk factors studied improved postsurgically (p < 0.01). CONCLUSION: In contrast to previous weight loss studies involving gastric banding, ghrelin levels decreased and obestatin levels remained stable after massive weight loss in long-term follow-up. The favorable gastrointestinal hormone profiles observed are likely to contribute to the long-term weight loss success rate attributed to RYGB.

Increase of osteopontin plasma concentrations after bariatric surgery independent from inflammation and insulin resistance.

BACKGROUND: Osteopontin (OPN) is a multifunctional matrix glycoprotein associated with bone metabolism and has been linked to chronic inflammation, insulin resistance, and atherosclerosis. Diet-induced weight loss decreases elevated OPN concentrations in obese patients. The aim of the current study was to investigate the role of OPN after bariatric surgery, where not only improvements of chronic inflammation, insulin resistance and comorbidities, but also malabsorption and altered bone metabolism have been reported. METHODS: OPN plasma concentrations were determined in 31 morbidly obese patients (5 men, 26 women, BMI 46.2+/-7.1 kg/m2, age 41+/-11 years; mean+/-SD) before and 18 months after bariatric surgery, together with parameters of bone metabolism and inflammation. RESULTS: OPN concentrations increased by +20.3+/-26.6 ng/ml (mean+/-SD, p<0.01), concomitant to a weight loss of -38+/-22 kg, and a decrease in BMI by -13.1+/-7.7 kg/m2 (both p<0.01). HOMA-index improved from 5.2+/-3.4 to 1.5+/-1.0 (p<0.01). Calcium concentrations slightly decreased, and phosphate increased (-0.06+/-0.13 mmol/l and +0.08+/-0.16 mmol/l, respectively; both p<0.05), while 25-OH-Vitamin D3 remained unchanged and PTH tended to increase (+5.1+/-14.0 pg/ml, p=0.054). Monocyte chemoattractant protein 1 and interleukin 18 were significantly decreased and associated with HOMA both before and after bariatric surgery. DeltaOPN was correlated with DeltaPTH, but not with other parameters. CONCLUSIONS: OPN plasma concentrations increased concomitant to weight loss after bariatric surgery, which was independent from an improvement of insulin sensitivity and a decrease of inflammatory markers. Further studies are needed to differentiate whether these changes in bone metabolism after bariatric surgery are secondary to calcium deficiency or an adaptation to weight loss.

Peptide YY and glucagon-like peptide-1 in morbidly obese patients before and after surgically induced weight loss.

BACKGROUND: Peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are cosecreted in the same enteroendocrine L-cells of the gut and reported to inhibit food intake additively. However, findings in human studies regarding these peptides are controversial. The aim of this study was to analyze the relationships between fasting PYY, GLP-1, and weight status in morbidly obese patients before and after surgically induced weight loss. METHODS: Fasting GLP-1, PYY, glucose, and insulin concentrations; blood pressure; and body-mass index (BMI) were determined in 30 morbidly obese adults (mean BMI 45.8, mean age 40 years) before bariatric surgery [Roux-en-Y gastric bypass (RYGB): n = 19; gastric banding (GB): n = 11] and after weight loss (mean 50% excess weight loss) in the course of mean 2 years. RESULTS: GLP-1 concentrations decreased (mean -20 pg/ml; mean -38%; p = 0.001) and PYY concentrations increased (mean +19 pg/ml; mean +19%, p = 0.036) after bariatric surgery. The weight loss and changes of GLP-1 were significantly (p < 0.05) more pronounced after RYGB as compared to GB, whereas the changes of PYY did not differ significantly between the patients who had undergone RYGB or GB. CONCLUSIONS: In morbidly obese adults reducing their weight by bariatric surgery, fasting PYY levels increased and GLP-1 concentrations decreased independently of each other. Therefore, the relationship between PYY and GLP-1 seems more complicated than might be anticipated from animal and in vitro studies.

Increase in visfatin after weight loss induced by gastroplastic surgery.

OBJECTIVE: The recently described adipokine visfatin is produced in visceral fat and has been suggested to influence insulin resistance. To investigate whether visfatin concentrations are related to changes in body weight, this adipokine was measured in insulin-resistant severely obese patients before and after gastroplastic surgery. RESEARCH METHODS AND PROCEDURES: Visfatin, interleukin-6, high-sensitivity C-reactive protein, homeostasis model assessment of insulin resistance (HOMA-IR), and other clinical parameters were assessed in 36 severely obese subjects (28 female; mean age, 43 years) with a median BMI of 44.3 kg/m(2) (95% confidence interval, 43.3 to 48.1 kg/m(2)). RESULTS: After surgery, BMI decreased to a median of 31.9 kg/m(2) (30.1 to 35.1 kg/m(2)) (p < 0.0001). Median visfatin concentrations increased significantly after weight loss [70.9 ng/mL (61.4 to 75.6 ng/mL) vs. 86.4 ng/mL (79.4 to 89.8 ng/mL); p < 0.0005]. This increase correlated with the decrease of insulin and HOMA-IR and was associated with a reduction in plasma interleukin-6 and high-sensitivity C-reactive protein concentrations. DISCUSSION: Massive weight loss after gastroplastic surgery is accompanied by an increase in circulating concentrations of the novel adipokine visfatin. This increase correlates with the decrease in plasma insulin concentrations and HOMA-IR.

Relationship of androgens to insulin resistance and chronic inflammation in morbidly obese premenopausal women: studies before and after vertical banded gastroplasty.

BACKGROUND: Morbid obesity is associated with insulin resistance (IR), type 2 diabetes, lipid abnormalities, and hypertension. The association of obesity with increased androgen production and low concentrations of sex hormone-binding globulin (SHBG) in women has been demonstrated as well as a strong association of androgens with markers of inflammation such as high-sensitive C-reactive protein (hsCRP). Because weight loss results in a significant decrease in cardiovascular risk factors, IR and inflammation, we questioned a possible interrelationship between androgens, IR and inflammation in a prospective study with 43 morbidly obese female patients undergoing bariatric surgery. METHODS: SHBG, dehydroepiandrosterone-sulfate (DHEA-S), and insulin were measured by ELISA, cortisol by fluorescence polarization immunoassay, androstendione by RIA, and testosterone by electrochemiluminescence immunoassay. The free androgen index (FAI) was calculated as the total testosterone/SHBG ratio. High sensitivity assays were used to obtain concentrations of fasting hsCRP, Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Weight loss resulted in a significant increase in SHBG (17+/-12 vs 70+/-30 nmol/l, P<0.0001). Serum concentrations of androstendione, total testosterone, DHEA-S and the FAI decreased significantly (2.05+/-0.78 vs 1.40+/-0.54 ng/ml, P<0.0001; 1.88+/-0.84 vs 1.16+/-0.57 nmol/L, P<0.0001; 1.72+/-0.86 vs 1.49+/-0.78 microg/ml, P<0.01; 0.15+/-0.10 vs 0.02+/-0.01, P<0.0001; respectively). Preoperatively and postoperatively, no association between androgens and IR, chronic subclinical inflammation and lipid parameters could be observed. CONCLUSION: Massive weight loss induced by bariatric surgery is associated with a significant reduction of androgen concentrations but not related to the concomitant decline of chronic inflammation, IR, glucose and lipid abnormalities in premenopausal morbidly obese women.

Effect of massive weight loss induced by bariatric surgery on serum levels of interleukin-18 and monocyte-chemoattractant-protein-1 in morbid obesity.

BACKGROUND: Morbid obesity is associated with insulin resistance (IR), chronic inflammation and premature atherosclerosis. Since vascular inflammation may contribute to the increased risk of cardiovascular morbidity and mortality of these patients, we studied circulating Interleukin-18 (L-18) and monocyte-chemoattractant-protein-1 (MCP-1) levels in 37 patients with morbid obesity before and after significant weight loss induced by bariatric surgery and their preoperative and postoperative associations with C-reactive protein (CRP) and IR-associated factors. METHODS: High sensitivity assays were used to measure concentrations of fasting CRP, IL-18 and MCP-1. Differences between patients before and after bariatric surgery were analyzed by Student's paired t-test. To investigate the associations of the observed reductions of values, delta of parameters were calculated and preoperative, postoperative and delta data were tested by univariate and multivariate linear regression. RESULTS: After a mean follow-up period of 26.5 months and a massive weight loss of 35 kg induced by bariatric surgery, circulating IL-18 levels decreased by 37% (P<0.001) and circulating MCP-1 levels by 47% (P<0.001). Multiple linear regression of delta values of IL-18 showed that only 2-hour glucose (P=0.008) remained independently and significantly associated with IL-18, whereas multiple linear regression analysis of delta values of MCP-1 revealed that only delta of HOMA-IR (P<0.001) remained independently and significantly associated with MCP-1, respectively. CONCLUSIONS: Because both biomarkers have been shown to play an important role in the development and progression of atherosclerosis, the observations presented in this study could be of clinical relevance for morbidly obese patients undergoing bariatric surgery.

Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women.

The endogenous nitric oxide-synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is elevated in patients with increased risk for arteriosclerosis. Obesity is a risk factor for cardiovascular disease. We measured plasma ADMA concentrations in morbidly obese women before and after weight loss following gastroplastic surgery. ADMA and symmetrical dimethyl-L-arginine concentrations were analyzed by HPLC from 34 female patients (age 41 +/- 7 yr) with a body mass index (BMI) of 49 +/- 1 kg/m2 before and 14 months after vertical ring gastroplasty. Age-matched healthy women (BMI < 25 kg/m2; n = 24) were studied as controls. After gastroplastic surgery, BMI decreased to 34 +/- 1 kg/m2 in obese women (P < 0.00001), and ADMA concentrations were reduced from 1.06 +/- 0.06 micromol/liter at baseline to 0.81 +/- 0.04 micromol/liter after weight loss (P < 0.00001). Symmetrical dimethyl-L-arginine plasma levels were not affected. ADMA correlated with high-sensitivity C-reactive protein at baseline (r = 0.42; P < 0.05) and after weight loss (r = 0.56; P < 0.005). No association with blood pressure or plasma lipids could be observed. ADMA concentrations were lower in controls (0.68 +/- 0.04 micromol/liter; P < 0.05) compared with obese patients before or after weight reduction. The decrease of highly elevated ADMA concentrations in morbidly obese patients is paralleled by improvement of parameters associated with the metabolic syndrome after weight loss.

Weight loss reduces tissue factor in morbidly obese patients.

OBJECTIVE: To investigate the tissue factor (TF) pathway in clinical obesity and associated metabolic syndrome. RESEARCH METHODS AND PROCEDURES: Thirty-seven morbidly obese patients (4 men; BMI, 48 +/- 7 kg/m(2); range, 42 to 53 kg/m(2)), undergoing elective gastroplasty for the induction of weight loss, were examined for hemostatic, metabolic, and inflammatory parameters at baseline and 14 +/- 5 months postoperatively. RESULTS: Weight loss significantly reduced circulating plasma TF (314 +/- 181 vs. 235 +/- 113 pg/mL, p = 0.04), coagulation factor VII (130 +/- 22% vs. 113 +/- 19%, p = 0.023), and prothrombin fragment F1.2 (2.4 +/- 3.4 vs. 1.14 +/- 1.1 nM, p = 0.04) and normalized glucose metabolism in 50% of obese patients preoperatively classified as diabetic or of impaired glucose tolerance. The postoperative decrease in plasma TF correlated with the decrease of F1.2 (r = 0.56; p = 0.005), a marker of in vivo thrombin formation. In subgroup analysis stratified by preoperative glucose tolerance, baseline circulating TF (402.6 +/- 141.6 vs. 176.2 +/- 58.2, p < 0.001) and TF decrease after gastroplasty (DeltaTF: 164.7 +/- 51.4 vs. -81 +/- 31 pg/mL, p = 0.02) were significantly higher in obese patients with impaired glucose tolerance than in patients with normal glucose tolerance. DISCUSSION: Procoagulant TF is significantly reduced with weight loss and may contribute to a reduction in cardiovascular risk associated with obesity.