Effect of ingesting a meal and orthostasis on the regulation of splanchnic and systemic hemodynamics and the responsiveness of cardiovascular α1-adrenoceptors

Background: Postprandial orthostasis activates mechanisms of cardiovascular homeostasis in order to maintain normal blood pressure (BP) and adequate blood flow to vital organs. The underlying mechanisms of cardiovascular homeostasis in postprandial orthostasis still require elucidation. Methods: Fourteen healthy volunteers were recruited to investigate the effect of an orthostatic challenge (600-head-up-tilt for 20 minutes) on splanchnic and systemic hemodynamics before and after ingesting an 800-kilocalorie composite meal. The splanchnic circulation was assessed by ultrasonography of the superior mesenteric and hepatic arteries and portal vein. Systemic hemodynamics were assessed non-invasively by continuous monitoring of BP, heart rate (HR), cardiac output (CO), and the pressor response to an intravenous infusion on increasing doses of phenylephrine, an α1-adrenoceptor agonist. Neurohumoral regulation was assessed by spectral analysis of HR and BP, plasma catecholamine and aldosterone levels and plasma renin activity. Results: Postprandial mesenteric hyperemia was associated with an increase in CO, a decrease in SVR and cardiac vagal tone, and reduction in baroreflex sensitivity with no change in sympathetic tone. Arterial α1-adrenoceptor responsiveness was preserved and reduced in hepatic sinusoids. Postprandial orthostasis was associated with a shift of 500 ml of blood from mesenteric to systemic circulation with preserved sympathetic-mediated vasoconstriction Conclusions: Meal ingestion provokes cardiovascular hyperdynamism, cardiac vagolysis, and resetting of the baroreflex without activation of the sympathetic nervous system. Meal ingestion also alters α1-adrenoceptor responsiveness in the hepatic sinusoids and participates in the redistribution of blood volume from the mesenteric to the systemic circulation in order to maintain a normal BP during orthostasis.

Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes.

The Change in Glucagon Following Meal Ingestion Is Associated with Glycemic Control, but Not with Incretin, in People with Diabetes

Background: We aimed to investigate the changes in glucagon levels in people with diabetes after the ingestion of a mixed meal and the correlations of variation in glucagon levels with incretin and clinico-biochemical characteristics. Methods: Glucose, C-peptide, glucagon, intact glucagon-like peptide 1 (iGLP-1), and intact glucose-dependent insulinotropic polypeptide (iGIP) were measured in blood samples collected from 317 people with diabetes before and 30 min after the ingestion of a standard mixed meal. The delta (Δ) is the 30-min value minus the basal value. Results: At 30 min after meal ingestion, the glucagon level showed no difference relative to the basal value, whereas glucose, C-peptide, iGLP-1, and iGIP levels showed a significant increase. In univariate analysis, Δglucagon showed not only a strong correlation with HbA1c but also a significant correlation with fasting glucose, Δglucose, and estimated glomerular filtration rate. However, Δglucagon showed no significant correlations with ΔiGLP-1 and ΔiGIP. In the hierarchical multiple regression analysis, HbA1c was the only variable that continued to show the most significant correlation with Δglucagon. Conclusions: People with diabetes showed no suppression of glucagon secretion after meal ingestion. Patients with poorer glycemic control may show greater increase in postprandial glucagon level, and this does not appear to be mediated by incretin.

Blood Sampling From Rat Ileal Mesenteric Vein Revealed a Major Role of Dietary Protein in Meal-Induced GLP-1 Response

The present study was conducted to examine region-dependent glucagon-like peptide-1 (GLP-1) responses to “meal ingestion” under physiological (conscious and unrestrained) conditions using rats with a catheter inserted into either the portal vein (PV) or the ileal mesenteric vein (ILMV). After recovery from the cannulation surgery, blood samples were collected from either PV or ILMV catheter before and after the voluntary ingestion of test diets. After an AIN-93G standard diet ingestion, GLP-1 concentration was higher in ILMV than in PV, and postprandial responses of peptide-YY (PYY) had similar trend, while that of glucose dependent-insulinotropic polypeptide showed an opposite trend to GLP-1/PYY responses. In a separated experiment, a protein-enriched diet containing casein at 25% wt/wt transiently increased GLP-1 concentration only in ILMV; however, a protein-free diet did not increase GLP-1 concentrations in PV or ILMV. These results indicate that postprandial GLP-1 is immediately released from the distal intestine under physiological conditions, and that dietary protein has a critical role in the enhancement of postprandial GLP-1 response.

Abdominothoracic Postural Tone Influences the Sensations Induced by Meal Ingestion

Postprandial objective abdominal distention is frequently associated with a subjective sensation of abdominal bloating, but the relation between both complaints is unknown. While the bloating sensation has a visceral origin, abdominal distention is a behavioral somatic response, involving contraction and descent of the diaphragm with protrusion of the anterior abdominal wall. Our aim was to determine whether abdominal distention influences digestive sensations. In 16 healthy women we investigated the effect of intentional abdominal distention on experimentally induced bloating sensation (by a meal overload). Participants were first taught to produce diaphragmatic contraction and visible abdominal distention. After a meal overload, sensations of bloating (0 to 10) and digestive well-being (−5 to + 5) were measured during 30-s. maneuvers alternating diaphragmatic contraction and diaphragmatic relaxation. Compared to diaphragmatic relaxation, diaphragmatic contraction was associated with diaphragmatic descent (by 21 + 3 mm; p < 0.001), objective abdominal distension (32 + 5 mm girth increase; p = 0.001), more intense sensation of bloating (7.3 + 0.4 vs. 8.0 + 0.4 score; p = 0.010) and lower digestive well-being (−0.9 + 0.5 vs. −1.9 + 0.5 score; p = 0.028). These results indicate that somatic postural tone underlying abdominal distention worsens the perception of visceral sensations (ClinicalTrials.gov ID: NCT04691882).

GFRAL-expressing neurons suppress food intake via aversive pathways

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α–like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non–meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

Acceleration of Gastric Emptying by Insulin-Induced Hypoglycemia is Dependent on the Degree of Hypoglycemia

Context Hypoglycemia is a major barrier to optimal glycemic control in insulin-treated diabetes. Recent guidelines from the American Diabetes Association have subcategorized “non-severe” hypoglycemia into level 1 (&lt;3.9 mmol/L) and 2 (&lt;3 mmol/L) hypoglycemia. Gastric emptying of carbohydrate is a major determinant of postprandial glycemia but its role in hypoglycemia counter-regulation remains underappreciated. “Marked” hypoglycemia (~2.6 mmol/L) accelerates gastric emptying and increases carbohydrate absorption in health and type 1 diabetes, but the impact of “mild” hypoglycemia (3.0-3.9 mmol/L) is unknown. Objective To determine the effects of 2 levels of hypoglycemia, 2.6 mmol/L (“marked”) and 3.6 mmol/L (“mild”), on gastric emptying in health. Design, Setting, and Subjects Fourteen healthy male participants (mean age: 32.9 ± 8.3 years; body mass index: 24.5 ± 3.4 kg/m2) from the general community underwent measurement of gastric emptying of a radiolabeled solid meal (100 g beef) by scintigraphy over 120 minutes on 3 separate occasions, while blood glucose was maintained at either ~2.6 mmol/L, ~3.6 mmol/L, or ~6 mmol/L in random order from 15 minutes before until 60 minutes after meal ingestion using glucose-insulin clamp. Blood glucose was then maintained at 6 mmol/L from 60 to 120 minutes on all days. Results Gastric emptying was accelerated during both mild (P = 0.011) and marked (P = 0.001) hypoglycemia when compared to euglycemia, and was more rapid during marked compared with mild hypoglycemia (P = 0.008). Hypoglycemia-induced gastric emptying acceleration during mild (r = 0.57, P = 0.030) and marked (r = 0.76, P = 0.0014) hypoglycemia was related to gastric emptying during euglycemia. Conclusion In health, acceleration of gastric emptying by insulin-induced hypoglycemia is dependent on the degree of hypoglycemia and baseline rate of emptying.

Regulation of direct adipose tissue free fatty acid storage during mixed meal ingestion and high free fatty acid concentration conditions

Direct free fatty acid (FFA) storage into adipocytes relates to body fat distribution. Adipose tissue CD36, acyl-CoA synthetase (ACS), and diacylglycerol acetyl-transferase (DGAT) may account for some of the between-depot and inter-individual variability in FFA storage. These studies were to test whether CD36, ACS or DGAT might be important for direct palmitate storage under meal-ingestion or high FFA conditions. We measured upper (UBSQ) and lower body subcutaneous (LBSQ) adipose tissue FFA storage rates by infusing palmitate tracers intravenously and performing adipose biopsies under hypoinsulinemic (high FFA) and mixed meal conditions. We recruited 5 postmenopausal women, physically active males (5) and females (5), and sedentary males (5) and females (5). We found: 1) the ratio of UBSQ to LBSQ DGAT activity predicted the ratio of palmitate storage (adjusted R = 0.25, F = 8.0, P = 0.01, 95% CI (0.07, 0.48)) under high FFA conditions; 2) the ratio of UBSQ to LBSQ ACS activity predicted the ratio of palmitate storage under meal conditions (adjusted R = 0.18, F = 6.3, P = 0.02, 95% CI (0.12, 1.28); 3) LBSQ direct palmitate storage rates were significantly less in physically active than sedentary adults; 3); 4) adipose tissue CD36 protein content, ACS or DGAT activities did not independently predict palmitate storage rates. We conclude that physically active adults have lesser fatty acid cycling back into adipose tissue and that adipose ACS and DGAT may affect competition between UBSQ and LBSQ adipose for direct palmitate storage.