Ketogenic propensity is differentially related to lipid-induced hepatic and peripheral insulin resistance.

AIM: Determine the ketogenic response (ß-hydroxybutyrate, a surrogate of hepatic ketogenesis) to a controlled lipid overload in humans. METHODS: In total, nineteen young, healthy adults (age: 28.4 ± 1.7 years; BMI: 22.7 ± 0.3 kg/m2 ) received either a 12 h overnight lipid infusion or saline in a randomized, crossover design. Plasma ketones and inflammatory markers were quantified by colorimetric and multiplex assays. Hepatic and peripheral insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies were obtained to quantify gene expression related to ketone body metabolism and inflammation. RESULTS: By design, the lipid overload-induced hepatic (50%, p < 0.001) and peripheral insulin resistance (73%, p < 0.01) in healthy adults. Ketones increased with hyperlipidemia and were subsequently reduced with hyperinsulinemia during the clamp procedure (Saline: Basal = 0.22 mM, Insulin = 0.07 mM; Lipid: Basal = 0.78 mM, Insulin = 0.51 mM; 2-way ANOVA: Lipid p < 0.001, Insulin p < 0.001, Interaction p = 0.07). In the saline control condition, ketones did not correlate with hepatic or peripheral insulin sensitivity. Conversely, in the lipid condition, ketones were positively correlated with hepatic insulin sensitivity (r = 0.59, p < 0.01), but inversely related to peripheral insulin sensitivity (r = -0.64, p < 0.01). Hyperlipidemia increased plasma inflammatory markers, but did not impact skeletal muscle inflammatory gene expression. Gene expression related to ketone and fatty acid metabolism in skeletal muscle increased in response to hyperlipidemia. CONCLUSION: This work provides important insight into the role of ketones in human health and suggests that ketone body metabolism is altered at the onset of lipid-induced insulin resistance.

Rationale and study design for lifestyle intervention in preparation for pregnancy (LIPP): A randomized controlled trial.

INTRODUCTION: Maternal obesity increases neonatal risk for obesity and metabolic syndrome later in life. Prior attempts to break this intergenerational obesity cycle by limiting excessive gestational weight gain have failed to reduce neonatal adiposity. Alternatively, pre-conception lifestyle interventions may improve the in utero metabolic milieu during early pregnancy leading to improved fetal outcomes. This randomized controlled trial (RCT) is evaluating whether a lifestyle intervention to reduce weight and improve maternal metabolism in preparation for pregnancy (LIPP) attenuates neonatal adiposity, compared to standard medical advice. MATERIAL AND METHODS: Overweight/class 1 obese women after a previous pregnancy, ~12 weeks postpartum, preparing for a subsequent pregnancy, will be block randomized (1:1) to either LIPP or standard of care in a parallel design. Randomization is stratified by lactation status and overweight vs. class 1 obesity. The LIPP program consists of intensive short-term weight loss followed by weight maintenance until conception using supervised exercise and a low glycemic Mediterranean diet. PRIMARY OUTCOMES: Group differences in neonatal adiposity at birth assessed by PEA POD and placental mitochondrial lipid metabolism. SECONDARY OUTCOMES: Group differences in maternal pregravid and gestational body composition, insulin sensitivity, ß-cell function, fasting metabolic and inflammatory biomarkers, and overall quality of life. Exploratory outcomes include umbilical cord blood insulin resistance, lipid profile and inflammation. DISCUSSION: This RCT will determine the efficacy of maternal weight loss prior to pregnancy on reducing neonatal adiposity. Findings may change standard obstetrical care by providing Level 1 evidence on lifestyle interventions improving neonatal outcomes for women planning for pregnancy. CLINICAL TRIAL REGISTRATION: NCT03146156.

Weight loss interventions for adults with overweight/obesity and chronic musculoskeletal pain: a mixed methods systematic review.

Worldwide prevalence of adult overweight and obesity is a growing public health issue. Adults with overweight/obesity often have chronic musculoskeletal pain. Using a mixed-methods review, we aimed to quantify the effectiveness and explore the appropriateness of weight loss interventions for this population. Electronic databases were searched for studies published between 01/01/90 and 01/07/16. The review included 14 randomized controlled trials that reported weight and pain outcomes and three qualitative studies that explored perceptions of adults with co-existing overweight/obesity and chronic musculoskeletal pain. The random-effects pooled mean weight loss was 4.9 kg (95%CI:2.9,6.8) greater for intervention vs control. The pooled mean reduction in pain was 7.3/100 units (95%CI:4.1,10.5) greater for intervention vs control. Study heterogeneity was substantial for weight loss (I2  = 95%, tau = ±3.5 kg) and pain change (I2  = 67%, tau = ±4.1%). Meta-regression slopes for the predictors of study quality, mean age and baseline mean weight on mean study weight reduction were shallow and not statistically significant (P > 0.05). The meta-regression slope between mean pain reduction and mean weight lost was shallow, and not statistically significant, -0.09 kg per unit pain score change (95%CI:-0.21,0.40, P = 0.54). Meta-synthesis of qualitative findings resulted in two synthesized findings; the importance of healthcare professionals understanding the effects of pain on ability to control weight and developing management/education programmes that address comorbidity.

Gastric bypass surgery is protective from high-fat diet-induced non-alcoholic fatty liver disease and hepatic endoplasmic reticulum stress.

AIM: High-fat diets are known to contribute to the development of obesity and related co-morbidities including non-alcoholic fatty liver disease (NAFLD). The accumulation of hepatic lipid may increase endoplasmic reticulum (ER) stress and contribute to non-alcoholic steatohepatitis and metabolic disease. We hypothesized that bariatric surgery would counter the effects of a high-fat diet (HFD) on obesity-associated NAFLD. METHODS: Sixteen of 24 male Sprague Dawley rats were randomized to Sham (N = 8) or Roux-en-Y gastric bypass (RYGB) surgery (N = 8) and compared to Lean controls (N = 8). Obese rats were maintained on a HFD throughout the study. Insulin resistance (HOMA-IR), and hepatic steatosis, triglyceride accumulation, ER stress and apoptosis were assessed at 90 days post-surgery. RESULTS: Despite eating a HFD for 90 days post-surgery, the RYGB group lost weight (-20.7 ± 6%, P < 0.01) and improved insulin sensitivity (P < 0.05) compared to Sham. These results occurred with no change in food intake between groups. Hepatic steatosis and ER stress, specifically glucose-regulated protein-78 (Grp78, P < 0.001), X-box binding protein-1 (XBP-1) and spliced XBP-1 (P < 0.01), and fibroblast growth factor 21 (FGF21) gene expression, were normalized in the RYGB group compared to both Sham and Lean controls. Significant TUNEL staining in liver sections from the Obese Sham group, indicative of accelerated cell death, was absent in the RYGB and Lean control groups. Additionally, fasting plasma glucagon like peptide-1 was increased in RYGB compared to Sham (P < 0.02). CONCLUSION: These data suggest that in obese rats, RYGB surgery protects the liver against HFD-induced fatty liver disease by attenuating ER stress and excess apoptosis.

How safe is metabolic/diabetes surgery?

Although recent studies have shown the impressive antidiabetic effects of laparoscopic Roux-en-Y gastric bypass (LRYGB), the safety profile of metabolic/diabetes surgery has been a matter of concern among patients and physicians. Data on patients with type 2 diabetes who underwent LRYGB or one of seven other procedures between January 2007 and December 2012 were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database and compared. Of the 66 678 patients included, 16 509 underwent LRYGB. The composite complication rate of 3.4% after LRYGB was similar to those of laparoscopic cholecystectomy and hysterectomy. The mortality rate for LRYGB (0.3%) was similar to that of knee arthroplasty. Patients who underwent LRYGB had significantly better short-term outcomes in all examined variables than patients who underwent coronary bypass, infra-inguinal revascularization and laparoscopic colectomy. In conclusion, LRYGB can be considered a safe procedure in people with diabetes, with similar short-term morbidity to that of common procedures such as cholecystectomy and appendectomy and a mortality rate similar to that of knee arthroplasty. The mortality risk for LRYGB is one-tenth that of cardiovascular surgery and earlier intervention with metabolic surgery to treat diabetes may eliminate the need for some later higher-risk procedures to treat diabetes complications.

A systematic review of behavioural techniques used in nutrition and weight loss interventions among adults with mobility-impairing neurological and musculoskeletal conditions.

Obesity is a common comorbidity in adults with mobility-impairing neurological and musculoskeletal conditions, such as stroke and arthritis. The interaction between mobility impairments and environmental factors often compromises motivation and ability to engage in healthy behaviours. Such difficulties to engage in healthy behaviours can result in energy imbalance, weight gain and a cycle of functional declines; i.e. obesity can exacerbate mobility impairments and symptoms and increase the likelihood of other comorbid conditions, all of which make it more difficult to engage in healthy behaviours. To help disrupt this cycle, there is a need to identify strategies to optimize energy balance. Thus, this review summarizes clinical trials of nutrition and weight loss interventions in adults with mobility-impairing conditions. Although adults with osteoarthritis were represented in large rigorous clinical trials, adults with neurological conditions were typically represented in studies characterized by a small number of participants, a short-term follow-up and high attrition rates. Studies varied greatly in outcome measures, description and implementation of the interventions, and the strategies used to promote behaviour change. Nutrition and weight loss research in adults with mobility-impairing conditions is still in its formative stages, and there is a substantial need to conduct randomized controlled trials.

Attenuated improvements in adiponectin and fat loss characterize type 2 diabetes non-remission status after bariatric surgery.

AIM: To identify the metabolic determinants of type 2 diabetes non-remission status after bariatric surgery at 12 and 24 months. METHODS: A total of 40 adults [mean ± sd body mass index 36 ± 3 kg/m(2) , age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] were enrolled in the present study, the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. Type 2 diabetes remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl (i.e. <7 mmol/l) without antidiabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide values during a 120-min mixed-meal tolerance test. Body fat, incretins (glucagon-like polypeptide-1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor-α, high-sensitivity C-reactive protein (hs-CRP)] were also assessed. RESULTS: At 24 months, 37 patients had available follow-up data (RYGB, n = 18; SG, n = 19). Bariatric surgery induced type 2 diabetes remission rates of 40 and 27% at 12 and 24 months, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity and ß-cell function (C-peptide0-120 /glucose0-120 × Matsuda index) improved more in those with remission at 12 and 24 months than in those without remission. Incretin levels were unrelated to type 2 diabetes remission, but, compared with those without remission, hs-CRP decreased and adiponectin increased more in those with remission. Only baseline adiponectin level predicted lower HbA1c levels at 12 and 24 months, and elevated adiponectin correlated with enhanced ß-cell function, lower triglyceride levels and fat loss. CONCLUSIONS: Smaller rises in adiponectin level, a mediator of insulin action and adipose mass, characterize type 2 diabetes non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key to achieving higher type 2 diabetes remission rates after bariatric surgery.

Exercise-induced lowering of chemerin is associated with reduced cardiometabolic risk and glucose-stimulated insulin secretion in older adults.

OBJECTIVE: To determine the effect of exercise on chemerin in relation to changes in fat loss, insulin action, and dyslipidemia in older adults. PARTICIPANTS: Thirty older (65.9±0.9yr) obese adults (BMI:34.5±0.7kg/m2). SETTING: Single-center, Cleveland Clinic. DESIGN: Prospective clinical trial. INTERVENTION: Twelve-weeks of exercise training (60minutes/day, 5day/week at ~85% HRmax). Subjects were instructed to maintain habitual nutrient intake. MEASUREMENTS: Plasma chemerin was analyzed using an enzyme-linked immunosorbent assay. Peripheral and hepatic insulin sensitivity was assessed using a euglycemic-hyperinsulinic clamp with glucose kinetics. First-phase and total glucose-stimulated insulin secretion (GSIS) was calculated from an oral glucose tolerance test. Fasting blood lipids (cholesterol, triglycerides), total/visceral fat (dual-x-ray absorptiometry and computerized tomography) and cardiorespiratory fitness (treadmill test) were also tested pre and post intervention. RESULTS: Exercise increased fitness and reduced total/visceral fat, blood lipids, and first-phase GSIS (P<0.05). Training also increased peripheral insulin sensitivity and lowered basal/insulin-related hepatic glucose production (P<0.01). The intervention reduced chemerin (87.1±6.0 vs. 78.1±5.8ng/ml; P=0.02), and the reduction correlated with decreased visceral fat (r=0.50, P=0.009), total body fat (r=0.42, P=0.02), cholesterol (r=0.38, P=0.04), triglycerides (r=0.36, P=0.05), and first-phase and total GSIS (r=0.39, P=0.03 and r=0.43, P=0.02, respectively). CONCLUSIONS: Lower chemerin appears to be an important hormone involved in cardiometabolic risk and GSIS reduction following exercise in older adults.

An investigation of association between chronic musculoskeletal pain and cardiovascular disease in the Health Survey for England (2008).

BACKGROUND: Chronic musculoskeletal pain (CMP) may be associated with cardiovascular disease (CVD). This study aimed to investigate the association between CMP and CVD, and the contribution of physical activity and sedentary behaviour to any association. METHODS: We performed a secondary analysis of 3332 middle-aged (45-64 years) and 2022 older (65+ years) adults included in the Health Survey for England (2008). The survey contained self-reported physical activity/sedentary behaviour data. Objectively measured physical activity/sedentary behaviour using accelerometry (Actigraph™) was also available for a subset of the middle-aged (n = 715) and older (n = 492) participants. Logistic regression examined the association between CMP and CVD adjusted for self-reported and objectively measured physical activity, sedentary behaviour and a range of other CVD risk factors. RESULTS: There was a higher prevalence of CVD in those with CMP for both the middle-aged (22.5% vs. 13.5%) and the older (46.8% vs. 28.2%) adults (p < 0.001). After adjusting for CVD risk factors, older adults with CMP were significantly more likely to have CVD {odds ratio [95% confidence interval (CI)] 1.828 (1.452, 2.300); p < 0.001}. A similar non-significant trend was shown for the middle-aged adults [odds ratio (95% CI) 1.271 (0.975, 1.656); p = 0.076]. Neither self-reported nor objectively measured physical activity (or sedentary behaviour) had any meaningful effect on the association between CMP and CVD. CONCLUSIONS: CMP is associated with an increased risk of CVD and the association is stronger in older adults. Neither physical activity nor sedentary behaviour contributed to this relationship. Longitudinal studies are warranted to better understand the relationship between CVD and CMP.

Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown. DESIGN: STAMPEDE (Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently) was a prospective, randomized controlled trial. SUBJECTS: Fifty-three (body mass index: 36±3 kg m(-2), age: 49±9 years) poorly controlled patients with T2D (HbA1c (glycated hemoglobin): 9.7±2%) were randomized to IMT, IMT+RYGB or IMT+SG and underwent a mixed-meal tolerance test at baseline, 12, and 24 months for evaluation of AG suppression (postprandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion × Matsuda index). Total/android body fat (dual-energy X-ray absorptiometry) was also assessed. RESULTS: RYGB and SG reduced body fat comparably (15-23 kg) at 12 and 24 months, whereas IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 months (P<0.001). However, there was no difference in insulin secretion between SG vs IMT at 24 months (P=0.32). Fasting AG was reduced fourfold following SG (P<0.01) and did not change with RYGB or IMT at 24 months. AG suppression improved more following RYGB than SG or IMT at 24 months (P=0.01 vs SG, P=0.07 vs IMT). At 24 months, AG suppression was associated with increased postprandial glucagon-like peptide-1 (r=-0.32, P<0.02) and decreased android fat (r=0.38; P<0.006). CONCLUSIONS: Enhanced AG suppression persists for up to 2 years after RYGB, and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery.

Ghrelin suppression is associated with weight loss and insulin action following gastric bypass surgery at 12 months in obese adults with type 2 diabetes.

Roux-en-Y gastric bypass (RYGB) surgery reverses type 2 diabetes mellitus (T2DM) in approximately 80% of patients. Ghrelin regulates glucose homeostasis, but its role in T2DM remission after RYGB surgery is unclear. Nine obese T2DM subjects underwent a mixed meal tolerance test before and at 1 and 12 months after RYGB surgery. Changes in ghrelin, body weight, glucagon-like polypeptide-1 (GLP-1, glucose tolerance and insulin sensitivity (IS) were measured. At 1 month, body weight, glycaemia and IS were improved, while ghrelin concentrations were reduced (p < 0.05). After 12 months, body weight and fasting glucose were reduced (30 and 16%, respectively; p < 0.05) and IS was enhanced (threefold; p < 0.05). Ghrelin suppression improved by 32% at 12 months (p < 0.05), and this was associated with weight loss (r = 0.72, p = 0.03), enhanced IS (r = -0.78, p = 0.01) and peak postprandial GLP-1 (r = -0.73, p = 0.03). These data suggest that postprandial ghrelin suppression may be part of the mechanism that contributes to diabetes remission after RYGB surgery.

Metabolic adaptations of skeletal muscle to voluntary wheel running exercise in hypertensive heart failure rats.

The Spontaneously Hypertensive Heart Failure (SHHF) rat mimics the human progression of hypertension from hypertrophy to heart failure. However, it is unknown whether SHHF animals can exercise at sufficient levels to observe beneficial biochemical adaptations in skeletal muscle. Thirty-seven female SHHF and Wistar-Furth (WF) rats were randomized to sedentary (SHHFsed and WFsed) and exercise groups (SHHFex and WFex). The exercise groups had access to running wheels from 6-22 months of age. Hindlimb muscles were obtained for metabolic measures that included mitochondrial enzyme function and expression, and glycogen utilization. The SHHFex rats ran a greater distance and duration as compared to the WFex rats (P<0.05), but the WFex rats ran at a faster speed (P<0.05). Skeletal muscle citrate synthase and beta-hydroxyacyl-CoA dehydrogenase enzyme activity was not altered in the SHHFex group, but was increased (P<0.05) in the WFex animals. Citrate synthase protein and gene expression were unchanged in SHHFex animals, but were increased in WFex rats (P<0.05). In the WFex animals muscle glycogen was significantly depleted after exercise (P<0.05), but not in the SHHFex group. We conclude that despite robust amounts of aerobic activity, voluntary wheel running exercise was not sufficiently intense to improve the oxidative capacity of skeletal muscle in adult SHHF animals, indicating an inability to compensate for declining heart function by improving peripheral oxidative adaptations in the skeletal muscle.

Management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease in the United States. Non-alcoholic steatohepatitis (NASH), the most severe form of NAFLD, has an increased risk for progression to cirrhosis and associated comorbidities such as cardiovascular disease. Metabolic syndrome (MS) including insulin resistance and obesity is central to the development of NASH. Currently there is no definitive treatment for NASH and most of the available treatment options are targeted towards improving various parameters of MS. Treatment of NAFLD includes diet and lifestyle modification, pharmacological interventions and surgical therapies, or a combination of these interventions. This review focuses on the available current and potential future therapies for treating NASH.

Age attenuates leucine oxidation after eccentric exercise.

Aging may alter protein metabolism during periods of metabolic and physiologic challenge. The purpose of this study was to assess the effects of age on whole-body amino acid turnover in response to eccentric exercise and hyperglycemia-induced hyperinsulinemia. 16 healthy men were divided into young (N=8) and older (N=8) groups. Protein metabolism was assessed using a [1-13C]-leucine isotopic tracer approach. Measures were obtained under fasted basal conditions and during 3-h hyperglycemic clamps that were performed without (control) and 48 h after eccentric exercise. Exercise reduced leucine oxidation in the younger men (P<0.05), but not in older men. Insulin sensitivity was inversely correlated with leucine oxidation (P<0.05), and was lower in older men (P<0.05). Healthy aging is associated with an impaired capacity to adjust protein oxidation in response to eccentric exercise. The decreased efficiency of protein utilization in older men may contribute to impaired maintenance, growth, and repair of body tissues with advancing age.

Fasting hyperglycaemia blunts the reversal of impaired glucose tolerance after exercise training in obese older adults.

AIM: Lifestyle modification, consisting of exercise and weight loss, delays the progression from prediabetes to type 2 diabetes (T2D). However, no study has determined the efficacy of exercise training on glucose metabolism in the different prediabetes subtypes. METHODS: Seventy-six older (65.1 ± 0.6 years) obese adults with impaired fasting glucose (IFG; n = 12), impaired glucose tolerance (IGT; n = 9) and combined glucose intolerance (IFG + IGT = CGI; n = 22) were compared with normal glucose tolerant (NGT; n = 15) and T2D (n = 18) groups after 12 weeks of exercise training (60 min/day for 5 days/week at ~85% HR(max)). An oral glucose tolerance test was used to assess glucose levels. Insulin sensitivity (IS; euglycaemic hyperinsulinaemic clamp at 40 mU/m(2)/min), ß-cell function (glucose-stimulated insulin secretion corrected for IS), body composition (hydrostatic weighing/computed tomography scan) and cardiovascular fitness (treadmill VO(2) max) were also assessed. RESULTS: Exercise training reduced weight and increased cardiovascular fitness (p < 0.05). Exercise training lowered fasting glucose levels in IFG, CGI and T2D (p < 0.05) and 2-h glucose levels in IGT, CGI and T2D (p < 0.05). However, 2-h glucose levels were not normalized in adults with CGI compared with IGT (p < 0.05). ß-Cell function improved similarly across groups (p < 0.05). Although not statistically significant, IS increased approximately 40% in IFG and IGT, but only 17% in CGI. CONCLUSION: The magnitude of improvement in glucose metabolism after 12 weeks of exercise training is not uniform across the prediabetes subtypes. Given the high risk of progressing to T2D, adults with CGI may require more aggressive therapies to prevent diabetes.

Overweight, obesity and intentional weight loss in chronic kidney disease: NHANES 1999-2006.

OBJECTIVE: Obesity and chronic kidney disease (CKD) have emerged as major public health problems. We aimed to examine: (a) lifestyle and behavioral factors, (b) factors related to pursuing weight loss and (c) weight loss modalities pursued by CKD and non-CKD individuals who are overweight and obese. METHODS: Cross-sectional analysis of 10,971 overweight and obese adult participants in the National Health and Nutrition Examination Surveys conducted between 1999 and 2006. We examined the differences in lifestyle and behavioral factors between CKD and non-CKD participants and factors associated with pursuing weight loss using survey regression models. RESULTS: The total daily energy intake of the CKD population was lower than the non-CKD group (1987 kcal per day versus 2063 kcal per day, P=0.02) even after adjusting for relevant covariates. However, the percentage of energy derived from protein was similar between the groups. Sixty six percent of the CKD population did not meet the minimum recommended leisure time physical activity goals compared with 57% among non-CKD (P<0.001). Fifty percent of CKD participants pursued weight loss (vs fifty-five percent of non-CKD individuals, P=0.01), but the presence of CKD was not independently associated with the pursuit of weight loss in the multivariate model. Among participants pursuing weight loss, modalities including dietary interventions utilized by CKD and non-CKD participants were similar. Eight percent of CKD participants used medications to promote weight loss. CONCLUSIONS: Among the overweight and obese population, lifestyle and behavioral factors related to obesity and weight loss are similar between CKD and non-CKD participants. Insufficient data exist on the beneficial effects of intentional weight loss in CKD and these data show that a significant proportion of the CKD population use diets that may have high-protein content and medications to promote weight loss that may be harmful. Future clinical trials evaluating the efficacy and optimal modalities to treat obesity in the CKD population are warranted.

Acute effects of gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes.

CONTEXT: Hyperglycemia resolves quickly after bariatric surgery, but the underlying mechanism and the most effective type of surgery remains unclear. OBJECTIVE: To examine glucose metabolism and beta-cell function in patients with type 2 diabetes mellitus (T2DM) after two types of bariatric intervention; Roux-en-Y gastric bypass (RYGB) and gastric restrictive (GR) surgery. DESIGN: Prospective, nonrandomized, repeated-measures, 4-week, longitudinal clinical trial. PATIENTS: In all, 16 T2DM patients (9 males and 7 females, 52+/-14 years, 47+/-9 kg m(-2), HbA1c 7.2+/-1.1%) undergoing either RYGB (N=9) or GR (N=7) surgery. OUTCOME MEASURES: Glucose, insulin secretion, insulin sensitivity at baseline, and 1 and 4 weeks post-surgery, using hyperglycemic clamps and C-peptide modeling kinetics; glucose, insulin secretion and gut-peptide responses to mixed meal tolerance test (MMTT) at baseline and 4 weeks post-surgery. RESULTS: At 1 week post-surgery, both groups experienced a similar weight loss and reduction in fasting glucose (P<0.01). However, insulin sensitivity increased only after RYGB, (P<0.05). At 4 weeks post-surgery, weight loss remained similar for both groups, but fasting glucose was normalized only after RYGB (95+/-3 mg 100 ml(-1)). Insulin sensitivity improved after RYGB (P<0.01) and did not change with GR, whereas the disposition index remained unchanged after RYGB and increased 30% after GR (P=0.10). The MMTT elicited a robust increase in insulin secretion, glucagon-like peptide-1 (GLP-1) levels and beta-cell sensitivity to glucose only after RYGB (P<0.05). CONCLUSION: RYGB provides a more rapid improvement in glucose regulation compared with GR. This improvement is accompanied by enhanced insulin sensitivity and beta-cell responsiveness to glucose, in part because of an incretin effect.

Nonalcoholic fatty liver disease: biochemical and therapeutic considerations.

Nonalcoholic fatty liver disease (NAFLD) is a rapidly emerging chronic liver disease and is reported to affect up to 70-80% of overweight and obese individuals. NAFLD represents a spectrum of liver diseases that range from simple hepatic steatosis, to a more severe and treatment resistant stage that features steatosis plus inflammation, termed nonalcoholic steatohepatitis (NASH), which may in turn progress to hepatic fibrosis, cirrhosis, and sub-acute liver failure. Thus, NAFLD and its subsequent complications create a significant health burden, and currently there is no effective treatment strategy. The biochemical mechanisms that underlie NAFLD are unclear at this time, but there is evidence that insulin resistance is a major contributing factor. In addition, circulating concentrations of inflammatory cytokines (e.g., TNF-alpha, IL-6) as well as decreased antiinflammatory factors (e.g., adiponectin, IL-10) are not only implicated in the development of insulin resistance and type 2 diabetes, but are also related to NAFLD. Such inflammatory mechanisms are fundamental in the progression of NAFLD toward higher risk cirrhotic states. This review outlines the leading theories of pathogenesis of NAFLD and highlights the potential role of exercise in treating and preventing NAFLD. Regular exercise can reverse insulin resistance, suppress low-grade systemic inflammation, and attenuate inflammatory markers associated with NAFLD. Thus, exercise has the potential to become an effective treatment and prevention modality for NAFLD and NASH.

In vitro evidence that hyperglycemia stimulates tumor necrosis factor-alpha release in obese women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are often insulin resistant and have chronic low-level inflammation. The purpose of this study was to determine the effects of hyperglycemia in vitro on tumor necrosis factor (TNF)-alpha release from mononuclear cells (MNC) in PCOS. Twelve reproductive-age women with PCOS (six lean, six obese) and 12 age-matched controls (six lean, six obese) were studied. Insulin sensitivity (IS(HOMA)) was estimated from fasting levels of glucose and insulin and percent truncal fat was determined by dual energy absorptiometry (DEXA). TNFalpha release was measured from MNC cultured under euglycemic and hyperglycemic conditions. IS(HOMA) was higher in obese women with PCOS than in lean women with PCOS (student's t-test; 73.7 +/- 14.8 vs 43.1 +/- 8.6, P < 0.05), but similar to that of obese controls. IS(HOMA) was positively correlated with percent truncal fat (r=0.57, P < 0.04). Obese women with PCOS exhibited an increase in the percent change in TNFalpha release from MNC in response to hyperglycemia compared with obese controls (10 mM, 649 +/- 208% vs 133 +/- 30%, P < 0.003; 15 mM, 799 +/- 347% vs 183 +/- 59%, P < 0.04). The TNFalpha response directly correlated with percent truncal fat (r=0.45, P < 0.03) and IS(HOMA) (r=0.40, P < 0.05) for the combined groups, and with plasma testosterone (r=0.60, P < 0.05) for women with PCOS. MNC of obese women with PCOS exhibit an increased TNFalpha response to in vitro physiologic hyperglycemia. MNC-derived TNFalpha release may contribute to insulin resistance and hyperandrogenism, particularly when the combination of PCOS and increased adiposity is present.