Personalized computational model quantifies heterogeneity in postprandial responses to oral glucose challenge.

Plasma glucose and insulin responses following an oral glucose challenge are representative of glucose tolerance and insulin resistance, key indicators of type 2 diabetes mellitus pathophysiology. A large heterogeneity in individuals' challenge test responses has been shown to underlie the effectiveness of lifestyle intervention. Currently, this heterogeneity is overlooked due to a lack of methods to quantify the interconnected dynamics in the glucose and insulin time-courses. Here, a physiology-based mathematical model of the human glucose-insulin system is personalized to elucidate the heterogeneity in individuals' responses using a large population of overweight/obese individuals (n = 738) from the DIOGenes study. The personalized models are derived from population level models through a systematic parameter selection pipeline that may be generalized to other biological systems. The resulting personalized models showed a 4-5 fold decrease in discrepancy between measurements and model simulation compared to population level. The estimated model parameters capture relevant features of individuals' metabolic health such as gastric emptying, endogenous insulin secretion and insulin dependent glucose disposal into tissues, with the latter also showing a significant association with the Insulinogenic index and the Matsuda insulin sensitivity index, respectively.

N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis.

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo, we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.

Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.

Insulin secretion and action and the response of endogenous glucose production to a lack of glucagon suppression in nondiabetic subjects.

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and endogenous glucose production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (nonsuppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50-g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose, and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to nonsuppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight, and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action.NEW & NOTEWORTHY In prediabetes, anthropometric characteristics as well as insulin action do not alter the hepatic response to glucagon. The postprandial suppression or lack of suppression of glucagon secretion is an important factor governing postprandial glucose tolerance independent of insulin secretion.

Effects of Totum-63 on glucose homeostasis and postprandial glycemia: a translational study.

Global prevalence of type 2 diabetes (T2D) is rising and may affect 700 million people by 2045. Totum-63 is a polyphenol-rich natural composition developed to reduce the risk of T2D. We first investigated the effects of Totum-63 supplementation in high-fat diet (HFD)-fed mice for up to 16 wk and thereafter assessed its safety and efficacy (2.5 g or 5 g per day) in 14 overweight men [mean age 51.5 yr, body mass index (BMI) 27.6 kg·m-2] for 4 wk. In HFD-fed mice, Totum-63 reduced body weight and fat mass gain, whereas lean mass was unchanged. Moreover, fecal energy excretion was higher in Totum-63-supplemented mice, suggesting a reduction of calorie absorption in the digestive tract. In the gut, metagenomic analyses of fecal microbiota revealed a partial restoration of HFD-induced microbial imbalance, as shown by principal coordinate analysis of microbiota composition. HFD-induced increase in HOMA-IR score was delayed in supplemented mice, and insulin response to an oral glucose tolerance test was significantly reduced, suggesting that Totum-63 may prevent HFD-related impairments in glucose homeostasis. Interestingly, these improvements could be linked to restored insulin signaling in subcutaneous adipose tissue and soleus muscle. In the liver, HFD-induced steatosis was reduced by 40% (as shown by triglyceride content). In the subsequent study in men, Totum-63 (5 g·day-1) improved glucose and insulin responses to a high-carbohydrate breakfast test (84% kcal carbohydrates). It was well tolerated, with no clinically significant adverse events reported. Collectively, these data suggest that Totum-63 could improve glucose homeostasis in both HFD-fed mice and overweight individuals, presumably through a multitargeted action on different metabolic organs.NEW & NOTEWORTHY Totum-63 is a novel polyphenol-rich natural composition developed to reduce the risk of T2D. Totum-63 showed beneficial effects on glucose homeostasis in HFD-fed mice, presumably through a multitargeted action on different metabolic organs. Totum-63 was well tolerated in humans and improved postprandial glucose and insulin responses to a high-carbohydrate breakfast test.

Daily mycoprotein consumption for 1 week does not affect insulin sensitivity or glycaemic control but modulates the plasma lipidome in healthy adults: a randomised controlled trial.

Mycoprotein consumption has been shown to improve acute postprandial glycaemic control and decrease circulating cholesterol concentrations. We investigated the impact of incorporating mycoprotein into the diet on insulin sensitivity (IS), glycaemic control and plasma lipoprotein composition. Twenty healthy adults participated in a randomised, parallel-group trial in which they consumed a 7 d fully controlled diet where lunch and dinner contained either meat/fish (control group, CON) or mycoprotein (MYC) as the primary source of dietary protein. Oral glucose tolerance tests were performed pre- and post-intervention, and 24 h continuous blood glucose monitoring was applied throughout. Fasting plasma samples were obtained pre- and post-intervention and were analysed using quantitative, targeted NMR-based metabonomics. There were no changes within or between groups in blood glucose or serum insulin responses, nor in IS or 24 h glycaemic profiles. No differences between groups were found for 171 of the 224 metabonomic targets. Forty-five lipid concentrations of different lipoprotein fractions (VLDL, LDL, intermediate-density lipoprotein and HDL) remained unchanged in CON but showed a coordinated decrease (7-27 %; all P < 0·05) in MYC. Total plasma cholesterol, free cholesterol, LDL-cholesterol, HDL2-cholesterol, DHA and n-3 fatty acids decreased to a larger degree in MYC (14-19 %) compared with CON (3-11 %; P < 0·05). Substituting meat/fish for mycoprotein twice daily for 1 week did not modulate whole-body IS or glycaemic control but resulted in changes to plasma lipid composition, the latter primarily consisting of a coordinated reduction in circulating cholesterol-containing lipoproteins.

The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial.

AIMS/HYPOTHESIS: Treatment of diabetes secondary to total pancreatectomy remains a challenge and insulin constitutes the only glucose-lowering treatment for these patients. We hypothesised that the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide would improve postprandial glucose tolerance in totally pancreatectomised patients. METHODS: In a double-blinded, randomised, crossover study, 12 totally pancreatectomised individuals (age: 65.0 ± 9.5 mean±SD years; BMI: 22.9 ± 3.9 kg/m2) and 12 healthy control individuals (age 66.1 ± 7.6 years; BMI: 24.0 ± 2.9 kg/m2) underwent two 3 h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20 µg of lixisenatide or placebo. Basal insulin was given the night before each experimental day; no insulin was given during study days. RESULTS: Compared with placebo, lixisenatide reduced postprandial plasma glucose excursions in the pancreatectomy group (baseline-subtracted AUC [bsAUC] [mean±SEM]: 548 ± 125 vs 1447 ± 95 mmol/l × min, p < 0.001) and in the control group (-126 ± 12 vs 222 ± 51 mmol/l × min, p < 0.001). In the pancreatectomy group a mean peak glucose concentration of 23.3 ± 1.0 mmol/l was reached at time point 134 ± 11 min with placebo, compared with a mean peak glucose concentration of 18 ± 1.4 mmol/l (p = 0.008) at time point 148 ± 13 min (p = 0.375) with lixisenatide. In the control group a mean peak concentration of 8.2 ± 0.4 mmol/l was reached at time point 70 ± 13 min with placebo, compared with a mean peak concentration of 5.5 ± 0.1 mmol/l (p < 0.001) at time point 8 ± 25 min (p = 0.054) with lixisenatide. Lixisenatide also reduced gastric emptying and postprandial glucagon responses in the pancreatectomy group (66 ± 84 vs 1190 ± 311 pmol/l × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100 pmol/l × min, p = 0.034). In the pancreatectomy group, C-peptide was undetectable in plasma. In the control group, postprandial plasma C-peptide responses were reduced with lixisenatide (18 ± 17 vs 189 ± 31 nmol/l × min, p < 0.001). CONCLUSIONS/INTERPRETATION: The GLP-1 receptor agonist lixisenatide reduces postprandial plasma glucose excursions in totally pancreatectomised patients. The mode of action seems to involve deceleration of gastric emptying and reduced postprandial responses of gut-derived glucagon. TRIAL REGISTRATION: ClinicalTrials.gov NCT02640118. FUNDING: This study was funded by an unrestricted investigator-initiated study grant from Sanofi. Support was also received from from the Novo Nordisk Foundation Center for Basic Metabolic Research, the A.P. Møller Foundation for the Advancement of Medical Science and the Faculty of Health and Medical Sciences, University of Copenhagen.

Production, safety, health effects and applications of diacylglycerol functional oil in food systems: a review.

Diacylglycerol (DAG) is a world leading anti-obesity functional cooking oil synthesized via structural modification of conventional fats and oils. DAG exits in three stereoisomers namely sn-1,2-DAG, sn-1,3-DAG, and sn-2,3-DAG. DAG particularly sn-1,3-DAG demonstrated to have the potential in suppressing body fat accumulation and lowering postprandial serum triacylglycerol, cholesterol and glucose level. DAG also showed to improve bone health. This is attributed to DAG structure itself that caused it to absorb and digest via different metabolic pathway than conventional fats and oils. With its purported health benefits, many studies attempt to enzymatically or chemically synthesis DAG through various routes. DAG has also received wide attention as low calorie fat substitute and has been incorporated into various food matrixes. Despite being claimed as healthy cooking oil the safety of DAG still remained uncertain. DAG was banned from sale as it was found to contain probable carcinogen glycidol fatty acid esters. The article aims to provide a comprehensive and latest review of DAG emphasizing on its structure and properties, safety and regulation, process developments, metabolism and beneficial health attributes as well as its applications in the food industry.

Effects of dietary fat quality on metabolic endotoxaemia: a systematic review.

In this systematic review, we critically evaluated human clinical trials that assessed the effects of dietary fat quality on metabolic endotoxaemia. The studies were selected from three databases (PubMed, Scopus and Cochrane Library), and the keywords were defined according to the Medical Subject Headings indexing terminology. Two authors searched independently, according to the pre-defined selection criteria. Quality and risk assessment of bias for each selected study were also evaluated. The results of the included studies demonstrated associations between higher SFA intake and increased postprandial lipopolysaccharide (LPS) concentrations. On the other hand, after the consumption of PUFA, bloodstream LPS concentrations were lower. However, in none of the long-term studies, the consumption of dietary fats did not seem to exert effects on LPS concentration. Hence, SFA seem to act as a risk factor for transient increase in endotoxaemia, while PUFA demonstrated exerting a protective effect. Taken together, the evidence suggests that the dietary fatty acid profile may influence bloodstream endotoxin concentrations through modulation of factors such LPS clearance, alkaline phosphatase activity, bile acid metabolism, intestinal permeability and intestinal microbiota composition.

The effect of postprandial glycaemia on cognitive function: a randomised crossover trial.

The effect on cognitive test scores of generating differences in postprandial glycaemia using test foods or beverages has been inconsistent. Methodological issues may account for some of the variable results requiring further investigation using strong study designs into the relationship between glycaemia and cognitive functioning. The objective of this study was to determine the effects of postprandial glycaemia on cognitive function by examining cognition after consumption of foods that differ only by the rate of digestion of available carbohydrate in a population of young adults. In a double-blind, randomised, crossover trial, sixty-five participants received trifle sweetened either with a higher-glycaemic index (GI) sugar (sucrose; GI 65) or a lower-GI sugar (isomaltulose; GI 34). Cognitive tests were completed prior to trifle consumption, and 60 and 120 min after. There was no between-trifle difference at 60 min in performance on free word recall (0·0 (95 % CI -0·6, 0·5)), short delay word recall (0·0 (95 % CI -0·5, 0·5)), long delay word recall (0·0 (95 % CI -0·6, 0·6)), letter-number sequence recall (0·3 (95 % CI - 0·2, 0·7)) and visuo-spatial recall (-0·2 (95 % CI -0·6, 0·2)) tests. At 120 min, no difference was detected in any of these tests. The participants performed 7·7 (95 % CI 0·5,14·9) s faster in Reitan's trail-making test B 60 min after the higher-GI trifle than the lower-GI trifle (P = 0·037). Our findings of a null effect on memory are generally consistent with other works in which blinding and robust control for confounding have been used.

Prevention of postprandial hypotension-related syncope by caffeine in a patient with long-standing diabetes mellitus.

A 74-year-old man who had type 2 diabetes mellitus of a duration of 20 years was admitted for syncope after eating a high carbohydrate meal. Although he had had episodes of pallor or syncope after carbohydrate-rich meals, such as with large amounts of white rice, several times within a year and he had been taken to hospitals emergently, the etiology of these episodes had remained unclear despite his undergoing several studies. Studies did show severe orthostatic hypotension during the head-up tilt test and a decrease in the coefficient of variation of the R-R interval (CVR-R) on resting electrocardiogram, suggesting severe autonomic nervous dysfunction. Because of the episodes of syncope after eating a carbohydrate-rich meal, we investigated whether he had postprandial hypotension (PPH). The 75 g oral glucose tolerance test revealed a significant decrease in his postprandial blood pressure by about 40 mmHg, leading to the diagnosis of PPH. The carbohydrate-rich meal test induced syncope with systolic blood pressure under 40 mmHg. Then 150 mg caffeine was administered before a second carbohydrate-rich meal. The marked decline in postprandial blood pressure was suppressed and plasma noradrenaline levels were gradually increased over a period of 60 minutes. Caffeine could be useful for prevention of postprandial hypotension-related syncope.

Glucomannan Inhibits Rice Gruel-Induced Increases in Plasma Glucose and Insulin Levels.

OBJECTIVE: Given the association between diabetes suppression and inhibition of diet-induced elevation in glucose and insulin, we investigated the effects of adding glucomannan to rice gruel on pre- and postprandial glucose and insulin concentrations. METHODS: A total of 25 Japanese subjects without a history of diabetes or gastrointestinal disease (all males; aged 37-60 years; body mass index 20.4-31.6) participated in this study. Subjects received a 75-g oral glucose tolerance test (75gOGTT) and rice gruel containing 0, 0.4, or 0.8% of glucomannan. Blood samples were then obtained at preload and at 30, 60, and 120 min after receiving 75 g of glucose or rice gruel with or without glucomannan. RESULTS: After the 75gOGTT, 8 subjects had normal glucose tolerance (NGT), whereas 17 showed a borderline pattern. Moreover, our data showed that greater amounts of glucomannan promoted lesser 30-min postload plasma glucose and insulin levels, with differences being larger in the borderline group than in the NGT group. CONCLUSIONS: Glucomannan dose-dependently inhibited the rice gruel-induced increase in 30-min postprandial plasma glucose and insulin levels. Furthermore, greater inhibitory effects on glucose and insulin elevation were observed in the borderline group than in the NGT group.

Fucus vesiculosus and Ascophyllum nodosum Ameliorate Liver Function by Reducing Diet-Induced Steatosis in Rats.

The Asian coastal communities have used the brown seaweeds Fucus vesiculosus and Ascophyllum nodosum since ancient times. Recently, some in vitro and in vivo studies have demonstrated their abilities in reducing risk factors for metabolic syndrome. Here, we analyzed the protective effect of a phytocomplex extracted from these seaweeds on the deposition of fat in the liver after the administration of a high-fat diet (HFD) to rats for five weeks. The administration of F. vesiculosus and A. nodosum led to significant reductions in microvescicular steatosis and plasma biochemical and lipid parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total and conjugated bilirubin, and triglycerides. Furthermore, the postprandial glycemic peak was delayed and significantly reduced (p < 0.01) by the algal extract administration. In conclusion, this extract is effective in reducing microvescicular steatosis and improving glycemic control, thereby lowering the risk of nonalcoholic fatty liver disease, obesity, and diabetes, diseases related to the consumption of fat and sugar-enriched diets.

Free Fatty Acid-Induced Peptide YY Expression Is Dependent on TG Synthesis Rate and Xbp1 Splicing.

Gut-derived satiety hormones provide negative feedback to suppress food intake and maintain metabolic function in peripheral tissues. Despite the wealth of knowledge of the systemic effects of these hormones, very little is known concerning the mechanisms by which nutrients, such as dietary fats, can promote the expression of genes involved in L-cell hormone production. We have tested the role of various dietary fats and found that after hydrolysis into free fatty acids (FFA's), there is a differential response in the extent to which they induce PYY gene and protein production. The effect of FFA's also seems to relate to triglyceride (TG) re-esterification rate, with MUFA re-esterifying faster with lower PYY production. We have also found that there are differences in potency of FFA's based on their desaturation patterns in vitro. The potency effect of FFA's is influenced by the rate of TG re-esterification, such that the longer FFA's are in contact with L-cells, the more PYY they produce. We found that chronic consumption of high-fat diets enables the small intestine to re-esterify FFA's into TG faster and earlier which resulted in a blunted postprandial PYY response. Lastly, we found that FFA's induce X-box-binding protein-1 activation (Xbp1s) in L-cells and that adenoviral delivery of Xbp1s was sufficient to induce PYY gene expression. Taken together, the present work indicates that dietary fat can induce satiety, in part, prior to re-esterification. Chronic high-fat diet consumption increases the rate of re-esterification which diminishes satiety and may lead to increased food intake. Targeting intestinal TG synthesis may prove beneficial in restoring obesity-associated reductions in postprandial satiety.

Inhibition of glycosidase by ursolic acid: in vitro, in vivo and in silico study.

BACKGROUND: Controlling the blood glucose level is an effective method to reduce type 2 diabetes and prevent diabetes-related complications. Ursolic acid is a plant extract that can reduce postprandial hyperglycemia effectively. This study aimed to explore the inhibitory effect and interaction mechanism of ursolic acid against α-amylase and α-glucosidase. RESULTS: In this study, the effect of ursolic acid on glycosidase was studied in vitro, in vivo, and in silico. The half-maximal inhibitory concentration (IC50 ) of ursolic acid on α-amylase and α-glucosidase was 0.482 ± 0.12 mg mL-1 and 0.213 ± 0.042 mg mL-1 , respectively. The results of enzymatic kinetics showed that ursolic acid inhibited α-amylase and α-glucosidase activity in a non-competitive manner. The fluorescence spectrum showed that the combination of ursolic acid and glycosidase caused the intrinsic fluorescence quenching of glycosidase. The observation of starch granules revealed that the activity of α-amylase was inhibited and the hydrolysis of starch granules was prevented in the presence of ursolic acid. Molecular docking results showed that ursolic acid bound to the inactive site of α-amylase and α-glucosidase through the formation of ursolic acid-glucosidase complex. Ursolic acid interacted with α-amylase and α-glucosidase mainly through hydrogen bonding. The postprandial hypoglycemic effect of ursolic acid in C57BL/6J mice showed that the high concentration of ursolic acid could quickly reduce postprandial blood glucose level. CONCLUSION: Ursolic acid can be considered as a natural ingredient in functional foods to control postprandial blood glucose levels and prevent diabetes by delaying the digestion of starch in foods. © 2019 Society of Chemical Industry.

Dietary protein affects both the dose and pattern of insulin delivery required to achieve postprandial euglycaemia in Type 1 diabetes: a randomized trial.

AIM: To quantify the insulin requirement for a high-protein meal compared with a low-protein meal, controlling for carbohydrate and fat content. METHODS: In this crossover study, young people with Type 1 diabetes were randomized to consume a high- (60 g) or low-protein meal (5 g), each containing 30 g carbohydrate and 8 g fat. A variation of the insulin clamp technique was used to determine the insulin requirements to maintain euglycaemia for the following 5 h. RESULTS: A total of 11 participants (mean ± sd age 16.5 ± 2.7 years, HbA1c 52 ± 8.7 mmol/mol [6.9 ± 0.8%], diabetes duration 6.9±5.1 years) completed the study. The mean insulin requirements for the high-protein meal were higher than for the low-protein meal [10.3 (CI 8.2, 12.57) vs 6.7 units (CI 4.7, 8.8); P=0.001], with inter-individual requirements ranging from 0.9 to six times the low-protein meal requirement. Approximately half the additional insulin [1.1 units/h (CI 0.5, 1.8; P=0.001)] was given in the first 2 h, compared with an additional 0.5 units/h (CI -0.2, 1.2; P=0.148) in the second 2 h and 0.1 units (CI -0.6, 0.8; P=0.769) in the final hour. CONCLUSIONS: A high-protein meal requires ~50% more insulin to maintain euglycaemia than a low-protein meal that contains the same quantity of carbohydrate. The majority is required within the first 2 h. Inter-individual differences exist in insulin requirements for dietary protein.

Mealtime fast-acting insulin aspart versus insulin aspart for controlling postprandial hyperglycaemia in people with insulin-resistant Type 2 diabetes.

AIM: This post hoc analysis explored whether mealtime fast-acting insulin aspart treatment provided an advantage in postprandial plasma glucose (PPG) control vs. insulin aspart in people with Type 2 diabetes receiving high doses of bolus insulin. METHODS: A post hoc, post-randomization, subgroup analysis of a 26-week, randomized, double-blind, treat-to-target trial (onset 2) that compared mealtime fast-acting insulin aspart vs. mealtime insulin aspart, both in a basal-bolus regimen, in people with Type 2 diabetes uncontrolled on basal insulin therapy and metformin. At the end of trial, the impact of fast-acting insulin aspart and insulin aspart on PPG control was assessed with a standard liquid meal test and participants were grouped into three post-randomization subgroups: meal test bolus insulin dose ≤ 10 units per dose (n = 171), > 10-20 units per dose (n = 289) and > 20 units per dose (n = 146). RESULTS: A statistically significant treatment difference in favour of fast-acting insulin aspart vs. insulin aspart was observed for the change in PPG increment at all post-meal time points (from 1 to 4 h) for those in the > 20 units bolus insulin subgroup. There was no difference in the magnitude of change from baseline in HbA1c level between fast-acting insulin aspart and insulin aspart in any of the bolus insulin dose subgroups (data herein). CONCLUSION: Fast-acting insulin aspart may hold promise as a more effective treatment compared with insulin aspart for controlling PPG in people with insulin-resistant Type 2 diabetes.

Effect of a single dose of insulin glargine/lixisenatide fixed ratio combination (iGlarLixi) on postprandial glucodynamic response in Japanese patients with type 2 diabetes mellitus: A phase I randomized trial.

This report describes novel clinical data assessing the pharmacodynamics of insulin glargine/lixisenatide (iGlarLixi) compared with placebo and insulin glargine alone, to determine pharmacokinetics of lixisenatide, and to assess safety of iGlarLixi in Japanese people with type 2 diabetes mellitus (T2DM). In a single-centre, open-label, randomized, placebo-controlled cross-over study, participants received subcutaneous iGlarLixi 5 U/5 µg and 10 U/10 µg, placebo, and 5 U insulin glargine. The primary endpoint was area under the postprandial plasma glucose (PPG) curve (AUC0-2h ). A total of 20 participants completed all study periods. iGlarLixi 5 U/5 µg and 10 U/10 µg reduced mean PPG dose-dependently compared with placebo and insulin glargine 5 U. Both combinations significantly reduced PPG-AUC0-2h dose-dependently compared with placebo (least squares mean difference -7.48 mmol h/L for 5 U/5 µg, -10.75 mmol h/L for 10 U/10 µg; P < 0.0001). iGlarLixi 5 U/5 µg reduced PPG-AUC0-2h significantly compared with insulin glargine 5 U (-0.76 mmol h/L; P < 0.0001). No symptomatic hypoglycaemia occurred during the study. iGlarLixi single subcutaneous injections significantly and dose-dependently reduced PPG compared to placebo or insulin glargine in Japanese participants with T2DM. iGlarLixi was safe and well tolerated, and would be expected to provide the 24-hour plasma glucose-lowering effects of insulin glargine and the postprandial antihyperglycaemic effects of lixisenatide.

Ascorbic acid supplementation improves postprandial glycaemic control and blood pressure in individuals with type 2 diabetes: Findings of a randomized cross-over trial.

AIM: The primary aim of this study was to investigate whether ascorbic acid (AA) supplementation improves postprandial glucose responses under free-living conditions in individuals with type 2 diabetes. A secondary aim was to investigate the effect of AA supplementation on blood pressure. MATERIALS AND METHODS: A total of 31 individuals with type 2 diabetes (26 males and 5 females; aged 61.8 ± 6.8 years; duration of diabetes, 5.6 ± 4.6 years; HbA1c, 7.6% ± 0.7% [mean ± SD]) were enrolled in a randomized cross-over study involving 4 months of supplementation with oral AA (2 × 500 mg/d) or placebo. Participants wore continuous glucose monitors for 48 hours and consumed standardized meals pre- and post-supplementation. Measurements included postprandial glucose incremental areas under the curve (iAUC), duration of day in hyper- and hypo-glycaemia status, average 24-hour and daily postprandial glucose concentrations, HbA1c, insulin, blood pressure (BP) and oxidative stress (F2 -isoprostanes). RESULTS: Following AA supplementation, significant decreases were observed in daily postprandial glucose iAUC (-36%), in duration of day with hyperglycaemia (-2.8 h/d) and postprandial hyperglycaemia (-1.7 h/d), in average 24-hour glucose (-0.8 mmol/L) and daily postprandial glucose (-1.1 mmol/L) concentrations, in systolic (-7 mm Hg) and diastolic (-5 mm Hg) blood pressures and in a specific fraction of free plasma F2 -isoprostanes (-47 pg/mL) as compared to placebo. CONCLUSIONS: Individuals with type 2 diabetes experienced improved postprandial and 24-hour glycaemia and decreased BP after 4 months of AA supplementation as compared to placebo. These findings offer evidence for the proposed use of AA as an adjunct therapy to improve glycaemic and BP control in individuals with type 2 diabetes.

Mineralocorticoid antagonism enhances brown adipose tissue function in humans: A randomized placebo-controlled cross-over study.

AIM: To investigate whether mineralocorticoid (MC) antagonism enhances brown adipose tissue (BAT) function in humans. MATERIALS AND METHODS: In a randomized double-blind, cross-over designed trial, 10 healthy adults (two men, eight women) underwent 2 weeks of spironolactone (100 mg/d) treatment and placebo, with an intervening 2-week wash-out period. BAT function was assessed in response to cooling and to a mixed meal. Metabolic activity was measured by fluoro-deoxyglucose (FDG) uptake (maximal standardized uptake value, SUVmax ) using PET-CT. Thermogenic activity was measured by skin temperatures overlying supraclavicular (SCL) BAT depots using infrared thermography. Postprandial metabolism was measured by energy production rate (EPR) and lipid synthesis using indirect calorimetry. RESULTS: During cooling, BAT metabolic activity (SUV 6.30 ± 2.16 vs 3.98 ± 1.34; P < 0.05) and volume (54.9 ± 22.8 vs 21.6 ± 11.8 cm3 ; P < 0.05) were significantly higher, and mean SCL temperature decreased by a smaller degree (-0.3°C°± 0.2°C vs -0.9°C ± 0.2°C; P = 0.05) with spironolactone treatment. A mixed meal increased SCL temperature and EPR. The postprandial rise in SCL temperature (+0.4°C ± 0.1°C vs +0.1°C ± 0.1°C; P < 0.05) but not in EPR was greater during spironolactone treatment. Postprandial lipid synthesis occurred in three participants with placebo but in none with spironolactone treatment (P = 0.06). CONCLUSION: MC antagonism enhanced human BAT function in response to cooling and to a meal during which lipid synthesis was suppressed. As postprandial EPR comprises energy dissipated as heat and energy required to store nutrients, the reduction in lipid synthesis during MC antagonism is a probable consequence of concurrent stimulation of BAT thermogenesis. The shift in energy usage from storage to heat dissipation indicates that MC antagonists may have therapeutic benefit for obesity.