Continuous glucose monitoring captures glycemic variability in obesity after sleeve gastrectomy: A prospective cohort study.

Objective: HbA1c is an insensitive marker for assessing real-time dysglycemia in obesity. This study investigated whether 1-h plasma glucose level (1-h PG) ≥155 mg/dL (8.6 mmol/L) during an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) measurement of glucose variability (GV) better reflected dysglycemia than HbA1c after weight loss from metabolic and bariatric surgery. Methods: This was a prospective cohort study of 10 participants with type 2 diabetes compared with 11 participants with non-diabetes undergoing sleeve gastrectomy (SG). At each research visit; before SG, and 6 weeks and 6 months post-SG, body weight, fasting lipid levels, and PG and insulin concentrations during an OGTT were analyzed. Mean amplitude of glycemic excursions (MAGE), a CGM-derived GV index, was analyzed. Results: The 1-h PG correlated with insulin resistance markers, triglyceride/HDL ratio and triglyceride glucose index in both groups before surgery. At 6 months, SG caused 22% weight loss in both groups. Despite a reduction in HbA1c by 3.0 ± 1.3% in the diabetes group (p < 0.01), 1-h PG, and MAGE remained elevated, and the oral disposition index, which represents pancreatic ß-cell function, remained reduced in the diabetes group when compared to the non-diabetes group. Conclusions: Elevation of GV markers and reduced disposition index following SG-induced weight loss in the diabetes group underscores persistent ß-cell dysfunction and the potential residual risk of diabetes complications.

Soluble Receptor for Advanced Glycation End Products (sRAGE) Isoforms Predict Changes in Resting Energy Expenditure in Adults with Obesity during Weight Loss.

Background: Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives: We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods: Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results: Participants (n = 41; 70% female; mean ± SD age: 57 ± 11 y; BMI: 38.7 ± 3.4 kg/m2) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions: This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.

Body Weight and Prandial Variation of Plasma Metabolites in Subjects Undergoing Gastric Band-Induced Weight Loss.

BACKGROUND: Bariatric procedures are safe and effective treatments for obesity, inducing rapid and sustained loss of excess body weight. Laparoscopic adjustable gastric banding (LAGB) is unique among bariatric interventions in that it is a reversible procedure in which normal gastrointestinal anatomy is maintained. Knowledge regarding how LAGB effects change at the metabolite level is limited. OBJECTIVES: To delineate the impact of LAGB on fasting and postprandial metabolite responses using targeted metabolomics. SETTING: Individuals undergoing LAGB at NYU Langone Medical Center were recruited for a prospective cohort study. METHODS: We prospectively analyzed serum samples from 18 subjects at baseline and 2 months after LAGB under fasting conditions and after a 1-hour mixed meal challenge. Plasma samples were analyzed on a reverse-phase liquid chromatography time-of-flight mass spectrometry metabolomics platform. The main outcome measure was their serum metabolite profile. RESULTS: We quantitatively detected over 4,000 metabolites and lipids. Metabolite levels were altered in response to surgical and prandial stimuli, and metabolites within the same biochemical class tended to behave similarly in response to either stimulus. Plasma levels of lipid species and ketone bodies were statistically decreased after surgery whereas amino acid levels were affected more by prandial status than surgical condition. CONCLUSIONS: Changes in lipid species and ketone bodies postoperatively suggest improvements in the rate and efficiency of fatty acid oxidation and glucose handling after LAGB. Further investigation is necessary to understand how these findings relate to surgical response, including long term weight maintenance, and obesity-related comorbidities such as dysglycemia and cardiovascular disease.

Fecal concentrations of bacterially derived vitamin K forms are associated with gut microbiota composition but not plasma or fecal cytokine concentrations in healthy adults.

Background: Emerging evidence suggests novel roles for bacterially derived vitamin K forms known as menaquinones in health and disease, which may be attributable in part to anti-inflammatory effects. However, the relevance of menaquinones produced by gut bacteria to vitamin K requirements and inflammation is undetermined.Objective: This study aimed to quantify fecal menaquinone concentrations and identify associations between fecal menaquinone concentrations and serum vitamin K concentrations, gut microbiota composition, and inflammation.Design: Fecal and serum menaquinone concentrations, fecal microbiota composition, and plasma and fecal cytokine concentrations were measured in 80 men and postmenopausal women (48 men, 32 women, age 40-65 y) enrolled in a randomized, parallel-arm, provided-food trial. After consuming a run-in diet for 2 wk, participants were randomly assigned to consume a whole grain-rich (WG) or a refined grain-based (RG) diet for 6 wk. Outcomes were measured at weeks 2 and 8.Results: The median total daily excretion of menaquinones in feces was 850 nmol/d but was highly variable (range: 64-5358 nmol/d). The total median (IQR) fecal concentrations of menaquinones decreased in the WG diet compared with the RG diet [-6.8 nmol/g (13.0 nmol/g) dry weight for WG compared with 1.8 nmol/g (12.3 nmol/g) dry weight for RG; P < 0.01)]. However, interindividual variability in fecal menaquinone concentrations partitioned individuals into 2 distinct groups based on interindividual differences in concentrations of different menaquinone forms rather than the diet group or the time point. The relative abundances of several gut bacteria taxa, Bacteroides and Prevotella in particular, differed between these groups, and 42% of identified genera were associated with ≥1 menaquinone form. Menaquinones were not detected in serum, and neither fecal concentrations of individual menaquinones nor the menaquinone group was associated with any marker of inflammation.Conclusion: Menaquinone concentrations in the human gut appear highly variable and are associated with gut microbiota composition. However, the health implications remain unclear. This trial was registered at clinicaltrials.gov as NCT01902394.

Substituting whole grains for refined grains in a 6-wk randomized trial favorably affects energy-balance metrics in healthy men and postmenopausal women.

Background: The effect of whole grains on the regulation of energy balance remains controversial.Objective: We aimed to determine the effects of substituting whole grains for refined grains, independent of body weight changes, on energy-metabolism metrics and glycemic control.Design: The study was a randomized, controlled, parallel-arm controlled-feeding trial that was conducted in 81 men and postmenopausal women [49 men and 32 women; age range: 40-65 y; body mass index (in kg/m2): <35.0]. After a 2-wk run-in period, participants were randomly assigned to consume 1 of 2 weight-maintenance diets for 6 wk. Diets differed in whole-grain and fiber contents [mean ± SDs: whole grain-rich diet: 207 ± 39 g whole grains plus 40 ± 5 g dietary fiber/d; refined grain-based diet: 0 g whole grains plus 21 ± 3 g dietary fiber/d] but were otherwise similar. Energy metabolism and body-composition metrics, appetite, markers of glycemic control, and gut microbiota were measured at 2 and 8 wk.Results: By design, body weight was maintained in both groups. Plasma alkylresorcinols, which are biomarkers of whole-grain intake, increased in the whole grain-rich diet group (WG) but not in the refined grain-based diet group (RG) (P-diet-by-time interaction < 0.0001). Beta ± SE changes (ΔWG compared with ΔRG) in the resting metabolic rate (RMR) (43 ± 25 kcal/d; P = 0.04), stool weight (76 ± 12 g/d; P < 0.0001), and stool energy content (57 ± 17 kcal/d; P = 0.003), but not in stool energy density, were higher in the WG. When combined, the favorable energetic effects in the WG translated into a 92-kcal/d (95% CI: 28, 156-kcal/d) higher net daily energy loss compared with that of the RG (P = 0.005). Prospective consumption (P = 0.07) and glycemia after an oral-glucose-tolerance test (P = 0.10) trended toward being lower in the WG than in the RG. When nonadherent participants were excluded, between-group differences in stool energy content and glucose tolerance increased, and between-group differences in the RMR and prospective consumption were not statistically significant.Conclusion: These findings suggest positive effects of whole grains on the RMR and stool energy excretion that favorably influence energy balance and may help explain epidemiologic associations between whole-grain consumption and reduced body weight and adiposity. This trial was registered at clinicaltrials.gov as NCT01902394.

Substituting whole grains for refined grains in a 6-wk randomized trial has a modest effect on gut microbiota and immune and inflammatory markers of healthy adults.

Background: Observational studies suggest an inverse association between whole-grain (WG) consumption and inflammation. However, evidence from interventional studies is limited, and few studies have included measurements of cell-mediated immunity.Objective: We assessed the effects of diets rich in WGs compared with refined grains (RGs) on immune and inflammatory responses, gut microbiota, and microbial products in healthy adults while maintaining subject body weights.Design: After a 2-wk provided-food run-in period of consuming a Western-style diet, 49 men and 32 postmenopausal women [age range: 40-65 y, body mass index (in kg/m2) <35] were assigned to consume 1 of 2 provided-food weight-maintenance diets for 6 wk.Results: Compared with the RG group, the WG group had increased plasma total alkyresorcinols (a measure of WG intake) (P < 0.0001), stool weight (P < 0.0001), stool frequency (P = 0.02), and short-chain fatty acid (SCFA) producer Lachnospira [false-discovery rate (FDR)-corrected P = 0.25] but decreased pro-inflammatory Enterobacteriaceae (FDR-corrected P = 0.25). Changes in stool acetate (P = 0.02) and total SCFAs (P = 0.05) were higher in the WG group than in the RG group. A positive association was shown between Lachnospira and acetate (FDR-corrected P = 0.002) or butyrate (FDR-corrected P = 0.005). We also showed that there was a higher percentage of terminal effector memory T cells (P = 0.03) and LPS-stimulated ex vivo production of tumor necrosis factor-α (P = 0.04) in the WG group than in the RG group, which were positively associated with plasma alkylresorcinol concentrations.Conclusion: The short-term consumption of WGs in a weight-maintenance diet increases stool weight and frequency and has modest positive effects on gut microbiota, SCFAs, effector memory T cells, and the acute innate immune response and no effect on other markers of cell-mediated immunity or systemic and gut inflammation. This trial was registered at clinicaltrials.gov as NCT01902394.

Caloric restriction favorably impacts metabolic and immune/inflammatory profiles in obese mice but curcumin/piperine consumption adds no further benefit.

BACKGROUND: Obesity is associated with low-grade inflammation and impaired immune response. Caloric restriction (CR) has been shown to inhibit inflammatory response and enhance cell-mediated immune function. Curcumin, the bioactive phenolic component of turmeric spice, is proposed to have anti-obesity and anti-inflammation properties while piperine, another bioactive phenolic compound present in pepper spice, can enhance the bioavailability and efficacy of curcumin. This study sought to determine if curcumin could potentiate CR's beneficial effect on immune and inflammatory responses in obesity developed in mice by feeding high-fat diet (HFD). METHODS: Mice were fed a HFD for 22 wk and then randomized into 5 groups: one group remained on HFD ad libitum and the remaining 4 groups were fed a 10% CR (reduced intake of HFD by 10% but maintaining the same levels of micronutrients) in the presence or absence of curcumin and/or piperine for 5 wk, after which CR was increased to 20% for an additional 33 wk. At the end of the study, mice were sacrificed, and spleen cells were isolated. Cells were stimulated with T cell mitogens, anti-CD3/CD28 antibodies, or lipopolysaccharide to determine T cell proliferation, cytokine production, and CD4+ T cell subpopulations. RESULTS: Compared to HFD control group, all CR mice, regardless of the presence of curcumin and/or piperine, had lower body weight and fat mass, lower levels of blood glucose and insulin, and fewer total spleen cells but a higher percentage of CD4+ T cells. Additionally, they demonstrated lower production of pro-inflammatory cytokines IL-1ß and TNF-α, a trend toward lower IL-6, and lower production of PGE2, a lipid molecule with pro-inflammatory and T cell-suppressive properties. Mice with CR alone had higher splenocyte proliferation and IL-2 production, but this effect of CR was diminished by spice supplementation. CR alone or in combination with spice supplementation had no effect on production of cytokines IL-4, IL-10, IFN-γ, and IL-17, or the proportion of different CD4+ T cell subsets. CONCLUSION: CR on an HFD favorably impacts both metabolic and immune/inflammatory profiles; however, the presence of curcumin and/or piperine does not amplify CR's beneficial effects.

Fish oil rich diet in comparison to saturated fat rich diet offered protection against lipopolysaccharide-induced inflammation and insulin resistance in mice.

BACKGROUND AND OBJECTIVE: Systemic chronic inflammation is linked to metabolic syndrome, type-2 diabetes, and heart disease. Lipopolysaccharide (LPS), a Gram negative microbial product, triggers inflammation through toll-like-receptor-4 (TLR-4) signaling. It has been reported that dietary fatty acids also modulate inflammation through TLR-4. We investigated whether fish oil (FO) rich diet in comparison to saturated fat (SF) rich diet would confer protection from pathologies induced by LPS. METHODS: Twenty C57BL/6 mice were divided into two groups. One group received FO-diet and other received SF-diet ad libitum for 60 days. Diets were isocaloric containing 45% energy from fat. After 60-days of feeding, blood was collected after overnight fast. Mice were allowed to recover for 4-days, fasted for 5-hours, challenged with 100 ng/mL of LPS intraperitonially, and bled after 2-hours. After 7-days of recuperation, mice were challenged with 500 ng/mL of LPS intraperitonially and observed for physical health. RESULTS: Food intake was similar in FO- and SF-fed mice. FO-fed mice compared to SF-fed mice had significantly less body weight gain (P = 0.005), epididymal fat weight (P = 0.005), fasting blood glucose (70.8 vs 83.3 ng/dL; P < 0.05), HOMA-IR (5.0 vs 13.6; P < 0.019), and serum cholesterol (167 vs 94 mg/dL; P < 0.05). When challenged with LPS, FO-fed mice had significantly lower serum IL-1ß compared to SF-fed mice (2.0 vs 30.0 pg/mL; P < 0.001). After LPS-challenge, SF-fed mice had higher mortality, lost more body weight, and had greater decrease in blood glucose compared to FO-fed mice. CONCLUSION: Overall, FO-diet compared to SF-diet offered protection against deleterious effects of LPS in mice.

Effects of basic fibroblast growth factor and a prostaglandin E2 receptor subtype 4 agonist on osteoblastogenesis and adipogenesis in aged ovariectomized rats.

UNLABELLED: bFGF stimulates osteo- and adipogenesis concurrently at skeletal sites with red but not with fatty marrow, whereas a PGE2 receptor subtype 4 agonist has bone anabolic effects at both skeletal sites and decreases adipose tissue within red and fatty marrow. INTRODUCTION: Basic fibroblast growth factor (bFGF) stimulates osteogenesis at skeletal sites with hematopoietic but not with fatty marrow. The prostaglandin E2 (PGE2) receptor subtype 4 agonist (EP4A) stimulates osteogenesis at the former skeletal sites, but its effects at fatty marrow sites are unknown. In addition, both bFGF and PGE2 through the EP4 receptor have also been implicated in adipogenesis. However, their specific effects on bone marrow adipogenesis and the inter-relationship with osteogenesis have never been studied in vivo. MATERIALS AND METHODS: Female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated and maintained for 1 yr after surgery. OVX rats were then injected daily with bFGF or with EP4A SC for 3 wk. The osteo- and adipogenic effects of these agents were assessed by histomorphometry and by determining changes in expression of genes associated with these events by real-time PCR in the lumbar and caudal vertebrae, bones with a predominance of hematopoietic and fatty marrow, respectively. Expression of FGFR1-4 and the EP4 receptor were also evaluated by real-time PCR and immunocytochemistry. RESULTS: bFGF and EP4A stimulated bone formation at skeletal sites with hematopoietic marrow, but only the later anabolic agent is also effective at fatty marrow sites. The diminished bone anabolic effect of bFGF at the fatty marrow site was not caused by a lack of cell surface receptors for the growth factor at this site. Interestingly, whereas EP4A decreased fatty marrow area and the number of adipocytes, bFGF increased osteogenesis and adipogenesis within the bone marrow. CONCLUSIONS: bFGF can stimulate osteogenesis and bone marrow adipogenesis concurrently at red marrow sites, but not at fatty marrow sites. In contrast, EP4A stimulates bone formation at skeletal sites with hematopoietic and fatty marrow and simultaneously decreased fatty marrow area and the number of adipocytes in the bone marrow, suggesting that osteogenesis occurs at the expense of adipogenesis.