Metabolic Effects of Selected Conventional and Alternative Sweeteners: A Narrative Review.

Sugar consumption is known to be associated with a whole range of adverse health effects, including overweight status and type II diabetes mellitus. In 2015, the World Health Organization issued a guideline recommending the reduction of sugar intake. In this context, alternative sweeteners have gained interest as sugar substitutes to achieve this goal without loss of the sweet taste. This review aims to provide an overview of the scientific literature and establish a reference tool for selected conventional sweeteners (sucrose, glucose, and fructose) and alternative sweeteners (sucralose, xylitol, erythritol, and D-allulose), specifically focusing on their important metabolic effects. The results show that alternative sweeteners constitute a diverse group, and each substance exhibits one or more metabolic effects. Therefore, no sweetener can be considered to be inert. Additionally, xylitol, erythritol, and D-allulose seem promising as alternative sweeteners due to favorable metabolic outcomes. These alternative sweeteners replicate the benefits of sugars (e.g., sweetness and gastrointestinal hormone release) while circumventing the detrimental effects of these substances on human health.

Diet-induced loss of adipose hexokinase 2 correlates with hyperglycemia.

Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia.

Prospective clinical cohort study: low incidence of Barrett esophagus but high rate of reflux disease at 5-year follow-up after sleeve gastrectomy versus Roux-en-Y gastric bypass.

BACKGROUND: Gastroesophageal reflux disease seems more frequent after laparoscopic sleeve gastrectomy (LSG) than Roux-en-Y gastric bypass (LRYGB). Retrospective case series have raised concerns about a high incidence of Barrett esophagus (BE) after LSG. OBJECTIVE: This prospective clinical cohort study compared the incidence of BE ≥5 years after LSG and LRYGB. SETTING: St. Clara Hospital, Basel, and University Hospital, Zürich, Switzerland. METHODS: Patients were recruited from 2 bariatric centers where preoperative gastroscopy is standard practice and LRYGB is preferred for patients with preexisting gastroesophageal reflux disease. At follow-up ≥5 years after surgery, patients underwent gastroscopy with quadrantic biopsies from the squamocolumnar junction and metaplastic segment. Symptoms were assessed using validated questionnaires. Wireless pH measurement assessed esophageal acid exposure. RESULTS: A total of 169 patients were included, with a median 7.0 ± 1.5 years after surgery. In the LSG group (n = 83), 3 patients had endoscopically and histologically confirmed de novo BE; in the LRYGB group (n = 86), there were 2 patients with BE, 1 de novo and 1 preexisting (de novo BE, 3.6% versus 1.2%; P = .362). At follow-up, reflux symptoms were reported more frequently by the LSG group than by the LRYGB group (51.9% versus 10.5%). Similarly, moderate-to-severe reflux esophagitis (Los Angeles grade B-D) was more common (27.7% versus 5.8%) despite greater use of proton pump inhibitors (49.4% versus 19.7%), and pathologic acid exposure was more frequent in patients who underwent LSG than in patients who underwent LRYGB. CONCLUSIONS: After at least 5 years of follow-up, a higher incidence of reflux symptoms, reflux esophagitis, and pathologic esophageal acid exposure was found in patients who underwent LSG compared with patients who underwent LRYGB. However, the incidence of BE after LSG was low and not significantly different between the 2 groups.

Metabolic Effects and Safety Aspects of Acute D-allulose and Erythritol Administration in Healthy Subjects.

The rapid increase in sugar consumption is associated with various negative metabolic and inflammatory effects; therefore, alternative sweeteners become of interest. The aim of this study was to investigate the metabolic effects and safety aspects of acute D-allulose and erythritol on glucose, insulin, ghrelin, blood lipids, uric acid, and high-sensitive C-reactive protein (hsCRP). In three study visits, 18 healthy subjects received an intragastric administration of 25 g D-allulose or 50 g erythritol, or 300 mL tap water (placebo) in a randomized, double-blind and crossover order. To measure the aforementioned parameters, blood samples were drawn at fixed time intervals. Glucose and insulin concentrations were lower after D-allulose compared to tap water (p = 0.001, dz = 0.91 and p = 0.005, dz = 0.58, respectively); however, Bayesian models show no difference for insulin in response to D-allulose compared to tap water, and there was no effect after erythritol. An exploratory analysis showed that ghrelin concentrations were reduced after erythritol compared to tap water (p = 0.026, dz = 0.59), with no effect after D-allulose; in addition, both sweeteners had no effect on blood lipids, uric acid and hsCRP. This combination of properties identifies both sweeteners as excellent candidates for effective and safe sugar alternatives.

Validation of the individualized metabolic surgery score for bariatric procedure selection in the merged data of two randomized clinical trials (SLEEVEPASS and SM-BOSS).

BACKGROUND: LSG and LRYGB are globally the most common bariatric procedures. IMS score categorizes T2D severity (mild, moderate, and severe) based on 4 independent preoperative predictors of long-term remission as follows: T2D duration, number of diabetes medications, insulin use, and glycemic control. IMS score has not been validated in a randomized patient cohort. OBJECTIVES: To assess the feasibility of individualized metabolic surgery (IMS) score in facilitating procedure selection between laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) for patients with severe obesity and type 2 diabetes (T2D). SETTING: Merged individual patient-level 5-year data of 2 large randomized clinical trials (SLEEVEPASS and SM-BOSS [Swiss Multicenter Bypass or Sleeve Study]). METHODS: IMS score was calculated for study patients and its performance was analyzed. RESULTS: One hundred thirty-nine out of 155 patients with T2D had available preoperative data to calculate IMS score as follows: mild stage (n = 41/139), moderate stage (n = 77/139), severe stage (n = 21/139). At 5 years, 135 (87.1%, 67 LSG/68 LRYGB) were available for follow-up and 121 patients had both pre- and postoperative data. Diabetes remission rates according to preoperative IMS score were as follows: mild stage 87.5% (n = 14/16) after LSG and 85.7% (n = 18/21) after LRYGB (P = .999), moderate stage 42.9% (n = 15/35) and 45.2% (n = 14/31) (P = .999), and severe stage 18.2% (n = 2/11) and 0% (n = 0/7) (P = .497), respectively. The T2D remission rate varied significantly between the stages as follows: mild versus moderate odds ratio (OR) 8.3 (95% CI, 2.8-24.0; P < .001), mild versus severe OR 52.2 (95% CI 9.0-302.3; P < .001), and moderate versus severe OR 6.3 (95% CI, 1.3-29.8; P = .020). CONCLUSIONS: In our study, remission rates of T2D were not statistically different after LSG and LRYGB among all patients and among patients with mild, moderate, and severe diabetes stratified by the IMS score. However, the study may be underpowered to detect differences due to small number of patients in each subgroup. IMS score seemed to be useful in predicting long-term T2D remission after bariatric surgery.

Effects of a 5-week intake of erythritol and xylitol on vascular function, abdominal fat and glucose tolerance in humans with obesity: a pilot trial.

Introduction: Previous studies in humans and rats suggest that erythritol might positively affect vascular function, xylitol decrease visceral fat mass and both substances improve glycaemic control. The objective of this study was to investigate the impact of a 5-week intake of erythritol and xylitol on vascular function, abdominal fat and blood lipids, glucose tolerance, uric acid, hepatic enzymes, creatinine, gastrointestinal tolerance and dietary patterns in humans with obesity. Methods: Forty-two participants were randomised to consume either 36 g erythritol, 24 g xylitol, or no substance daily for 5 weeks. Before and after the intervention, arterial stiffness (pulse wave velocity, arteriolar-to-venular diameter ratio), abdominal fat (liver volume, liver fat percentage, visceral and subcutaneous adipose tissue, blood lipids), glucose tolerance (glucose and insulin concentrations), uric acid, hepatic enzymes, creatinine, gastrointestinal tolerance and dietary patterns were assessed. Data were analysed by linear mixed effect model. Results: The 5-week intake of erythritol and xylitol showed no statistically significant effect on vascular function. Neither the time nor the treatment effects were significantly different for pulse wave velocity (time effect: p=0.079, Cohen's D (95% CI) -0.14 (-0.54-0.25); treatment effect: p=0.792, Cohen's D (95% CI) control versus xylitol: -0.11 (-0.61-0.35), control versus erythritol: 0.05 (0.44-0.54), erythritol versus xylitol: 0.07 (-0.41-0.54)). There was no statistically significant effect on abdominal fat, glucose tolerance, uric acid, hepatic enzymes and creatinine. Gastrointestinal tolerance was good except for a few diarrhoea-related symptoms. Participants of all groups reduced their consumption of sweetened beverages and sweets compared with preintervention. Conclusions: The 5-week intake of erythritol and xylitol showed no statistically significant effects on vascular function, abdominal fat, or glucose tolerance in people with obesity. Clinical trial registration: NCT02821923.

Oral Erythritol Reduces Energy Intake during a Subsequent ad libitum Test Meal: A Randomized, Controlled, Crossover Trial in Healthy Humans.

The impact of oral erythritol on subsequent energy intake is unknown. The aim was to assess the effect of oral erythritol compared to sucrose, sucralose, or tap water on energy intake during a subsequent ad libitum test meal and to examine the release of cholecystokinin (CCK) in response to these substances. In this randomized, crossover trial, 20 healthy volunteers received 50 g erythritol, 33.5 g sucrose, or 0.0558 g sucralose dissolved in tap water, or tap water as an oral preload in four different sessions. Fifteen minutes later, a test meal was served and energy intake was assessed. At set time points, blood samples were collected to quantify CCK concentrations. The energy intake (ad libitum test meal) was significantly lower after erythritol compared to sucrose, sucralose, or tap water (p < 0.05). Before the start of the ad libitum test meal, erythritol led to a significant increase in CCK compared to sucrose, sucralose, or tap water (p < 0.001). Oral erythritol given alone induced the release of CCK before the start of the ad libitum test meal and reduced subsequent energy intake compared to sucrose, sucralose, or tap water. These properties make erythritol a useful sugar alternative.

Absorption and Metabolism of the Natural Sweeteners Erythritol and Xylitol in Humans: A Dose-Ranging Study.

The natural sweeteners erythritol and xylitol might be helpful to reduce sugar consumption and therefore prevent obesity and diabetes. The aim of the present study was to determine the absorption and metabolization into erythronate of different concentrations of erythritol and xylitol. Seventeen healthy lean participants received intragastric solutions of 10, 25, or 50 g erythritol or 7, 17, or 35 g xylitol on three study days in a randomized order. The study was double blinded with respect to the doses administered. We assessed plasma concentrations of erythritol, xylitol, and erythronate at fixed time intervals after administration with gas chromatography-mass spectrometry. We found: (i) a dose-dependent and saturable absorption of erythritol, (ii) a very low absorption of xylitol, (iii) a dose-dependent metabolization of erythritol into erythronate, and (iv) no metabolization of xylitol into erythronate. The implications of the metabolization of erythritol into erythronate for human health remain to be determined and more research in this area is needed.

The Role of D-allulose and Erythritol on the Activity of the Gut Sweet Taste Receptor and Gastrointestinal Satiation Hormone Release in Humans: A Randomized, Controlled Trial.

BACKGROUND: Glucose induces the release of gastrointestinal (GI) satiation hormones, such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), in part via the activation of the gut sweet taste receptor (T1R2/T1R3). OBJECTIVES: The primary objective was to investigate the importance of T1R2/T1R3 for the release of cholecystokinin (CCK), GLP-1, and PYY in response to D-allulose and erythritol by assessing the effect of the T1R2/T1R3 antagonist lactisole on these responses and as secondary objectives to study the effect of the T1R2/T1R3 blockade on gastric emptying, appetite-related sensations, and GI symptoms. METHODS: In this randomized, controlled, double-blind, crossover study, 18 participants (5 men) with a mean ± SD BMI (in kg/m2) of 21.9 ± 1.7 and aged 24 ± 4 y received an intragastric administration of 25 g D-allulose, 50 g erythritol, or tap water, with or without 450 parts per million (ppm) lactisole, respectively, in 6 different sessions. 13C-sodium acetate was added to all solutions to determine gastric emptying. At fixed time intervals, blood and breath samples were collected, and appetite-related sensations and GI symptoms were assessed. Data were analyzed with linear mixed-model analysis. RESULTS: D-allulose and erythritol induced a significant release of CCK, GLP-1, and PYY compared with tap water (all PHolm < 0.0001, dz >1). Lactisole did not affect the D-allulose- and erythritol-induced release of CCK, GLP-1, and PYY (all PHolm > 0.1). Erythritol significantly delayed gastric emptying, increased fullness, and decreased prospective food consumption compared with tap water (PHolm = 0.0002, dz = -1.05; PHolm = 0.0190, dz = 0.69; and PHolm = 0.0442, dz = -0.62, respectively). CONCLUSIONS: D-allulose and erythritol stimulate the secretion of GI satiation hormones in humans. Lactisole had no effect on CCK, GLP-1, and PYY release, indicating that D-allulose- and erythritol-induced GI satiation hormone release is not mediated via T1R2/T1R3 in the gut.

Erythritol and xylitol differentially impact brain networks involved in appetite regulation in healthy volunteers.

BACKGROUND: There is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown. AIM: The study's objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release. METHODS: The study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose. RESULTS: We found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin. CONCLUSION: Xylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose.

Effect of a Chronic Intake of the Natural Sweeteners Xylitol and Erythritol on Glucose Absorption in Humans with Obesity.

In patients with obesity, accelerated nutrients absorption is observed. Xylitol and erythritol are of interest as alternative sweeteners, and it has been shown in rodent models that their acute ingestion reduces intestinal glucose absorption. This study aims to investigate whether a chronic intake of xylitol and erythritol impacts glucose absorption in humans with obesity. Forty-six participants were randomized to take either 8 g of xylitol or 12 g of erythritol three times a day for five to seven weeks, or to be part of the control group (no substance). Before and after the intervention, intestinal glucose absorption was assessed during an oral glucose tolerance test with 3-Ortho-methyl-glucose (3-OMG). The effect of xylitol or erythritol intake on the area under the curve for 3-OMG concentration was not significant. Neither the time (pre or post intervention), nor the group (control, xylitol, or erythritol), nor the time-by-group interaction effects were significant (p = 0.829, p = 0.821, and p = 0.572, respectively). Therefore, our results show that a chronic intake of the natural sweeteners xylitol and erythritol does not affect intestinal glucose absorption in humans with obesity.

Gastric emptying of solutions containing the natural sweetener erythritol and effects on gut hormone secretion in humans: A pilot dose-ranging study.

AIM: To determine whether a dose-dependent effect in the stimulation of gut hormone release (plasma cholecystokinin [CCK], active glucagon-like peptide-1 [aGLP-1] and peptide tyrosine tyrosine [PYY]) is found for the natural sweetener erythritol. MATERIALS AND METHODS: Twelve healthy, lean volunteers received solutions with 10, 25 or 50 g erythritol, or tap water enriched with 13 C-sodium acetate on four study days via a nasogastric tube in this randomized (active treatments), placebo-controlled, double-blind, cross-over trial. Blood samples and breath samples (13 C-sodium acetate method for measurement of gastric emptying [GE]) were taken at regular intervals, and sensations of appetite and gastrointestinal symptoms were rated. RESULTS: We found (a) a dose-dependent stimulation of CCK, aGLP-1 and PYY, and slowing of GE, (b) no effect on blood glucose, insulin, motilin, glucagon or glucose-dependent insulinotropic polypeptide, (c) no effect on blood lipids and uric acid, and (d) no abdominal pain, nausea or vomiting. CONCLUSIONS: Solutions with 10 and 50 g of erythritol stimulated gut hormone release. Emptying of erythritol-containing solutions from the stomach was slower compared with placebo. There was no effect on plasma glucose, insulin, glucagon, blood lipids or uric acid. All doses were well tolerated.

Effect of the Natural Sweetener Xylitol on Gut Hormone Secretion and Gastric Emptying in Humans: A Pilot Dose-Ranging Study.

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.

Metabolic effects of the natural sweeteners xylitol and erythritol: A comprehensive review.

Xylitol and erythritol are widely used in a variety of food and oral care products as sugar substitutes. Although a number of studies have been conducted on the health benefits of xylitol since the 1960s, erythritol only attracted the attention of researchers during the early 1990s. Historically, researchers mainly focused on the effects of xylitol and other sugar alcohols on oral and dental healthcare while the anti-diabetic or antihyperglycemic effects have only been revealed recently. Though a few reviews have been published on the health benefits of sugar alcohols in the last few decades, none of them closely evaluated the antihyperglycemic potential and underlying mechanisms, particularly with a focus on xylitol and erythritol. The current review thoroughly analyzes the anti-diabetic and antihyperglycemic effects as well as other metabolic effects of xylitol and erythritol using articles published in PubMed since the 1960s, containing research done on experimental animals and humans. This review will help researchers ascertain the controversies surrounding sugar alcohols, investigate further beneficial effects of them as well as aid food industries in exploring the possibilities of using sugar alcohols as anti-diabetic supplements in diabetic foods and food products.

Quantification of Liver, Subcutaneous, and Visceral Adipose Tissues by MRI Before and After Bariatric Surgery.

BACKGROUND: Morbid obesity is a worldwide epidemic and is increasingly treated by bariatric surgery. Fatty liver is a common finding; almost half of all patients with non-alcoholic steatohepatitis develop steatohepatitis. Bariatric surgery improves steatohepatitis documented by liver biopsy and single voxel magnetic resonance imaging (MRI) techniques. OBJECTIVE: To investigate changes before and after bariatric surgery using whole organ MRI quantification of liver, visceral, and subcutaneous fat. SETTING: University of Basel Hospital and St. Clara Research Ltd, Basel, Switzerland. METHODS: Sixteen morbidly obese patients were evaluated by abdominal MRI-scanning before and 3, 6, 12, and 24 months after bariatric surgery to measure percentage liver fat (%-LF), total liver volume (TLV) and visceral and subcutaneous adipose tissues (VAT and SAT). Fasting plasma samples were taken for measurement of glucose, insulin, blood lipids, and liver biomarkers. In a control group of 12 healthy lean volunteers, the liver biomarker was also measured. RESULTS: The reproducibility of fat quantification by use of MRI was excellent. LF decreased significantly faster than VAT and SAT (%-LF vs. VAT p < 0.001 and %-LF vs. SAT p < 0.001). At certain time points, %-LF, VAT, and SAT were associated with changes in blood lipids and insulin. CONCLUSIONS: MRI quantification offers excellently reproducible results in measurement of liver fat and visceral and subcutaneous adipose tissues. Liver fat decreased significantly faster than visceral or subcutaneous adipose tissue. Decrease in %-LF and VAT is associated with decrease in total cholesterol, LDL, and plasma insulin.

Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy.

AIMS: Peripheral infusion of glucagon-like peptide-1 (GLP-1) can affect brain activity in areas involved in the regulation of appetite, including hypothalamic and reward-related brain regions. In contrast, the physiological role of endogenous GLP-1 in the central regulation of appetite has hardly been investigated. MATERIALS AND METHODS: This was a randomized, cross-over trial that involved 12 healthy volunteers who received an intragastric (ig) glucose (gluc) load, with or without intravenous (iv) exendin9-39 (ex9-39; specific GLP-1 receptor antagonist). Functional magnetic resonance imaging was used to investigate the effect of endogenous GLP-1 on resting state functional connectivity (rsFC) between homeostatic and reward-related brain regions. Visual analogue scales were used to rate appetite-related sensations. Blood samples were collected for GI hormone measurements. RESULTS: Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the hypothalamus and the left lateral orbitofrontal cortex (OFC) as well as the left amygdala (P ≤ .001, respectively). Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the right nucleus accumbens and the right lateral OFC (P < .001). Administration of iv-ex9-39/ig-gluc induced a significantly lower rsFC, relative to ig-gluc administration, between the midbrain and the right caudate nucleus (P = .001). Administration of ig-gluc significantly decreased prospective food consumption and increased sensations of fullness compared to pre-infusion baseline (P = .028 and P = .019, respectively); these effects were not present in the iv-ex9-39/ig-gluc condition. CONCLUSIONS: This pilot trial provides preliminary experimental evidence that glucose-induced endogenous GLP-1 affects central regulation of appetite by modulating rsFC in homeostatic and reward-related brain regions in healthy lean male participants in a GLP-1 receptor-mediated fashion.

Deregulation of transcription factors controlling intestinal epithelial cell differentiation; a predisposing factor for reduced enteroendocrine cell number in morbidly obese individuals.

Morbidly obese patients exhibit impaired secretion of gut hormones that may contribute to the development of obesity. After bariatric surgery there is a dramatic increase in gut hormone release. In this study, gastric and duodenal tissues were endoscopically collected from lean, and morbidly obese subjects before and 3 months after laparoscopic sleeve gastrectomy (LSG). Tissue morphology, abundance of chromogranin A, gut hormones, α-defensin, mucin 2, Na+/glucose co-transporter 1 (SGLT1) and transcription factors, Hes1, HATH1, NeuroD1, and Ngn3, were determined. In obese patients, the total number of enteroendocrine cells (EEC) and EECs containing gut hormones were significantly reduced in the stomach and duodenum, compared to lean, and returned to normality post-LSG. No changes in villus height/crypt depth were observed. A significant increase in mucin 2 and SGLT1 expression was detected in the obese duodenum. Expression levels of transcription factors required for differentiation of absorptive and secretory cell lineages were altered. We propose that in obesity, there is deregulation in differentiation of intestinal epithelial cell lineages that may influence the levels of released gut hormones. Post-LSG cellular differentiation profile is restored. An understanding of molecular mechanisms controlling epithelial cell differentiation in the obese intestine assists in the development of non-invasive therapeutic strategies.

Characterizing the dynamic interaction among gastric emptying, glucose absorption, and glycemic control in nondiabetic obese adults.

The effects of altered gastric emptying on glucose absorption and kinetics are not well understood in nondiabetic obese adults. The aim of this work was to develop a physiology-based model that can characterize and compare interactions among gastric emptying, glucose absorption, and glycemic control in nondiabetic obese and lean healthy adults. Dynamic glucose, insulin, and gastric emptying (measured with breath test) data from 12 nondiabetic obese and 12 lean healthy adults were available until 180 min after an oral glucose tolerance test (OGTT) with 10, 25, and 75 g of glucose. A physiology-based model was developed to characterize glucose kinetics applying nonlinear mixed-effects modeling with NONMEM7.3. Glucose kinetics after OGTT was described by a one-compartment model with an effect compartment to describe delayed insulin effects on glucose clearance. After the interactions between individual gastric emptying and glucose absorption profiles were accounted for, the glucose absorption rate was found to be similar in nondiabetic obese and lean controls. Baseline glucose concentration was estimated to be only marginally higher in nondiabetic obese subjects (4.9 vs. 5.2 mmol/l), whereas insulin-dependent glucose clearance in nondiabetic obese subjects was found to be cut in half compared with lean controls (0.052 vs. 0.029 l/min) and the insulin concentration associated with 50% of insulin-dependent glucose elimination rate was approximately twofold higher in nondiabetic obese subjects compared with lean controls (7.1 vs. 15.3 µU/ml). Physiology-based models can characterize and compare the dynamic interaction among gastric emptying, glucose absorption and glycemic control in populations of interest such as lean healthy and nondiabetic obese adults.

Differential effects of L-tryptophan and L-leucine administration on brain resting state functional networks and plasma hormone levels.

Depending on their protein content, single meals can rapidly influence the uptake of amino acids into the brain and thereby modify brain functions. The current study investigates the effects of two different amino acids on the human gut-brain system, using a multimodal approach, integrating physiological and neuroimaging data. In a randomized, placebo-controlled trial, L-tryptophan, L-leucine, glucose and water were administered directly into the gut of 20 healthy subjects. Functional MRI (fMRI) in a resting state paradigm (RS), combined with the assessment of insulin and glucose blood concentration, was performed before and after treatment. Independent component analysis with dual regression technique was applied to RS-fMRI data. Results were corrected for multiple comparisons. In comparison to glucose and water, L-tryptophan consistently modifies the connectivity of the cingulate cortex in the default mode network, of the insula in the saliency network and of the sensory cortex in the somatosensory network. L-leucine has lesser effects on these functional networks. L-tryptophan and L-leucine also modified plasma insulin concentration. Finally, significant correlations were found between brain modifications after L-tryptophan administration and insulin plasma levels. This study shows that acute L-tryptophan and L-leucine intake directly influence the brain networks underpinning the food-reward system and appetite regulation.