Ivana R. Sequeira

Standardising the lactulose mannitol test of gut permeability to minimise error and promote comparability.

Background Lactulose mannitol ratio tests are clinically useful for assessing disorders characterised by changes in gut permeability and for assessing mixing in the intestinal lumen. Variations between currently used test protocols preclude meaningful comparisons between studies. We determined the optimal sampling period and related this to intestinal residence. Methods Half-hourly lactulose and mannitol urinary excretions were determined over 6 hours in 40 healthy female volunteers after administration of either 600 mg aspirin or placebo, in randomised order at weekly intervals. Gastric and small intestinal transit times were assessed by the SmartPill in 6 subjects from the same population. Half-hourly percentage recoveries of lactulose and mannitol were grouped on a basis of compartment transit time. The rate of increase or decrease of each sugar within each group was explored by simple linear regression to assess the optimal period of sampling. Key Results The between subject standard errors for each half-hourly lactulose and mannitol excretion were lowest, the correlation of the quantity of each sugar excreted with time was optimal and the difference between the two sugars in this temporal relationship maximal during the period from 2½-4 h after ingestion. Half-hourly lactulose excretions were generally increased after dosage with aspirin whilst those of mannitol were unchanged as was the temporal pattern and period of lowest between subject standard error for both sugars. Conclusion The results indicate that between subject variation in the percentage excretion of the two sugars would be minimised and the differences in the temporal patterns of excretion would be maximised if the period of collection of urine used in clinical tests of small intestinal permeability were restricted to 2½-4 h post dosage. This period corresponds to a period when the column of digesta column containing the probes is passing from the small to the large intestine.

The effect of aspirin and smoking on urinary excretion profiles of lactulose and mannitol in young women: toward a dynamic, aspirin augmented, test of gut mucosal permeability.

Background  We explored the temporal dynamics of the lactulose mannitol test and the influence of a single dose of aspirin.

Prevalence of Pre-Diabetes across Ethnicities: A Review of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) for Classification of Dysglycaemia

Prediabetes can be defined by the presence of impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), or glycated haemoglobin (HbA1c) to identify individuals at increased risk of developing type 2 diabetes (T2D). The World Health Organization (WHO, 1999) and the American Diabetes Association (ADA, 2003) utilise different cut-off values for IFG (WHO: 6.1–6.9 mmol/L; ADA: 5.6–6.9 mmol/L) but the same cut-off values for IGT (7.8–11.0 mmol/L). This review investigates whether there are differences in prevalence of IFG, IGT, and combined IFG&IGT between ethnicities, in particular Asian Chinese and European Caucasians. In total, we identified 19 studies using the WHO1999 classification, for which the average proportional prevalence for isolated (i)-IFG, i-IGT, and combined IFG&IGT were 43.9%, 41.0%, and 13.5%, respectively, for Caucasian and 29.2%, 49.4%, and 18.2%, respectively, for Asian. For the 14 studies using ADA2003 classification, the average proportional i-IFG, i-IGT, and combined IFG&IGT prevalences were 58.0%, 20.3%, and 19.8%, respectively, for Caucasian; 48.1%, 27.7%, and 20.5%, respectively, for Asian. Whilst not statistically different, there may be clinically relevant differences in the two populations, with our observations for both classifications indicating that prevalence of i-IFG is higher in Caucasian cohorts whilst i-IGT and combined IFG&IGT are both higher in Asian cohorts.

Differential trafficking of saccharidic probes following aspirin in clinical tests of intestinal permeability in young healthy women

The effects of inflammatory changes on the absorption of different‐sized probes and their permeability ratios are poorly understood. The aim of the present study was to determine the effects of a pharmacological agent on the permeability of the gut mucosa to saccharidic probes of larger and smaller molecular weight. Permeability was assessed by half‐hourly urinary excretion of a combined dose of d‐mannitol, l‐rhamnose and lactulose following consumption of a single 600 mg dose of aspirin and compared with a placebo in a cross‐over study in 20 healthy female volunteers. The temporal patterns of excretion of all probes were bimodal, being best fitted by polynomial functions. The relatively small early peak was evident for at least 4 h for smaller sugars, but was less evident with lactulose, being overshadowed by a larger second peak. These conclusions were further supported by separate analyses of the segments of the temporal plots between 2.5 and 4 h and between 4.5 and 6 h. The forms of these curves did not change significantly following dosing with aspirin. A greater proportion of the total dose of mannitol than rhamnose was excreted over the collection period. Following the consumption of aspirin, the cumulative rate of excretion of the smaller sugars (i.e. mannitol and rhamnose) was significantly reduced whereas that of lactulose was increased over the 6 h collection period. Aspirin has opposite effects on the absorption of larger and smaller probes, influencing the outcome of the test. These results have important consequences for the design and comparison of clinical tests of permeability.

Assessment of the Effect of Intestinal Permeability Probes (Lactulose And Mannitol) and Other Liquids on Digesta Residence Times in Various Segments of the Gut Determined by Wireless Motility Capsule: A Randomised Controlled Trial.

Background Whilst the use of the mannitol/lactulose test for intestinal permeability has been long established it is not known whether the doses of these sugars modify transit time Similarly it is not known whether substances such as aspirin that are known to increase intestinal permeability to lactulose and mannitol and those such as ascorbic acid which are stated to be beneficial to gastrointestinal health also influence intestinal transit time. Methods Gastric and intestinal transit times were determined with a SmartPill following consumption of either a lactulose mannitol solution, a solution containing 600 mg aspirin, a solution containing 500 mg of ascorbic acid or an extract of blackcurrant, and compared by doubly repeated measures ANOVA with those following consumption of the same volume of a control in a cross-over study in six healthy female volunteers. The dominant frequencies of cyclic variations in gastric pressure recorded by the Smartpill were determined by fast Fourier transforms. Results The gastric transit times of lactulose mannitol solutions, of aspirin solutions and of blackcurrant juice did not differ from those of the control. The gastric transit times of the ascorbic acid solutions were significantly shorter than those of the other solutions. There were no significant differences between the various solutions either in the total small intestinal or colonic transit times. The intraluminal pHs during the initial quartiles of the small intestinal transit times were lower than those in the succeeding quartiles. This pattern did not vary with the solution that was consumed. The power of the frequencies of cyclic variation in intragastric pressure recorded by the Smartpill declined exponentially with increase in frequency and did not peak at the reported physiological frequencies of gastric contractile activity. Conclusions Whilst the segmental residence times were broadly similar to those using other methods, the high degree of variation between subjects generally precluded the identification of all but gross variation between treatments. The lack of any differences between treatments in either total small or large intestinal transit times indicates that the solutions administered in the lactulose mannitol test of permeability had no consistent influence on the temporal pattern of absorption. The negatively exponential profile and lack of any peaks in the frequency spectra of cyclic variation in gastric intraluminal pressure that were consistent with reported physiological frequencies of contractile activity profile suggests that the principal source of this variation is stochastic likely resulting from the effects of external events occasioned by normal daily activities on intra-abdominal pressure. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12615000596505

Unfolding Novel Mechanisms of Polyphenol Flavonoids for Better Glycaemic Control: Targeting Pancreatic Islet Amyloid Polypeptide (IAPP)

Type 2 diabetes (T2D) is characterised by hyperglycaemia resulting from defective insulin secretion, insulin resistance, or both. The impact of over-nutrition and reduced physical activity, evidenced by the exponential rise in obesity and the prevalence of T2D, strongly supports the implementation of lifestyle modification programs. Accordingly, an increased consumption of fruits and plant-derived foods has been advocated, as their intake is inversely correlated with T2D prevalence; this has been attributed, in part, to their contained polyphenolic compounds. Over the last decade, a body of work has focussed on establishing the mechanisms by which polyphenolic compounds exert beneficial effects to limit carbohydrate digestion, enhance insulin-mediated glucose uptake, down-regulate hepatic gluconeogenesis and decrease oxidative stress; the latter anti-oxidative property being the most documented. Novel effects on the inhibition of glucocorticoid action and the suppression of amylin misfolding and aggregation have been identified more recently. Amyloid fibrils form from spontaneously misfolded amylin, depositing in islet cells to elicit apoptosis, beta cell degeneration and decrease insulin secretion, with amyloidosis affecting up to 80% of pancreatic islet cells in T2D. Therefore, intervening with polyphenolic compounds offers a novel approach to suppressing risk or progression to T2D. This review gives an update on the emerging mechanisms related to dietary polyphenol intake for the maintenance of glycaemic control and the prevention of T2D.

Ascorbic Acid may Exacerbate Aspirin‐Induced Increase in Intestinal Permeability

Ascorbic acid in combination with aspirin has been used to prevent aspirin‐induced oxidative GI damage. We aimed to determine whether ascorbic acid reduces or prevents aspirin‐induced changes in intestinal permeability over a 6‐hr period using saccharidic probes mannitol and lactulose. The effects of administration of 600 mg aspirin alone, 500 mg ascorbic acid alone and simultaneous dosage of both agents were compared in a cross‐over study in 28 healthy female volunteers. These effects were also compared with that of a placebo. The ability of ascorbic acid to mitigate the effects of aspirin when administered either half an hour before or after dosage with aspirin was also assessed in 19 healthy female volunteers. The excretion of lactulose over the 6‐hr period was augmented after consumption of either aspirin or ascorbic acid compared with that after consumption of placebo. Dosage with ascorbic acid alone augmented the excretion of lactulose more than did aspirin alone. Simultaneous dosage with both agents augmented the excretion of lactulose in an additive manner. The timing of dosage with ascorbic acid in relation to that with aspirin had no significant effect on the excretion of the two sugars. These findings indicate that ascorbic acid does not prevent aspirin‐induced increase in gut permeability rather that both agents augment it to a similar extent. The additive effect on simultaneous dosage with both agents in augmenting the absorption of lactulose suggests that each influences paracellular permeability by different pathways.

Mucosal permeability testing: response.

To the Editors We concur with the view of the correspondents that the lactulose mannitol ratio (LMR) is a useful parameter for the clinical assessment of gut permeability. However, their letter appears to misquote our work in that they mention only mannitol rather than lactulose and mannitol. This statement is founded on the need to distinguish the effects of the two variables that contribute to the LMR if we are to increase its sensitivity. The use of the LMR was originally founded on the premise thatmannitolwouldbeabsorbed inproportion to the number of enterocytes in the absorbing segment and hence enable comparisons between subjects with gut components of differing surface area. However, the use of a ratio as a surface standardized index of permeability to larger probes canonlybe as strong as the invariance of the denominator. As the correspondents point out, the levels of excretion of mannitol are variant in this respect. Moreover, the publishedwork suggested, and subsequent work (currently in submission) further confirms, that the rate of excretion of mannitol peaks at 2 h in contrast to that of lactulose which remains relatively constant over 6 h. Hence, mannitol excretion could differently confound the LMR when it is determined from urine collected over a single 2 h or a 3 h period. Furthermore, when the test is carried out after a single dose of aspirin, an agent that is known to influence small intestinal permeability, the excretion of lactulose is increased while that of mannitol is decreased, with the timings of the peaks unaffected. Hence, mucosal disruption or inflammation is likely to increase the magnitude of the effect of mannitol in confounding the ratio. We repeated the sameworkusing rhamnose andobtained the same effects. Our opinion is that the fidelity of the test, and comparability with other tests taken over the same time periods, will be increased if due regard is paid to any temporal variation in excretion of both sugars. Hence, the test should quantify the excretion of the two sugars over a minimum of two time intervals so as to allow the relative temporal variation in each to be assessed. A suitably standardized test using this data could increase sensitivity and thus be more likely to detect subjects with borderline disturbances of intestinal permeability.