Glucose Absorption In Small Intestine Research Articles

Correlation of Differentially Expressed lncRNAs with Intestinal Flora Imbalance, Small Intestinal Permeability, and Glucose Uptake in T2DM Mice.

Diabetes is a major global health concern. This study aimed to investigate the correlation between differentially expressed lncRNAs in mice with type 2 diabetes mellitus (T2DM) and alterations in the intestinal flora and intestinal pathology. A T2DM mouse model was constructed by feeding mice a high-fat diet. Serum fat metabolism-related indices and insulin levels were biochemically detected. Serum inflammatory factors (IL-1β, IL-6, TNF-α, IL-10) and endotoxin (LPS) were measured by ELISA. Histopathological changes in the small intestines of mice were observed by HE. The short-chain fatty acid (SCFA) content was analyzed using GC-MS. Analysis of altered intestinal flora in T2DM mice was performed using a 16sRNA sequencing assay. Differences in lncRNA expression profiles in small intestinal tissues were analyzed using RNA-seq assays. Spearman's correlation analysis was used to correlate the expression of candidate lncRNAs with changes in differential gut flora. Spearman's correlation analysis was used to analyze the correlation between the expression of candidate differentially expressed lncRNAs, small intestinal permeability, and glucose absorption. We found that serum levels of LPS, BUN, Scr, TC, TG, LDL-C, IL-1β, IL-6, and TNF-α were elevated and levels of HDL-C, insulin, and IL-10 were decreased in T2DM mice. The ileal enterochromes of T2DM mice were disorganized and broken, the number of enterochromes was reduced, the local epithelial cells were necrotic, and the plasma membrane layer was locally absent. In addition, the protein expression of ZO-1 and occludin was decreased, and the protein expression of SGLT-1 and GLUT-2 was elevated in the model group compared to the control group.The levels of Acetic acid, Propionic acid and Butyric acid were decreased and the levels of Isobutyric acid andIsovaleric acid were increased, the abundance of beneficial bacteria was decreased and the abundance of harmfulbacteria was increased in the feces of T2DM mice. RNA-seq identified nine differentially expressed lncRNAs (LINC00675, Gm33838, Gm11655, LOC6613926, LOC6613788, LOC6613791, LOC6613795, Arhgap27os3, and A330023F24Rik). In addition, we found significant correlations between differentially expressed lncRNAs and a variety of intestinal flora, as well as between small intestinal permeability and glucose absorption. A significant correlation was observed between differentially expressed lncRNAs in the intestinal tissues of T2DM mice and intestinal flora imbalance, small intestinal permeability, and glucose absorption.

D-allulose reduces postprandial glucose absorption in small intestine by competitive binding to glucose transport sites

d-allulose, a C3-epimer of d-fructose, is a naturally occurring non-metabolic sugar found in small amounts. Since d-allulose can inhibit the intestinal absorption of glucose,it is necessary to investigate the role of the sodium-coupled glucose cotransporter 1 (SGLT1) in intestinal transport of d-allulose. In this study, the transcellular pathway of d-allulose in small intestinal epithelial cells was investigated by constructing a monolayer model of Caco-2 cells and in situ single-pass intestinal perfusion experiment. We observed a notable decrease in the permeation rate of d-allulose with the addition of phlorizin, a SGLT1 inhibitor, and that phloretin, a GLUT2 inhibitor, leads to a moderate decrease in the permeation rate. This suggests that both SGLT1 and GLUT2 can mediate the transport of d-allulose in small intestine. These observations were supported by computer molecular simulation. Additionally, the mRNA abundance of sugar transporters in Caco-2 cells treated with d-allulose were decreased, determined by quantitative real-time PCR. This study suggests that d-allulose can competitively bind to the sugar transport sites and reduce the mRNA abundance of sugar transporter proteins within the small intestine to effect postprandial glucose absorption.

Regulatory mechanisms of glucose absorption in the mouse proximal small intestine during fasting and feeding

Fasting is known to alter the function of various organs and the mechanisms of glucose metabolism, which affect health outcomes and slow aging. However, it remains unclear how fasting and feeding affects glucose absorption function in the small intestine. We studied the effects of the fasting and feeding on glucose-induced short-circuit current (Isc) in vitro using an Ussing chamber technique. Glucose-induced Isc by SGLT1 was observed in the ileum, but little or no Isc was observed in the jejunum in ad libitum-fed mice. However, in mice fasted for 24–48 h, in addition to the ileum, robust glucose-induced Isc was observed over time in the jejunum. The expression of SGLT1 in the brush border membranes was significantly decreased in the jejunum under fed conditions compared to 48 h fasting, as analyzed by western blotting. Additionally, when mice were fed a 60% high glucose diet for 3 days, the increase in glucose-induced Isc was observed only in the ileum, and totally suppressed in the jejunum. An increase in Na+ permeability between epithelial cells was concomitantly observed in the jejunum of fasted mice. Transepithelial glucose flux was assessed using a non-metabolizable glucose analog, 14C-methyl α-d-glucopyranoside glucose (MGP). Regardless of whether fed or fasted, no glucose diffusion mechanism was observed. Fasting increased the SGLT1-mediated MGP flux in the jejunum. In conclusion, segment-dependent up- and down-regulation mechanisms during fasting and feeding are important for efficient glucose absorption once the fast is broken. Additionally, these mechanisms may play a crucial role in the small intestine's ability to autoregulate glucose absorption, preventing acute hyperglycemia when large amounts of glucose are ingested.

Mendelian randomisation reveals Sodium-glucose Cotransporter-1 inhibition's potential in reducing Non-Alcoholic Fatty Liver Disease risk.

Non-alcoholic fatty liver disease (NAFLD) has no approved pharmacological treatments. Sodium-glucose cotransporter (SGLT)-1 is a glucose transporter that mediates small intestinal glucose absorption. We evaluated the impact of genetically proxied SGLT-1 inhibition (SGLT-1i) on serum liver transaminases and NAFLD risk. We used a missense variant, rs17683430, in the SLC5A1 gene (encoding SGLT1) associated with HbA1c in a genome-wide association study (n = 344 182) to proxy SGLT-1i. Outcome genetic data comprised 1483 NAFLD cases and 17 781 controls. Genetically proxied SGLT-1i was associated with reduced NAFLD risk (OR 0.36; 95%CI 0.15, 0.87; P = .023) per 1 mmol/mol HbA1c reduction, and with reductions in liver enzymes (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase). Genetically proxied HbA1c, not specifically via SGLT-1i, was not associated with NAFLD risk. Colocalisation did not demonstrate genetic confounding. Overall, genetically proxied SGLT-1i is associated with improved liver health, this may be underpinned by SGLT-1-specific mechanisms. Clinical trials should evaluate the impact of SGLT-1/2 inhibitors on the prevention and treatment of NAFLD.

Jianpi Qinghua Fomula alleviates insulin resistance via restraining of MAPK pathway to suppress inflammation of the small intestine in DIO mice

BackgroundJianpi Qinghua Fomula (JPQHF), a clinically proven prescription,has been applied to cure insulin resistance(IR) and type 2 diabetes (T2DM) for more than 20 years. Here, we will unravel the underlying molecular mechanisms relevant to the therapeutic actions of JPQHF.MethodsHigh-fat(HF)diet-induced obesity(DIO)mouse were established in our research, along with insulin resistance. After the administration of JPQHF 5 or 6 weeks, the parameters of the glucose and lipid metabolism were measured. Flow cytometry and Luminex were utilized to assess the inflammation in small intestine,whilst Western blot was used to determine the relative expression levels of the MAPK pathway-related proteins. The glucose and lipid transporter of small intestine was assessed by immunofluorescence and ELISA, and the expression of insulin signaling pathway was detected by Western blot.ResultsThe metabolic phenotypes of DIO mouse were ameliorated after 6-week oral administration of JPQHF; Meanwhile,JPQHF downregulated levels of IL-1β,IL-6, TNF-α and IFN-γ but upregulated the ratio of M2/M1 macrophages in the small intestine. The elevated expressions of p-P38 MAPK/P38 MAPK、p-JNK/JNK and p-ERK1/2/ERK1/2 were reversed by JPQHF. Moreover, JPQHF enhanced expression of PI3K,p-AKT/AKT, p-IRS1/ IRS1, p-IRS2/ IRS2 and apoB48 in small intestine, and facilitated the translocation of GLUT2 to the basal side of small intestine epithelial cells.ConclusionJPQHF alleviates insulin resistance in DIO mice, and this effect may be associated with its restraining of inflammation of small intestine via attenuating MAPK pathway, and then diminishes small intestinal glucose and lipid absorption.

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence.

Sodium–glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research.

Nutritional and Physiological Constraints Contributing to Limitations in Small Intestinal Starch Digestion and Glucose Absorption in Ruminants

Increased efficiency of nutrient utilization can potentially be gained with increased starch digestion in the small intestine in ruminants. However, ruminants have quantitative limits in the extent of starch disappearance in the small intestine. The objective is to explore the nutritional and physiological constraints that contribute to limitations of carbohydrate assimilation in the ruminant small intestine. Altered digesta composition and passage rate in the small intestine, insufficient pancreatic α-amylase and/or small intestinal carbohydrase activity, and reduced glucose absorption could all be potentially limiting factors of intestinal starch assimilation. The absence of intestinal sucrase activity in ruminants may be related to quantitative limits in small intestinal starch hydrolysis. Multiple sequence alignment of the sucrase-isomaltase complex gives insight into potential molecular mechanisms that may be associated with the absence of intestinal sucrase activity, reduced capacity for intestinal starch digestion, and limitations in the efficiency of feed utilization in cattle and sheep. Future research efforts in these areas will aid in our understanding of small intestinal starch digestion and glucose absorption to optimize feeding strategies for increased meat and milk production efficiency.

IL-25 Treatment Improves Metabolic Syndrome in High-Fat Diet and Genetic Models of Obesity.

IntroductionEndemic obesity is considered the driving force for the dramatic increase in incidence of type 2 diabetes (T2D). There is mounting evidence that chronic, low-grade inflammation driven by Th1/Th17 cells and M1 macrophages, is a critical link between obesity and insulin resistance. IL-25 promotes development of a Th2 immune response and M2 macrophages that counteract the inflammation associated with obesity and T2D.MethodsMice were fed a high-fat diet (HFD) for 16 weeks and then treated with IL-25 or BSA as a control for 21 days. Body weight, blood glucose levels, intraperitoneal glucose tolerance, and gene expression were evaluated in mice treated with BSA or IL-25. Ob/ob mice fed a normal control diet were also treated with BSA or IL-25 and body weight and blood glucose levels were measured. Transepithelial electrical resistance and sodium-linked glucose absorption were determined in muscle-free small intestinal tissue and glucose absorption assessed in vitro in intestinal epithelial and skeletal muscle cell lines.ResultsAdministration of IL-25 to HFD fed mice reversed glucose intolerance, an effect mediated in part by reduction in SGLT-1 activity and Glut2 expression. Importantly, the improved glucose tolerance in HFD mice treated with IL-25 was maintained for several weeks post-treatment indicating long-term changes in glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. In vitro studies demonstrated that glucose absorption was inhibited by IL-25 treatment in the epithelial IPEC-1 cells but increased glucose absorption in the L6 skeletal muscle cells. This supports a direct cell-specific effect of IL-25 on glucose metabolism.ConclusionThese results suggest that the IL-25 pathway may be a useful target for the treatment of metabolic syndrome.

Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation.

The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.

Small intestinal glucose and sodium absorption through calcium‐induced calcium release and store‐operated Ca2+ entry mechanisms

Background and PurposeLuminal glucose enhances intestinal Ca2+ absorption through apical Cav1.3 channels necessary for GLUT2‐mediated glucose absorption. As these reciprocal mechanisms are not well understood, we investigated the regulatory mechanisms of intestinal [Ca2+]cyt and SGLT1‐mediated Na+‐glucose co‐transports.Experimental ApproachGlucose absorption and channel expression were examined in mouse upper jejunal epithelium using an Ussing chamber, immunocytochemistry and Ca2+ and Na+ imaging in single intestinal epithelial cells.Key ResultsGlucose induced jejunal Isc via Na+‐glucose cotransporter 1 (SGLT1) operated more efficiently in the presence of extracellular Ca2+. A crosstalk between luminal Ca2+ entry via plasma Cav1.3 channels and the ER Ca2+ release through ryanodine receptor (RYR) activation in small intestinal epithelial cell (IEC) or Ca2+‐induced Ca2+ release (CICR) mechanism was involve in Ca2+‐mediated jejunal glucose absorption. The ER Ca2+ release through RyR triggered basolateral Ca2+ entry or store‐operated Ca2+ entry (SOCE) mechanism and the subsequent Ca2+ entry via Na+/Ca2+ exchanger 1 (NCX1) were found to be critical in Na+‐glucose cotransporter‐mediated glucose absorption. Blocking RyR, SOCE and NCX1 inhibited glucose induced [Na+]cyt and [Ca2+]cyt in single IEC and protein expression and co‐localization of STIM1/Orai1, RyR1 and NCX1 were detected in IEC and jejunal mucosa.Conclusion and ImplicationsLuminal Ca2+ influx through Cav1.3 triggers the CICR through RyR1 to deplete the ER Ca2+, which induces the basolateral STIM1/Orai1‐mediated SOCE mechanism and the subsequent Ca2+ entry via NCX1 to regulate intestinal glucose uptake via Ca2+ signalling. Targeting these mechanisms in IEC may help to modulate blood glucose and sodium in the metabolic disease.

Modeling of fluid flow, carbohydrate digestion, and glucose absorption in human small intestine

The aim of this study was to develop a numerical model for simulating fluid flow, carbohydrate digestion, and glucose absorption in human small intestine. COMSOL Multiphysics® software was used to develop the numerical model. The intestinal geometry parameters, motility parameters, intestinal content properties, and digestion kinetics were obtained from the literature. The glucose absorption process was simulated by assuming that the intestinal tube is enclosed in an outer cylindrical tube with an intermediate diffusion wall. The properties of the intermediate diffusion wall were estimated by comparing numerical predictions with experimental results of in vitro digestion of 5 g glucose and 5 g maltodextrin in water-based food solutions. The jejunum numerical model with the intermediate diffusion wall of 2 mm thickness and the glucose diffusivity value of 5.25 × 10−9 m2/s, predicted the experimental cumulative jejunal glucose absorption values of 3.67 g (glucose feed) and 3.74 g (maltodextrin feed) with an average error of 0.07 g and 0.2 g, respectively.

The Effects of a Whey Protein and Guar Gum-Containing Preload on Gastric Emptying, Glycaemia, Small Intestinal Absorption and Blood Pressure in Healthy Older Subjects.

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.

BMAL1 controls glucose uptake through paired-homeodomain transcription factor 4 in differentiated Caco-2 cells.

The transcription factor aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) is an essential regulator of the circadian clock, which controls the 24-h cycle of physiological processes such as nutrient absorption. To examine the role of BMAL1 in small intestinal glucose absorption, we used differentiated human colon adenocarcinoma cells (Caco-2 cells). Here, we show that BMAL1 regulates glucose uptake in differentiated Caco-2 cells and that this process is dependent on the glucose transporter sodium-glucose cotransporter 1 (SGLT1). Mechanistic studies show that BMAL1 regulates glucose uptake by controlling the transcription of SGLT1 involving paired-homeodomain transcription factor 4 (PAX4), a transcriptional repressor. This is supported by the observation that clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated endonuclease Cas9 (Cas9) knockdown of PAX4 increases SGLT1 and glucose uptake. Chromatin immunoprecipitation (ChIP) and ChIP-quantitative PCR assays show that the knockdown or overexpression of BMAL1 decreases or increases the binding of PAX4 to the hepatocyte nuclear factor 1-α binding site of the SGLT1 promoter, respectively. These findings identify BMAL1 as a critical mediator of small intestine carbohydrate absorption and SGLT1.

Su1096 – Calcium Signaling in the Regulation of Small Intestinal Glucose Absorption

Su1096 – Calcium Signaling in the Regulation of Small Intestinal Glucose Absorption

D-mannitol modulates glucose uptake ex vivo; suppresses intestinal glucose absorption in normal and type 2 diabetic rats

Mannitol is a widely used reduced-calorie sweetener with limited studies on its anti-hyperglycemic potential. The anti-hyperglycemic potential of mannitol was investigated using different experimental models. Mannitol inhibited α-glucosidase (IC50 = 180 ± 20% w/v) and α-amylase (IC50 = 75 ± 20% w/v) activities in a dose dependent (2.5–20% w/v) manner, in vitro, although the effective doses are not gastrointestinally tolerable. Mannitol inhibited glucose absorption (IC50 = 19 ± 3% w/v) in isolated rat jejunum in a dose dependent (2.5–20% w/v) manner, perhaps by entrapment of glucose molecules. Acute administration of 0.3 g/kg bw reduced small intestinal glucose absorption in type 2 diabetic rats, which was accompanied by reduced blood glucose. The reduced intestinal glucose absorption may be influenced by the concomitant delayed gastric emptying observed in the mannitol-treated diabetic animals. On the other hand, mannitol increased glucose uptake in a yeast cell suspension (GU50 = 4.7 ± 1.2% w/v), 3T3-L1 adipocytes (GU50 = 1.2 ± 0.4% w/v) and isolated rat muscle (GU50 = 25 ± 3% w/v) in a dose dependent manner. In silico docking suggested that GLUT-4 (binding energy = −15.5 kcal/mol) is a possible molecular target of mannitol. Data from this study suggest that mannitol may be used as a dietary supplement in controlling postprandial blood glucose increase by reducing intestinal glucose absorption and increasing muscle glucose uptake, which needs further study.

Different functional roles for K+ channel subtypes in regulating small intestinal glucose and ion transport.

ABSTRACTAlthough K+ channels are important in mediating the driving force for colonic ion transport, their role in small intestinal transport is poorly understood. To investigate this, small intestinal short circuit currents (Isc) and HCO3− secretion were measured in mice, and intracellular pH (pHi) was measured in small intestinal epithelial SCBN cells. The expression and location of Kv subtypes were verified by RT-PCR, western blotting and immunohistochemistry. Diabetic mice were also used to investigate the role of Kv subtypes in regulating intestinal glucose absorption. We found that KV7.1 is not involved in duodenal ion transport, while KCa3.1 selectively regulates duodenal Isc and HCO3− secretion in a Ca2+-mediated but not cAMP-mediated manner. Blockade of KCa3.1 increased the rate of HCO3− fluxes via cystic fibrosis transmembrane conductance regulator (CFTR) channels in SCBN cells. Jejunal Isc was significantly stimulated by glucose, but markedly inhibited by 4-aminopyridine (4-AP) and tetraethylammonium (TEA). Moreover, both Kv1.1 and Kv1.3 were expressed in jejunal mucosae. Finally, 4-AP significantly attenuated weight gain of normal and diabetic mice, and both 4-AP and TEA significantly lowered blood glucose of diabetic mice. This study not only examines the contribution of various K+ channel subtypes to small intestinal epithelial ion transport and glucose absorption, but also proposes a novel concept for developing specific K+ channel blockers to reduce weight gain and lower blood glucose in diabetes mellitus.

Na+ /H+ exchanger 3 blockade ameliorates type 2 diabetes mellitus via inhibition of sodium-glucose co-transporter 1-mediated glucose absorption in the small intestine.

To elucidate the role of Na+ /H+ exchanger 3 (NHE3) in sodium-glucose co-transporter 1 (SGLT1)-mediated small intestinal brush border membrane (BBM) glucose absorption and its functional implications in type 2 diabetes mellitus (T2DM). Human jejunal samples were obtained from patients undergoing gastrectomy. 14 C-glucose absorption was measured by liquid scintillation counting. NHE3 expression was suppressed by siRNA-mediated knockdown or augmented in Caco2 cells. Glucose and insulin tolerance in db/db and m+/db mice was assessed with oral and intraperitoneal glucose tolerance tests, and an intraperitoneal insulin tolerance test. Insulin resistance and β-cell function were assessed using homeostatic model assessment of insulin resistance and β-cell function. NHE3 expression was upregulated in db/db mouse jejunal BBM and high-glucose-treated Caco2 cells. NHE3 blockade impaired SGLT1-mediated glucose absorption in human jejunum, m+/db and db/db mouse jejunums, and Caco2 cells, via serum/glucocorticoid-regulated kinase 1 (SGK1). NHE3 knockdown suppressed SGLT1-mediated glucose uptake and reduced mRNA and protein levels of SGK1 and SGLT1, which were conversely enhanced by NHE3 overexpression. Chronic S3226 treatment diminished postprandial glucose levels and ameliorated glucose intolerance in db/db mice. NHE3 is essential in the modulation of small intestinal BBM glucose absorption. Our findings provide a rationale for future possible clinical application of NHE3 for treatment of T2DM through reducing intestinal glucose uptake and counteracting postprandial hyperglycaemia.

Expression profiling and immunolocalization of Na+-d-glucose-cotransporter 1 in mice employing knockout mice as specificity control indicate novel locations and differences between mice and rats

The expression and localization of sodium-d-glucose cotransporter SGLT1 (SLC5A1), which is involved in small intestinal glucose absorption and renal glucose reabsorption, is of high biomedical relevance because SGLT1 inhibitors are currently tested for antidiabetic therapy. In human and rat organs, detailed expression profiling of SGLT1/Sglt1 mRNA and immunolocalization of the transporter protein has been performed. Using polyspecific antibodies and preabsorption with antigenic peptide as specificity control, in several organs, different immunolocalizations of SGLT1/Sglt1 between human and rat were obtained. Because the preabsorption control does not exclude cross-reactivity with similar epitopes, some localizations remained ambiguous. In the present study, we performed an immunocytochemical localization of Sglt1 in various organs of mice. Specificities of the immunoreactions were evaluated using antibody preabsorption with the Sglt1 peptide and the respective organs of Sglt1 knockout mice. Because staining in some locations was abolished after antibody preabsorption but remained in the knockout mice, missing staining in knockout mice was used as specificity criterion. The immunolocalization in mouse was identical or similar to rat in many organs, including small intestine, liver, and kidney. However, the male-dominant renal Sglt1 protein expression in mice differed from the female-dominant expression in rats, and localization in lung, heart, and brain observed in rats was not detected in mice. In mice, several novel locations of Sglt1, e.g., in eyes, tongue epithelial cells, pancreatic ducts, prostate, and periurethral glands were detected. Using end-point and quantitative RT-PCR in various organs, different Sglt1 expression in mice and rats was confirmed.

Erythritol reduces small intestinal glucose absorption, increases muscle glucose uptake, improves glucose metabolic enzymes activities and increases expression of Glut-4 and IRS-1 in type 2 diabetic rats.

Studies have reported that erythritol, a lowor non-glycemic sugar alcohol possesses anti-hyperglycemic and anti-diabetic potentials but the underlying mode of actions is not clear. This study investigated the underlying mode of actions behind the anti-hyperglycemic and anti-diabetic potentials of erythritol using different experimental models (experiment 1, 2 and 3). Experiment 1 examined the effects of increasing concentrations (2.5-20%) of erythritol on glucose absorption and uptake in isolated rat jejunum and psoas muscle, respectively. Experiments 2 and 3 examined the effects of a single oral dose of erythritol (1g/kg bw) on intestinal glucose absorption, gastric emptying and postprandial blood glucose increase, glucose tolerance, serum insulin level, muscle/liver hexokinase and liver glucose-6 phosphatase activities, liver and muscle glycogen contents and mRNA and protein expression of muscle Glut-4 and IRS-1 in normal and type 2 diabetic animals. Experiment 1 revealed that erythritol dose dependently enhanced muscle glucose ex vivo. Experiment 2 demonstrated that erythritol feeding delayed gastric emptying and reduced small intestinal glucose absorption as well as postprandial blood glucose rise, especially in diabetic animals. Experiment 3 showed that erythritol feeding improved glucose tolerance, muscle/liver hexokinase and liver glucose-6 phosphatase activities, glycogen storage and also modulated expression of muscle Glut-4 and IRS-1 in diabetic animals. Data suggest that erythritol may exert anti-hyperglycemic effects not only via reducing small intestinal glucose absorption, but also by increasing muscle glucose uptake, improving glucose metabolic enzymes activity and modulating muscle Glut-4 and IRS-1 mRNA and protein expression. Hence, erythritol may be a useful dietary supplement for managing hyperglycemia, particularly for T2D.

Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes.

In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon-like peptide-1 (GLP-1) secretion. We evaluated the effects of metformin on serum 3-O-methylglucose (3-OMG; a marker of glucose absorption) and plasma total GLP-1 concentrations during a standardized intraduodenal infusion of glucose and 3-OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double-blind, randomized, crossover design (14 days' washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3-OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3-OMG ( P < .001) and higher plasma total GLP-1 ( P = .003) concentrations. The increment in plasma GLP-1 after metformin vs placebo was related to the reduction in serum 3-OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP-1 secretion in type 2 diabetes.