Blueberry anthocyanin intake attenuates the postprandial cardiometabolic effect of an energy-dense food challenge: Results from a double blind, randomized controlled trial in metabolic syndrome participants.

BACKGROUND & AIMS: Whilst the cardioprotective effects of blueberry intake have been shown in prospective studies and short-term randomized controlled trials (RCTs), it is unknown whether anthocyanin-rich blueberries can attenuate the postprandial, cardiometabolic dysfunction which follows energy-dense food intakes; especially in at-risk populations. We therefore examined whether adding blueberries to a high-fat/high-sugar meal affected the postprandial cardiometabolic response over 24 h. METHODS: A parallel, double-blind RCT (n = 45; age 63.4 ± 7.4 years; 64% male; BMI 31.4 ± 3.1 kg/m2) was conducted in participants with metabolic syndrome. After baseline assessments, an energy-dense drink (969 Kcals, 64.5 g fat, 84.5 g carbohydrate, 17.9 g protein) was consumed with either 26 g (freeze-dried) blueberries (equivalent to 1 cup/150 g fresh blueberries) or 26 g isocaloric matched placebo. Repeat blood samples (30, 60, 90, 120, 180, 360 min and 24 h), a 24 h urine collection and vascular measures (at 3, 6, and 24 h) were performed. Insulin and glucose, lipoprotein levels, endothelial function (flow mediated dilatation (FMD)), aortic and systemic arterial stiffness (pulse wave velocity (PWV), Augmentation Index (AIx) respectively), blood pressure (BP), and anthocyanin metabolism (serum and 24 h urine) were assessed. RESULTS: Blueberries favorably affected postprandial (0-24 h) concentrations of glucose (p < 0.001), insulin (p < 0.01), total cholesterol (p = 0.04), HDL-C, large HDL particles (L-HDL-P) (both p < 0.01), extra-large HDL particles (XL-HDL-P; p = 0.04) and Apo-A1 (p = 0.01), but not LDL-C, TG, or Apo-B. After a transient higher peak glucose concentration at 1 h after blueberry intake ([8.2 mmol/L, 95%CI: 7.7, 8.8] vs placebo [6.9 mmol/L, 95%CI: 6.4, 7.4]; p = 0.001), blueberries significantly attenuated 3 h glucose ([4.3 mmol/L, 95%CI: 3.8, 4.8] vs placebo [5.1 mmol/L, 95%CI: 4.6, 5.6]; p = 0.03) and insulin concentrations (blueberry: [23.4 pmol/L, 95%CI: 15.4, 31.3] vs placebo [52.9 pmol/L, 95%CI: 41.0, 64.8]; p = 0.0001). Blueberries also improved HDL-C ([1.12 mmol/L, 95%CI: 1.06, 1.19] vs placebo [1.08 mmol/L, 95%CI: 1.02, 1.14]; p = 0.04) at 90 min and XL-HDLP levels ([0.38 × 10-6, 95%CI: 0.35, 0.42] vs placebo [0.35 × 10-6, 95%CI: 0.32, 0.39]; p = 0.02) at 3 h. Likewise, significant improvements were observed 6 h after blueberries for HDL-C ([1.17 mmol/L, 95%CI: 1.11, 1.24] vs placebo [1.10 mmol/L, 95%CI: 1.03, 1.16]; p < 0.001), Apo-A1 ([1.37 mmol/L, 95%CI: 1.32, 1.41] vs placebo [1.31 mmol/L, 95%CI: 1.27, 1.35]; p = 0.003), L-HDLP ([0.70 × 10-6, 95%CI: 0.60, 0.81] vs placebo [0.59 × 10-6, 95%CI: 0.50, 0.68]; p = 0.003) and XL-HDLP ([0.44 × 10-6, 95%CI: 0.40, 0.48] vs placebo [0.40 × 10-6, 95%CI: 0.36, 0.44]; p < 0.001). Similarly, total cholesterol levels were significantly lower 24 h after blueberries ([4.9 mmol/L, 95%CI: 4.6, 5.1] vs placebo [5.0 mmol/L, 95%CI: 4.8, 5.3]; p = 0.04). Conversely, no effects were observed for FMD, PWV, AIx and BP. As anticipated, total anthocyanin-derived phenolic acid metabolite concentrations significantly increased in the 24 h after blueberry intake; especially hippuric acid (6-7-fold serum increase, 10-fold urinary increase). In exploratory analysis, a range of serum/urine metabolites were associated with favorable changes in total cholesterol, HDL-C, XL-HDLP and Apo-A1 (R = 0.43 to 0.50). CONCLUSIONS: For the first time, in an at-risk population, we show that single-exposure to the equivalent of 1 cup blueberries (provided as freeze-dried powder) attenuates the deleterious postprandial effects of consuming an energy-dense high-fat/high-sugar meal over 24 h; reducing insulinaemia and glucose levels, lowering cholesterol, and improving HDL-C, fractions of HDL-P and Apo-A1. Consequently, intake of anthocyanin-rich blueberries may reduce the acute cardiometabolic burden of energy-dense meals. CLINICAL TRIAL REGISTRY: NCT02035592 at www.clinicaltrials.gov.

Whey Protein Drink Ingestion before Breakfast Suppressed Energy Intake at Breakfast and Lunch, but Not during Dinner, and Was Less Suppressed in Healthy Older than Younger Men.

Ageing is associated with changes in feeding behavior. We have reported that there is suppression of energy intake three hours after whey protein drink ingestion in young, but not older, men. This study aimed to determine these effects over a time period of 9 h. Fifteen younger (27 ± 1 years, 25.8 ± 0.7 kg/m2) and 15 older (75 ± 2 years, 26.6 ± 0.8 kg/m2) healthy men were studied on three occasions on which they received, in a randomized order, a 30 g/120 kcal, 70 g/280 kcal whey-protein, or control (~2 kcal) drink. Ad-libitum energy intake (sum of breakfast, lunch, and dinner) was suppressed in a protein load responsive fashion (P = 0.001). Suppression was minimal at breakfast, substantial at lunch (~-16%, P = 0.001), no longer present by dinner, and was less in older than younger men (-3 ± 4% vs. -8 ± 4%, P = 0.027). Cumulative protein intake was increased in the younger and older men (+20% and +42%, P < 0.001). Visual analogue scale ratings of fullness were higher and desire to eat and prospective food consumption were lower after protein vs. control, and these effects were smaller in older vs. younger men (interaction effect P < 0.05). These findings support the use of whey-protein drink supplements in older people who aim to increase their protein intake without decreasing their overall energy intake.

Effects of intragastric tryptophan on acute changes in the plasma tryptophan/large neutral amino acids ratio and relationship with subsequent energy intake in lean and obese men.

Circulating tryptophan/large neutral amino acids (tryptophan/LNAA) ratio, an indicator of brain serotonin levels, may be important in appetite regulation, together with gastrointestinal (gastric emptying, plasma cholecystokinin) mechanisms. We have compared effects of intragastric tryptophan ('Trp') on the plasma tryptophan/LNAA ratio in lean and obese men, and the associations of the tryptophan/LNAA ratio, gastric emptying and CCK concentrations with energy intake. Lean and obese male participants (n = 16 each) received 3 g Trp or volume-matched control intragastrically, 15 min before a mixed-nutrient drink (300 mL, 400 kcal) (t = 0 min) in randomised, double-blind fashion. Plasma amino acid (for calculation of the plasma tryptophan/LNAA ratio) and CCK concentrations were measured from t = -20-60 min. Gastric emptying was assessed from t = 0-60 min, and ad-libitum energy intake from a standardised buffet-style meal from t = 60-90 min. The increase in the plasma tryptophan/LNAA ratio was less in obese, than lean, participants (P < 0.05), and greater in lean participants who reduced their energy intake (by >0 kcal) after Trp compared with those who did not (by ≤0 kcal) (P < 0.05). Moreover, in participants who reduced their energy intake, the ratio was lower in obese, than in lean (P < 0.05). There was a trend for an inverse correlation between energy intake with the plasma tryptophan/LNAA ratio in lean (r = -0.4, P = 0.08), but not in obese, participants. There was no significant difference in gastric emptying or CCK between participants who reduced their energy intake and those who did not. In conclusion, the plasma tryptophan/LNAA ratio appears to be a determinant of the suppression of energy intake in response to tryptophan in normal-weight people, but not in those with obesity. The role of the plasma tryptophan/LNAA ratio to regulate energy intake, and potential changes in obesity, warrant evaluation in prospective studies.

Randomised clinical trial: the effectiveness of Gaviscon Advance vs non-alginate antacid in suppression of acid pocket and post-prandial reflux in obese individuals after late-night supper.

BACKGROUND: Late-night supper increases the risk of postprandial reflux from the acid pocket especially in obesity. An alginate-based, raft-forming medication may be useful for obese patients with GERD. AIMS: To compare the efficacy of Gaviscon Advance (Reckitt Benckiser, UK) and a non-alginate antacid in post-supper suppression of the acid pocket and post-prandial reflux among obese participants. METHODS: Participants underwent 48 h wireless and probe-based pH-metry recording of the acid pocket and lower oesophagus, respectively, and were randomised to single post-supper (10 pm) dose of either Gaviscon Advance or a non-alginate antacid on the second night. Primary outcomes were suppression of median pH of acid pocket and lower oesophagus, measured every 10-minutes post-supper for 1 h. Secondary outcomes were suppression of % time pH < 4 at lower oesophagus and improvement in frequency and visual analogue score (VAS) of regurgitation. RESULTS: Of the 81 screened participants, 55 were excluded and 26 (mean age 33.5 years, males 77.8% and BMI 32.8 kg/m2 ) were randomised to Gaviscon Advance (n = 13) or antacid (n = 13). Median pH of the acid pocket but not the lower oesophagus was suppressed with Gaviscon Advance vs antacid (all P < 0.04) Gaviscon Advance but not antacid significantly reduced in % time pH < 4, symptom frequency and VAS on day 2 vs day 1 (all P < 0.05). CONCLUSIONS: Among obese individuals, Gaviscon Advance was superior to a non-alginate antacid in post-supper suppression of the acid pocket. (Clinical trial registration unique identifier: NCT03516188).

Switching from glargine+insulin aspart to glargine+insulin aspart 30 before breakfast combined with exercise after dinner and dividing meals for the treatment of type 2 diabetes patients with poor glucose control - a prospective cohort study.

BACKGROUND: This study aimed to examine the switch from glargine+once daily insulin aspart (1 + 1 regimen) to glargine+insulin aspart 30 before breakfast combined with exercise and in patients with type 2 diabetes mellitus (T2DM) with poorly controlled blood glucose levels. METHODS: Consecutive patients with poorly controlled T2DM (n = 182) were switched from the 1 + 1 regimen to glargine+insulin aspart 30 before breakfast in combination with exercise after dinner and dividing meals in two (same final calories intake). The insulin doses were adjusted according to blood glucose levels within 4 weeks after the switch and maintained for 12 weeks. Fasting blood glucose (FBG), 2-hpostprandial glucose (2hPG), glycosylated hemoglobin (HbA1c), body mass index (BMI), daily insulin dose, and hypoglycemia events were assessed. RESULTS: Sixteen weeks after the switch, 2 h PG levels and HbA1c levels (from 8.5 to 7.4%, P = 0.001) were improved. The proportions of patients reaching the HbA1c targets of 7.5% were improved (from 22.5 to 58.7%, P = 0.001). Among the 182 patients, 24 (13.2%) divided one meal into two meals, and 23 (12.6%) divided two meals into four meals. Among all patients, 8.5% had to reuse insulin aspart before dinner after the study. One patient with diarrhea and poor appetite experienced severe hypoglycemia. The rate of hypoglycemia was 3.76 events/patient-year. The daily insulin Aspart 30 dose was higher than the original insulin aspart dose (P = 0.001). CONCLUSIONS: For patients with poorly controlled T2DM under the 1 + 1 regimen, switching to glargine+insulin aspart 30 before breakfast combined with exercise after dinner and dividing meals showed promising benefits.

Fast-acting insulin aspart versus insulin aspart in the setting of insulin degludec-treated type 1 diabetes: Efficacy and safety from a randomized double-blind trial.

AIM: To evaluate the efficacy and safety of mealtime or post-meal fast-acting insulin aspart (faster aspart) vs mealtime insulin aspart (IAsp), both in combination with insulin degludec, in participants with type 1 diabetes (T1D). METHODS: This multicentre, treat-to-target trial (Clinical trial registry: NCT02500706, ClinicalTrials.gov) randomized participants to double-blind mealtime faster aspart (n = 342) or IAsp (n = 342) or open-label post-meal faster aspart (n = 341). The primary endpoint was change from baseline in HbA1c 26 weeks post randomization. All available information, regardless of treatment discontinuation, was used for evaluation of the effect. RESULTS: Non-inferiority for the change from baseline in HbA1c was confirmed for mealtime and post-meal faster aspart vs IAsp (estimated treatment difference [ETD]: 95%CI, -0.02% [-0.11; 0.07] and 0.10% [0.004; 0.19], respectively). Mealtime faster aspart was superior to IAsp for 1-hour PPG increment using a meal test (ETD, -0.90 mmol/L [-1.36; -0.45]; P < 0.001). Self-monitored 1-hour PPG increment favoured faster aspart at breakfast (ETD, -0.58 mmol/L [-0.99; -0.17]; P = 0.006) and across all meals (-0.48 mmol/L [-0.74; -0.21]; P < 0.001). Safety profiles and overall rate of severe or blood glucose-confirmed hypoglycaemia were similar between treatments, but significantly less hypoglycaemia was seen 3 to 4 hours after meals with mealtime faster aspart. CONCLUSION: Mealtime and post-meal faster aspart in conjunction with insulin degludec provided effective glycaemic control compared with IAsp, with no increased safety risk. Mealtime faster aspart provided PPG control superior to that of IAsp.

The acute effects of inulin and resistant starch on postprandial serum short-chain fatty acids and second-meal glycemic response in lean and overweight humans.

BACKGROUND/OBJECTIVES: Colonic fermentation of dietary fiber to short-chain fatty acids (SCFA) may protect against obesity and diabetes, but excess production of colonic SCFA has been implicated in the promotion of obesity. We aimed to compare the effects of two fermentable fibers on postprandial SCFA and second-meal glycemic response in healthy overweight or obese (OWO) vs lean (LN) participants. SUBJECTS/METHODS: Using a randomized crossover design, 13 OWO and 12 LN overnight fasted participants were studied for 6 h on three separate days after consuming 300 ml water containing 75 g glucose (GLU) as control or with 24 g inulin (IN) or 28 g resistant starch (RS). A standard lunch was served 4 h after the test drink. RESULTS: Within the entire group, compared with control, IN significantly increased serum SCFA (P<0.001) but had no effect on free-fatty acids (FFA) or second-meal glucose and insulin responses. In contrast, RS had no significant effect on SCFA but reduced FFA rebound (P<0.001) and second-meal glucose (P=0.002) and insulin responses (P=0.024). OWO had similar postprandial serum SCFA and glucose concentrations but significantly greater insulin and FFA than LN. However, the effects of IN and RS on SCFA, glucose, insulin and FFA responses were similar in LN and OWO. CONCLUSIONS: RS has favorable second-meal effects, likely related to changes in FFA rather than SCFA concentrations. However, a longer study may be needed to demonstrate an effect of RS on SCFA. We found no evidence that acute increases in SCFA after IN reduce glycemic responses in humans, and we were unable to detect a significant difference in SCFA responses between OWO vs LN subjects.

Effects of a meal replacement system alone or in combination with phentermine on weight loss and food cravings.

OBJECTIVE: To examine the effects of phentermine combined with a meal replacement program on weight loss and food cravings and to investigate the relationship between food cravings and weight loss. METHODS: In a 12-week randomized, double-blind, placebo-controlled clinical trial, 77 adults with obesity received either phentermine or placebo. All participants were provided Medifast® meal replacements, were instructed to follow the Take Shape for Life® Optimal Weight 5&1 Plan for weight loss, and received lifestyle coaching in the Habits of Health program. The Food Craving Inventory and the General Food Cravings State and Trait Questionnaires were used to measure food cravings. RESULTS: The phentermine group lost 12.1% of baseline body weight compared with 8.8% in the placebo group. Cravings for all food groups decreased in both groups; however, there was a greater reduction in cravings for fats and sweets in the phentermine group compared with the placebo group. Percent weight loss correlated significantly with reduced total food cravings (r = 0.332, P = 0.009), cravings for sweets (r = 0.412, P < 0.000), and state food cravings (r = 0.320, P = 0.007). CONCLUSIONS: Both phentermine combined with a meal replacement program and meal replacements alone significantly reduced body weight and food cravings; however, the addition of phentermine enhanced these effects.

Failure of sucrose replacement with the non-nutritive sweetener erythritol to alter GLP-1 or PYY release or test meal size in lean or obese people.

There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake.

Upper gastrointestinal sensitivity to meal-related signals in adult humans - relevance to appetite regulation and gut symptoms in health, obesity and functional dyspepsia.

Both the stomach and small intestine play important roles in sensing the arrival of a meal, and its physico-chemical characteristics, in the gastrointestinal lumen. The presence of a meal in the stomach provides a distension stimulus, and, as the meal empties into the small intestine, nutrients interact with small intestinal receptors, initiating the release of gut hormones, associated with feedback regulation of gastrointestinal functions, including gut motility, and signaling to the central nervous system, modulating eating behaviours, including energy intake. Lipid appears to have particularly potent effects, also in close interaction with, and modulating the effects of, gastric distension, and involving the action of gut hormones, particularly cholecystokinin (CCK). These findings have not only provided important, and novel, insights into how gastrointestinal signals interact to modulate subjective appetite perceptions, including fullness, but also laid the foundation for an increasing appreciation of the role of altered gastrointestinal sensitivities, e.g. as a consequence of excess dietary intake in obesity, or underlying the induction of gastrointestinal symptoms in functional dyspepsia (a condition characterized by symptoms, including bloating, nausea and early fullness, amongst others, after meals, particularly those high in fat, in the absence of any structural or functional abnormalities in the gastrointestinal tract). This paper will review the effects of dietary nutrients, particularly lipid, on gastrointestinal function, and associated effects on appetite perceptions and energy intake, effects of interactions of gastrointestinal stimuli, as well as the role of altered gastrointestinal sensitivities (exaggerated, or reduced) in eating-related disorders, particularly obesity and functional dyspepsia.

Improvement of meal-related symptoms and epigastric pain in patients with functional dyspepsia treated with acotiamide was associated with acylated ghrelin levels in Japan.

BACKGROUND: The aim of this study is to clarify whether acotiamide and rabeprazole combination therapy can improve clinical symptoms, gastric emptying, and satisfaction with treatment in functional dyspepsia (FD) patients more effectively than acotiamide or rabeprazole monotherapy alone. We also aimed to determine whether acotiamide affects these changes via its effect on gastric emptying and appetite-related hormones such as ghrelin. METHODS: We used Rome III criteria to evaluate upper abdominal symptoms and anxiety by the State-Trait Anxiety Inventory (STAI). Gastric motility was evaluated by the (13) C-acetate breath test. Eighty-one FD patients were treated with acotiamide (300 mg/day) (n = 35), acotiamide (300 mg/day) and rabeprazole (10 mg/day) (n = 28), or rabeprazole (10 mg/day) (n = 18) for a period of 4 weeks and followed after 4 weeks of no treatment. Adenocorticotropic hormone (ACTH), cortisol, leptin and ghrelin levels were measured in all FD patients. KEY RESULTS: Acotiamide and rabeprazole combination therapy significantly improved postprandial distress syndrome (PDS)-like symptoms (p = 0.018, p = 0.04 and p = 0.041, respectively) and epigastric pain (p = 0.024) as wells as STAI-state scores (p = 0.04) compared to rabeprazole monotherapy. Both acotiamide monotherapy, and acotiamide taken in combination with rabeprazole, significantly (p = 0.001 and p = 0.02, respectively) improved satisfaction with treatment, compared to rabeprazole monotherapy. Acotiamide and rabeprazole combination therapy had no significant effect on ACTH and cortisol levels in FD patients. Of interest, acotiamide monotherapy, and acotiamide and rabeprazole combination therapy, significantly (p < 0.0001 and p = 0.018, respectively) increased acylated ghrelin/total ghrelin ratios and significantly (p = 0.04) improved impaired gastric emptying compared to rabeprazole monotherapy. CONCLUSIONS & INFERENCES: Further studies are warranted to clarify how acotiamide treatment improves clinical symptoms in FD patients.

Effect of Glycemic Index of Breakfast on Energy Intake at Subsequent Meal among Healthy People: A Meta-Analysis.

Meals with low glycemic index (GI) may suppress short-term appetite and reduce subsequent food intake compared with high-GI meals. However, no meta-analysis has been conducted to synthesize the evidence. This meta-analytic study was conducted to assess the effect of high- and low-GI breakfast on subsequent short-term food intake. Trials were identified through MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled trials, and manual searches of bibliographies until May 2015. Randomized controlled and cross-over trials comparing the effect of low- with high-GI breakfast on subsequent energy intake among healthy people were included. Nine studies consisting of 11 trials met the inclusion criteria. Only one trial was classified with high methodological quality. A total of 183 participants were involved in the trials. The meta-analytic results revealed no difference in breakfast GI (high-GI vs. low-GI) on subsequent short-term energy intake. In conclusion, it seems that breakfast GI has no effect on short-term energy intake among healthy people. However, high quality studies are still warranted to provide more concrete evidence.

Emulsion oil droplet size significantly affects satiety: A pre-ingestive approach.

Previous research has demonstrated that the manipulation of oil droplet size within oil-in-water emulsions significantly affects sensory characteristics, hedonics and expectations of food intake, independently of energy content. Smaller oil droplets enhanced perceived creaminess, increased Liking and generated greater expectations of satiation and satiety, indicating that creaminess is a satiety-relevant sensory cue within these systems. This paper extends these findings by investigating the effect of oil droplet size (d4,3: 2 and 50 µm) on food intake and appetite. Male participants (n = 34 aged 18-37; BMI of 22.7 ± 1.6 kg/m(2); DEBQ restricted eating score of 1.8 ± 0.1.) completed two test days, where they visited the laboratory to consume a fixed-portion breakfast, returning 3 h later for a "drink", which was the emulsion preload containing either 2 or 50 µm oil droplets. This was followed 20 min later with an ad libitum pasta lunch. Participants consumed significantly less at the ad libitum lunch after the preload containing 2 µm oil droplets than after the 50 µm preload, with an average reduction of 12% (62.4 kcal). Despite the significant differences in intake, no significant differences in sensory characteristics were noted. The findings show that the impact that an emulsion has on satiety can be enhanced without producing significantly perceivable differences in sensory properties. Therefore, by introducing a processing step which results in a smaller droplets, emulsion based liquid food products can be produced that enhance satiety, allowing covert functional redesign. Future work should consider the mechanism responsible for this effect.

The (lack of) effect of alprazolam on eating behavior in anorexia nervosa: a preliminary report.

OBJECTIVE: Anxiety is a prominent symptom in anorexia nervosa (AN), and higher pre-meal anxiety has been associated with lower caloric intake. Yet, the causal relationship has not been assessed. We proposed that reducing anxiety with a short acting benzodiazepine would increase caloric intake among individuals with AN. METHOD: In a randomized, double-blind, placebo controlled cross-over study, we administered alprazolam 0.75 mg to inpatients with AN (n = 17) and assessed caloric intake in a laboratory test meal. Within-subject differences in caloric intake, anxiety, and fatigue were compared between alprazolam and placebo days. RESULTS: Caloric intake did not differ on alprazolam versus placebo (t(15) = 1.72, p = .11). Alprazolam did not reduce anxiety, but was associated with increased fatigue. DISCUSSION: This study was not able to evaluate the causal role of anxiety in meal intake among individuals with AN, as alprazolam did not alter anxiety symptoms. These data further suggest that the therapeutic role for short-acting benzodiazepines in AN is likely limited.

Equal improvement in glycaemia with lixisenatide given before breakfast or the main meal of the day.

AIMS: The aim of this study is to explore whether administration timing affects glycaemic control by lixisenatide once-daily in type 2 diabetes mellitus (T2DM). METHODS: A phase IIIb, open-label, 1:1 randomized, active-controlled, 24-week multicentre study of T2DM patients inadequately controlled on metformin was conducted. Patients were administered lixisenatide before breakfast or the main meal. The primary endpoint was change from baseline at week 24 in glycated haemoglobin (HbA1c). Other endpoints: changes in body weight, fasting plasma glucose (FPG), 7-point self-monitored plasma glucose (SMPG) and Diabetes Treatment Satisfaction Questionnaire status (DTSQs) score. Adverse events (AEs) were monitored. RESULTS: Mean change in HbA1c from baseline at week 24 was -0.65% (-7.1mmol/mol; main meal) and -0.74% (-8.1mmol/mol; breakfast). Mean changes in FPG, body weight and DTSQs score were comparable between groups. The mean change in body weight (kg) was -2.60 (main meal) and -2.80 (breakfast group). The 7-point SMPG profiles showed greatest reductions in postprandial glucose after the meal at which lixisenatide was administered, with a residual effect seen on the subsequent meal. AE rates were similar between groups, including gastrointestinal AEs. CONCLUSIONS: Lixisenatide before the main meal was noninferior to lixisenatide before breakfast in patients insufficiently controlled on metformin. Lixisenatide treatment allows flexibility in administration timing.

Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase.

Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 µg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 µg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr(389) and AMPK at Ser(485/491) in the mediobasal hypothalamus, while AMPK phosphorylation at Thr(172) was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.

Blocking alpha2A adrenoceptors, but not dopamine receptors, augments bupropion-induced hypophagia in rats.

OBJECTIVE: Anti-obesity drugs have adverse effects which limit their use, creating a need for novel anti-obesity compounds. We studied effects of dopamine (DA) and norepinephrine (NE) reuptake inhibitor bupropion (BUP), alone and after blocking α1- or α2-adrenoceptors (AR), D1/5, D2/3, or D4 receptors, to determine which receptors act downstream of BUP. DESIGN AND METHODS: Effects on caloric intake, meal patterning and locomotion were assessed, using an automated weighing system and telemetry in male rats with 18-h access to Western Human style diet. RESULTS: BUP (30 mg/kg) induced hypophagia by reducing meal size and postponing meal initiation. WB4101 (α1-AR; 2 mg/kg) and imiloxan (α2B-AR; 5 mg/kg) attenuated BUP's effect on meal size, while WB4101 and BRL 44408 (α2A/D-AR; 2 mg/kg) counteracted effect on meal initiation. Atipamezole (α2-AR; 1 mg/kg) and imiloxan further postponed initiation of meals. SKF 83566 (D1/5; 0.3 mg/kg), raclopride (D2/3; 0.5 mg/kg) and to a lesser extent FAUC 213 (D4; 0.5 mg/kg), attenuated BUP-induced hypophagia. BUP stimulated locomotion, which was blocked by all antagonists, except FAUC 213 or BRL 44408. CONCLUSIONS: Alpha1-, α2A/D- and α2B-ARs, and DA receptors underlie BUP's effects on size and initiation of meals, while blocking pre-synaptic α2-ARs enhanced BUP-induced hypophagia. An inverse agonist of (pre-synaptic) α2A-ARs could enhance BUP-induced anorexia and treat eating disorders and obesity.

Differential effects of chronic social stress and fluoxetine on meal patterns in mice.

Both chronic stress and antidepressant medications have been associated with changes in body weight. In the current study, we investigate mechanisms by which stress and antidepressants interact to affect meal patterns. A group of mice was subjected to the chronic social defeat stress model of major depression followed by fluoxetine treatment and was subsequently analyzed for food intake using metabolic cages. We report that chronic social defeat stress increases food intake by specifically increasing meal size, an effect that is reversed by fluoxetine treatment. In an attempt to gain mechanistic insight into changes in meal patterning induced by stress and fluoxetine, fasting serum samples were collected every 4h over a 24-h period, and acyl-ghrelin, leptin, and corticosterone levels were measured. Chronic stress induces a peak in acyl-ghrelin levels just prior to the onset of the dark phase, which is shifted in mice treated with fluoxetine. Taken together, these results indicate that stress increases food intake by decreasing satiation, and that fluoxetine can reverse stress-induced changes in meal patterns.

Meal time shift disturbs circadian rhythmicity along with metabolic and behavioral alterations in mice.

In modern society, growing numbers of people are engaged in various forms of shift works or trans-meridian travels. Such circadian misalignment is known to disturb endogenous diurnal rhythms, which may lead to harmful physiological consequences including metabolic syndrome, obesity, cancer, cardiovascular disorders, and gastric disorders as well as other physical and mental disorders. However, the precise mechanism(s) underlying these changes are yet unclear. The present work, therefore examined the effects of 6 h advance or delay of usual meal time on diurnal rhythmicities in home cage activity (HCA), body temperature (BT), blood metabolic markers, glucose homeostasis, and expression of genes that are involved in cholesterol homeostasis by feeding young adult male mice in a time-restrictive manner. Delay of meal time caused locomotive hyperactivity in a significant portion (42%) of subjects, while 6 h advance caused a torpor-like symptom during the late scotophase. Accordingly, daily rhythms of blood glucose and triglyceride were differentially affected by time-restrictive feeding regimen with concurrent metabolic alterations. Along with these physiological changes, time-restrictive feeding also influenced the circadian expression patterns of low density lipoprotein receptor (LDLR) as well as most LDLR regulatory factors. Strikingly, chronic advance of meal time induced insulin resistance, while chronic delay significantly elevated blood glucose levels. Taken together, our findings indicate that persistent shifts in usual meal time impact the diurnal rhythms of carbohydrate and lipid metabolisms in addition to HCA and BT, thereby posing critical implications for the health and diseases of shift workers.