Several studies have identified relationships between weight loss and adipokine levels; however none have looked at the combined effect of aerobic exercise training with consumption of a low, or high glycemic diet. We examined the effects of 12-weeks of aerobic exercise combined with either a low- (GI: ~40, LoGIX) or high-glycemic (GI: ~80, HiGIX) diet on plasma leptin and adiponectin (total and high molecular weight - HMW) in 27 older obese adults (age 65±0.5 years; BMI 34.5±0.7 kg/m2).
Insulin sensitivity was calculated from an oral glucose tolerance test (ISIOGTT). Fasting HMW adiponectin and leptin were quantified from plasma samples obtained prior to the ISIOGTT. Glucose and insulin measures were obtained before and every 30 min during the test. Dual-energy X-ray absorptiometry and computerized tomography was used to determine body composition and to quantify subcutaneous and visceral abdominal adiposity, respectively.
Fasting leptin was significantly decreased in both groups (LoGIX, pre: 33.8±4.7, post: 19.2±4.5; HiGIX, pre: 27.9±4.2, post: 11.9±2.2 ng/ml, P=0.004), and HMW adiponectin was significantly increased (LoGIX, pre: 1606.9±34.6, post: 3502.3±57; HiGIX, pre: 3704.8±38.1, post: 4284.3±52.8 pg/ml; P=0.003) following the 12-week intervention. Total body fat was reduced after both interventions, and visceral fat mass was inversely correlated with HMW adiponectin, while subcutaneous fat correlated with leptin.
The data suggest that exercise training, independent of dietary GI, favorably alters HMW adiponectin and leptin secretion, and that a reduction in visceral fat mass is a key factor regulating HMW adiponectin in older obese persons.
adiponectin; leptin; aerobic exercise; glycemic diet
Background: Metabolic syndrome is prevalent in adults characterized by increased visceral adiposity and insulin resistance (IR). However, the link between pancreatic β-cell function and metabolic syndrome severity in adults across the glucose spectrum is unknown. We hypothesized that poor β-cell function would independently predict a higher metabolic syndrome Z-score (i.e., severity).
Methods: Seventy (12 normal glucose tolerant, 37 prediabetic, 21 type 2 diabetic) obese adults [62.4±1.1 year; 34.6±0.6 kg/m2; data are mean±standard error of the mean (SEM)] participated in this cross-sectional study. A 2-hr 75-gram oral glucose tolerance test (OGTT) was administered, and insulin and glucose area under the curve was determined for calculations of insulin action. Fasting and glucose-stimulated insulin secretion was calculated using homeostasis model assessment of insulin secretion (HOMA-B) and the insulinogenic index (i.e., I0–30/Glc0–30 or I60–120/Glc60–120), respectively. Fasting and postprandial insulin sensitivity was assessed by HOMA-IR and the Matsuda Index, respectively. β-cell function was estimated using the disposition index via HOMA-B/HOMA-IR, I0–30/Glc0–30 or I60–120/Glc60–120×Matsuda Index, which represents basal, first-, and second-phase insulin release, respectively. Body composition (via computerized tomography and dual X-ray absorptiometry) and sex-specific metabolic syndrome Z-scores were calculated from waist circumference, blood pressure, fasting glucose, triglycerides, and high-density lipoproteins.
Results: Compared to those with normal glucose tolerance, visceral fat and IR were higher and β-cell function was lower in adults with glucose intolerance and type 2 diabetes mellitus. Elevated visceral fat and IR (HOMA-IR and Matsuda Index) correlated with elevated Z-scores (r=0.51, r=0.54, r=−0.49; all P<0.002, respectively). Basal, first-, and second-phase β-cell function correlated with low Z-scores (r=−0.59, r=−0.51, and r=−0.43, all P<0.001). Insulin secretion significantly predicted the Z-score independent of sex, body fat, blood lipids, blood pressure, IR, and glucose metabolism (P<0.005).
Conclusion: β-cell dysfunction is highly correlated with the severity of metabolic syndrome in adults. Future work is warranted to elucidate the mechanism by which cardiometabolic disturbances influence insulin secretion.
Transgenic mice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC 126.96.36.199) was linked to the α-skeletal actin gene promoter, express PEPCK-C in skeletal muscle (1–3 units/g). Breeding two founder lines together produced mice with an activity of PEPCK-C of 9 units/g of muscle (PEPCK-Cmus mice). These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-Cmus mice ran up to 6 km at a speed of 20 m/min, whereas controls stopped at 0.2 km. PEPCK-Cmus mice had an enhanced exercise capacity, with a VO2max of 156 ± 8.0 ml/kg/min, a maximal respiratory exchange ratio of 0.91 ± 0.03, and a blood lactate concentration of 3.7 ± 1.0 mm after running for 32 min at a 25° grade; the values for control animals were 112 ± 21 ml/kg/min, 0.99 ± 0.08, and 8.1 ± 5.0 mm respectively. The PEPCK-Cmus mice ate 60% more than controls but had half the body weight and 10% the body fat as determined by magnetic resonance imaging. In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-Cmus mice were greatly increased as compared with controls. PEPCK-Cmus mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6 −12-month-old control animals. We conclude that overexpression of PEPCK-C repatterns energy metabolism and leads to greater longevity.
Women with polycystic ovary syndrome (PCOS) have chronic low-grade inflammation, which can increase the risk of atherogenesis. We examined the effect of glucose ingestion and lipopolysaccharide (LPS) on markers of proatherogenic inflammation in the mononuclear cells (MNC) and plasma of women with PCOS. Sixteen women with PCOS (8 lean, 8 obese) and 15 weight-matched controls (8 lean, 7 obese) underwent a 3-h oral glucose tolerance test (OGTT). Interleukin-6 (IL-6) and interleukin-1β (IL-1β) release from MNC cultured in the presence of LPS and plasma IL-6, C-reactive protein (CRP), and soluble vascular adhesion molecule-1 (sVCAM-1) were measured from blood samples drawn while fasting and 2 h after glucose ingestion. Truncal fat was measured by dual-energy absorptiometry (DEXA). Lean women with PCOS and obese controls failed to suppress LPS-stimulated IL-6 and IL-1β release from MNC after glucose ingestion. In contrast, obese women with PCOS suppressed these MNC-derived cytokines under the same conditions. In response to glucose ingestion, plasma IL-6 and sVCAM-1 increased and CRP suppression was attenuated in both PCOS groups and obese controls compared with lean controls. Fasting plasma IL-6 and CRP correlated positively with percentage of truncal fat. The absolute change in plasma IL-6 correlated positively with testosterone. We conclude that glucose ingestion promotes proatherogenic inflammation in PCOS with a systemic response that is independent of obesity. Based on the suppressed MNC-derived cytokine responses suggestive of LPS tolerance, chronic low-grade inflammation may be more profound in obese women with PCOS. Excess abdominal adiposity and hyperandrogenism may contribute to atherogenesis in PCOS.
inflammation; glucose; atherosclerosis; abdominal adiposity; hyperandrogenism
Retinol binding-protein 4 (RBP4), a recently identified adipokine and retinol transporter, has been shown to play a causative role in insulin resistance, an underpinning between obesity and colon neoplasia. Yet, the relationship between RPB4 and cancer, including colon neoplasia is largely unexplored. We carried out a cross-sectional study to determine the risk association between RBP4 and colon adenomas. We determined pre-diagnostic serum levels of RBP4 in 626 patients undergoing screening colonoscopies from January 2006 to March 2007. The cases had statistically significant higher levels of RBP4 than the controls (58.5µg/mL ± 38.2 vs. 51.9µg/mL ± 32.5, p=0.03). Multivariate logistic regression model revealed a statistically significant overall association of RBP4 with risk of colon adenoma (OR = 3.10 for each increment of 35µg/mL, CI = 1.15 – 8.66; p = 0.03). Stratified analysis by the median BMI showed that the risk association was largely limited to those with BMI < 27.8 kg/m2. Compared to those in the bottom tertile of RBP4, the ORs for the 2nd and 3rd tertiles were 1.84 (CI = 0.89–3.8) and 2.14 (CI = 1.08–4.23) respectively (p for trend = 0.03); there was little evidence for such an association among those with BMI ≥ 27.8 kg/m2. This is the first study to show colon adenoma risk association with high circulating levels of RBP4. Further study is merited to investigate the mechanism that underlies the RBP4-colon neoplasia link.
retinol-binding protein 4; RBP4; colon adenoma; insulin resistance
Dipeptidyl peptidase-4 (DPP-4) is a circulating glycoprotein that impairs insulin-stimulated glucose uptake and is linked to obesity and metabolic syndrome. However, the effect of exercise on plasma DPP-4 in adults with metabolic syndrome is unknown. Therefore, we determined the effect of exercise on DPP-4 and its role in explaining exercise-induced improvements in insulin sensitivity. Fourteen obese adults (67.9±1.2yr, BMI: 34.2±1.1kg/m2) with metabolic syndrome (ATP III criteria) underwent a 12-week supervised exercise intervention (60 min/d for 5 d/wk at ~85% HRmax). Plasma DPP-4 was analyzed using an enzyme-linked immunosorbent assay. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp (40mU/m2/min) and estimated by HOMA-IR. Visceral fat (computerized tomography), 2-hour glucose levels (75g oral glucose tolerance), and basal fat oxidation as well as aerobic fitness (indirect calorimetry) were also determined before and after exercise. The intervention reduced visceral fat, lowered blood pressure, glucose and lipids, and increased aerobic fitness (P<0.05). Exercise improved clamp-derived insulin sensitivity by 75% (P<0.001) and decreased HOMA-IR by 15% (P<0.05). Training decreased plasma DPP-4 by 10% (421.8±30.1 vs. 378.3±32.5ng/ml; P<0.04), and the decrease in DPP-4 was associated with clamp-derived insulin sensitivity (r=−0.59; P<0.04), HOMA-IR (r=0.59; P<0.04) and fat oxidation (r=−0.54; P<0.05). Increased fat oxidation also correlated with lower 2-hour glucose levels (r=−0.64; P<0.02). Exercise training reduces plasma DPP-4, which may be linked to elevated insulin sensitivity and fat oxidation. Maintaining low plasma DPP-4 concentrations is a potential mechanism whereby exercise plus weight loss prevents/delays the onset of type 2 diabetes in adults with metabolic syndrome.
impaired glucose tolerance; obesity; cytokine; diabetes
Cardiovascular disease (CVD) is a serious comorbidity in nonalcoholic fatty liver disease (NAFLD). Since plasma ceramides are increased in NAFLD and sphingomyelin, a ceramide metabolite, is an independent risk factor for CVD, the role of ceramides in dyslipidemia was assessed using LDLR-/- mice, a diet-induced model of NAFLD and atherosclerosis. Mice were fed a standard or Western diet (WD), with or without myriocin, an inhibitor of ceramide synthesis. Hepatic and plasma ceramides were profiled and lipid and lipoprotein kinetics were quantified. Hepatic and intestinal expression of genes and proteins involved in insulin, lipid and lipoprotein metabolism were also determined. WD caused hepatic oxidative stress, inflammation, apoptosis, increased hepatic long-chain ceramides associated with apoptosis (C16 and C18) and decreased very-long-chain ceramide C24 involved in insulin signaling. The plasma ratio of ApoB/ApoA1 (proteins of VLDL/LDL and HDL) was increased 2-fold due to increased ApoB production. Myriocin reduced hepatic and plasma ceramides and sphingomyelin, and decreased atherosclerosis, hepatic steatosis, fibrosis, and apoptosis without any effect on oxidative stress. These changes were associated with decreased lipogenesis, ApoB production and increased HDL turnover. Thus, modulation of ceramide synthesis may lead to the development of novel strategies for the treatment of both NAFLD and its associated atherosclerosis.
To determine the influence of dietary glycemic index on exercise training-induced adaptations in substrate oxidation in obesity.
Design and Methods
Twenty older, obese individuals undertook 3-months of fully-supervised aerobic exercise and were randomised to low (LoGIX) or high glycemic (HiGIX) diets. Changes in indirect calorimetry (VO2; VCO2) were assessed at rest, during a hyperinsulinemic-euglycemic clamp, and during submaximal exercise (walking: 65% VO2max, 200 kcal energy expenditure). Intramyocellular lipid (IMCL) was measured by 1H-magnetic resonance spectroscopy.
Weight loss (−8.6±1.1%) and improvements (P<0.05) in VO2max, glycemic control, fasting lipemia, and metabolic flexibility were similar for both LoGIX and HiGIX groups. During submaximal exercise, energy expenditure was higher following the intervention (P<0.01) in both groups. Respiratory exchange ratio (RER) during exercise was unchanged in the LoGIX group but increased in the HiGIX group (P<0.05). However, fat oxidation during exercise expressed relative to changes in body weight was increased in the LoGIX group (+10.6±3.6%; P<0.05). Fasting IMLC was unchanged, however extramyocellular lipid was reduced (P<0.05) after LoGIX.
A low glycemic diet/exercise weight-loss intervention increases fat utilization during exercise independent of changes in energy expenditure. This highlights the potential therapeutic value of low glycemic foods for reversing metabolic defects in obesity.
glycemic index; weight loss; obesity; type 2 diabetes; exercise training; energy expenditure; fat oxidation
Older, obese, and sedentary individuals are at high risk of developing diabetes and cardiovascular disease. Exercise training improves metabolic anomalies associated with such diseases, but the effects of caloric restriction in addition to exercise in such a high risk group are not known. Changes in body composition and metabolism during a lifestyle intervention were investigated in twenty three older, obese men and women (aged 66 ± 1 years, BMI 33.2 ± 1.4 kg.m−2) with impaired glucose tolerance. All volunteers undertook twelve weeks of aerobic exercise training (5 days per week for 60 min @ 75% VO2max) with either normal caloric intake (eucaloric group, 1901 ± 277 kcal.day−1, n = 12) or a reduced-calorie diet (hypocaloric group, 1307 ± 70 kcal.day−1, n = 11), as dictated by nutritional counseling. Body composition (decreased fat mass; maintained fat-free mass), aerobic fitness (VO2max), leptinemia, insulin sensitivity, and intramyocellular lipid accumulation (IMCL) in skeletal muscle improved in both groups (P < 0.05). Improvements in body composition, leptin and basal fat oxidation were greater in the hypocaloric group. Following the intervention there was a correlation between the increase in basal fat oxidation and the decrease in IMCL (r = −0.53, P = 0.04). In addition, basal fat oxidation was associated with circulating leptin after (r = 0.65, P = 0.0007), but not before the intervention (r = 0.05, P = 0.84). In conclusion, these data show that exercise training improves resting substrate oxidation and creates a metabolic milieu that appears to promote lipid utilization in skeletal muscle, thus facilitating a reversal of insulin resistance. We also demonstrate that leptin sensitivity is improved, but that such a trend may rely on reducing caloric intake in addition to exercise training.
obesity; leptin; substrate oxidation; insulin sensitivity
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.
Seventy-six older (65.1 ± 0.6yr) 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 to normal glucose tolerant (NGT; n=15) and T2D (n=18) groups after 12 weeks of exercise training (60 min/d for 5d/wk at ~85% HRmax). An oral glucose tolerance test was used to assess glucose levels. Insulin sensitivity (euglycemic hyperinsulinemic clamp at 40 mU/m2·min−1), β-cell function (glucose stimulated insulin secretion corrected for insulin sensitivity), body composition (hydrostatic weighing/CT scan), and cardiovascular fitness (treadmill VO2max) were also assessed.
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-hour glucose levels in IGT, CGI and T2D (p < 0.05). However, 2-hour glucose levels were not normalized in adults with CGI compared to IGT (p < 0.05). β-cell function improved similarly across groups (p < 0.05). Although not statistically significant, insulin sensitivity increased approximately 40% in IFG and IGT, but only 17% in CGI.
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.
obesity; prediabetes; insulin resistance; beta-cell dysfunction; exercise
Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with a histological spectrum ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH). The latter is associated with an increased risk for progression to cirrhosis. Ceramides are a lipid species that exert biological effects through cellular proliferation, differentiation and cell death, and interact with several pathways involved in insulin resistance, oxidative stress, inflammation, and apoptosis, all of which are linked to NAFLD. Herein, we propose a mechanism through which ceramides contribute to the development of NAFLD and progression to NASH, due in part to second messenger effects via TNF-α. A better understanding of the role of ceramides in steatohepatitis has both diagnostic and therapeutic implications for the treatment of fatty liver disease.
Insulin resistance; obesity; sphingolipids; apoptosis; oxidative stress
The efficacy of combining carbohydrate quality with exercise on metabolic syndrome risk is unclear. Thus, we determined the effects of exercise training with a low or high glycemic diet on metabolic syndrome severity (Z-score).
Twenty-one adults (66.2 ± 1.1 yr; BMI = 35.3 ± 0.9 kg/m2) with metabolic syndrome were randomized to 12 weeks of exercise (60 minutes/d for 5 d/week at ~85% HRmax) and provided a low-glycemic (n=11; LoGIx) or high glycemic (n=10; HiGIx) diet. Z-scores were determined from: blood pressure, triglycerides (TG), high-density lipoproteins (HDL), fasting plasma glucose (FPG), and waist circumference (WC) before and after the intervention. Body composition, aerobic fitness, insulin resistance, and non-esterfied fatty acid (NEFA) suppression were also assessed.
LoGIx and HiGIx decreased body mass and insulin resistance and increased aerobic fitness comparably (p < 0.05). LoGIx and HiGIx decreased the Z-score similarly, as each intervention decreased blood pressure, TG, FPG, and WC (p < 0.05). HiGIx tended to suppress NEFA during insulin stimulation compared to LoGIx (p = 0.06).
Our findings highlight that exercise with weight loss reduces metabolic syndrome severity whether individuals were randomized to a high or low glycemic index diet.
aging; obesity; lifestyle modification; diabetes; impaired glucose tolerance
To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition.
RESEARCH DESIGN AND METHODS
This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m2) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of β-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months.
Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (−16 vs. −10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. β-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, β-cell function inversely correlated with truncal fat and prandial free fatty acid levels.
Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic β-cell function and reduces truncal fat, thus reversing the core defects in diabetes.
Evaluate the long-term effects of bariatric surgery on type 2 diabetes (T2DM) remission and metabolic risk factors.
Although the impressive antidiabetic effects of bariatric surgery have been shown in short- and medium-term studies, the durability of these effects is uncertain. Specifically, long-term remission rates following bariatric surgery are largely unknown.
Clinical outcomes of 217 patients with T2DM who underwent bariatric surgery between 2004 and 2007 and had at least 5-year follow-up were assessed. Complete remission was defined as glycated hemoglobin (A1C) less than 6% and fasting blood glucose (FBG) less than 100 mg/dL off diabetic medications. Changes in other metabolic comorbidities, including hypertension, dyslipidemia, and diabetic nephropathy, were assessed.
At a median follow-up of 6 years (range: 5–9) after surgery (Roux-en-Y gastric bypass, n = 162; gastric banding, n = 32; sleeve gastrectomy, n = 23), a mean excess weight loss (EWL) of 55% was associated with mean reductions in A1C from 7.5% ± 1.5% to 6.5% ± 1.2% (P < 0.001) and FBG from 155.9 ± 59.5 mg/dL to 114.8 ± 40.2 mg/dL (P < 0.001). Long-term complete and partial remission rates were 24% and 26%, respectively, whereas 34% improved (>1% decrease in A1C without remission) from baseline and 16% remained unchanged. Shorter duration of T2DM (P < 0.001) and higher long-term EWL (P = 0.006) predicted long-term remission. Recurrence of T2DM after initial remission occurred in 19% and was associated with longer duration of T2DM (P = 0.03), less EWL (P = 0.02), and weight regain (P = 0.015). Long-term control rates of low high-density lipoprotein, high low-density lipoprotein, high triglyceridemia, and hypertension were 73%, 72%, 80%, and 62%, respectively. Diabetic nephropathy regressed (53%) or stabilized (47%).
Bariatric surgery can induce a significant and sustainable remission and improvement of T2DM and other metabolic risk factors in severely obese patients. Surgical intervention within 5 years of diagnosis is associated with a high rate of long-term remission.
bariatric; diabetes; gastric banding; gastric bypass; LAGB; long term; metabolic; nephropathy; RYGB; sleeve gastrectomy
Obesity and physical inactivity are major public health problems. We studied the associations between measures of adiposity, lean body mass, leisure time physical activity (LTPA), and death in those with and without chronic kidney disease (CKD).
Associations between body mass index (BMI), waist circumference (WC), percent body fat, lean body mass (assessed with Dual-Energy X-ray Absorptiometry[DEXA]), leisure time physical activity (LTPA) and death were examined using the National Health and Nutrition Examination Surveys (NHANES 1999–2004). All-cause mortality was ascertained by linkage of NHANES files with the National Death Index.
9,433 non-CKD participants and 2,153 CKD participants who had fat mass measured using DEXA, BMI, WC, LTPA and mortality data were included. After adjusting for demographics, comorbid conditions, kidney function measures, C-Reactive Protein (CRP), and sodium intake there was no significant risk for death noted with higher WC, fat mass and BMI in those with and without CKD. When examining normal, overweight, and obese groups based on BMI criteria, being overweight (BMI 25–29.9 kg/m2) was associated with lower risk of death in those without CKD (Hazard ratio 0.62, 95% CI 0.40, 0.95). Higher lean body mass was associated with lower risk for death in those without kidney disease but not in the CKD population. There was a significantly higher risk for death among those who did not meet the minimum LTPA goals compared to those who met or exceeded the recommended activity levels (>450 MET/min/week) in those with and without CKD (CKD Hazard ratio: 1.36, 95% CI 1.003, 1.85; non-CKD HR 1.65, 95% CI 1.21, 2.26).
In a representative sample of the US population, higher LTPA levels and lean body mass were associated with lower mortality in those without kidney disease. In CKD, higher LTPA was associated with lower risk of death. There was no association between adiposity measures and death in those with and without CKD except for lower mortality associated with overweight among those without CKD. The data suggests the need to develop programs to facilitate an increase in physical activity in people with and without kidney disease.
Obesity; Physical activity; Muscle mass; Kidney disease and death
Type 2 diabetes (T2D) is now recognized as an independent risk factor for accelerated cognitive decline and neurological conditions like Alzheimer's disease. Less is known about the neurocognitive function of T2D patients with comorbid metabolic syndrome, despite their elevated risk for impairment. Computerized testing in 47 adults with T2D that met criteria for NCEP metabolic syndrome revealed that cognitive impairment was prevalent, including 13% in tests of memory, 50% in attention, and 35% in executive function. Partial correlations showed that longer duration of diabetes was associated with poorer performance on tests of basic attention (r = −0.43), working memory (r = 0.43), and executive function (r = 0.42). Strong associations between very low density lipoprotein and poor cognitive function also emerged, including tests of set shifting (r = 0.47) and cognitive inhibition (r = −0.51). Findings suggest that patients with T2D that meet criteria for metabolic syndrome are at high risk for cognitive impairment. Prospective studies should look to replicate these findings and examine the possible neuroprotective effects of lipid-lowering medication in this population.
African-American (AA) women have higher rates of breast cancer (BCa) mortality than Caucasian women, and a recent study using data from the Surveillance, Epidemiology and End Results (SEER) registry suggests that this disparity may be due, in part, to the poorer health status of AAs at diagnosis and not treatment related issues. Randomized controlled trials involving supervised aerobic and resistance exercise have shown improved body composition and improvement in cancer-related biomarkers in BCa patients and may lead to improved recurrence and survival rates; however, most trials have focused on Caucasians and many have been conducted in academic- and clinic-based settings. We evaluated the feasibility of conducting a 20-week, supervised, resistance training, group exercise intervention coupled with a support group and home walking program utilizing facilities and personnel at a community cancer support center (The Gathering Place, Beachwood, Ohio) in AA Stage I–III BCa survivors who were within 12 months of completing treatment (surgery, chemotherapy, and/or breast irradiation); and, evaluated the potential effects of this intervention on physical measures and cancer-related biomarkers. 27 patients provided informed consent and 19 participated in the program. On average, attendance rates were 70.0% ± 19.1% for the exercise sessions and 63.1% ± 13.8% for the support group. We observed a significant decrease in circulating C-peptide levels (B: 893.9 ± 399.1 pg/mL; EOI: 723.9 ± 319.0 pg/mL; p=0.01). Although we did not observe a significant decrease in weight in the entire sample, there was a significant decrease in waist circumference and percent total body fat among those who attended 70% or more of the exercise sessions. In summary, we demonstrated that conducting lifestyle interventions in AA BCa survivors in a community setting is feasible. Future interventions should invoke strategies to enhance adherence and include a structured dietary intervention to enable greater weight loss.
Breast Cancer; Exercise; African-American; Community-Based; Biomarkers
Obesity-associated hyperlipidemia and hyperlipoproteinemia are risk factors for cardiovascular disease (CVD). Recently, ceramide-derived sphingolipids were identified as a novel independent CVD risk factor. We hypothesized that the beneficial effect of RYGB on CVD risk is related to ceramide-mediated improvement in lipoprotein profile.
A prospective study of patients undergoing RYGB was conducted. Patients clinical data and biochemical markers related to cardiovascular risk were documented. Plasma ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1), ApoB100 and ApoA-1 were quantified preoperatively, 3 and 6 months post-RYGB, as was Framingham risk score. Brachial artery reactivity testing (BART) was performed before and 6 months after RYGB.
Ten patients (9 female; age 48 yrs; BMI, 48.5±5.8 kg/m2) were included in the study. At 6 months post-op, mean BMI decreased to 35.7±5.0 corresponding to 51.3±10.0 % excess weight loss. Fasting total cholesterol, triglycerides, LDL, free fatty acids, ApoB100, ApoB100/ApoA-1 ratio and insulin resistance estimated from HOMA-IR were significantly reduced compared to pre-surgery values. The ratio of ApoB100/ApoA-1 correlated with a reduction in ceramide subspecies (C18:0, C18:1, C20, C24:0 and C24:1) (p<0.05). ApoB100 and the ApoB100/ApoA-1 ratio also positively correlated with the reduction in TG, LDL and HOMA-IR (p<0.05). BART inversely correlated with ApoB100 and total ceramide (p=0.05). Furthermore, the change in BART correlated with the decrease in C16:0 (p<0.03).
Our data suggests that improvements in lipid profiles and CVD risk factors after gastric bypass surgery may be linked to changes in ceramide lipid. Mechanistic studies are needed to determine if this link is causative or purely correlative.
RYGB; bariatric surgery; cardiovascular risk; ceramide; sphingolipids; apolipoproteins; ApoB100; Apo A-1; ApoB100/Apo A-1 ratio
Although individuals with obesity and type 2 diabetes are insulin resistant, pancreatic beta cell failure is the core defect that distinguishes individuals who eventually develop diabetes. This process is known to occur well before the onset of hyperglycemia. Although clinical trial data support the effectiveness of intensive lifestyle modification in delaying the onset of diabetes in obese subjects, less is known about the effects of and mechanisms underlying bariatric surgery, particularly gastric bypass surgery, on diabetes. The paper under evaluation clarifies the role of both lifestyle intervention and gastric bypass surgery on pancreatic beta cell function and raises questions regarding the role of weight loss versus incretin related mechanisms on recovery of beta cell failure.
obesity; type 2 diabetes; gastric bypass surgery; weight loss; lifestyle modification; beta cell function; insulin resistance
glucose tolerance; aerobic exercise; glucotoxicity; beta-cell function; type 2 diabetes; VO2max; insulin resistance
Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in β-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion in type 2 diabetes have also not been examined but may involve the incretin axis.
RESEARCH DESIGN AND METHODS
Twenty-nine older, obese (aged 65 ± 1 years; BMI 33.6 ± 1.0 kg/m2) subjects, including individuals with newly diagnosed type 2 diabetes (obese-type 2 diabetic) and individuals with normal glucose tolerance (obese-NGT), underwent 3 months of nutritional counseling and exercise training. β-Cell function (oral glucose–induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic-euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) were examined.
After exercise and diet-induced weight loss (−5.0 ± 0.7 kg), oral glucose–induced insulin secretion was increased in the obese-type 2 diabetic group and decreased in the obese-NGT group (both P < 0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the obese-type 2 diabetic group (1.23 ± 0.26 vs. 2.04 ± 0.46 arbitrary units; P < 0.01). Changes in insulin secretion were directly related to the GIP responses to oral glucose (r = 0.64, P = 0.005), which were augmented in the obese-type 2 diabetic group and only moderately suppressed in the obese-NGT group.
After lifestyle-induced weight loss, improvements in oral glucose–induced insulin secretion in older, obese, nondiabetic subjects seem to be largely dependent on improved insulin sensitivity. However, in older obese diabetic patients, improved insulin secretion is a consequence of elevated β-cell function. We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells.
Pentoxifylline (PTX) improved histological features of nonalcoholic steatohepatitis (NASH) in a recent randomized placebo-controlled trial. However, the underlying mechanism responsible for the beneficial effects of PTX in NASH remains unidentified. A key role of lipid oxidation in the pathogenesis and progression of NASH has been established. PTX is known to decrease free-radical mediated oxidative stress and inhibit lipid oxidation. The primary aim of this study was to evaluate the effects of PTX on levels of lipid oxidation products in patients with NASH.
Levels of multiple structurally specific oxidized fatty acids including hydroxy-octadecadenoic acids (HODEs), oxo-octadecadenoic acids (oxoODEs), and hydroxy-eicosatetraenoic acids (HETEs) were quantified by mass spectrometry in plasma obtained at baseline and at study completion in patients who completed 1 year of therapy with PTX or placebo in a randomized controlled trial.
Therapy with PTX resulted in significant decreases on 9-HODE and 13-oxoODE, oxidized lipid products of linoleic acid (LA) linked to histological severity in NAFLD. Similarly, PTX therapy was associated with significant decreases in 8-HETE, 9-HETE, and 11-HETE compared to placebo. Statistically significant correlations were demonstrated between the decrease in HODEs and oxoODEs and improved histological scores of fibrosis; and between the decrease in HETEs and improved lobular inflammation.
Therapy with PTX compared to placebo was associated with a significant reduction of oxidized fatty acids. This novel evidence supports that the beneficial effects of PTX in patients with NASH are likely partly mediated through decreasing lipid oxidation, largely free-radical mediated lipid oxidation. Additionally, this is the first report on the link between decreased oxidized lipid products and improved histological disease in the setting of a therapeutic trial in NASH.
nonalcoholic fatty liver disease; pentoxifylline; clinical trials; oxidative stress
To examine the effects of acute altitude-induced hypoxia on the hormonal and metabolic response to ingested glucose, 8 young, healthy subjects (5 men/3 women; 26±2 yrs; BMI, 23.1±1.0 kg/m2) performed two randomized trials in a hypobaric chamber where a 75 g glucose solution was ingested under simulated altitude (ALT, 4,300m), or ambient (AMB, 362m) conditions. Plasma glucose, insulin, c-peptide, epinephrine, leptin and lactate concentrations were measured at baseline and 30, 60, 90 and 120 min after glucose ingestion during both trials. Compared to AMB, the plasma glucose response to glucose ingestion was reduced during the ALT trial (P=0.04). There were no differences in the insulin and c-peptide responses between trials, or in insulin sensitivity based on HOMA-IR. Epinephrine and lactate were both elevated during the ALT trial (P<0.05), while the plasma leptin response was reduced compared to AMB (P<0.05). The data suggest that the plasma glucose response is suppressed at ALT, but this is not due to insulin per se, since insulin and c-peptide levels were similar for both trials. Elevated plasma epinephrine and lactate during ALT is indicative of increased glycogenolysis, which may have masked the magnitude of the reduced glucose response. We conclude that during acute altitude exposure there is a rapid metabolic response that is accompanied by a shift in the hormonal milieu that appears to favor increased glucose utilization.
glucose uptake; insulin resistance; altitude chamber