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1.  A low glycemic diet lifestyle intervention improves fat utilization during exercise in older obese humans 
Obesity (Silver Spring, Md.)  2013;21(11):2272-2278.
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.
PMCID: PMC3696477  PMID: 23512711
glycemic index; weight loss; obesity; type 2 diabetes; exercise training; energy expenditure; fat oxidation
2.  Plasma Ceramides Target Skeletal Muscle in Type 2 Diabetes 
Diabetes  2013;62(2):352-354.
PMCID: PMC3554378  PMID: 23349544
3.  A Community-Based Exercise and Support Group Program in African-American Breast Cancer Survivors (ABCs) 
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.
PMCID: PMC3975605  PMID: 24707505
Breast Cancer; Exercise; African-American; Community-Based; Biomarkers
4.  Exercise and diet enhance fat oxidation and reduce insulin resistance in older obese adults 
Journal of applied physiology (Bethesda, Md. : 1985)  2008;104(5):10.1152/japplphysiol.00890.2007.
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 ± 277−1, n = 12) or a reduced-calorie diet (hypocaloric group, 1307 ± 70−1, 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.
PMCID: PMC3860368  PMID: 18323464
obesity; leptin; substrate oxidation; insulin sensitivity
5.  Reduced cardiovascular risk after bariatric surgery is linked to plasma ceramides, apolipoprotein-B100 and the ApoB100/A1 ratio 
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.
PMCID: PMC3337956  PMID: 22264909
RYGB; bariatric surgery; cardiovascular risk; ceramide; sphingolipids; apolipoproteins; ApoB100; Apo A-1; ApoB100/Apo A-1 ratio
6.  Fasting hyperglycemia blunts the reversal of impaired glucose tolerance after exercise training in obese older adults 
Diabetes, obesity & metabolism  2012;14(9):835-841.
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.
PMCID: PMC3407343  PMID: 22510250
obesity; prediabetes; insulin resistance; beta-cell dysfunction; exercise
7.  Role of Ceramides in Nonalcoholic Fatty Liver Disease 
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.
PMCID: PMC3408814  PMID: 22609053
Insulin resistance; obesity; sphingolipids; apoptosis; oxidative stress
8.  Hyperglycemia blunts the therapeutic effect of exercise on glycemic control in patients with type 2 diabetes 
JAMA internal medicine  2013;173(19):10.1001/jamainternmed.2013.7783.
PMCID: PMC3837468  PMID: 23817567
glucose tolerance; aerobic exercise; glucotoxicity; beta-cell function; type 2 diabetes; VO2max; insulin resistance
9.  Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: New evidence on the potential therapeutic mechanism 
Hepatology (Baltimore, Md.)  2012;56(4):1291-1299.
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.
PMCID: PMC3430813  PMID: 22505276
nonalcoholic fatty liver disease; pentoxifylline; clinical trials; oxidative stress
10.  Obesity, anthropometric measures and chronic kidney disease complications 
American journal of nephrology  2012;36(3):219-227.
Anthropometric measures such as body mass index (BMI) and waist circumference (WC) have differential associations with incident chronic kidney disease (CKD) and mortality. We examined the associations of BMI and WC with various CKD complications.
We conducted a cross-sectional analysis of 2853 adult participants with CKD in the National Health and Nutrition Examination Surveys 1999-2006. The associations of BMI and WC (both as categorical and continuous variables) with CKD complications such as anemia, secondary hyperparathyroidism, hyperphosphatemia, metabolic acidosis, hypoalbuminemia, and hypertension were examined using logistic regression models while adjusting for relevant confounding variables.
When examined as a continuous variable, an increase in BMI by 2 kg/m2 and WC by 5 cm was associated with higher odds of secondary hyperparathyroidism, hypoalbuminemia, and hypertension among those with CKD. CKD participants with a BMI ≥30 kg/m2 have higher odds of hypoalbuminemia and hypertension than CKD participants with BMI <30 kg/m2. CKD participants with a high WC (>102 cm in men and >88 cm in women) have higher odds of hypoalbuminemia and hypertension and lower odds of having anemia than CKD participants with a low WC. CKD participants with BMI <30 kg/m2 and high WC (vs. BMI <30 kg/m2 and low WC) was not associated with CKD complications.
Anthropometric measures such as BMI and WC are associated with secondary hyperparathyroidism, hypoalbuminemia, and hypertension among adults with CKD. Higher WC among those with BMI <30 kg/m2 is not associated with CKD complications.
PMCID: PMC3542766  PMID: 22948230
Obesity; body mass index; waist circumference; chronic kidney disease
11.  Exercise training with weight loss and either a high or low glycemic diet reduces metabolic syndrome severity in older adults 
Annals of nutrition & metabolism  2012;61(2):135-141.
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.
PMCID: PMC3586384  PMID: 23036993
aging; obesity; lifestyle modification; diabetes; impaired glucose tolerance
12.  Overweight, obesity and intentional weight loss in chronic kidney disease: NHANES 1999-2006 
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.
Cross-sectional analysis of 10,971 overweight and obese adult participants in the National Health and Nutrition Examination Surveys conducted between 1999-2006. 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.
The total daily energy intake of the CKD population was lower than the non-CKD group (1987 kcal/day vs. 2063 kcal/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 to 57% among non-CKD (p<0.001). Fifty percent of CKD participants pursued weight loss (vs. 55% 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.
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.
PMCID: PMC3342418  PMID: 22290538
Chronic kidney disease; diet; physical activity; obesity; weight loss
13.  Increasing Whole Grain Intake as Part of Prevention and Treatment of Nonalcoholic Fatty Liver Disease 
In conjunction with the rise in rates of obesity, there has been an increase in the rate of nonalcoholic fatty liver disease (NAFLD). While NAFLD at least partially originates from poor diet, there is a lack of nutritional recommendations for patients with suspected or confirmed diagnosis of NAFLD, beyond eating a healthy diet, increasing physical activity, and emphasising weight loss. The limited current literature suggests that there may be opportunities to provide more tailored dietary advice for people diagnosed with or at risk of NAFLD. Epidemiological studies consistently find associations between whole grain intake and a reduced risk of obesity and related diseases, yet no work has been done on the potential of whole grains to prevent and/or be a part of the treatment for fatty liver diseases. In this review, we examine the potential and the current evidence for whole grains having an impact on NAFLD. Due to their nutrient and phytochemical composition, switching from consuming mainly refined grains to whole grains should be considered as part of the nutritional guidelines for patients diagnosed with or at risk for fatty liver disease.
PMCID: PMC3670556  PMID: 23762052
14.  Randomized controlled pilot study of a SystemCHANGE™ weight management intervention in stroke survivors: rationale and protocol 
Trials  2013;14:130.
Over 65% of stroke survivors are either overweight or obese and have multiple cardiovascular risk factors. However, few studies have examined the effects of comprehensive lifestyle behavior interventions to promote weight loss and control cardiovascular risk factors in stroke survivors. Thus, the purpose of this study is to examine a novel behavior change approach - SystemCHANGE™ - to promote weight loss and improve health and function in stroke survivors. SystemCHANGE™ focuses on redesigning the social environment to achieve a specific goal.
We will conduct a randomized controlled pilot study to examine the efficacy, feasibility, and safety of the SystemCHANGE™ weight management program in overweight and obese stroke survivors. The central hypothesis of the study is that the SystemCHANGE™ intervention will help overweight and obese stroke survivors lose 5% of their body weight, thereby improving health and function. Thirty-five stroke survivors will be randomized into either the 6-month SystemCHANGE™ intervention or a contact-control intervention. Outcome measures will be assessed at baseline and again at 3 and 6 months after the interventions. Body composition will be assessed using a Bod Pod. Patient-reported outcomes will be the Stroke Impact Scale and Reintegration to Normal Living Index. Objective outcomes will include the 6-Minute Walking Test and Rivermead Motor Assessment.
This study will be the first randomized controlled trial to evaluate the efficacy and safety of a weight management intervention in stroke survivors using the SystemCHANGE™ approach. Furthermore, it will be the first empirically-examined comprehensive lifestyle intervention designed to target physical activity, nutrition, and sleep to promote weight loss in stroke survivors.
Trial registration Identifier: NCT01776034
PMCID: PMC3663646  PMID: 23782741
Stroke; Weight management; Obesity; Self-management; Exercise; Physical activity; Nutrition; Diet; Sleep hygiene
15.  Computational Model of Cellular Metabolic Dynamics in Skeletal Muscle Fibers during Moderate Intensity Exercise 
Human skeletal muscles have different fiber types with distinct metabolic functions and physiological properties. The quantitative metabolic responses of muscle fibers to exercise provide essential information for understanding and modifying the regulatory mechanisms of skeletal muscle. Since in vivo data from skeletal muscle during exercise is limited, a computational, physiologically based model has been developed to quantify the dynamic metabolic responses of many key chemical species. This model distinguishes type I and II muscle fibers, which share the same blood supply. An underlying hypothesis is that the recruitment and metabolic activation of the two main types of muscle fibers differ depending on the pre-exercise state and exercise protocols. Here, activation measured by metabolic response (or enzymatic activation) in single fibers is considered linked but distinct from fiber recruitment characterized by the number (or mass) of each fiber type involved during a specific exercise. The model incorporates species transport processes between blood and muscle fibers and most of the important reactions/pathways in cytosol and mitochondria within each fiber type. Model simulations describe the dynamics of intracellular species concentrations and fluxes in muscle fibers during moderate intensity exercise according to various experimental protocols and conditions. This model is validated by comparing model simulations with experimental data in single muscle fibers and in whole muscle. Model simulations demonstrate that muscle-fiber recruitment and metabolic activation patterns in response to exercise produce significantly distinctive effects depending on the exercise conditions.
PMCID: PMC3431029  PMID: 22942911
computational modeling; skeletal muscle; fiber types; metabolism; exercise
16.  Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes 
The New England Journal of Medicine  2012;366(17):1567-1576.
Observational studies have shown improvement in patients with type 2 diabetes mellitus after bariatric surgery.
In this randomized, nonblinded, single-center trial, we evaluated the efficacy of intensive medical therapy alone versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients with uncontrolled type 2 diabetes. The mean (±SD) age of the patients was 49 ± 8 years, and 66% were women. The average glycated hemoglobin level was 9.2 ± 1.5%. The primary end point was the proportion of patients with a glycated hemoglobin level of 6.0% or less 12 months after treatment.
Of the 150 patients, 93% completed 12 months of follow-up. The proportion of patients with the primary end point was 12% (5 of 41 patients) in the medical-therapy group versus 42% (21 of 50 patients) in the gastric-bypass group (P = 0.002) and 37% (18 of 49 patients) in the sleeve-gastrectomy group (P = 0.008). Glycemic control improved in all three groups, with a mean glycated hemoglobin level of 7.5 ± 1.8% in the medical-therapy group, 6.4 ± 0.9% in the gastric-bypass group (P<0.001), and 6.6 ± 1.0% in the sleeve-gastrectomy group (P = 0.003). Weight loss was greater in the gastric-bypass group and sleeve-gastrectomy group (−29.4 ± 9.0 kg and −25.1 ± 8.5 kg, respectively) than in the medical-therapy group (−5.4 ± 8.0 kg) (P<0.001 for both comparisons). The use of drugs to lower glucose, lipid, and blood-pressure levels decreased significantly after both surgical procedures but increased in patients receiving medical therapy only. The index for homeostasis model assessment of insulin resistance (HOMA-IR) improved significantly after bariatric surgery. Four patients underwent reoperation. There were no deaths or life-threatening complications.
In obese patients with uncontrolled type 2 diabetes, 12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone. Further study will be necessary to assess the durability of these results. (Funded by Ethicon Endo-Surgery and others; number, NCT00432809.)
PMCID: PMC3372918  PMID: 22449319
17.  Weight Loss as a Cure for Type 2 Diabetes? Fact or Fantasy 
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.
PMCID: PMC3145356  PMID: 21804860
obesity; type 2 diabetes; gastric bypass surgery; weight loss; lifestyle modification; beta cell function; insulin resistance
18.  Improved Pancreatic β-Cell Function in Type 2 Diabetic Patients After Lifestyle-Induced Weight Loss Is Related to Glucose-Dependent Insulinotropic Polypeptide 
Diabetes Care  2010;33(7):1561-1566.
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.
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.
PMCID: PMC2890359  PMID: 20200305
19.  Higher Bone Mineral Density is Associated with a Decreased Risk of Colorectal Adenomas 
Bone mineral density (BMD) is a biomarker for cumulative exposure to multiple factors including estrogen, calcium, vitamin D and physical activity, which have all been independently associated with colorectal cancer. Furthermore, higher levels of BMD have been inversely associated with colorectal cancer risk, particularly in postmenopausal women. However, no prior studies have examined the potential association between BMD and colorectal adenomas, which are precursor lesions to most colorectal cancers. Therefore, we evaluated the association between BMD, which was measured using a whole body, dual-energy X-ray absorptiometry scan, and colorectal adenomas in 167 patients who underwent colonoscopy screening. We found that patients in the highest tertile of total body BMD (>1.294 g/cm2) and in the middle tertile (≥1.167 to ≤1.294 g/cm2) compared to those with a total body BMD in the lowest tertile (<1.167 g/cm2) had a lower risk of colorectal adenomas (highest vs. lowest tertile: OR=0.29 (0.10–0.84); middle vs. lowest tertile: OR=0.26 (0.08–0.80); p-trend=0.02). Stratification by gender revealed that this association was more pronounced in women (highest (>1.280 g/cm2) vs. lowest (<1.130 g/cm2) tertile: OR=0.08 (0.01–0.70); middle (≥1.130 to ≤1.280 g/cm2) vs. lowest tertile: OR=0.15 (0.04–0.94); p-trend=0.02) even after excluding hormone replacement therapy users (highest (>1.295 g/cm2) and middle (≥1.132 to ≤1.295 g/cm2) vs. lowest (<1.132 g/cm2) tertile: OR=0.17 (0.03–0.97); p-trend=0.04). Our results show, for the first time, that BMD is inversely associated with colorectal adenomas, particularly in women. Although additional larger, prospective studies are needed, our results suggest that BMD may be a biomarker for colorectal cancer precursor lesions.
PMCID: PMC3125467  PMID: 20949624
Bone mineral density; colorectal adenomas; biomarkers
20.  Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans 
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.
PMCID: PMC2813366  PMID: 19765784
glucose uptake; insulin resistance; altitude chamber
21.  Exercise Training and Dietary Glycemic Load May Have Synergistic Effects on Insulin Resistance in Older Obese Adults 
Annals of Nutrition & Metabolism  2009;55(4):326-333.
The aim of this study was to assess the combined effects of exercise and dietary glycemic load on insulin resistance in older obese adults.
Eleven men and women (62 ± 2 years; 97.6 ± 4.8 kg; body mass index 33.2 ± 2.0) participated in a 12-week supervised exercise program, 5 days/week, for about 1 h/day, at 80–85% of maximum heart rate. Dietary glycemic load was calculated from dietary intake records. Insulin resistance was determined using the euglycemic (5.0 mM) hyperinsulinemic (40 mU/m2/min) clamp.
The intervention improved insulin sensitivity (2.37 ± 0.37 to 3.28 ± 0.52 mg/kg/min, p < 0.004), increased VO2max (p < 0.009), and decreased body weight (p < 0.009). Despite similar caloric intakes (1,816 ± 128 vs. 1,610 ± 100 kcal/day), dietary glycemic load trended towards a decrease during the study (140 ± 10 g before, vs. 115 ± 8 g during, p < 0.04). The change in insulin sensitivity correlated with the change in glycemic load (r = 0.84, p < 0.009). Four subjects reduced their glycemic load by 61 ± 8%, and had significantly greater increases in insulin sensitivity (78 ± 11 vs. 23 ± 8%, p < 0.003), and decreases in body weight (p < 0.004) and plasma triglycerides (p < 0.04) compared to the rest of the group.
The data suggest that combining a low-glycemic diet with exercise may provide an alternative and more effective treatment for insulin resistance in older obese adults.
PMCID: PMC2853590  PMID: 19844089
Diabetes; Obesity; Aging; Insulin sensitivity; Physical activity; Glycemic index
22.  Retinol-binding Protein 4 (RBP4) Protein Expression Is Increased in Omental Adipose Tissue of Severely Obese Patients 
Obesity (Silver Spring, Md.)  2009;18(4):663-666.
Visceral fat has been linked to insulin resistance and type 2 diabetes mellitus (T2DM); and emerging data links RBP4 gene expression in adipose tissue with insulin resistance. In this study, we examined RBP4 protein expression in omental adipose tissue obtained from 24 severely obese patients undergoing bariatric surgery, and 10 lean controls (4 males/6 females, BMI = 23.2 ± 1.5 kg/m2) undergoing elective abdominal surgeries. Twelve of the obese patients had T2DM (2 males/10 females, BMI: 44.7 ± 1.5 kg/m2) and 12 had normal glucose tolerance (NGT: 4 males/8 females, BMI: 47.6 ± 1.9 kg/m2). Adipose RBP4, glucose transport protein-4 (GLUT4), and p85 protein expression were determined by western blot. Blood samples from the bariatric patients were analyzed for serum RBP4, total cholesterol, triglycerides, and glucose. Adipose RBP4 protein expression (NGT: 11.0 ± 0.6; T2DM: 11.8 ± 0.7; lean: 8.7 ± 0.8 arbitrary units) was significantly increased in both NGT (P = 0.03) and T2DM (P = 0.005), compared to lean controls. GLUT4 protein was decreased in both NGT (P = 0.02) and T2DM (P = 0.03), and p85 expression was increased in T2DM subjects, compared to NGT (P = 0.03) and lean controls (P = 0.003). Regression analysis showed a strong correlation between adipose RBP4 protein and BMI for all subjects, as well as between adipose RBP4 and fasting glucose levels in T2DM subjects (r = 0.76, P = 0.004). Further, in T2DM, serum RBP4 was correlated with p85 expression (r = 0.68, P = 0.01), and adipose RBP4 protein trended toward an association with p85 protein (r = 0.55, P = 0.06). These data suggest that RBP4 may regulate adiposity, and p85 expression in obese-T2DM, thus providing a link to impaired insulin signaling and diabetes in severely obese patients.
PMCID: PMC2919818  PMID: 19816414
23.  Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance 
Diabetes  2009;58(2):337-343.
OBJECTIVE—To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these plasma levels to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation of ceramides within tissues in obese and diabetic subjects has been well described.
RESEARCH DESIGN AND METHODS—We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp technique and with plasma tumor necrosis factor-α (TNF-α) levels, a marker of inflammation. Ceramide species (C18:1, 18:0, 20:0, 24:1, and 24:0) were quantified using electrospray ionization tandem mass spectrometry after separation with high-performance liquid chromatography.
RESULTS—Insulin sensitivity (mg · kg−1 · min−1) was lower in type 2 diabetic patients (4.90 ± 0.3) versus control subjects (9.6 ± 0.4) (P < 0.0001). Type 2 diabetic subjects had higher (P < 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely correlated with C18:0, C20:0, C24:1, C24:0, and total ceramide (all P < 0.01). Plasma TNF-α concentration was increased (P < 0.05) in type 2 diabetic subjects and correlated with increased C18:1 and C18:0 ceramide subspecies.
CONCLUSIONS—Plasma ceramide levels are elevated in type 2 diabetic subjects and may contribute to insulin resistance through activation of inflammatory mediators, such as TNF-α.
PMCID: PMC2628606  PMID: 19008343
24.  Effects of Exercise and Caloric Restriction on Insulin Resistance and Cardiometabolic Risk Factors in Older Obese Adults—A Randomized Clinical Trial 
The prevalence of insulin resistance, metabolic syndrome, and cardiovascular disease is greatest in older obese patients, and effective evidence-based treatment strategies are lacking.
A prospective controlled study was conducted on 24 older (65.5 ± 5.0 years) obese (body mass index, 34.3 ± 5.2 kg/m2) adults with clinically diagnosed metabolic syndrome. We examined the effect of exercise alone (EX) or exercise combined with moderate caloric restriction (−500 kcal, EX + CR) on metabolic and cardiovascular risk factors. Measures of insulin sensitivity assessed by euglycemic hyperinsulinemic clamp and by oral glucose tolerance test, lipid profiles, blood pressure, body composition, abdominal fat, and aerobic capacity were all obtained before and after the interventions.
Both groups experienced significant weight loss, but the reduction was greater in the EX + CR group than in the EX group (−6.8 ± 2.7 kg vs −3.7 ± 3.4 kg, respectively, p = .02). Both interventions improved insulin sensitivity (2.4 ± 2.4 mg/kg FFM/min and 1.4 ± 1.7 mg/kgFFM/min, respectively, p < .001) and indices of metabolic syndrome (systolic/diastolic blood pressure, waist circumference, glucose, and triglycerides; p < .05). High-density lipoprotein levels remained unchanged. Total abdominal, subcutaneous, and visceral fat; aerobic capacity; and total and low-density lipoprotein cholesterol were also improved. With the exception of weight loss and subcutaneous fat, there was no difference in the magnitude of improvement between the interventions.
These data suggest that exercise alone is an effective nonpharmacological treatment strategy for insulin resistance, metabolic syndrome, and cardiovascular disease risk factors in older obese adults.
PMCID: PMC2691195  PMID: 19164269
Aging; Obesity; Diabetes; Impaired glucose tolerance
25.  Reduced Cardiovascular Risk Following Bariatric Surgeries is Related to a Partial Recovery from “Adiposopathy” 
Obesity surgery  2011;21(12):1928-1936.
Altered cytokine secretion from dysfunctional adipose tissue or “adiposopathy” is implicated in obesity related inflammation and may mediate reduced CVD risk in response to weight loss after bariatric surgery. We hypothesized that bariatric surgery reduces CVD risk by favorably altering the pro-inflammatory profile of adipose tissue as a result of weight loss.
In this observational study with repeated measures, 142 patients underwent bariatric surgery of which 45 returned for follow up at ~6 months. At both time-points, lipid profiles and levels of plasma adiponectin, leptin, and TNF-α were obtained. Ratios of various adipokine parameters were related to pre- and post- surgical (gastric bypass vs. other restrictive bariatric procedures) lipid ratios.
Prior to surgery, circulating adiponectin and the adiponectin/TNF-α ratio was strongly associated with CVD risk characterized by levels of triglycerides, HDL, and the TC/HDL, LDL/HDL and TG/HDL ratios (all P < 0.05). Following bariatric surgery, BMI was decreased by 22%, adiponectin was increased by 93%, and leptin decreased by 50% as compared to baseline (all P < 0.01). TNF-α levels increased by 120% (P < 0.01) following surgery. Post-surgical changes in adiponectin and the leptin/adiponectin ratio were strongly associated with incremental improvements in triglycerides, HDL, and TC/HDL, LDL/HDL and TG/HDL ratios (all P < 0.05). Roux-en-y gastric bypass surgery (RYGB) as compared to other bariatric procedures was associated with more robust improvements in BMI, HDL, and leptin/adiponectin ratio than other gastric restrictive procedures (P < 0.05).
Thus, bariatric surgery, especially RYGB, ameliorates CVD risk through a partial recovery from “adiposopathy”, distinctively characterized by improved adiponectin and the leptin/adiponectin ratio.
PMCID: PMC3165064  PMID: 21625910
obesity; cholesterol; adipokines; adiponectin; tumor necrosis factor; leptin; bariatric surgery; gastric bypass

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