Fat-containing Meal Research Articles

The oral disposition index calculated from a meal tolerance test is a crucial indicator for evaluating differential normalization of postprandial glucose and triglyceride excursions in morbidly obese patients after laparoscopic sleeve gastrectomy.

To determine the normalization of postprandial blood glucose (PG) and triglyceride (TG) excursions in 30 morbidly obese patients with or without diabetes mellitus (DM) 1-year after they underwent a laparoscopic sleeve gastrectomy (LSG) vs. their pre-surgery data, we administered the 75-g oral glucose tolerance test (OGTT) and a meal tolerance test (MTT) using a 75-g glucose-equivalent carbohydrate- and fat-containing meal. The results were as follows; (i) Postoperative body-weight reduction was associated with DM remission and reduced multiple cardiometabolic risks. (ii) OGTT data showing postprandial hyper-insulinemic hypoglycemia in many post-surgery patients were associated with overdiagnosis of improved glucose tolerance. However, postoperative MTT data without hypoglycemia showed no improvement in the glucose tolerance vs. pre-surgery data. (iii) The disposition index (DI) i.e., [Matsuda index] × (Glucose-induced insulin secretion) was progressively worsened from normal glucose tolerance to DM patients after LSG. These post-surgery DI values measured by the MTT were correlated with 2h-plasma glucose levels and were not normalized in DM patients. (iv) The baseline, 2h-TG, and an increase in 2h-TG values above baseline were correlated with the insulin resistance index, DI, or HbA1c; These TG values were normalized post-LSG. In conclusion, the glucose tolerance curve measured by the MTT was not normalized in T2DM patients, which was associated with impaired normalization of the DI values in those patients 1-year after the LSG. However, the baseline TG and a fat-induced 2h-TG values were normalized postoperatively. The MTT can be used to assess normalization in postprandial glucose and TG excursions after LSG.

Monocyte subsets display age-dependent alterations at fasting and undergo non-age-dependent changes following consumption of a meal

BackgroundMonocytes are a heterogenous population of immune cells whose subsets and functions become substantially dysregulated with advanced age. Although much of our current understanding of the age-related changes in monocytes is derived from fasting blood samples, most people are predominately in the postprandial state during waking hours. As hormonal, metabolic, and immunological changes in response to the consumption of a meal are manifested in postprandial blood, it’s unclear how age-dependent changes in peripheral monocytes at fasting are impacted by a dietary challenge.ObjectiveWe investigated the impact of age and meal consumption on circulating monocyte frequencies and subsets defined as classical (CD14 + CD16-), intermediate (CD14 + CD16 +), or non-classical (CD14dim CD16 +) in a cohort of 349 healthy adult volunteers grouped into categories based on their age: young adults (18–33 y, n = 123), middle adults (34–49 y, n = 115), and older adults (50–66 y, n = 111).ResultsFollowing 12-h fast total monocyte counts inversely correlated with subject age. Older adults had significantly fewer circulating monocytes along with elevated levels of TGs, cholesterol, glucose, IL-6, IL-8, TNF, neopterin, and CCL2 compared with young adults. Circulating monocyte pools in older adults consisted of smaller proportions of classical but larger proportions of intermediate and non-classical monocytes. Proportions of classical monocytes were inversely correlated with plasma TNF, IL-8, and neopterin while intermediate monocytes were positively correlated with plasma IL-6, TNF, and neopterin. Three hours after consuming a fat-containing meal postprandial monocyte counts increased in all age groups. Despite age-dependent differences in monocyte subsets at fasting, consumption of a meal induced similar changes in the proportions of classical and non-classical monocytes across age groups. Within the circulating postprandial monocyte pool, percentages of classical monocytes decreased while non-classical monocytes increased. However no change in precursory intermediate monocytes were detected. Our study confirms that ageing is associated with changes in monocyte frequencies and subsets and shows that consuming a fat-containing meal induces temporal changes in monocyte frequency and subsets independently of subject age.Clinical trialRegistered on ClincialTrials.gov (Identifier: NCT02367287)

Rats learn to prefer the late-consumed flavor over the early-consumed flavor in a multi-flavored meal paired with oral glucose and corn oil

Conditioned flavor preference (CFP) is established by association: where a neutral flavor (conditioned stimulus, CS) is paired with orosensory and post-ingestive components of nutrients, including sugar and fat (unconditioned stimulus, US). A previous study reported that rats can learn to prefer flavors that they consumed earlier and later in a multi-flavored solution paired with an intragastric infusion of glucose, but they expressed only a preference for a late-consumed flavor when they were tested after feeding (Myers and Whitney, 2011). This paradigm can be a suitable rodent model to explain how humans acquire a selective preference for routinely late-served “dessert” foods and why these foods remain attractive even in the absence of hunger. Here, we examined whether oral glucose (Experiment 1) or fat (Experiment 2) acts as a US for flavor preference learning processes in this paradigm. In Experiment 1, adult female rats under food restriction were trained in 16 daily sessions with two distinct flavor CSs in succession per session; eight CS(+) sessions in which two distinct flavor CSs (early(+), late(+)) were sequentially presented for 8 min each with oral glucose (12%) as a US, and eight CS(-) sessions in which different CSs (early(-), late(-)) were unpaired with the US. In the 30-minute two-bottle choice test, rats preferred late(+) over late(-) only when tested 90 min after consumption of normal chow (fed test) but not after overnight deprivation (hungry test). Early(+) was not preferred over early(-) in both tests. Moreover, a significant preference for late(+) over early(+) was observed only in the fed test, which is a unique feature of oral glucose-CFP. These results indicate that taste sensations of oral glucose promote a rewarding effect of late-onset glucose nutrients. In Experiment 2, separate rats were trained with the same conditioning paradigm, but used a caloric matched fat solution (5.3% corn oil) for a US. The results showed that they expressed stronger preferences for early(+) and late(+) relative to their respective CS(-) flavors in both tests. Similar to Experiment 1, it was observed in the fed test that there was a preference for late(+) over early(+) in oral fat-CFP. Taken together, the present results suggest that routine timing arrangements can cause qualitative differences in conditioned preferences between multiple flavors within a sugar or fat-containing meal in rats, and that rats prefer the late-consumed flavor over the early-consumed flavor in the absence of hunger.

Postprandial Responses of Energy Substrates in Dogs Fed High Fat‐ vs High Protein‐Low Carbohydrate Ketogenic Foods Relative to a High Carbohydrate Food

ObjectiveReduction of dietary carbohydrate (CHO) can increase circulating ketone availability and may aid disease management including inflammatory bowel disease, cancer, diabetes and cognitive decline. Companion animal dogs are prone to all of these maladies. Postprandial to a mixed macronutrient meal, non‐esterified fatty acids (NEFA) and beta‐hydroxybutyrate (BHB) decrease. In contrast, both glucose and blood urea nitrogen (BUN) increase. Triglycerides (TG) comprise circulating fat energy after a fat‐containing meal although medium chain TG (MCT) are preferentially catabolized to ketones. The postprandial responses of dogs to habitual feeding of high fat versus high protein low CHO foods, relative to high CHO foods, is not known. Therefore, we compared fasting (0 hr) and 2‐0 hr delta values for BHB, NEFA, TG, glucose, BUN as markers of available energy for these foods in dogs.MethodsDogs housed in pairs, with daily group exercise in outdoor grassy runs. Dogs returned to the colony healthy after the study; no invasive procedures. Blood collections under approved protocols at 0 hours (immediately before a meal) and at 2 hours postprandial. Macronutrients (P/F/C; % energy) for the 3 foods: HiCHO (25/37/38); LoCHOprot (50/44/6); LoCHOfat (28/68/4). The LoCHOfat food further contained 22% of dietary fat energy as MCT. Prospective randomized crossover trial (2 groups, n = 18). HiCHO was the wash‐in food followed by LoCHOprot or LoCHOfat in randomized order (5 wk feeding each food). Foods analyzed according to AOAC methods. Energy substrates BHB, NEFA, TG, glucose and BUN measured by Cobas or enzymatic reaction. Individual diet differences by dependent samples t‐test, linear mixed modeling for overall diet effect. Significance at α = 0.05.ResultsAnalyzed ketogenic ratios of the foods: HiCHO (0.46), LoCHOprot (1.1), and LoCHOfat (1.7). At fasting, LoCHOprot and LoCHOfat elevated circulating BHB above HiCHO food with LoCHOfat BHB higher than LoCHOprot. Between 0‐2 hours postprandial, BHB decreased for HiCHO (‐23%) and increased more for LoCHOfat (+100%) than LoCHOprot (+33%). Fasting NEFA were higher in LoCHOprot than LoCHOfat, and not different otherwise. From 0‐2 hours postprandial all foods showed decreased NEFA: HiCHO (‐43%), LoCHOprot (‐57%), LoCHOfat (‐12%). Fasting glucose was not different between groups. From 0‐2 hours postprandial LoCHOprot (‐4%) and LoCHOfat (‐8%) showed decreased glucose while HiCHO was unchanged. Fasting TG levels were different between all foods with the LoCHOprot (‐45%) and LoCHOfat (‐37%) lower than HiCHO. From 0‐2 hours postprandial all dogs showed increased TG with all values different between groups: HiCHO (+135%), LoCHOprot (+356%), LoCHOfat (+591%). Fasting BUN was higher with LoCHOprot than either HiCHO (‐27%) or LoCHOfat (‐26%). From 0‐2 hours postprandial all dogs showed increased BUN with all changes different: HiCHO (+17%), LoCHOprot (+42%), LoCHOfat (+23%).ConclusionsThe LoCHOfat food increased postprandial availability of BHB, NEFA and TG energy while decreasing glucose energy. LoCHOprot primarily enhanced available energy from protein as shown by increased amino acid catabolism to BUN, with additional contributions from BHB, NEFA and TG. The HiCHO food presented only glucose and TG as energy postprandial. Together these data show that a moderate protein, high fat, low CHO food with added MCT can selectively apportion postprandial energy toward ketone and fats while decreasing availability of glucose.

Effects of a new 75 g glucose- and high fat-containing cookie meal test on postprandial glucose and triglyceride excursions in morbidly obese patients.

A new meal tolerance test (MTT) using a 75 g glucose- and high fat-containing meal was applied to classify glucose intolerance in morbidly obese patients. According to the MTT data, the concordance rate of diagnosis was 82.5% compared to the 75 g oral glucose tolerance test (OGTT) in patients with normal glucose tolerance (NGT, n = 40). In the NGT patients, the insulinogenic index (r = 0.833), Matsuda index (r = 0.752), and disposition index (r = 0.845) calculated from the MTT data were each significantly (p < 0.001) correlated with those derived from the OGTT data. However, in patients with impaired glucose tolerance (IGT, n = 23) or diabetes mellitus (DM, n = 17), the postprandial glucose levels post-MTT were significantly lower than those post-OGTT, without increases in the postprandial insulin levels post-MTT. Thus, the severity of glucose intolerance measured by the MTT was milder than that indicated by the OGTT. Plasma levels of both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) were increased at the postprandial state, but only the GIP levels post-MTT were significantly higher than those post-OGTT. The enhancement of glucose disposal rates in patients with NGT or IGT after the MTT was associated with increased GIP levels. The postprandial hypertriglyceridemia induced by the MTT was associated with insulin resistance, but it was not associated with the impaired insulinogenic index or the disposition index. These results indicate that the new MTT is clinically useful to evaluate both abnormal glucose and triglyceride excursions caused by abnormal insulin sensitivity and secretions of insulin and gut hormones in morbidly obese patients.

The effect of fatty meal and water on interfering extracardiac activity in myocardial perfusion single-photon emission computed tomography

BackgroundThere are several ways to diagnose coronary artery disease. Myocardial perfusion imaging (MPI) is used for the diagnosis of coronary artery disease. One of the practical challenges in scan’s interpretation is interfering liver radiotracer uptake with appropriate cardiac visualization. For many years, different approaches were evaluated for conquering this problem. A relatively common method is using fat-containing meals before imaging. Fatty meals may cause some problems for some patients, especially elderly with digestive disorders, as well as an extra cost. We designed a study to compare the efficacy of water and fatty meal as a liver clearing agents to facilitate MPI results interpretation.ResultTotally, 30 patients (consist of 30 stress phases and 30 rest phases), including 18 women and 12 men, were evaluated. The fatty meal was used before 32 scans and cold water in the other 28 scans. Finally, 40 scans had the suitable quality for reporting by nuclear physicians among 60 scans, which included 20 of 28 scans with water and 20 of 32 scans with a fatty meal.ConclusionsThis comparison showed that scans performed with the water group had similar results with the fatty meal group. Water is better than fatty meals because of its ease of use and lower cost. Therefore, the use of water can be a good alternative for routine use in NM centers.

&lt;p&gt;Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects&lt;/p&gt;

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fat-containing meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebo-controlled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.

Postprandial dyslipidemia in insulin resistant states in adolescent populations.

Obesity and the metabolic syndrome are becoming increasingly prevalent not only in adults, but also in adolescents. The metabolic syndrome, a complex cluster of metabolic abnormalities, increases one's risk of developing type 2 diabetes and cardiovascular disease (CVD). Dyslipidemia, a key component of the metabolic syndrome, is highly associated with insulin resistance and contributes to increased CVD risk. Dyslipidemia has traditionally been assessed using a fasting lipid profile [i.e. fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)]. However, the postprandial state predominates over the course of a day and non-fasting triglycerides independently predict CVD risk. In insulin resistant states, the intestine overproduces triglyceride-rich lipoprotein (TRL) particles, termed chylomicrons (CMs), following ingestion of a fat-containing meal, as well as in the fasting state. Along with elevated hepatic TRLs (i.e. very-low density lipoproteins), CMs contribute to remnant lipoprotein accumulation, small dense LDL particles, and reduced HDL-C, which collectively increase CVD risk. Given the early genesis of atherosclerosis and physiological metabolic changes during adolescence, studying postprandial dyslipidemia in the adolescent population is an important area of study. Postprandial dyslipidemia in the pediatric population poses a significant public health concern, warranting a better understanding of its pathogenesis and association with insulin resistance and CVD. This review discusses the metabolic syndrome, focusing on the link between insulin resistance, postprandial dyslipidemia, and CVD risk. Furthermore, the clinical significance and functional assessment of postprandial dyslipidemia, specifically in the adolescent population, is discussed in more detail.

Strategies to improve bioavailability of omega-3 fatty acids from ethyl ester concentrates.

To describe recent strategies that have been developed to enhance absorption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from dietary supplements. The long-chain omega-3 fatty acids EPA and DHA have important physiologic functions, and numerous potential health benefits have been suggested by results from observational studies and randomized, controlled trials. EPA and DHA intakes in the average American diet are substantially below recommended levels. Dietary supplements are available for consumers wishing to increase their intakes, but many of these are in ethyl ester formulations from which EPA and DHA are poorly absorbed when consumed without a meal containing dietary fat. Technologies have been developed to enhance EPA and DHA absorption through in-situ emulsification, which facilitates bioavailability, even in the absence of a fat-containing meal. Findings from randomized controlled trials of absorption enhancers incorporated into omega-3 fatty acid supplements demonstrate that they can markedly improve the bioavailability of EPA and DHA. The development of absorption enhancement technology to increase bioavailability of long-chain omega-3 fatty acids has important implications for studies on the health effects of dietary supplement and pharmaceutical products containing EPA and/or DHA.

Intestinal absorption of vitamin D: a systematic review.

Vitamin D is frequently prescribed as a supplement, yet its absorption remains poorly understood. This systematic review was performed to evaluate data on mechanisms involved in the intestinal absorption of vitamin D. PubMed, Embase, and Cochrane Library databases were searched. The following studies were included: experimental laboratory studies of vitamin D absorption through the enterocyte brush-border membrane; absorption tests that used radiolabeled vitamin D; and clinical trials in adults that investigated a single dose of cholecalciferol or ergocalciferol and reported at least 2 measurements of serum cholecalciferol, ergocalciferol, or 25-hydroxyvitamin D. From 2069 articles identified, 46 met the inclusion criteria. Different methods were employed to evaluate vitamin D absorption. Recent research suggests that vitamin D absorption is not an exclusive simple diffusion process. Vitamin D was better absorbed when it was consumed with fat-containing meals, but absorption also occurred without fat or oily vehicles. Factors that modified cholesterol absorption also altered vitamin D absorption. Vitamin D is probably absorbed through passive diffusion and a mechanism involving membrane carriers, especially cholesterol transporters, although data remain scarce. Some data suggest that fat, when consumed concomitantly with vitamin D, improves vitamin D absorption.

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals.

BackgroundA high-fat diet promotes postprandial systemic inflammation and metabolic endotoxemia. We investigated the effects of three consecutive high-fat meals on endotoxemia, inflammation, vascular function, and postprandial lipid metabolism in patients with type 1 diabetes.MethodsNon-diabetic controls (n = 34) and patients with type 1 diabetes (n = 37) were given three high-caloric, fat-containing meals during one day. Blood samples were drawn at fasting (8:00) and every two hours thereafter until 18:00. Applanation tonometry was used to assess changes in the augmentation index during the investigation day.ResultsThree consecutive high-fat meals had only a modest effect on serum LPS-activity levels and inflammatory markers throughout the day in both groups. Of note, patients with type 1 diabetes were unable to decrease the augmentation index in response to the high-fat meals. The most profound effects of the consecutive fat loads were seen in chylomicron and HDL-metabolism. The triglyceride-rich lipoprotein remnant marker, apoB-48, was elevated in patients compared to controls both at fasting (p = 0.014) and postprandially (p = 0.035). The activities of the HDL-associated enzymes PLTP (p < 0.001), and CETP (p = 0.007) were higher and paraoxonase (PON-1) activity, an anti-oxidative enzyme bound to HDL, decreased in patients with type 1 diabetes (p = 0.027).ConclusionsIn response to high-fat meals, early signs of vascular dysfunction alongside accumulation of chylomicron remnants, higher augmentation index, and decreased PON-1 activity were observed in patients with type 1 diabetes. The high-fat meals had no significant impact on postprandial LPS-activity in non-diabetic subjects or patients with type 1 diabetes suggesting that metabolic endotoxemia may be more central in patients with chronic metabolic disturbances such as obesity, type 2 diabetes, or diabetic kidney disease.

The Effect of α-Cyclodextrin on postprandial lipid and glycemic responses to a fat-containing meal

Objectiveα-Cyclodextrin (α-CD), a soluble dietary fiber derived from corn, marketed under the trade name FBCx®, has the potential to help individuals manage their weight and improve their lipid profiles. Initial studies in healthy overweight and/or obese diabetic individuals found that, in those consuming a normal to high fat diet over a 4 or 12week period, α-CD use was associated with weight loss or maintenance and a reduction in triglyceride (TG) and cholesterol levels in hyperlipidemic individuals. Furthermore, α-CD use was associated with the positive effects of increasing insulin and leptin sensitivities. To date, the immediate post-prandial glucose and lipid responses to a fat-containing meal have not been reported. Materials/MethodThis double blinded placebo controlled cross-over trial examined the effect of 2g of α-CD taken immediately following consumption of a commercially prepared high-fat breakfast meal on the acute postprandial responses in healthy adults. ResultsThe coincidental consumption of α-CD with a fat-containing meal was associated with a significant reduction in postprandial TG responses over time when compared to placebo. When incremental area under the curve was calculated, the area under the curve associated with α-CD consumption was significantly smaller than the Placebo area (0.30±1.07mmol/L/3h vs. 0.98±0.88mmol/L/3h, p<0.05). There were no significant changes in glucose or cholesterol levels. Conclusionα-Cyclodextrin was shown to significantly lower acute postprandial blood triglyceride levels.

Effects of milk and milk constituents on postprandial lipid and glucose metabolism in overweight and obese men

Studies have suggested that two major milk constituents, casein and Ca, favourably affect postprandial responses. However, effects of milk on postprandial metabolism are unknown. We therefore investigated effects of using milk with a fat-containing meal on lipid and glucose responses in overweight men. To identify the constituent responsible for possible effects, we also studied responses to Ca and protein. A total of sixteen men (BMI .27 kg/m2) participated in four postprandial tests. They consumed a breakfast (44 g of fat) plus a drink: a control drink, low-fat milk or a protein and Ca drink (500 ml). Blood samples were taken before the meals and at regular time points during 6 h thereafter. Compared with control, the incremental AUC (iAUC) for serum TAG was increased by 44% after the protein meal (P¼0·015). Although the iAUC were not different (P¼0·051), peak glucose concentrations were reduced by 24% after protein intake, as compared with control (P¼0·021). The decrease of 18% after milk intake did not reach statistical significance. Compared with the milk meal, the iAUC for insulin was 52% lower after the control meal (P¼0·035) and 51% after the protein meal (P¼0·005). The present results indicate that the intake of milk with a fat-containing meal enhances postprandial TAG and insulin responses and may blunt glucose increases. The protein fraction of milk seems to be the main determinant for the effects on TAG and glucose. Ca did not change any of the postprandial responses.

Comparable reduction in cholesterol absorption after two different ways of phytosterol administration in humans

Consumption of phytosterols is a nutritional strategy to reduce cholesterol absorption, but the efficacy of various phytosterol intake modalities remains uncertain. The main objective was to investigate the effects of phytosterol esters (PE) provided either as a spread (dispersed in fat) during a mixed meal or as a minidrink (micro-dispersed in liquid form) after a meal. In a randomized, single-blinded crossover design, 12 healthy intubated volunteers tested three different liquid meal sequences with and without PE. The liquid meal (500 mL, Fortisip) contained an oral dose (80 mg) of deuterium-enriched cholesterol (D7C). The intubation was stopped at 240 min, and the fate of sterols was determined in the different phases of duodenal content samples as function of time. A second solid fat-containing meal without sterols was consumed at 270 min. D7C was quantified in chylomicrons and plasma for 8 h. The conditions tested were as follows: (1) no PE added (control), (2) PE in a spread added into a liquid meal (PE-spread meal) and (3) PE given 30 min after a liquid meal as 100-g yoghurt drink (PE-minidrink meal). Addition of PE decreased the incorporation of cholesterol into the duodenum aqueous phase including micelles. PE added as a spread or as a minidrink significantly and comparably lowered meal cholesterol occurrence in chylomicrons (-40 % for PE-spread and -54 % for PE-minidrink, p < 0.0001) compared with the control meal. PE either dispersed in fat during a meal or micro-dispersed in a liquid form after a meal resulted in a markedly reduced occurrence of meal-derived cholesterol in the circulation at a comparable extent.

Preclinical pharmacology of the new GLP-1 receptor agonist AVE0010

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is secreted by cells of the lower gastro-intestinal tract following ingestion of a carbohydrate - or fat-containing meal. GLP-1 has multiple sites of action — it increases pancreatic responsiveness to high glucose, delays gastric emptying, reduces appetite and food intake which altogether results in improved glycemic control and weight reduction. However, in vivo native GLP-1 is rapidly degraded and therefore of limited value for diabetes therapy. AVE0010 is a new synthetic GLP-1 receptor agonist with extended biological activity being developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The effects of AVE0010 in some preclinical pharmacology studies are provided below.

Using the lymph fistula rat model to study the potentiation of GIP secretion by the ingestion of fat and glucose

Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin produced in the K cells of the intestine and secreted into the circulating blood following ingestion of carbohydrate- and fat-containing meals. GIP contributes to the regulation of postprandial insulin secretion and is essential for normal glucose tolerance. We have established a method of assaying GIP in response to nutrients using the intestinal lymph fistula model. Administration of Ensure, a mixed-nutrient liquid meal, stimulated a significant increase in intestinal lymphatic GIP levels that were approximately threefold those of portal plasma. Following the meal, lymph GIP peaked at 60 min (P < 0.001) and remained elevated for 4 h. Intraduodenal infusions of isocaloric and isovolumetric lipid emulsions or glucose polymer induced lymph GIP concentrations that were four and seven times the basal levels, respectively. The combination of glucose plus lipid caused an even greater increase of lymph GIP than either nutrient alone. In summary, these findings demonstrated that intestinal lymph contains high concentrations of GIP that respond to both enteral carbohydrate and fat absorption. The change in lymphatic GIP concentration is greater than the change observed in the portal blood. These studies allow the detection of GIP levels at which they exert their local physiological actions. The combination of glucose and lipid has a potentiating effect in the stimulation of GIP secretion. We conclude from these studies that the lymph fistula rat is a novel approach to study in vivo GIP secretion in response to nutrient feeding in conscious rats.

Postprandial plasma adiponectin decreases after glucose and high fat meal and is independently associated with postprandial triacylglycerols but not with − 11388 promoter polymorphism

Adiponectin is discussed to regulate energy balance and insulin sensitivity. Several studies indicated an association of fasting adiponectin with parameters of the metabolic syndrome. We investigated postprandial adiponectin release and its relation to traits of the metabolic syndrome. Serum adiponectin concentration after an oral glucose tolerance test and after ingestion of a standardised mixed, fat-containing meal in 110 male non-diabetic subjects was assessed. Fasting and postprandial adiponectin and the decrease of adiponectin were correlated with anthropometric and metabolic parameters. Subjects were genotyped for adiponectin - 11 388 G/A promoter single nucleotide polymorphism. Adiponectin slightly decreased after both test meals. A significant decrease was attained 5 and 6 h after the lipid load and 2 h after the glucose load. Particularly, the mixed meal postprandial adiponectin showed stronger correlations with most traits of the metabolic syndrome than fasting adiponectin: postprandial adiponectin with HDL (r 0.30) v. fasting adiponectin with HDL (r 0.23); with postprandial insulin (area under the curve): r - 0.20 v. r - 0.16; with fasting insulin: r 0.10 v. r 0.14; with BMI: r - 0.23 v. r - 0.20; with waist: r - 0.18 v. - 0.16; with systolic blood pressure: r - 0.14 v. r - 0.12; with diastolic blood pressure: r - 0.18 v. r - 0.15. In multivariate analysis, postprandial TAG were the only independent predictor of adiponectin. There was no significant association of adiponectin, NEFA and TAG with - 11 388 G/A adiponectin promoter polymorphism. Our findings favour the interpretation that postprandial adiponectin has the strongest and independent associations to postprandial TAG metabolism.

Free Fatty Acids Have More Potent Effects on Gastric Emptying, Gut Hormones, and Appetite Than Triacylglycerides

The effects of fat on gastric emptying (GE), gut hormones, and energy intake are dependent on digestion to free fatty acids (FFAs). In animals, small intestinal oleic acid inhibits energy intake more potently than the triacylglyceride (TG) triolein, but there is limited information about the comparative effects of FFA and TG in human beings. We compared the effects of FFA and TG on GE, gut hormone secretion, appetite, and energy intake in healthy males. Nine men (age, 23 +/- 2 y; body mass index, 22 +/- 1 kg/m(2)) were studied on 3 occasions to evaluate the effects of (1) 40 g oleic acid (FFA, 1830 kJ), (2) 40 g macadamia oil (TG, 1856 kJ; both 600-mL oil-in-water emulsions stabilized with 4% milk protein and labeled with 15 MBq (123)I), or (3) 600 mL 4% milk protein (control, 352 kJ), administered intragastrically, on GE, plasma cholecystokinin (CCK) and peptide-YY (PYY) levels, appetite perceptions, and subsequent energy intake. GE of FFA was much slower than that of TG (P < .05), with greater retention of FFA, than TG, in the proximal stomach (P < .001). Hunger was less (P < .05), and fullness was greater (P < .05), after FFA when compared with control and TG. Increases in plasma CCK and PYY levels were greater after FFA than TG or control (P < .05). Energy intake tended to be less after FFA compared with TG (control, 4754 +/- 610 kJ; TG, 5463 +/- 662 kJ; FFA, 4199 +/- 410 kJ). FFAs empty from the stomach more slowly, but stimulate CCK and PYY and suppress appetite more potently than TG in healthy human beings.

Liver Fatty Acid-binding Protein Initiates Budding of Pre-chylomicron Transport Vesicles from Intestinal Endoplasmic Reticulum

The rate-limiting step in the transit of absorbed dietary fat across the enterocyte is the generation of the pre-chylomicron transport vesicle (PCTV) from the endoplasmic reticulum (ER). This vesicle does not require coatomer-II (COPII) proteins for budding from the ER membrane and contains vesicle-associated membrane protein 7, found in intestinal ER, which is a unique intracellular location for this SNARE protein. We wished to identify the protein(s) responsible for budding this vesicle from ER membranes in the absence of the requirement for COPII proteins. We chromatographed rat intestinal cytosol on Sephacryl S-100 and found that PCTV budding activity appeared in the low molecular weight fractions. Additional chromatographic steps produced a single major and several minor bands on SDS-PAGE. By tandem mass spectroscopy, the bands contained both liver and intestinal fatty acid-binding proteins (L- and I-FABP) as well as four other proteins. Recombinant proteins for each of the six proteins identified were tested for PCTV budding activity; only L-FABP and I-FABP (23% the activity of L-FABP) were active. The vesicles generated by L-FABP were sealed, contained apolipoproteins B48 and AIV, were of the same size as PCTV on Sepharose CL-6B, and by electron microscopy, excluded calnexin and calreticulin but did not fuse with cis-Golgi nor did L-FABP generate COPII-dependent vesicles. Gene-disrupted L-FABP mouse cytosol had 60% the activity of wild type mouse cytosol. We conclude that L-FABP can select cargo for and bud PCTV from intestinal ER membranes.

The minor allele of the PPARγ2 Pro12Ala polymorphism is associated with lower postprandial TAG and insulin levels in non-obese healthy men

The PPARgamma Pro12Ala polymorphism has been associated in several studies with a decreased risk of obesity, type 2 diabetes and insulin resistance. Weak hints are available about the influence of PPARgamma Pro12Ala on postprandial metabolism. In 708 men, aged 45 to 65 years the PPARgamma2 Pro12Ala genotypes were determined and postprandial TAG, insulin, glucose and NEFA after a standardized mixed fat meal and insulin and glucose after a glucose load (oral glucose tolerance test; OGTT) were assessed. Using the total sample, we did not find a significant impact of the genotype on the postprandial metabolism. In the subgroup with BMI <30 kg/m2, fasting and postprandial TAG and insulin levels as well as homeostasis model assessment of insulin resistance (HOMA) were significantly lower in the Ala12Ala group than in the Pro12Pro group after the mixed meal. In contrast, the groups did not differ in insulin levels and HOMA after the OGTT. To investigate if differences between a fat-containing meal and OGTT are caused by adiponectin, we examined a BMI- and age-matched subgroup. No differences were found between the genotypic groups. The effects of the PPARgamma2 polymorphism on insulin sensitivity are mediated by affluent dietary fat. We did not find evidence that adiponectin as a fatty-acid-dependent adipocyte factor is a causative factor for this phenomenon.