Weight Loss-independent Effects Research Articles

Mechanisms by Which Pharmacotherapy May Impact Cancer Risk among Individuals with Overweight and Obesity.

Diets geared to reduce cancer risk in overweight and obese individuals focus on (1) caloric restriction (every day, some days, or most hours of each day); (2) changes in macronutrient intake; or (3) a combination of the prior two strategies. Diets generally fail because of nonadherence or due to limited sustained weight loss. This is in contrast to a diet supplemented with a weight loss medication, so long as the participant continues the medication or after bariatric surgery, in which adherence tends to be much higher. Among individuals who regain weight after surgery, weight loss medications are proving beneficial in maintaining weight loss. Both maximum and sustained weight loss are essential for all forms of effective metabolic improvement, including cancer risk reduction. The focus of this report is to assess the state of research on the consequence of pharmacotherapy use on weight loss and proposed weight loss-independent effects on subsequent cancer risk reduction, including the potential role of medication use in conjunction with metabolic (bariatric) surgery (MBS). Finally, we present Notices of Funding Opportunities (NOFOs) by the National Cancer Institute (NCI) to better understand the mechanism(s) that are driving the efficacy of pharmacotherapy in cancer risk reduction.

Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program

BackgroundTirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (− 1.9 to − 2.6%), body weight (− 6.6 to − 13.9%) and systolic blood pressure (SBP) (− 2.8 to − 12.6 mmHg) at the end of study treatment.MethodsPost-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials.ResultsThe difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was − 1.3 to − 5.1 mmHg (tirzepatide 5 mg), − 1.7 to − 6.5 mmHg (tirzepatide 10 mg) and − 3.1 to − 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP.ConclusionsTirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension.

Sleeve Gastrectomy Reduces Glycemia but Does Not Affect Cognitive Impairment in Lean 5xFAD Mice.

Obesity and hyperglycemia are risk factors for cognitive decline and for the development of Alzheimer’s Disease (AD). Bariatric surgery is an effective treatment for obesity that was shown to improve cognitive decline in obese patients. Bariatric surgery was shown to exert weight loss independent effects on metabolic diseases such as type 2 diabetes. We tested whether sleeve gastrectomy (SG), a common bariatric surgery, can affect the cognitive impairment in lean, normoglycemic female 5xFAD mice, a genetic model for AD. 5xFAD mice and wild-type (WT) littermates underwent SG or sham surgery at the age of 5 months and were tested for metabolic, behavioral, and molecular phenotypes 90 days later. SG led to a reduction in blood glucose levels and total plasma cholesterol levels in 5xFAD mice without inducing weight loss. However, the surgery did not affect the outcomes of long-term spatial memory tests in these mice. Analysis of β-Amyloid plaques corroborated the behavioral studies in showing no effect of surgery on the molecular phenotype of 5xFAD mice. In conclusion, SG leads to an improved metabolic profile in lean female 5xFAD mice without inducing weight loss but does not affect the brain pathology or behavioral phenotype. Our results suggest that the positive effects of bariatric surgery on cognitive decline in obese patients are likely attributed to weight loss and improvement in obesity sequelae, and not to weight loss independent effects of surgery.

716-P: Systolic Blood Pressure Reduction with Tirzepatide across SURPASS Program: A Mediation Analysis Using Weight Loss as a Factor

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist for the treatment of type 2 diabetes. Across the SURPASS 1-5 clinical studies, TZP 5, and 15 mg demonstrated significant improvements in HbA1c (-1.9 to -2.6%) , body weight (-6.6 to -13.9%) and systolic blood pressure (SBP) (-2.8 to -12.6 mmHg) at primary endpoint. Post-hoc mediation analyses were conducted to evaluate weight loss dependent (WL-D) and independent (WL-IND) effects of TZP on SBP reductions across 5 SURPASS studies. The difference in mean SBP change from baseline at 40-weeks (Total effect) between TZP and comparator group was -1.3 to -5.1 mmHg (TZP 5 mg) , -1.7 to -6.5 mmHg (TZP mg) and -3.1 to -11.5 mmHg (TZP 15 mg) . The contribution of WL-D and WL-IND effects on these treatment differences are presented below (Figure) . In SURPASS-4 study which enrolled patients with established cardiovascular disease, WL-IND effects explained 33% to 57% of difference in SBP change between TZP and insulin glargine groups, with the remainder of 67% to 43% of the effect being WL-D. In a pooled analysis of SURPASS 1-5 studies, there was a significant (p&amp;lt;0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. In conclusion, TZP induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight loss independent effects across the different trials. Disclosure I. Lingvay: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Mannkind, TARGET PharmaSolutions; Valeritas;; Altimmune; DataRevive; Click; Medscape Duke CRI; Janssen Pharma; Bayer; Intercept, Novo Nordisk, Sanofi, Zealand Pharma A/S. Consultant; Novo Nordisk. Research Support; NovoNordisk; Mylan; Merck, Sanofi. O. Mosenzon: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, BOL Pharma, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Sanofi. Research Support; AstraZeneca, Novo Nordisk. Speaker's Bureau; AstraZeneca, Bayer AG, Eli Lilly and Company, Novo Nordisk, Sanofi. K. Brown: Employee; Eli Lilly and Company. X. Cui: Employee; Eli Lilly and Company. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Patel: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

561-P: The Effect of Time-Restricted Eating on Glycemic Control and Insulin Sensitivity in Women with Prediabetes: A Pilot Study

Time-restricted eating (TRE) is a dietary pattern in which daily food intake is restricted to a 6-h period without any caloric intake for the rest of the day. TRE improves glucose homeostasis in animal models even independent of weight loss and calorie intake. However, the weight-loss independent effect of TRE on glucose homeostasis in people remains debatable. We conducted a pilot study to investigate whether TRE without weight loss improves glycemic control and insulin sensitivity in women with prediabetes. Participants were randomized to the TRE (9-h daily eating period) or Control group (15-h daily eating period) for 12 weeks. We studied five participants (TRE n = 3 and Control n = 2) with overweight/obesity, prediabetes, and habitual daily eating period greater than 14 hours ([means and SD] age 50 ± 16 years, BMI 31 ± 5 kg/m2) . The daily eating period decreased in the TRE group (13.8 ± 0.5 vs. 8.5 ± 0.5 h) , but not in the Control group (13.9 ± 0.9 vs. 14.1 ± 1.1 h) . Participants’ weight, diet composition, and number of eating occasions remained unchanged during the study period for both groups. Glycemic control in free-living conditions assessed by using continuous glucose monitoring tended to improve in the TRE group (24-h area under the curve for interstitial glucose concentration: 2572 ± 286 vs. 2161 ± 216 mg/dl/24 h) , but not in the Control group (23± 59 vs. 2374 ± 2mg/dl/24 h) . Skeletal muscle insulin sensitivity assessed by using a hyperinsulinemic-euglycemic clamp procedure tended to increase in the TRE group (median and IQR: 27 (21, 37) vs. 34 (27, 41) μmol/kg/min) , but not in the Control group (41 ± 9 vs. 36 ± μmol/kg/min) . These preliminary results suggest that TRE may lead to weight-loss-independent improvements in glycemic control and insulin sensitivity in women with prediabetes. Further ongoing research will establish the effect of TRE without weight loss on glucose homeostasis and insulin sensitivity in people at high risk for type 2 diabetes mellitus. Disclosure M.Chondronikola: None. S.Zhu: None. P.Surampudi: n/a. B.Roshanravan: None. C.Sanchez: None. Funding NIH-UL1-TR001860, Clinical and Translational Science Center-Highly Innovative Pilot Award and USDA NationalInstitute of Food and Agriculture, Hatch project numberCA-D-NTR-2618-H

Effects of SGLT2 inhibition on lipid transport in adipose tissue in type 2 diabetes.

SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blinded, placebo-controlled crossover design of 4 weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal s.c. adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss-independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect free fatty acids (FFA) uptake in abdominal s.c. adipose tissue but increased FFA uptake in visceral adipose tissue by 27% (P < 0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (P = 0.03) and mRNA content (P = 0.01) in abdominal s.c. adipose tissue but without affecting glucose uptake. In addition, SGLT2 inhibition decreased the expression of genes involved in insulin signaling in adipose tissue. We conclude that SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal s.c. adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

Weight and organ specific immune cell profiling of sleeve gastrectomy in mice

ObjectiveSleeve gastrectomy (SG) has profound, immediate weight-loss independent effects on obesity related diabetes (T2D). Our prior studies have shown that immunologic remodeling may play a part in this metabolic improvement. However, to date, little is known about how the major immune cell populations change following SG and whether these are weight loss dependent. MethodsUsing mass cytometry with time of flight analysis (CyTOF), we broadly quantified the organ-specific immune cell repertoire induced by SG from splenic, jejunal, ileal, colonic, and hepatic lymphocyte fractions. Surgeries were performed in both diet-induced obese (DIO), insulin resistant mice and lean mice, which leads to sustained and non-sustained weight loss in SG animals compared to shams, respectively. Intergroup comparisons allow understanding of the relative contribution of diet, weight-loss, and surgery on immune profiling. Conserved immune changes represent surgery-specific, weight-independent, and diet-independent phenotypic changes. ResultsInitial analysis by way of visualization of t-distributed stochastic neighbor embedding analysis revealed changes in the B cell compartment following SG in both DIO and lean mice compared to Sham animals. In depth, traditional gating showed a shift within the splenic B cell compartment toward innate-like phenotype. There was a 1.3-fold reduction in follicular B cells within DIO SG (14% absolute reduction; p = 0.009) and lean SG (15% absolute reduction; p = 0.031) animals with a significant increase in innate-like B cell subsets in DIO SG mice(2.2 to 4.3-fold increase; p < 0.05). There was a similar trend toward increased innate B cell subsets in lean SG mice. There was a concomitant increase in multiple circulating immunoglobulin classes in both models. Further, lean (p = 0.009) and DIO SG animals (p = 0.015) had a conserved 5.5-fold and 5.7-fold increase, respectively, in splenic neutrophils and tendency toward M2 macrophage polarization. ConclusionsSG induces surgery-specific, weight-loss independent immune cells changes that have been previously linked to improved glucose metabolism. This immune phenotype may be a major contributor to post SG physiology. Characterizing the complex immune milieu following SG is an important step toward understanding the physiology of SG and the potential therapies therein.

Intermittent fasting as a nutrition approach against obesity and metabolic disease.

Intermittent fasting has been proposed as a potential nutrition approach against obesity and metabolic disease. Although data from studies in rodents convincingly support the antiobesity and cardiometabolic benefits of intermittent fasting, its effects in human health are still debatable. Recent studies have examined the effect of two intermittent fasting approaches, that is, alternate day fasting (ADF) and time-restricted eating (TRE), on weight loss and cardiometabolic risk factors. ADF seems to be an equally effective weight loss approach to caloric restriction, but adherence to ADF is more challenging. ADF improves cardiometabolic risk factors, whereas it may have superior metabolic benefits compared to caloric restriction in people with insulin resistance. TRE with ad libitum food intake is well tolerated and induces 2-4% weight loss in approximatively 3 months. Additionally, TRE may have metabolic benefits particularly in people with metabolically abnormal obesity even without weight loss. Intermittent fasting is a promising nutritional approach against obesity and its related metabolic diseases. Further research is needed to: i) establish the long-term effectiveness of TRE in weight loss and metabolic health, ii) improve the long-term adherence to ADF and investigate its weight loss independent effects in metabolic health, and iii) determine the mechanisms underlying the potential cardiometabolic benefits of intermittent fasting in humans.

1774-P: Neurally Mediated Prandial Islet-Cell Function Is Glucose-Independent and Preserved after Gastric Bypass and Sleeve Gastrectomy

The weight-loss independent glycemic effects of gastric bypass (GB) are characterized by prandial short-lived hyperinsulinemia as a result of β-cell stimulation by glucose and incretins. To investigate the effect of parasympathetic nervous system (PNS) activity, a neural component of the enteroinsular axis, on islet function, 9 subjects with history of GB, 6 with prior sleeve gastrectomy (SG), and 4 non-surgical controls were recruited. The GB, SG, and CN groups were matched for BMI, FFM, A1C, and age; and the GB and SG for weight loss and time postsurgery; none had diabetes. To measure islet hormone responses to meal ingestion when the effect of GI hormones and glycemia is minimal, subjects consumed a liquid meal (280 kcal, 20% glucose) at 2 hr of a 5-hr hyperinsulinemic (120 mU/m2/min) hypoglycemic (55mg/dl) clamp with and without atropine infusion on two separate studies. Fasting levels of glucose, islet and gut hormones were similar among 3 groups and 2 studies. Despite similar insulin sensitivity among the groups the insulin clearance estimated before meal ingestion was larger in surgical patients (P=0.08). Suppression of endogenous β-cell secretion by hypoglycemia was less in both surgical groups compared to controls (P&amp;lt;0.001), but it was reduced by atropine in 3 groups (P&amp;lt;0.05). Hypoglycemia-induced glucagon secretion was not affected by PNS blockade. Blocking PNS diminished both β- and α-cell secretory response to meal ingestion (P &amp;lt; 0.05) in both surgical and non-surgical groups. Pre- and post-meal pancreatic polypeptide, marker of vagal input to the islet, declined to baseline values during atropine infusion. Meal-induced GIP secretion was similar in studies with and without atropine whereas blocking PNS significantly reduced GLP-1 secretion (P &amp;lt; 0.05) in all subjects. Our data shows that in nondiabetic subjects with prior GB and SG, PNS activity regulates islet and gut hormone secretory response to meal ingestion independent of glucose levels. Disclosure H. Honka: None. A.M. Al Zubaidi: None. R.A. DeFronzo: None. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc. M. Salehi: None. Funding Finnish Cultural Foundation (00180071); National Institutes of Health (DK105379)

Postprandial hypoglycemia after gastric bypass surgery: from pathogenesis to diagnosis and treatment.

The Roux-en-Y gastric bypass surgery (RYGB) improves glucose control in majority of patients with type 2 diabetes. However, a minority group of individuals develop a life-threatening complication of hyperinsulinemic hypoglycemia. The goal of this review is to identify underlying mechanisms by which RYGB cause hypoglycemia and describe pathogenesis-driven strategies to diagnose and treat this condition. Gastric bypass leads to higher and earlier peak levels of glucose and lower nadir glucose after eating along with larger insulin and glucagon-like peptide 1 (GLP-1) secretion, resetting the balance between glucose appearance and clearance after this procedure. These weight-loss independent glycemic effects of RYGB have been attributed to changes in ingested glucose appearance as a result of rapid nutrient emptying from stomach pouch to the intestine and increased glucose clearance as a result of prandial hyperinsulinemia. The exaggerated effect of RYGB on postmeal glucose metabolism is a syndrome of postprandial hyperinsulinemic hypoglycemia manifesting in a group of individuals several years after this surgery. Affected patients have larger systemic appearance of ingested glucose and greater postmeal secretion of insulin and GLP-1 compared to those with history of RYGB without symptomatic hypoglycemia. Current evidence supporting a multifactorial model of glucose dysregulation among patients with hypoglycemia will be highlighted in this review. Hypoglycemia after RYGB is a life-threatening condition and likely represents the extreme glycemic phenotype of this procedure. Diagnosis is challenging and treatment options are limited.

Mechanisms Responsible for Metabolic Improvements of Bariatric Surgeries.

Given the seemingly unstoppable diabetes crisis, new efficient therapies for the prevention and treatment of this devastating and costly disease are sorely needed, and bariatric surgeries intended for weight loss seem to fill this gap. In addition to weight loss, there is remarkable short- to medium-term diabetes remission, particularly after Roux-en-Y gastric bypass and sleeve gastrectomy (1). However, broad longer-term effectiveness and complete cure are more elusive (2,3). It is also clear that bariatric surgery is not the answer for the staggering numbers of people with obesity and type 2 diabetes on either a national or global scale. This, in turn, has stimulated intense research efforts to find out the molecular and behavioral mechanisms behind the success of bariatric surgeries so that they can eventually be exploited with improved pharmacological and lifestyle/behavioral strategies but without the surgery. The question of whether diabetes remission is mainly due to weight loss or weight loss–independent effects of the surgery is fundamental, as it guides experimental approaches and may lead us to very different sets of key underlying pathways …

Early Weight Loss Independent Effects of Sleeve Gastrectomy on Diet-Induced Cardiac Dysfunction in Obese, Wistar Rats.

Several reports suggest that bariatric surgery significantly improves cardiac function in patients with obesity cardiomyopathy. The mechanism is unknown but may be due to weight-loss independent factors. We predict that the changes in gastrointestinal anatomy after a rodent model of sleeve gastrectomy (SG) will have weight-loss independent effects on cardiac dysfunction. Cardiac dysfunction was induced by feeding a 60%kcal from fat diet to male Wistar rats for 10weeks. Rats underwent either a SG (n=12) or pair-fed, PF (n=8) sham surgery. Echocardiograms were performed pre- and post-operatively at 6 and 13weeks. Blood samples were obtained at 10weeks post-operatively for assessment of insulin sensitivity and heart failure. Forty-four percent of SG rats had a normal ejection fraction (EF) at 13weeks ("responders") compared to five SG rats who did not recover EF ("non-responders"). Zero percent of the PF rats normalized EF (p=0.03). SG responders had a smaller left ventricular internal diameter in systole and end systolic volume with improved systolic function compared to SG non-responders (EF 90.7±1.7 vs. 75.4±3.6%, p=<0.001). At 10weeks post-operatively, plasma glucose and B-type natriuretic peptide levels were significantly lower in SG rats compared to PF rats. A SG significantly improved systolic function in 44% of rats with diet-induced obesity and cardiac dysfunction. This improvement is related to weight-loss independent effects of the surgery on the entero-cardiac axis. These results offer a novel weight-loss independent, metabolic role for bariatric surgery as a potential treatment modality for obesity-associated cardiac dysfunction.

The Physiology and Molecular Underpinnings of the Effects of Bariatric Surgery on Obesity and Diabetes.

Bariatric surgeries, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, produce significant and durable weight loss in both humans and rodents. Recently, these surgical interventions have also been termed metabolic surgery because they result in profound metabolic improvements that often surpass the expected improvement due to body weight loss alone. In this review we focus on the weight-loss independent effects of bariatric surgery, which encompass energy expenditure and macronutrient preference, the luminal composition of the gut (i.e., the microbiota and bile acids), the transformation of the gastrointestinal lining, increases in postprandial gut hormone secretions, glycemic control, pancreas morphology, and micronutrient and mineral absorption. Taken together, these data point to several important physiological changes that contribute to the profound benefits of these surgical procedures. Identifying the underlying molecular mechanisms for these physiological effects will allow better utilization of these existing procedures to help patients and develop new treatments that harness these surgical effects with less invasive interventions.

Bariatric surgery and type 2 diabetes: are there weight loss‐independent therapeutic effects of upper gastrointestinal bypass?

Type 2 diabetes (T2D) is a major worldwide public health concern. Despite a large armamentarium of T2D medications, a large proportion of patients fail to achieve recommended treatment goals for glycemic control. Weight loss has profound beneficial effects on the metabolic abnormalities involved in the pathogenesis of T2D. Accordingly, bariatric surgery, which is the most effective available weight loss therapy, is also the most effective therapy for treating patients with T2D. Surgical procedures that bypass the upper gastrointestinal (UGI) tract are particularly effective in achieving partial and even complete remission of T2D, suggesting that UGI bypass has weight loss-independent effects on glycemic control. Although a number of hypotheses (e.g. a role for multiorgan insulin sensitivity, β-cell function, incretin response, the gut microbiome, bile acid metabolism, intestinal glucose metabolism and browning of adipose tissue) have been proposed to explain the potential unique effects of UGI tract bypass surgery, none has yet been adequately evaluated to determine therapeutic importance in patients with T2D. Here, we review the efficacy of UGI bypass surgery in treating T2D and the mechanisms that have been proposed to explain its potential weight loss-independent therapeutic effects.

Physiological and molecular responses to bariatric surgery: markers or mechanisms underlying T2DM resolution?

Bariatric surgery is currently the most effective treatment for obesity and associated comorbidities, including rapid resolution of type 2 diabetes mellitus (T2DM). Although the weight loss itself has substantial impact, bariatric surgery also has weight loss-independent effects on T2DM. Several variations of bariatric surgery exist, including the widely studied Roux-en-Y gastric bypass and vertical sleeve gastrectomy. The success of both of these bariatric surgeries was originally attributed to restrictive and malabsorptive modes of action; however, mounting evidence from both human and animal studies implicates mechanisms beyond surgery-induced mechanical changes to the gastrointestinal (GI) system. In fact, with bariatric surgery comes a spectrum of physiological responses, including postprandial enhancement of gut peptide and bile acids levels, restructuring of microbial composition, and changes in GI function and morphology. Although many of these processes are also essential for glucoregulation, the independent role of each in the success of surgery is still an open question. In this review, we explore whether these changes are necessary for the improvements in body mass and glucose homeostasis or whether they are simply markers of the physiological effect of surgery.

Differential response of plasma plasminogen activator inhibitor 1 after weight loss surgery in patients with or without type 2 diabetes

BackgroundObesity and type 2 diabetes (T2D) are associated with a suppression of fibrinolysis and an increased risk of intravascular thrombi because of elevated plasma plasminogen activator inhibitor 1 (PAI-1). ObjectivesThe aim was to investigate PAI-1 levels in obese patients in the early phase after bariatric surgery, before any weight loss, and in the late phase, to identify the impact of reduced adipose mass versus weight loss independent effects on PAI-1 levels. We also studied the impact of T2D on the rate of PAI-1 reduction. SettingsTwelve obese patients with and without T2D (n = 6) who were scheduled for surgery at a designated Center of Excellence. MethodsPlasma PAI-1 antigen was measured by enzyme-linked immunosorbent assay (ELISA) preoperatively and at 4 and 42 days after gastric bypass surgery. ResultsIn the early phase, plasma PAI-1 was significantly decreased by 53% (P = .023). This difference did not remain significant in the late phase. However, PAI-1 levels in T2D and non-T2D patients were significantly different (P = .005). In non-T2D patients, plasma PAI-1 levels decreased significantly in both early and late phases (P = .038). Interestingly, in the T2D group, the PAI-1 levels tended to increase in the late phase and differed significantly from the non-T2D group. ConclusionWe report decreased PAI-1 levels in the immediate postoperative period after gastric bypass, indicating that a mechanism not related to the fat mass regulates the PAI-1 levels. Additionally, there may be a difference in PAI-1 levels between T2D and non-T2D patients 42 days postoperatively. Further studies are required to verify this difference and to elucidate the specific mechanisms responsible for PAI-1 synthesis.

Weight Change-Adjusted Effects of Gastric Bypass Surgery on Glucose Metabolism: 2- and 10-Year Results From the Swedish Obese Subjects (SOS) Study.

It has been suggested that weight change-independent effects on fasting insulin and glucose levels are present after gastric bypass (GBP) but not after banding and vertical banded gastroplasty (VBG). We therefore evaluated weight change-adjusted effects of GBP, compared with restrictive surgical procedures, on long-term changes in fasting levels of glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in the Swedish Obese Subjects (SOS) study. Participants who completed the 2-year (n = 1,762) and/or the 10-year (n = 1,216) follow-up were divided into three weight change classes (weight loss >30%, 20-30%, or ≤20%), and by surgical method (banding, VBG, or GBP). Glucose, insulin, and HOMA-IR changes were analyzed in relation to weight change over 2 and 10 years. Analyses were performed in the full cohort and also in subgroups based on baseline glucose status. Within weight change classes, reductions in glucose, insulin, and HOMA-IR were similar in the three surgery groups both at 2 and at 10 years. Reductions in glucose, insulin, and HOMA-IR increased with increasing weight loss, and changes were typically related to weight change within each surgery group. Moreover, the association between weight change and change in glucose, insulin, or HOMA-IR did not differ between the surgery groups at 2 and 10 years. When patients were subdivided also by baseline glucose status, similar relationships between weight changes and changes in glucose, insulin, and HOMA-IR were observed. Even though weight loss-independent effects are important for short-term diabetes remission, our results suggest that degree of weight loss is more important for long-term reductions in fasting insulin and glucose than choice of bariatric surgery procedure.

Gastric bypass surgery has a weight-loss independent effect on post-challenge serum glucose levels.

BackgroundGastric bypass surgery seems to have an effect on glucose metabolism beyond what is mediated through weight reduction. The magnitude of this effect on fasting and post-challenge glucose levels remains unknown.ResultsMorbidly obese subjects without known diabetes performed a 75 g oral glucose tolerance test before and after either gastric bypass surgery (n = 64) or an intensive lifestyle intervention programme (n = 55), ClinicalTrials.gov identifier NCT00273104. The age-adjusted effects of the therapeutic procedures and percentage weight change on fasting and 2-h glucose levels at 1 year were explored using multiple linear regression analysis. Mean (SD) serum fasting and 2-h glucose levels at baseline did not differ between the surgery and lifestyle groups. Weight-loss after surgical treatment and lifestyle intervention was 30 (8) and 9 (10) % (p < 0.001). At 1 year, fasting and 2-h glucose levels were significantly lower in the surgery group than in the lifestyle group, 4.7 (0.4) versus 5.4 (0.7) mmol/l and 3.4 (0.8) versus 6.0 (2.4) mmol/l, respectively (both p < 0.001). Gastric bypass and weight-loss had both independent glucose-lowering effects on 2-h glucose levels [B (95 % CI) 1.4 (0.6–2.3) mmol/l and 0.4 (0.1–0.7) mmol/l per 10 % weight-loss, respectively]. Fasting glucose levels were determined by weight change [0.2 (0.1–0.3) mmol/l per 10 % weight-loss] and not by type of treatment.ConclusionsGastric bypass surgery has a clinically relevant glucose-lowering effect on post-challenge glucose levels which is seemingly not mediated through weight-loss alone.

Early Increases in Bile Acids Post Roux-en-Y Gastric Bypass Are Driven by Insulin-Sensitizing, Secondary Bile Acids.

Roux-en-Y gastric bypass (RYGB) is the most effective treatment for morbid obesity and resolution of diabetes. Over the last decade, it has become well accepted that this resolution of diabetes occurs before significant weight loss; however, the mechanisms behind this effect remain unknown and could represent novel therapeutic targets for obesity and diabetes. Bile acids have been identified as putative mediators of these weight loss-independent effects. To identify the longitudinal changes in bile acids after RYGB, which may provide mechanistic insight into the weight loss-independent effects of RYGB. Observational study before/after intervention. Academic medical center. Samples were collected from morbidly obese patients (n = 21) before and after RYGB. RYGB. Seventeen individual bile acid species were measured preoperatively and at 1, 6, 12, and 24 months postoperatively. Anthropometric, hormonal, and hyperinsulinemic-euglycemic clamp data were also examined to identify physiological parameters associated with bile acid changes. Fasting total plasma bile acids increased after RYGB; however, increases were bimodal and were observed only at 1 (P < .05) and 24 months (P < .01). One-month increases were secondary to surges in ursodeoxycholic acid and its glycine and taurine conjugates, bacterially derived bile acids with putative insulin-sensitizing effects. Increases at 24 months were due to gradual rises in primary unconjugated bile acids as well as deoxycholic acid and its glycine conjugate. Plasma bile acid changes were not significantly associated with any anthropometric or hormonal measures, although hepatic insulin sensitivity was significantly improved at 1 month. Overall findings suggest that bacterially derived bile acids may mediate the early improvements at 1 month after RYGB. Future studies should examine the changes in specific bile acid chemical species after bariatric procedures and bile acid-specific signaling changes.

Effects of glucagon like peptide-1 to mediate glycemic effects of weight loss surgery.

To date, weight loss surgeries are the most effective treatment for obesity and glycemic control in patients with type 2 diabetes. Roux-en-Y gastric bypass surgery (RYGB) and sleeve gastrectomy (SG), two widely used bariatric procedures for the treatment of obesity, induce diabetes remission independent of weight loss while glucose improvement after adjustable gastric banding (AGB) is proportional to the amount of weight loss. The immediate, weight-loss independent glycemic effect of gastric bypass has been attributed to postprandial hyperinsulinemia and an enhanced incretin effect. The rapid passage of nutrients into the intestine likely accounts for significantly enhanced glucagon like-peptide 1 (GLP-1) secretion, and postprandial hyperinsulinemia after GB is typically attributed to the combined effects of elevated glucose and GLP-1. For this review we focus on the beneficial effects of the three most commonly performed bariatric procedures, RYGB, SG, and AGB, on glucose metabolism and diabetes remission. Central to this discussion will be the extent to which the effects of surgery are mediated by GLP-1. Better understanding of these mechanisms could provide insight to development of novel therapeutic strategies for treatment of diabetes as well as refinement of surgical techniques.