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 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

Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia

Chronically high blood glucose (hyperglycemia) leads to diabetes, fatty liver disease, and cardiovascular 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 caused enhanced gluconeogenesis and lipogenesis in liver, a condition known as selective insulin resistance, leading to glucose intolerance. 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 systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved, non-cell-autonomous mechanism for the development of hyperglycemia

Insulin resistance causes inflammation in adipose tissue

Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa

Gut induced biomarkers of appetite and satiety

Obesity is basically caused by an imbalance between food intake and energy expenditure. It is well documented that the gastrointestinal tract plays a key role in the control of food intake, but the regulatory circuits and their interactions are complex. Food enters the gastrointestinal tract, which then trigger specific mechanisms that respond to specific components of food. The anatomical bases for the sensing machinery are enteroendocrine cells in the small intestine, which act as neural triggers or as intestinal satiation peptide secreting cells. These cells express chemosensory receptors that respond to luminal stimuli. This thesis addresses specific mechanisms regarding enteroendocrine cells and how nutrient components interact with this machinery to stimulate and regulate the secretion of gut peptides, which play a key role in the regulation of food intake and a wide range of metabolic functions. In a first set of experiments, we investigated the involvement of two potential targets of peptide release, such as glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY) and cholecystokinin (CCK): i) bile acids (BAs) as possible TGR5 agonists and ii) glucose stimulating the sweet receptor T1R2/T1R3. To investigate the physiological role of BAs, subjects received intraduodenal infusions of different loads of chenodeoxycholic acid (CDCA, a primary BA in humans) in comparison to sodium-oleate (a potent secretagogue for the peptides mentioned above) or vehicle as a control. Administration of CDCA resulted in a significant increase of both plasma GLP-1 and CCK levels; however, the stimulatory potency was small, if we compare the magnitude of the GLP-1 and CCK responses to other well-known secretagogues such as glucose or fatty acids. To investigate the physiological role of T1R2/T1R3 in the secretion of intestinal satiation peptides we used lactisole, a T1R2/T1R3 receptor antagonist. Subjects received i) intragastric and intraduodenal infusions of glucose and ii) intragastric and intraduodenal infusions of a liquid mixed meal, both with and without lactisole. Lactisole induced a significant reduction of plasma GLP-1 levels in both, the intragastric and intraduodenal glucose-stimulated parts. However, we observed no effect of lactisole on gastrointestinal peptide secretion in the mixed liquid meal-stimulated parts. The liquid meal consisted beside glucose also of proteins, fats and other complex carbohydrates. The lack of effect of lactisole suggests that these nutrients induced the release of gastrointestinal peptides probably via other receptor mechanisms and thus outweighed the effect of T1R2/T1R3 blockade. These findings indicate that the receptor is not alone responsible for peptide secretion; it is rather a complex interaction between different receptor mechanisms. In addition, we found that the inhibitory effect of lactisole on the secretion of GLP-1 was greater in response to intragastric glucose administration compared to the intraduodenal infusion. These results let assume interaction mechanisms between gastric signals and signals from the small intestine and indicate a relevant contribution of the stomach in the regulation of gastrointestinal peptide secretion. Indeed, several studies in animals and humans suggest that gastric and intestinal signals interact to elicit optimal satiation and adequate control of eating. In humans, little information is available on the underlying mechanisms of this interaction. In addition, uncertainties exist about the role of both gastric and intestinal parameters, as well as their interaction in the control of satiation in relation to body mass. In a second set of experience, we investigated the reciprocal control between gastric functions and intestinal parameters in the control of appetite in lean as well as in obese persons. To investigate this potential interaction, lean subjects received either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. We found that infusions of glucose directly into the small intestine elicit only weak effects on appetite and the secretion of GLP-1 and PYY. In contrast, identical amounts of glucose delivered into the stomach markedly suppressed appetite paralleled by significantly greater plasma levels of GLP-1 and PYY. Administration of the mixed liquid meal showed a similar outcome. It seems that an initial more rapid rate of duodenal delivery after intragastric infusions account for the accelerated secretion of GLP-1 and PYY. These findings suggest again a role of the stomach in the control of appetite and indicate interaction mechanisms between gastric emptying rates and the release of intestinal satiation peptides. In a last series of experiments, we compared gastric emptying, intestinal peptide release and satiation parameters in response to nutrients between normal weight and obese healthy subjects. We found that gastric emptying rates were delayed in obese subjects, possible due to impaired gastric sensory functions. In addition, the increase in post-prandial plasma GLP-1 and PYY levels was reduced and the caloric intake was higher in obese compared to lean subjects. These results document once more the importance of gastric signals in the control of appetite. Together, chemosensing receptors like T1R2/T1R3 are involved in the secretion of gastrointestinal peptides, however each receptor by itself is probably not alone responsible for peptide release – it is rather a complex interaction between different receptor mechanisms. In addition, complex interactions between different gastrointestinal signals are responsible for the control of eating. The understanding of each of these signals and interaction mechanisms is essential and could constitute a promising therapeutic approach for the treatment of obesity

Effect of L-Tryptophan and L-Leucine on Gut Hormone Secretion, Appetite Feelings and Gastric Emptying Rates in Lean and Non-Diabetic Obese Participants: A Randomized, Double-Blind, Parallel-Group Trial

<br> <p><b>Background/Objectives</b></p> <p>Gut hormones such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) play a role as satiation factors. Strategies to enhance satiation peptide secretion could provide a therapeutic approach for obesity. Carbohydrates and lipids have been extensively investigated in relation to peptide release. In contrast, the role of proteins or amino acids is less clear. Our aim was to compare the effects of the amino acids L-tryptophan (L-trp) and L-leucine (L-leu) separately on gastric emptying and gut peptide secretion. </p> <p><b>Participants/Methods</b></p> <p>The study was conducted as a randomized (balanced), double-blind, parallel-group trial. A total of 10 lean and 10 non-diabetic obese participants were included. Participants received intragastric loads of L-trp (0.52 g and 1.56 g) and L-leu (1.56 g), dissolved in 300 mL tap water; 75 g glucose and 300 mL tap water served as control treatments. </p> <p><strong>Results</strong></p> <p>Results of the study are: i) L-trp at the higher dose stimulates CCK release (p=0.0018), and induces a significant retardation in gastric emptying (p=0.0033); ii) L-trp at the higher dose induced a small increase in GLP-1 secretion (p=0.0257); iii) neither of the amino acids modulated subjective appetite feelings; and iv) the two amino acids did not alter insulin or glucose concentrations. </p> <p><strong>Conclusions</strong></p> L-trp is a luminal regulator of CCK release with effects on gastric emptying, an effect that could be mediated by CCK. L-trp’s effect on GLP-1 secretion is only minor. At the doses given, the two amino acids did not affect subjective appetite feelings

Mechanisms regulating insulin response to intragastric glucose in lean and non-diabetic obese subjects

<p><b>Background/Objectives</b></p> <p>The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads. </p> <p><b>Subjects/Methods</b></p> <p>The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit.<b> </b>A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric<b> </b>loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water. </p> <p><b>Results</b></p> <p>Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (<i>P </i>< 0.001) and hyperinsulinemia (<i>P </i>< 0.001); ii) decreased insulin disposal (<i>P</i> < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (<i>P </i>< 0.001) in obese subjects. </p> <p><b>Conclusions</b></p> <p>It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance.</p