Search

Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA-PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression. A decrease in the PAI-1 (SERPINE1) gene corepressor Rev-Erbα increased PAI-1, which then increased the tPA gene PLAT via a PAI-1/LRP1/PKA/p-CREB1 pathway. This pathway was partially counterbalanced by increased DACH1, a PLAT-negative regulator. We focused on the PAI-1/PLAT pathway, which mitigates the reduction in fibrinolysis in obesity. Thus, silencing hepatocyte PAI-1, CREB1, or tPA in obese mice lowered plasma tPA and further impaired fibrinolysis. The PAI-1/PLAT pathway was present in primary human hepatocytes, and associations among PAI-1, tPA, and PLAT in livers from obese and lean humans were consistent with these findings. Knowledge of PAI-1 and tPA regulation in hepatocytes in obesity may suggest therapeutic strategies for improving fibrinolysis and lowering the risk of thrombosis in this setting.

Background: Roux-en-Y gastric bypass (RYGB) produces greater weight loss compared with a purely restrictive procedure such as laparoscopic adjustable gastric banding (LAGB)., Objective: The objective of this study was to quantify changes in hormones that regulate energy homeostasis and appetitive sensations before and after LAGB (n = 18) and RYGB (n = 38) in order to better understand the mechanisms underlying the greater weight loss after RYGB., Methods: A standardized test meal was administered prior to surgery, at 6 months, and annually thereafter to year 2 after LAGB and year 4 after RYGB. Blood samples were obtained in the fasted state and 30, 60, 90, and 120 min post-meal., Results: Progressive increases in fasting PYY were observed after RYGB together with increases in postprandial area under the curve (AUC) levels that were unchanged after LAGB. GLP-1 AUC increased only after RYGB. There was a weight loss-related increase in fasting ghrelin levels after LAGB that was unchanged 1 year after RYGB despite greater percentage weight loss; ghrelin subsequently increased at years 2-4 post-RYGB. HOMA-IR decreased after both procedures but correlated with weight loss only after LAGB, whereas leptin correlated with weight loss in both groups. Sweet cravings decreased after RYGB., Conclusion: A number of weight loss-independent changes in the gut hormonal milieu likely act in concert to promote a decrease in insulin resistance and greater weight loss efficacy after RYGB. A progressive change in hormone levels over time may reflect gut enteroplasticity after RYGB. A decrease in sweet cravings specific to RYGB may further promote superior weight loss outcomes.

Bariatric surgery is a treatment option for obese patients with type 2 diabetes mellitus (T2DM). Although sleeve gastrectomy (SG) is growing in favor, some randomized trials show less weight loss and HbA1c improvement compared with Roux-en-Y gastric bypass (RYGB). The study objective was to compare changes in beta-cell function with similar weight loss after SG and RYGB in obese patients with T2DM. Subjects undergoing SG or RYGB were studied with an intravenous glucose tolerance test before surgery and at 5-12% weight loss post-surgery. The primary endpoint was change in the disposition index (DI). Baseline BMI, HbA1c, and diabetes-duration were similar between groups. Mean total weight loss percent was similar (8.4% ± 0.4, p = 0.22) after a period of 21.0 ± 1.7 days. Changes in fasting glucose, acute insulin secretion (AIR), and insulin sensitivity (Si) were similar between groups. Both groups showed increases from baseline to post-surgery in DI (20.2 to 163.3, p = 0.03 for SG; 31.2 to 232.9, p = 0.02 for RYGB) with no significant difference in the change in DI between groups (p = 0.53). Short-term improvements in beta-cell function using an IVGTT were similar between SG and RYGB. It remains unclear if longer-term outcomes are better after RYGB due to greater weight loss and/or other factors.

Although vitamin D deficiency is prevalent among obese individuals, its cause is poorly understood. Few studies have measured vitamin D concentrations in adipose of obese (OB) subjects, and none have included normal weight controls (C). The goal of this study was to investigate whether the relationship between body composition, serum 25-hydroxyvitamin D (25OHD), vitamin D in subcutaneous (SQ) and omental (OM) adipose, and total adipose stores of vitamin D differ among OB and C. Obese women undergoing bariatric surgery and normal-weight women undergoing abdominal surgery for benign gynecologic conditions were enrolled. Subjects had measurements of serum 25OHD by high-performance liquid chromatography (HPLC) and body composition by dual-energy X-ray absorptiometry (DXA). Vitamin D concentrations in SQ and OM adipose were measured by mass spectroscopy. Thirty-six women were enrolled. Serum 25OHD was similar between groups (OB 27 ± 2 versus C 26 ± 2 ng/mL; p = 0.71). Adipose vitamin D concentrations were not significantly different in either SQ (OB 34 ± 9 versus C 26 ± 12 ng/g; p = 0.63) or OM compartments (OB 51 ± 13 versus C 30 ± 18 ng/g; p = 0.37). The distribution of vitamin D between SQ and OM compartments was similar between groups. Serum 25OHD was directly related to adipose vitamin D in both groups. Total body vitamin D stores were significantly greater in OB than in C (2.3 ± 0.6 versus 0.4 ± 0.8 mg, respectively; p < 0.01). In summary, although OB had significantly greater total vitamin D stores than C, the relationship between serum 25OHD and fat vitamin D and the overall pattern of distribution of vitamin D between the OM and SQ fat compartments was similar. Our data demonstrate that obese subjects have greater adipose stores of vitamin D. They support the hypotheses that the enlarged adipose mass in obese individuals serves as a reservoir for vitamin D and that the increased amount of vitamin D required to saturate this depot may predispose obese individuals to inadequate serum 25OHD. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR), represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA) increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study examined whether changes in adipocyte long chain fatty acid (LCFA) uptake kinetics explain the weight regain increasingly observed following bariatric surgery., Methods: Three groups (10 patients each) were studied: patients without obesity (NO: BMI 24.2 ± 2.3 kg m(-2) ); patients with obesity (O: BMI 49.8 ± 11.9); and patients classified as super-obese (SO: BMI 62.6 ± 2.8). NO patients underwent omental and subcutaneous fat biopsies during clinically indicated abdominal surgeries; O were biopsied during bariatric surgery, and SO during both a sleeve gastrectomy and at another bariatric operation 16 ± 2 months later, after losing 113 ± 13 lbs. Adipocyte sizes and [(3) H]-LCFA uptake kinetics were determined in all biopsies., Results: Vmax for facilitated LCFA uptake by omental adipocytes increased exponentially from 5.1 ± 0.95 to 21.3 ± 3.20 to 68.7 ± 9.45 pmol/sec/50,000 cells in NO, O, and SO patients, respectively, correlating with BMI (r = 0.99, P < 0.001). Subcutaneous results were virtually identical. By the second operation, the mean BMI (SO patients) fell significantly (P < 0.01) to 44.4 ± 2.4 kg m(-2) , similar to the O group. However, Vmax (40.6 ± 11.5) in this weight-reduced group remained ~2X that predicted from the BMI:Vmax regression among NO, O, and SO patients., Conclusions: Facilitated adipocyte LCFA uptake remains significantly upregulated ≥1 year after bariatric surgery, possibly contributing to weight regain., (© 2015 The Obesity Society.)

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin-supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8 ± 0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2 ± 86.6 vs. 55.9 ± 19.9; P < 0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point.

Background: The current National Institutes of Health guidelines have recommended bariatric surgery for patients with a body mass index (BMI) >40 kg/m(2) or BMI >35 kg/m(2) with significant co-morbidities. However, some preliminary studies have shown that patients with a BMI that does not meet these criteria could also experience similar weight loss and the benefits associated with it., Methods: An institutional review board-approved protocol was obtained to study the effectiveness of laparoscopic adjustable gastric banding in patients with a low BMI. A total of 66 patients with a BMI of 30-35 kg/m(2) and co-morbidities (n = 22) or a BMI of 35-40 kg/m(2) without co-morbidities (n = 44) underwent laparoscopic adjustable gastric banding. These patients were compared with 438 standard patients who had undergone laparoscopic adjustable gastric banding who met the National Institutes of Health criteria for bariatric surgery. The excess weight loss at 3, 6, 12, and 18 months and the status of their co-morbidities were compared between the 2 groups., Results: The average BMI for the study group was 36.1 +/- 2.6 kg/m(2) compared with 46.0 +/- 7.3 kg/m(2) for the control group. Both groups had significant co-morbidities, including hypertension, diabetes, hyperlipidemia, arthritis, gastroesophageal reflux disease, stress incontinence, and obstructive sleep apnea. The mean percentage of excess weight loss was 20.3% +/- 9.0%, 28.5% +/- 14.0%, 44.7% +/- 19.3%, and 42.2% +/- 33.7% at 3, 6, 12, and 18 months, respectively. This was not significantly different from the excess weight loss in the control group, except for at 12 months. Both groups showed similar improvement of most co-morbidities., Conclusion: Moderately obese patients whose BMI is less than the current guidelines for bariatric surgery will have similar weight loss and associated benefits. Laparoscopic adjustable gastric banding is a safe and effective treatment for patients with a BMI of 30-35 kg/m(2)., (Copyright 2010 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Context Roux-en-Y gastric bypass (RYGB) is associated with postprandial hyperinsulinemia. Objective This study assessed whether increased blood insulin levels may be due to an increase in maximal β -cell function. Design, Setting, and Participants We performed a cross-sectional study at Columbia University Medical Center, New York, New York. Subjects without a history of diabetes were studied after surgery (n = 12) and were compared with nonsurgical controls (n = 10) who were mean matched for body mass index, insulin sensitivity, and hemoglobin A1c and with nonobese controls (n = 8). Methods Subjects underwent a mixed-meal tolerance test and on a separate day an intravenous glucose tolerance test followed by a hyperglycemic clamp (450 mg/dL; 25 mM blood glucose) and arginine stimulation. The main outcome measure was maximal insulin secretion quantified after arginine stimulation (AinsRmax). Results The RYGB group exhibited greater peak postprandial glucose levels and fourfold greater peak insulin levels than control groups; however, there were no significant differences in insulinogenic index or AinsRmax. Another finding was significantly greater postprandial glucagon levels in the RYGB group compared with controls. Conclusions Our results suggest that after RYGB, the increase in postprandial levels of insulin are not due to changes in maximal β -cell function but appear to be an appropriate response to altered nutrient flow and absorption. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Children and adolescents who fail to lose weight through diet and exercise programs have been offered weight loss surgery for several years. We report our early results on laparoscopic adjustable gastric banding (LAGB) in 100 teenagers. Methods: Candidates for surgery underwent rigorous assessment for medical eligibility, compliance, and psychological well-being. Patients who met criteria and were approved by our team were offered LAGB. Postoperatively, patients were followed monthly until steady weight loss was achieved, then every 3 months thereafter. Results: One hundred patients aged 14 to 19 years underwent LAGB. Preoperative average weight was 136.7 kg, and median body mass index was 48.7. Comorbid medical conditions were common. Five reoperations were performed for port site bleeding, hiatal hernia repair, possible intestinal obstruction, and port slippage. Eighty-seven patients were followed for a minimum of 6 months. Average weight loss at 6 months was 12.4 (range, 33.2 to 16.2) kg, and average change in body mass index was 4.4 (range, 11.8 to −5.6). Conclusion: Laparoscopic adjustable gastric banding may be performed safely in adolescents, and short-term results suggest that LAGB may serve as an important tool to help them lose weight. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aim of this study was to measure the circulating levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon in patients who had undergone adjustable gastric banding (BND) or Roux-en-Y gastric bypass (RYGB) to understand the differences in glucose and insulin regulation after these procedures. Methods: This was a cross-sectional study of 3 groups of women matched for age and body mass index: group 1, overweight controls (n = 13); group 2, BND (n = 10); and group 3, RYGB (n = 13). Venous blood was drawn with the patient in the fasted state and throughout a 3-hour period after a liquid meal. Results: The fasting glucose level was similar between the 2 surgery groups; however, the fasting insulin concentrations were greater in the BND (10.0 μU/mL) than in the RYGB (6.2 μU/mL; P <0.05) group. The glucose level at 60 minutes was significantly lower in the RYGB group (70 mg/dL, range 38–82) than in the BND group (83 mg/dL, range 63–98). The GLP-1 levels at 30 minutes were more than threefold greater in the RYGB group (96 pmol/L) compared with the BND and overweight control (28 pmol/L) groups. The GLP-1 and insulin concentrations correlated at 30 minutes only in the RYGB group (r = .66; P = .013). The glucose-dependent insulinotropic peptide levels at 30 minutes were lower in the RYGB group (20 pmol/L) than in the BND group (31 pmol/L) or overweight control group (33 pmol/L). The peak glucagon levels were similar among the 3 groups. Conclusion: Exaggerated postprandial GLP-1 and blunted glucose-dependent insulinotropic peptide secretion after RYGB might contribute to the greater weight loss and improved glucose homeostasis compared with BND. [Copyright &y& Elsevier]

Abstract: Background: Banded gastric bypass has been reported to result in superior weight loss compared with standard nonbanded gastric bypass. However, an adequate comparison of these procedures has not yet been reported. Methods: A total of 90 patients were enrolled in this prospective randomized double-blind trial comparing banded and nonbanded open gastric bypass for the treatment of super obesity. The banding technique involved placement of a 1.5 × 5.5-cm polypropylene band around the proximal gastric pouch of a standard gastric bypass procedure using the technique of Capella. Chi-square testing and analysis of variance were performed to find any differences in patient characteristics (gender, age, and initial body mass index), percentage of excess weight lost at 6, 12, 24, and 36 months postoperatively, improvement or resolution of co-morbidities, and complications in the banded versus nonbanded gastric bypass groups. Results: As expected, no differences were present in the patient characteristics or incidence of co-morbidities between the banded (n = 46) and nonbanded (n = 44) groups. The body mass index, percentage of women, and mean age was 59.5 and 56.5 kg/m2, 64% and 73.8% (P = .09), and 40.6 ± 7.4 and 42.6 ± 7.2 years for the banded and nonbanded groups, respectively; all differences were nonsignificant. No significant differences were found in the resolution of co-morbidities. No significant difference was present in the percentage of excess weight loss at 6, 12, and 24 months (43.1% versus 24.7%, 64.0% versus 57.4%, and 64.2% versus 57.2%, respectively) postoperatively; however, the banded patients had achieved a significantly greater percentage of excess weight loss at 36 months (73.4% versus 57.7%; P <.05). The incidence of intolerance to meat and bread was greater in the banded patients. The overall number of complications was 12 (26%) in the banded and 13 (29.5%) in the nonbanded group, a nonsignficant difference. No band erosions had occurred at the last follow-up visit, and no patients in either group died. Conclusion: These results suggest that although the initial weight loss was not significantly different between the 2 groups, the banded patients continued to lose weight for ≤3 years. The polypropylene band appeared to be well tolerated. We plan longer follow-up to confirm the possibility of additional weight loss and the prevention of weight regain in the banded group, as well as to document any long-term band complications. [Copyright &y& Elsevier]

Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA-PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression. A decrease in the PAI-1 (SERPINE1) gene corepressor Rev-Erbα increased PAI-1, which then increased the tPA gene PLAT via a PAI-1/LRP1/PKA/p-CREB1 pathway. This pathway was partially counterbalanced by increased DACH1, a PLAT-negative regulator. We focused on the PAI-1/PLAT pathway, which mitigates the reduction in fibrinolysis in obesity. Thus, silencing hepatocyte PAI-1, CREB1, or tPA in obese mice lowered plasma tPA and further impaired fibrinolysis. The PAI-1/PLAT pathway was present in primary human hepatocytes, and associations among PAI-1, tPA, and PLAT in livers from obese and lean humans were consistent with these findings. Knowledge of PAI-1 and tPA regulation in hepatocytes in obesity may suggest therapeutic strategies for improving fibrinolysis and lowering the risk of thrombosis in this setting. [ABSTRACT FROM AUTHOR]