Acute carbohydrate overfeeding: a redox model of insulin action and its impact on metabolic dysfunction in humans.

A role for fat overfeeding in metabolic dysfunction in humans is commonly implied in the literature. Comparatively less is known about acute carbohydrate overfeeding (COF). We tested the hypothesis that COF predisposes to oxidative stress by channeling electrons away from antioxidants to support energy storage. In a study of 24 healthy human subjects with and without obesity, COF was simulated by oral administration of excess carbohydrates; a two-step hyperinsulinemic clamp was used to evaluate insulin action. The distribution of electrons between oxidative and reductive pathways was evaluated by the changes in the reduction potentials (Eh) of cytoplasmic (lactate, pyruvate) and mitochondrial (ß-hydroxybutyrate, acetoacetate) redox couples. Antioxidant redox was measured by the ratio of reduced to oxidized glutathione. We used cross-correlation analysis to evaluate the relationships between the trajectories of Eh, insulin, glucose, and respiratory exchange during COF. DDIT3 and XBP1s/u mRNA were measured as markers of endoplasmic reticulum stress (ER stress) in adipose tissue before and after COF. Here, we show that acute COF is characterized by net transfer of electrons from mitochondria to cytoplasm. Circulating glutathione is oxidized in a manner that significantly cross-correlates with increasing insulin levels and precedes the decrease in cytoplasmic Eh. This effect is more pronounced in overweight individuals (OW). Markers of ER stress in subcutaneous fat are detectable in OW within 4 h. We conclude that acute COF contributes to metabolic dysfunction through insulin-dependent pathways that promote electron transfer to the cytoplasm and decrease antioxidant capacity. Characterization of redox during overfeeding is important for understanding the pathophysiology of obesity and type 2 diabetes.NEW & NOTEWORTHY Current principles assume that conversion of thermic energy to metabolically useful energy follows fixed rules. These principles ignore the possibility of variable proton uncoupling in mitochondria. Our study shows that the net balance of electron distribution between mitochondria and cytoplasm is influenced by insulin in a manner that reduces proton leakage during overfeeding. Characterization of the effects of insulin on redox balance is important for understanding obesity and insulin resistance.

Obesity: Overview of Weight Management.

INTRODUCTION: Obesity is a chronic illness that requires a multifaceted personalized treatment approach. METHODS & FINDINGS: Using current guidelines and recent studies in weight management, this article reviews the multiple components of weight management: lifestyle intervention (dietary intervention, physical activity, and behavioral interventions), pharmacotherapy, endoscopic procedures, and surgical procedures. This review briefly discusses specific diets and dietary strategies, compensatory mechanisms acting against weight loss, recent changes to Food and Drug Administration approved antiobesity medications, and technological advances in weight management delivery. CONCLUSION: Current literature is lacking large studies on the safety and efficacy of combination therapies involving pharmacotherapy plus 1 or more procedures.

ETHNIC AND RACIAL DISPARITIES IN THE BEHAVIORAL, PHARMACOLOGIC, AND SURGICAL TREATMENT OF OBESITY.

Abbreviation: GLP-1 = glucagon-like peptide-1.

Comparison of weight loss outcomes between Roux-en-Y gastric bypass and sleeve gastrectomy in a racially mixed urban patient population.

BACKGROUND: National data show a trend favoring laparoscopic sleeve gastrectomy (SG) over Roux-en-Y gastric bypass (RYGB). Published data demonstrating the differences in weight loss between the two procedures are mixed. OBJECTIVE: In this retrospective study using clinical data from 2010 to 2020, we compared the clinical and demographic characteristics of patients undergoing either SG or RYGB to evaluate their long-term weight loss outcomes. SETTING: University hospital in the United States. METHODS: A total of 3329 patients were identified in our institutional Metabolic and Bariatric Surgery Accreditation and Quality Improvement database using Current Procedural Terminology codes for either RYGB or SG. A general linear model was used for baseline characteristics. Logistic regression was used for factors favoring RYGB versus SG. A multivariable linear mixed model was used for weight-trajectory analysis. Cox regression was used for a cumulative hazard ratio of 10% weight regained from nadir. RESULTS: Factors favoring RYGB were diagnoses of type 2 diabetes and gastroesophageal reflux disease, Hispanic ethnicity, and surgeon's preference. SG was favored among Black patients and smokers. RYGB was associated with more weight loss at all time points. The risk of weight regain was significantly higher after SG versus RYGB. CONCLUSIONS: The bariatric procedure choice is significantly influenced by race, medical history, and surgeon's experience. RYGB results in a significantly more durable weight loss compared with SG regardless of race or other stratification factors.

Approach to the Patient: Management of the Post-Bariatric Surgery Patient With Weight Regain.

CONTEXT: Weight regain (WR) after bariatric surgery is emerging as a common clinical problem due to the increase in the number of procedures performed. Early interventions are necessary to curtail the potential recurrence of comorbid conditions. However, it is often difficult to recognize WR early enough to introduce mitigating measures because there are no current guidelines for timely diagnosis and assessment of the severity of this condition. OBJECTIVE: We present a practical approach for the early recognition of WR, based on 11-year follow-up data from our multiethnic bariatric surgery patient population. METHODS: We classify WR according to the rate of increase in weight relative to nadir weight, normalized per 30-day interval. We also review pertinent literature about the etiologic factors contributing to WR after bariatric surgery. RESULTS: According to our algorithm, mild, moderate, and rapid WR are defined as weight increases of 0.2% to <0.5%, 0.5% to 1.0%, and more than 1.0% of nadir weight per 30 days, respectively. Treatment options, including dietary counseling, use of antiobesity medication, and consideration of surgical revision, are described. A case is presented to illustrate the utility of timely identification of WR and the importance of collaboration between bariatric surgeons, obesity medicine specialists, and dietitians. CONCLUSION: Our approach emphasizes the importance of regular long-term follow-up for all bariatric surgery patients.

The Mitigating Effect of Phentermine and Topiramate on Weight Regain After Roux-en-Y Gastric Bypass Surgery.

OBJECTIVE: Weight regain (WR) after Roux-en-Y gastric bypass surgery (RYGB) starts to occur 2 years after surgery, ultimately affecting at least 25% of patients. A limited number of studies have evaluated the impact of antiobesity medications (AOMs) on this phenomenon. METHODS: This study reviewed the electronic medical records of 1,196 patients who underwent RYGB between 2004 and 2015. WR was evaluated by comparing each patient's weight during subsequent postoperative office visits to nadir weight (lowest weight after RYGB, n = 760), taking into consideration the interval during which WR occurred. Patients who were prescribed AOMs and came to follow-up visits were classified as adherent users, whereas those who missed their follow-up visits were considered nonadherent. This study used a linear mixed model, Cox regression, and generalized equation estimator to determine the impact of AOMs on WR trajectory, hazard ratio for time to event, and odds ratio for repeated event occurrence, respectively. RESULTS: Despite the lack of a unified protocol for using AOMs, the three statistical models converged to show that phentermine and topiramate, used individually or in combination, can significantly reduce WR after RYGB. CONCLUSIONS: Phentermine and topiramate are effective in mitigating WR after RYGB. Further studies are needed to help ascertain optimal use of AOMs after bariatric surgery.

Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction.

Hyperinsulinemia is strongly associated with type 2 diabetes. Racial and ethnic minority populations are disproportionately affected by diabetes and obesity-related complications. This mini-review provides an overview of the genetic and environmental factors associated with hyperinsulinemia with a focus on racial and ethnic differences and its metabolic consequences. The data used in this narrative review were collected through research in PubMed and reference review of relevant retrieved articles. Insulin secretion and clearance are regulated processes that influence the development and progression of hyperinsulinemia. Environmental, genetic, and dietary factors are associated with hyperinsulinemia. Certain pharmacotherapies for obesity and bariatric surgery are effective at mitigating hyperinsulinemia and are associated with improved metabolic health. Hyperinsulinemia is associated with many environmental and genetic factors that interact with a wide network of hormones. Recent studies have advanced our understanding of the factors affecting insulin secretion and clearance. Further basic and translational work on hyperinsulinemia may allow for earlier and more personalized treatments for obesity and metabolic diseases.

Effects of medium chain triglycerides supplementation on insulin sensitivity and beta cell function: A feasibility study.

OBJECTIVE: Medium chain triglycerides (MCT) have unique metabolic properties which may improve insulin sensitivity (Si) and beta cell function but data in humans are limited. We conducted a 6-week clinical trial of MCT oil supplementation. METHODS: 22 subjects without diabetes (8 males, 14 females, mean ± standard error age 39±2.9 years, baseline BMI 27.0±1.4 kg/m2) were counseled to maintain their body weight and physical activity (PA) during the trial. Dietary intake, PA data, body composition, and resting energy expenditure (REE) were obtained through dietary recall, international PA questionnaire, dual x-ray absorptiometry, and indirect calorimetry, respectively. MCT prescriptions were given based on REE and PA to replace part of dietary fat with 30 grams of MCT per 2000 kcal daily. Insulin-modified frequently sampled intravenous glucose tolerance tests were performed before and after MCT to measure changes in Si, acute insulin response (AIR), disposition index (DI), and glucose effectiveness (Sg). RESULTS: MCT were well tolerated and weight remained stable (mean change 0.3 kg, p = 0.39). Fasting REE, respiratory quotient, and body composition were stable during the intervention. There were no significant changes in mean fasting glucose, insulin, insulin resistance, fasting total ketones, Si, AIR, DI, Sg, leptin, fructosamine, and proinsulin. The mean change in Si was 0.5 10-4 min-1 per mU/L (95% CI: -1.4, 2.4), corresponding to a 12% increase from baseline, and the range was -4.7 to 12.9 10-4 min-1 per mU/L. Mean total adiponectin decreased significantly from 22925 ng/mL at baseline to 17598 ng/mL at final visit (p = 0.02). The baseline clinical and laboratory parameters were not significantly associated with the change in Si. DISCUSSION: There were a wide range of changes in the minimal model parameters of glucose and insulin metabolism in subjects following 6 weeks of MCT as an isocaloric substitution for part of usual dietary fat intake. Since this was a single-arm non-randomized study without a control group, it cannot be certain whether these changes were due to MCT so further randomized controlled trials are warranted.

Weight Recidivism After Roux-en-Y Gastric Bypass Surgery: An 11-Year Experience in a Multiethnic Medical Center.

OBJECTIVE: Weight recidivism following Roux-en-Y gastric bypass (RYGB) is common and is associated with recurrence of comorbidities. Studies with long-term follow-up of recidivism quantified by weight regain (WR) are lacking. A retrospective review of all RYGB at our center from 2004 to 2015 was performed to examine the effects of race and type 2 diabetes on WR following RYGB. METHODS: Multivariable linear mixed models were used for the effects of time and race on weight, WR relative to nadir weight (WR/nadir), and WR relative to maximal weight loss, and Cox regressions were used for low, moderate, and high WR/nadir. RESULTS: A total of 1,395 participants were identified. The sample was limited to African American (AA), Caucasian American (CA), and Hispanic American (HA) participants. The effects of time (P < 0.0001), race (P < 0.0001), and race × time interaction (P = 0.0008) on weight trajectory were significant. AA had significantly more WR than CA (P < 0.01). AA and HA had a higher hazard ratio for having low, moderate, and rapid WR/nadir. CONCLUSIONS: Racial disparities after RYGB include WR and particularly affect AA. Understanding the etiologic factors that contribute to these disparities is important to optimize the long-term clinical outcomes of bariatric surgery.

Relation of cumulative weight burden to vascular endothelial dysfunction in obesity.

Although excess fat mass is linked to increased cardiovascular risk, the relation between vascular phenotype and degree of obesity in high weight categories is unknown. We examined brachial artery vasomotor responses using ultrasound in 203 consecutive patients with severe obesity (mean age 44 +/- 11 years; body mass index [BMI] 46 +/- 9 kg/m(2), range 30 to 72; and body weight 128 +/- 29 kg, range 69 to 207). We studied a unique population in which 71% of subjects were characterized as morbidly obese (BMI > or =40 kg/m(2)), which included a 31% group of super-obese subjects (BMI > or =50 kg/m(2)). Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were examined as measures of endothelium-dependent and -independent dilation, respectively, in relation to clinical, hemodynamic, and metabolic variables. Endothelial function was significantly impaired in the highest compared with the lowest tertile of body weight (FMD 6.5 +/- 4.6% vs 9.8 +/- 4.8%, p <0.001), whereas nitroglycerin-mediated dilation was similar in all groups. Univariate correlates of FMD were gender, weight, waist circumference, BMI, diastolic blood pressure, and creatinine. In multivariate analysis, weight was a strong independent significant predictor of FMD (beta = -0.23, p = 0.005) in addition to gender. Within an overweight population, cumulative weight burden remains strongly linked to progressive arterial dysfunction. In conclusion, these results suggest that cardiovascular risks intensify with higher degrees of obesity and underscore the importance of therapeutic weight loss interventions.

Protein sparing therapies in acute illness and obesity: a review of George Blackburn's contributions to nutrition science.

Protein sparing therapies were developed to mitigate the harms associated with protein-calorie malnutrition and nitrogen losses induced by either acute illness or hypocaloric diets in patients with obesity. We review the development of protein sparing therapies in illness and obesity with a focus on the pioneering contributions of George Blackburn, MD, PhD. He recognized that protein-calorie malnutrition is a common and serious clinical condition and developed new approaches to its treatment in hospitalized patients. His work with stable isotopes and with animal models provided answers about the physiological nutritional requirements and metabolic changes across a spectrum of conditions with varying degrees of stress and catabolism. This led to improvements in enteral and parenteral nutrition for patients with acute illness. Blackburn also demonstrated that lean body mass can be preserved during weight loss with carefully designed very low calorie treatments which became known as the protein sparing modified fast (PSMF). We review the role of the PSMF as part of the comprehensive management of obesity.

Racial differences in weight loss, hemoglobin A1C, and blood lipid profiles after Roux-en-Y gastric bypass surgery.

BACKGROUND: It is known that African American (AA) patients with obesity achieve less weight loss after Roux-en-Y gastric bypass surgery (RYGB) than their Caucasian (CA) counterparts. However, it is unclear how these differences in weight loss are reflected in clinical outcomes. OBJECTIVES: To determine the effects of RYGB on hemoglobin A1c (A1c) and blood lipids in relationship to the variability in weight loss outcomes in a racially mixed patient population. SETTING: University medical center. METHODS: Retrospective analysis of clinical data from electronic medical records of CA, AA, and Hispanic American (HA) patients undergoing RYGB. RESULTS: We used 2-way cluster analysis and identified 4 distinct weight loss×race clusters. CA patients separated into 2 clusters (45.5% and 28.2% weight loss, respectively), whereas, AA and HA patients separated into 1 cluster each (33.2% and 34.4% weight loss, respectively). Factors that significantly affected weight loss were race, age, gender, and physical activity as well as presence of hypertension and degenerative joint disease. Although all clusters had significant improvements in blood lipids, HA had an increase in total cholesterol (Total-c) and low-density lipoprotein cholesterol (LDL-c) at 2 years after surgery. All clusters had significant decreases in A1c in the first year. At 2 years after RYGB, A1c levels remained stable in CA and HA; however, AA had a significant increase. These racial differences in A1c could not be explained by the smaller weight loss in AA patients. CONCLUSION: Race is an important factor in the clinical outcomes of RYGB, especially in regard to diabetes control; however, its effect is not completely understood.

Effect of medical and surgical weight loss on endothelial vasomotor function in obese patients.

We prospectively examined brachial artery endothelial function using vascular ultrasound in 41 obese subjects treated with medical or surgical (gastric bypass) weight loss interventions. Surgical intervention produced greater weight loss and more pronounced improvement in endothelial function than medical treatment alone. Improved endothelial function with weight loss correlated strongly with fasting glucose but not with alteration in blood pressure, lipids, degree of weight loss, or plasma resistin concentrations. These data demonstrate that weight loss in markedly obese patients improves endothelial function and glycemic control that may represent important mechanisms of the cardiovascular benefit associated with weight reduction.

Racial/Ethnic Differences in Insulin Resistance and Beta Cell Function: Relationship to Racial Disparities in Type 2 Diabetes among African Americans versus Caucasians.

Both biological and sociocultural factors have been implicated in the well-documented racial disparity in incidence and prevalence of type 2 diabetes (T2D) between African Americans (AA) and non-Hispanic whites (NHW). This review examines the extent to which biological differences in glucose metabolism, specifically insulin resistance and beta cell function (BCF), contribute to this disparity. The majority of available data suggests that AA are more insulin resistant and have upregulated BCF compared to NHW. Increasing evidence implicates high insulin secretion as a cause rather than consequence of T2D; therefore, upregulated BCF in AA may specifically confer increased risk of T2D in this cohort. Racial disparities in the metabolic characteristics of T2D have direct implications for the treatment and health consequences of this disease; therefore, future research is needed to determine whether strategies to reduce insulin secretion in AA may prevent or delay T2D and lessen racial health disparities.

Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects.

OBJECTIVE: High fat, low carbohydrate (HFLC) diets have become popular tools for weight management. We sought to determine the effects of a HFLC diet compared to a low fat high carbohydrate (LFHC) diet on the change in weight loss, cardiovascular risk factors and inflammation in subjects with obesity. METHODS: Obese subjects (29.0-44.6 kg/m2) recruited from Boston Medical Center were randomized to a hypocaloric LFHC (n=26) or HFLC (n=29) diet for 12 weeks. RESULTS: The age range of subjects was 21-62 years. As a percentage of daily calories, the HFLC group consumed 33.5% protein, 56.0% fat and 9.6% carbohydrate and the LFHC group consumed 22.0% protein, 25.0% fat and 55.7% carbohydrate. The change in percent body weight, lean and fat mass, blood pressure, flow mediated dilation, hip:waist ratio, hemoglobin A1C, fasting insulin and glucose, and glucose and insulin response to a 2h oral glucose tolerance test did not differ (P>0.05) between diets after 12 weeks. The HFLC group had greater mean decreases in serum triglyceride (P=0.07), and hs-CRP (P=0.03), and greater mean increases in HDL cholesterol (P=0.004), and total adiponectin (P=0.045) relative to the LFHC. Secreted adipose tissue adiponectin or TNF-α did not differ after weight loss for either diet. CONCLUSIONS: Relative to the LFHC group, the HFLC group had greater improvements in blood lipids and systemic inflammation with similar changes in body weight and composition. This small-scale study suggests that HFLC diets may be more beneficial to cardiovascular health and inflammation in free-living obese adults compared to LFHC diets.

Fructose consumption and cancer: is there a connection?

PURPOSE OF REVIEW: Cancer cell metabolism is characterized by high rates of glucose uptake and anaerobic glycolysis. Sugar consumption has increased dramatically in the industrialized world, with refined fructose intake skyrocketing upwards in the USA over the past 30 years. Fructose provides an alternative carbon source for glycolysis, entering downstream of glucose and bypassing two key rate-limiting steps. Considering that glycolysis is the major pathway which fuels cancer growth, this review will focus on regulation and flux of glucose versus fructose through this pathway, and consider whether epidemiologic and experimental data support a mechanism whereby fructose might potentiate cancer growth in transformed cells.(Figure is included in full-text article.) RECENT FINDINGS: Fructose intake is associated with increased risk of pancreatic and small intestinal cancers, and possibly others. Fructose promotes flux through the pentose phosphate, which enhances protein synthesis and may indirectly increase tumor growth. Fructose treatment is associated with more aggressive cancer behavior and may promote metastasis. SUMMARY: Whereas glucose favors overall growth kinetics, fructose enhances protein synthesis and appears to promote a more aggressive cancer phenotype. Fructose has become ubiquitous in our food supply, with the highest consumers being teens and young adults. Therefore, understanding the potential health consequences of fructose and its role in chronic disease development is of critical importance.

Preoperative weight gain might increase risk of gastric bypass surgery.

BACKGROUND: Weight loss improves the cardiovascular and metabolic risk associated with obesity. However, insufficient data are available about the health effects of weight gain, separate from the obesity itself. We sought to determine whether the changes in body weight before open gastric bypass surgery (OGB) would have a significant effect on the immediate perioperative hospital course. METHODS: A retrospective chart review of 100 consecutive patients was performed to examine the effects of co-morbidities and body weight changes in the immediate preoperative period on the hospital length of stay and the rate of admission to the surgical intensive care unit (SICU). RESULTS: Of our class III obese patients undergoing OGB, 95% had ≥1 co-morbid condition and an overall SICU admission rate of 18%. Compared with the patients with no perioperative SICU admission, the patients admitted to the SICU had a greater degree of insulin resistance (homeostatic model analysis-insulin resistance 10.8 ± 1.3 versus 5.9 ± 0.5, P = .001), greater serum triglyceride levels (225 ± 47 versus 143 ± 8 mg/dL, P = .003), and had gained more weight preoperatively (.52 ± .13 versus .06 ± .06 lb/wk, P = .003). The multivariate analyses showed that preoperative weight gain was a risk factor for a longer length of stay and more SICU admissions lasting ≥3 days, as were a diagnosis of sleep apnea and an elevated serum triglyceride concentration. CONCLUSION: The results of the present retrospective study suggest that weight gain increases the risk of perioperative SICU admission associated with OGB, independent of the body mass index. Sleep apnea and elevated serum triglyceride levels were also important determinants of perioperative morbidity. In view of the increasing epidemic of obesity and the popularity of bariatric surgical procedures, we propose that additional clinical and metabolic research focusing on the understanding of the complex relationship among obesity, positive energy balance, weight gain, and perioperative morbidity is needed.