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GIP contributes to postprandial regulation of splanchnic blood supply in humans with type 2 diabetes: a randomised, single-blinded, placebo-controlled, crossover study.

AIMS/HYPOTHESIS: In healthy lean humans, endogenous glucose-dependent insulinotropic polypeptide (GIP) contributes significantly to the postprandial increase in arteria mesenterica superior blood flow. The vascular biology related to activation of the GIP receptor is markedly impaired in individuals with type 2 diabetes and is sometimes absent. In this population, we investigated the role of endogenous GIP on postprandial splanchnic blood flow by using the GIP receptor antagonist, GIP(3-30)NH2. The primary outcome of this study was the changes in blood flow in arteria mesenterica superior during oral glucose with or without GIP receptor antagonist infusion. METHODS: Ten participants with type 2 diabetes (age 20-80 years, BMI 20-35 kg/m2, and HbA1c >48 mmol/mol and <75 mmol/mol) were investigated in a randomised, placebo-controlled, crossover study. On four separate occasions, participants received the following treatment: oral glucose + i.v. GIP(3-30)NH2; oral glucose + i.v. saline (154 mmol/l NaCl); oral water + i.v. GIP(3-30)NH2; oral water + i.v. saline. Participants were randomly assigned to intervention groups using (random.org). Participants were unaware of allocation, while investigators were aware. No additional allocation concealment procedures were used. During all four interventions, splanchnic blood flow was measured using phase-contrast MRI in the arteria mesenterica superior, truncus coeliacus and vena portae during oral glucose (75 g) or water ingestion. The study was conducted at Rigshospitalet, Copenhagen. Liver volume and oxygenation, as well as gallbladder volume, were assessed. Blood samples were collected and analysed for insulin, C-peptide, GIP, glucagon and glucose. RESULTS: Oral glucose alone increased mean blood flow in arteria mesenterica superior by 57% (95% CI 26, 88) and this was 15% (95% CI -2, 32) lower during concomitant GIP receptor antagonist infusion, p=0.012. Infusion of GIP receptor antagonist during oral glucose treatment did also result in lower insulin secretion, C-peptide and C-peptide/glucose ratio compared with saline infusion, whereas glucagon levels and plasma glucose were unaffected. Oral water did not affect any outcomes. CONCLUSIONS/INTERPRETATION: Endogenous GIP contributes to postprandially increased splanchnic blood flow in people with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT06426823 FUNDING: This work was supported by the Novo Nordisk Foundation.

Humans

Premeal insulin administration lowers postprandial blood glucose and increases myocardial microvascular blood flow in people with type 1 diabetes: a randomised, crossover clinical trial.

AIMS/HYPOTHESIS: We aimed to evaluate whether prandial insulin timing affects vascular function in people with type 1 diabetes. Our hypothesis was that premeal insulin administration would lead to greater myocardial microvascular blood flow (MBF) via blunting postprandial hyperglycaemia. METHODS: People with type 1 diabetes between 18 and 35 years of age with BMI <30 kg/m2 underwent two protocols with a 1:1 randomised crossover design wherein prandial insulin was injected either 15 min before or 15 min after meal intake began. To provide a physiological comparison, age-, sex- and BMI-matched control participants completed one study where they consumed the same meal but received no exogenous insulin. Glucose, insulin, vascular function (including ultrasound measures of myocardial and skeletal muscle microvascular perfusion, aortic stiffness, brachial artery endothelial function) and biomarkers of systemic inflammation and endothelial dysfunction were assessed at baseline and then 2 h after meal ingestion within each protocol. The primary outcome was change in myocardial MBF within each protocol. Study personnel assessing outcomes were masked to group assignment. RESULTS: Eighteen people with type 1 diabetes and 18 matched control participants were analysed within each protocol. Glucose area under the curve was significantly greater (p=0.015) in the postmeal insulin study compared with the premeal insulin study in participants with type 1 diabetes. Myocardial microvascular flow velocity significantly increased (p=0.031) with premeal insulin administration in people with type 1 diabetes and this consequently led to greater myocardial MBF (p=0.044). There were no changes in myocardial MBF within the other protocols. Changes in vital signs were similar between all protocols. CONCLUSIONS/INTERPRETATION: Appropriately timed premeal insulin led to lower postprandial blood glucose along with increased myocardial MBF in people with type 1 diabetes. Further work is needed to determine the underlying aetiology of these changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04730882.

Humans

Interaction of melatonin receptor 1B (MTNR1B) genotype and type of breakfast (protein-enriched v carbohydrate-rich) on postprandial glucose response: a randomised crossover trial.

BACKGROUND: The risk allele (G) of MTNR1B rs10830963 has been associated with impaired glucose tolerance, increased fasting glucose and type 2 diabetes (T2D). Late evening eating, when endogenous melatonin levels are elevated, is associated with impaired glucose control in MTNR1B risk carriers. Endogenous melatonin levels remain elevated into the morning so may influence glucose response to breakfast. OBJECTIVE: To investigate the interaction of MTNR1B genotype and type of breakfast on postprandial glucose response in a real-world setting. METHODS: Following an overnight fast, participants consumed either a standard carbohydrate-rich or protein-enriched porridge breakfast. Post-prandial glucose levels were recorded for two hours using a continuous glucose monitor (CGM). One week later, participants repeated the protocol consuming the alternate breakfast. A two-way mixed ANOVA determined the effect of breakfast and genotype on post-prandial glucose levels. RESULTS: Fifty-four adults completed the study. Fasting glucose was significantly higher (p&#x2009;=&#x2009;0.008) in GG (5.53&#x2009;&#xb1;&#x2009;0.43&#x2009;mmol/L) compared to CC or CG participants (5.02&#x2009;&#xb1;&#x2009;0.42 and 5.19&#x2009;&#xb1;&#x2009;0.52&#x2009;mmol/L). Post-prandial iAUC was significantly greater following the carbohydrate-rich breakfast compared to the protein-enriched breakfast (p&#x2009;<&#x2009;0.001). Following the carbohydrate-rich breakfast iAUC was significantly greater in GG participants compared to CC (p&#x2009;=&#x2009;0.026) and CG participants (p&#x2009;=&#x2009;0.029). There was no significant difference between genotype groups following the protein-enriched breakfast (p&#x2009;>&#x2009;0.05). CONCLUSION: The study findings demonstrate, in a relatively young and healthy population, MTNR1B genotype significantly affects markers associated with T2D risk. Personalised genotype-based advice to adjust timing and composition of meals consumed when endogenous melatonin levels are increased may reduce subsequent T2D risk.

Humans

Aldosterone and postprandial renal excretion of sodium and potassium in sheep.

When sheep rapidly eat a meal of dry feed a period of antinatriuresis and antidiuresis is rapidly initiated and lasts for 2-3 hrs. This is followed by a postprandial period of natriuresis and diuresis. This study tested the hypothesis that the postprandial natriuresis was due to a reduction in the secretion of aldosterone. In unanesthetized ewes of about 50 kg body wt, measurements were made of sodium and potassium excretion beginning in the terminal phase of the feed-induced antinatriuresis and continuing through the period of postprandial natriuresis. Aldosterone, given by constant infusion at a physiological dose (10 microgram/h), inhibited the natriuresis. Spironolactone, a competitive inhibitor of aldosterone given as a single intravenous injection of 5 mg/kg body wt, did not significantly increase the natriuresis. These results support the stated hypothesis. Neither aldosterone nor spironolactone had a significant effect on potassium excretion. This finding supports earlier view that aldosterone has only a small role in the homeostatic control of potassium excretion in sheep.

Aldosterone

Regulation of plasma potassium in hyperkalemic periodic paralysis.

Hyperkalemic periodic paralysis is frequently considered a disorder in which episodes of weakness and an attendant rise in plasma potassium interrupt a baseline of normal strength and potassium. We studied venous potassium throughout a 36-hour period in two patients with hyperkalemic periodic paralysis and in nine normals under rigidly controlled conditions. At no time did the patients with periodic paralysis have an attack of weakness, but their mean potassium concentrations were above the normal range for 33 to 36 hours. In hyperkalemic periodic paralysis, the postprandial change in potassium relative to insulin release exceeded normal. There appears to be a continuous alteration in potassium regulation in our patients with hyperkalemic periodic paralysis.

Female

Postprandial glucose, insulin, free fatty acid and growth hormone responses in children consuming all the day's protein in one meal.

BLOOD GLUCOSE, INSULIN (IRI), growth hormone, and plasma free fatty acids (FFA) were determined in six children consuming a diet of uneven distribution of protein relative to energy (study period). Preprandial and postprandial samples surrounding the 8 AM protein-free feeding and the 3 PM feeding containing all the day's protein were compared with values obtained in the same children similarly sampled while consuming an isonitrogenous isoenergetic diet of even protein distribution (control period). After the 8 AM feeding during the study period there was a mean maximal rise of blood glucose at 30 min of 51 mg/dl compared with a rise of 16 mg/dl during the control period. Glucose remained significantly elevated above fasting values at 120 min during the study but not the control period. IRI response after the 8 AM feeding was significantly greater and suppression of FFA was more marked during the study than during the control period. Glucose concentration 30 min after the 3 PM feeding was significantly lower during the study period than during the control period. A peak value occurred at 60 min during the study period which was equal to the 30 min peak control value. Despite the slower elevation of blood glucose during the study period, IRI rose at 30 min, possibly related to a larger influx of amino acids from the protein-containing meal. FFA rose at 30 and 60 min and were then suppressed by the slowly rising blood glucose. Growth hormone after both meals while consuming both diets was variable but considered normal. The qualitative changes in glucose-IRI-FFA responses were for the most part attributable to differences in the test meals and suggested little long-term adaptation to the uneven protein distribution diet.

Adaptation, Physiological

The artificial beta cell (Biostator) in the adjustment of instable diabetics--results after 20 months.

In 55 poorly controlled insulin-dependent diabetics, we tried to discover criteria for an improvement of metabolism by means of the "artificial beta-cell" (Biostator). To this end, during the first 24 h of hospitalization, blood glucose was monitored continuously under conventional insulin therapy (monitoring period). Insulin requirement was determined during the next 24 h by the artificial beta-cell (feedback period). Corrections of diabetes regimen were made with reference to the insulin consumption during the feedback period and to the extent of the postprandial blood sugar increases and decreases during the monitoring period. The resulting new diabetes regimen led to a significant improvement of the daily blood sugar profiles.

Artificial Organs

Nutritive value of elemental formula with reduced osmolality.

The osmolality of an elemental formula was reduced from 627 to 338 mOsm/kg H2O by replacing dextrose with corn syrup solids, reducing the content of casein hydrolysate, and replacing a portion of the medium-chain triglycerides with corn oil. In three convalescent malnourished infants, the protein quality of the formula was compared at isonitrogenous levels with that of a casein-sucrose-vegetable oil formula and was found to be at least as high: in all three nitrogen retention was higher than during a preceding casein period, and in one of the three it was also higher than during a following casein period. The levels of postprandial plasma amino acids suggested that threonine might be the first-limiting amino acid. Four severely malnourished infants received the formula as their only food during initial rehabilitation. The formula was well tolerated and supported satisfactory weight gain, linear growth, and serum protein regeneration.

Evaluation Studies as Topic

[The effect of combined therapy with buformin and dichloracetate on blood lactate concentrations in diabetics].

In animals, dichloroacetate (DCA) which activates pyruvate dehydrogenase has been shown to diminish increased blood lactate concentrations due to biguanide treatment. In 10 maturity onset diabetics, therefore, the effect of a combined therapy with buformin and DCA (200 mg b.i.d.) was studied on blood lactate concentrations and compared with an analogous pre- and postinvestigation period of 6 days with buformin treatment alone (100 mg b.i.d.). Mean blood glucose concentrations remained the same during all 3 investigation periods. Also, neither fasting nor postprandially significant differences were found in blood lactate and ketones. In association with a standardized ergometer test, however, the rise in blood lactate was significantly smaller (p less than 0.05) while the patients were on buformin plus DCA, compared to the periods when only buformin was given. Furthermore, less ketone bodies appeared to be utilized by the exercising muscle under the influence of the combined treatment (p less than 0.05). These results are in good agreement with animal studies and suggest that DCA might be as effective in decreasing enhanced blood lactate concentrations in biguanide treated man as in animals.

Acetates

[Pancreatic atrophy: its effect on the plasma concentration of pancreatic polpeptide, gastrin and motilin in dogs].

One hour postprandial responses of plasma concentrations of pancreatic polypeptide, gastrin and motilin were detected in healthy dogs. Pancreatic atrophy was produced in these animals by obstructing their pancreatic juice flow. Basal hormone concentrations in four animals did not change significantly during 11 months of pancreatic atrophy. During this period the animals displayed a significant postprandial response. These preliminary results suggest that hormonal mechanisms involved in the digestive process are maintained during pancreatic atrophy.

Amylases

Experimental hypoglycemizing tumor of B-cells of Langerhans islets produced by the combined action of streptozotocin annd nicotinamide in the rat.

Young male and female Wistar-Velaz rats were treated with streptozotocin-nicotinamide combination according to the method of Rakieten and examined periodically for 23 months for fasting and postprandial glycemia, by intravenous, intraperitoneal or intragastric glucose tolerance and tolbutamide tests with the aim to detect in vivo the experimentally produced nesidiomas. One male rat with severe hypoglycemia, apparent first on tolbutamide test after twelve months, later also on glucose tolerance test and fasting hypoglycemia associated with paraplegia with macroscopically and microscopically documented nesidioma is described. The exstirpation of this nesidioma was followed first by normalization and later by development of latent diabetes.

Adenoma, Islet Cell

[Late hypoglycaemia in chemical diabetes. Abnormalities of pancreatic glucagon secretion and effect of pectine (author's transl)].

Nineteen patients suffering from chemical diabetes either with (group A, ten cases) or without (group B, nine cases) reactive hypoglycaemia were included in the study and compared with seven control (group C). The following variables were measured over a 5 hour period during a standard oral glucose tolerance test (OGTT): (i) blood glucose by continuous monitoring; (ii) plasma insulin and glucagon levels by radioimmunoassay. Furthermore, in five diabetics of group A, the data from the standard OGTT were compared with those from a pectin-supplemented OGTT (9 g per square meter of body surface). Although the insulin response was similar glucagon levels were significantly higher (45.1 +/- 11.8 pmol/l) (p less than 0.01) in group B than in group A (9.6 +/- 1.3) and C (8.1 +/- 1.4 at 30 minutes). The high glucagon levels noted in group B may explain the absence of reactive hypoglycaemia. The pectin supplementation improved the OGTT pattern by blunting the blood glucose peak (p less than 0.05), and avoiding the reactive hypoglycaemia (p less than 0.01). The addition of pectin did not produce any significant effect on the insulin response while a significant increase in glucagon concentrations (p less than 0.05) was observed beyond the 150th minute. Therefore, the data suggest that pectin may improve the OGTT pattern by increasing the glucagon response in the late period of the test. The development of postprandial reactive hypoglycaemia seldom coincides with a plasma glucagon peak, while the absence of reactive hypoglycaemia tends to be associated with high levels of glucagon, as is the case in overt diabetes mellitus.

Adult

Spontaneous recovery from streptozotocin-induced diabetes in rats pretreated with pertussis vaccine or hydrocortisone.

Following the intravenous injection of streptozotocin into rats, postprandial hyperglycaemia was sustained from 24 hours over a subsequent period of some weeks and the rats were glucose intolerant. When streptozotocin was similarly injected into pertussis-sensitized or hydrocortisone treated rats, the postprandial hyperglycaemia observed at 24 hours did not persist, but showed a progressive decline until near normoglycaemia was obtained a week later. These animals manifested normal glucose tolerance one week after streptozotocin. Thus, a spontaneous recovery from streptozotocin-induced diabetes occurred under these conditions. This spontaneous recovery from diabetes was associated with hyperinsulinaemia in the fed state.

Animals

Effect of diet on plasma aminograms of low birth weight infants.

The composition of nutrient mixtures for the low birth weight infant is a matter of considerable concern, and questions have been raised about the adequacy of the cystine and tyrosine contents of available preparations. Low birth weight infants were fed isonitrogenous isocaloric formulas whose content of tyrosine and cystine varied 3- and 7-fold, respectively, for 3-day periods in a Latin Square design. Two-hour postprandial plasma aminograms indicate a statistically significant difference (P = 0.05) between plasma cystine levels noted in infants fed the formula containing cystine at 6 mg/100 ml and those fed the formula containing cystine at 28 mg/100 ml. No significant differences were noted between other formula groupings. Plasma tyrosine concentrations were rapidly reduced whenever tyrosine intake was less then 50 mg/kg of body weight. Such a dietary approach may be of value in reduction of the elevated plasma tyrosine levels seen in infants with transient tyrosinemia of prematurity. Postprandial concentrations of plasma amino acids for the low birth weight infant are a useful reference standard for evaluation of the response of the low birth weight infant to new therapeutic feeding mixtures, particularly parental or jejunal feedings.

Amino Acids

[Therapy of chronic postprandia dyspepsia. Crossed double-blind study with Domperidon (Motilium)].

In a double-blind cross-over study over eight weeks two groups of 24 patients each with symptoms of chronic postprandial dyspepsia received during the first four-week period either 10 mg domperidon t.i.d. or placebo. After four weeks the medication was exchanged. Despite some improvement of symptoms under placebo, statistical analysis revealed a significantly higher improvement rate after domperidon.

Adolescent

Effect of proximal gastric vagotomy on gastric acid hypersecretion and hypergastrinemia after massive small bowel resection in dogs.

Fasting and postprandial gastric acid secretion and gastrin were determined in Heidenhain pouch dogs before (C) and after (R) massive enterectomy (five dogs) and after additional proximal gastric vagotomy (PGV) in three dogs. Basal acid output was unchanged (C = 7 +/- 2 microneq/hour; R = 11 +/- 4 microneq/hour), but postprandially the hourly (third through eighth hour) and cumulative acid outputs (C = 3.6 +/- 0.3 mEq/8 hour; R = 7.2 +/- 0.4 MEq/8 hour) were significantly increased by resection (P less than 0.001). Similarly, fasting gastrin was unaltered by resection (C = 41 +/- 2 pg/ml; R = 46 +/- 8 pg/ml), whereas hourly gastrin concentrations significantly (P less than 0.05) exceeded control values. Increased gastrin correlated linearly (P less than 0.02) with increased acid output. After PGV, basal acid levels remained unchanged (R = 4 +/- 2 micronEq/hour; PGV = 9 +/- 4 micronEq/hour), but postprandial acid output significantly exceeded prevagotomy values at all time periods (P less than 0.05). Cumulative acid output also was increased (R = 6.8 +/- 0.6 MEq/8 hour; PGV = 11.2 +/- 0.6 mEq/8 hour; P less than 0.001). Serum gastrin, however, remained unchanged. Hypersecretion of acid from Heidenhain pouches after massive enterectomy is increased further by PGV without a concomitant increase in serum gastrin.

Animals

Serum bile acids after a test meal in Crohn's disease.

The serum levels of conjugated cholic and chenodeoxycholic acid have been studied before and during a 4 h period after the intake of a liquid test meal in seven control subjects and in fourteen patients with Crohn's disease. The concentrations of serum bile acids were determined by radioimmunoassay. The control group showed a postprandial increase of both conjugates with a return to the fasting level for cholic acid within 4 h. The chenodeoxycholic acid conjugate did not return to the fasting level within the test period. The serum bile acid concentration in Crohn's disease divided the patients in two groups; one group with decreased or normal fasting levels and low postprandial increase and another group with elevated fasting levels and a postprandial increase without return to the fasting levels within the test period.

Adolescent

Improved metabolic profiles in insulin-treated diabetic patients given an alpha-glucosidehydrolase inhibitor.

An alpha-glucosidehydrolase inhibitor (acarbose; BAY g 5421) taken with food was compared with dummy tablets in seven insulin-treated diabetic patients over eight-hour periods that included breakfast, lunch, and two snacks. Acarbose diminished the postprandial increases in blood glucose, lactate, and pyruvate concentrations and may therefore be of value in the management of insulin-dependent diabetes.

Administration, Oral