Intestinal SGLT1 Research Articles

Peptide Tyrosine-Tyrosine Triggers GLP-2-Mediated Intestinal Hypertrophy After Roux-en-Y Gastric Bypass

Purpose Intestinal remodeling and adaptation of the alimentary limb after Roux-en-Y gastric bypass (RYGB) play an important role in the pathophysiological events that lead to type 2 diabetes mellitus (T2DM) improvement. Intestinal absorptive loop hypertrophy and growth following surgery have been related to GLP-2 secretion by ileal L-cells. The secretion of peptide tyrosine-tyrosine (PYY) enterohormone after a meal has been proposed as a trigger for ileal secretion of GLP-1. Our aim is to determine the role of PYY as a GLP-2 secretion modulator as an adaptation result in the alimentary limb after RYGB.MethodWe used a non-obese euglycemic rodent model. Circulating glucose, insulin, PYY, and GLP-2 were measured in the experimental and control groups. We used four groups: fasting control, Sham-operated, RYGB-operated (RYGB), and RYGB-operated and treated with BIIE0246 (RYGB + BII). BIIE0246 is a NPY2 receptor antagonist in L-cells. Intestinal glucose transporters and GLP-1 and PYY gut expression and hypertrophy were analyzed after 12 weeks of surgery.ResultsRYGB increased PYY3-36 plasma levels in rats with or without BII treatment. A high-insulin response was observed in the RYGB group but not in the control or RYGB + BII groups. BIIE0246 treatment limited plasma GLP-2 levels. In the alimentary intestinal limb, hypertrophy and SGLT1 and GLUT1 expression appeared to be reduced after RYGB compared to controls.ConclusionThe postprandial ileal PYY secretion is enhanced after RYGB. This increase mediates GLP-2 release through its binding to the Y2 receptor on L-cells. This mechanism plays a role in alimentary limb hypertrophy after surgery.Graphical abstract

Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future Perspectives.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure-activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.

Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study.

OBJECTIVEInhibiting sodium–glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters.RESEARCH DESIGN AND METHODSUsing a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h.RESULTSChanges from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed.CONCLUSIONSChanges from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069).

Developmental alterations of intestinal SGLT1 and GLUT2 induced by early weaning coincides with persistent low-grade metabolic inflammation in female pigs.

Early-life adversity (ELA) is linked with the increased risk for inflammatory and metabolic diseases in later life, but the mechanisms remain poorly understood. Intestinal epithelial glucose transporters sodium-glucose-linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are the major route for intestinal glucose uptake but have also received increased attention as modulators of inflammatory and metabolic diseases. Here, we tested the hypothesis that early weaning (EW) in pigs, an established model of ELA, alters the development of epithelial glucose transporters and coincides with elevated markers of metabolic inflammation. The jejunum and ileum of 90-day-old pigs previously exposed to EW (16 days wean age), exhibited reduced SGLT1 activity (by ∼ 30%, P < 0.05) than late weaned (LW, 28 days wean age) controls. In contrast, GLUT2-mediated glucose transport was increased (P = 0.003) in EW pigs than in LW pigs. Reciprocal changes in SGLT1- and GLUT2-mediated transport coincided with transporter protein expression in the intestinal brush-border membranes (BBMs) that were observed at 90 days and 150 days of age. Ileal SGLT1-mediated glucose transport and BBM expression were inhibited by the β-adrenergic receptor (βAR) blocker propranolol in EW and LW pigs. In contrast, propranolol enhanced ileal GLUT2-mediated glucose transport (P = 0.015) and brush-border membrane vesicle (BBMV) abundance (P = 0.035) in LW pigs, but not in EW pigs. Early-weaned pigs exhibited chronically elevated blood glucose and C-reactive protein (CRP) levels, and adipocyte hypertrophy and upregulated adipogenesis-related gene expression in visceral adipose tissue. Altered development of intestinal glucose transporters by EW could underlie the increased risk for later life inflammatory and metabolic diseases.NEW & NOTEWORTHY These studies reveal that early-life adversity in the form of early weaning in pigs causes a developmental shift in intestinal glucose transport from SGLT1 toward GLUT2-mediated transport. Early weaning also induced markers of metabolic inflammation including persistent elevations in blood glucose and the inflammatory marker CRP, along with increased visceral adiposity. Altered intestinal glucose transport might contribute to increased risk for inflammatory and metabolic diseases associated with early-life adversity.

SGLT-1-specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine-induced renal failure.

Sodium‐dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut‐derived uremic toxins (phenyl sulfate and trimethylamine‐N‐oxide) in an adenine‐induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol‐producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low‐absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.

The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree.

Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in Xenopus laevis oocytes using biophysical and biochemical methods. The mutant failed to transport the specific SGLT1 sugar analog α-methyl-D-glucopyranoside (αMDG). Q457R SGLT1 was synthesized in amounts comparable to the wild-type (WT) transporter. SGLT1 charge measurements and freeze-fracture electron microscopy demonstrated that the mutant protein was inserted into the plasma membrane. Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter. Together with our previous studies on Q457C and Q457E mutants, we established that the positive charge on Q457R prevented the translocation of sugar from the outward-facing to inward-facing conformation. This is contrary to other GGM cases where missense mutations caused defects in trafficking SGLT1 to the plasma membrane. Thirteen GGM patients are now added to the pedigree traced back to the late 17th century. The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden.

Molecular characterization and nutritional regulation of sodium-dependent glucose cotransporter 1 (Sglt1) in blunt snout bream (Megalobrama amblycephala)

Fish has poor utilization capacity for glucose metabolism. The possible reasons are related to the core regulatory elements of glucose metabolism: transport proteins. Studies on the species and functions of Sglt1 in aquatic animals are scarce, therefore further studies are needed. In this study, the full length of blunt snout bream (Megalobrama amblycephala) sglt1 (Masglt1) was 2965 bp including 5′-UTR region of 168 bp and a 3′-UTR region of 820 bp. Masglt1 have a highest sequence homology in Cypriniformes fish. MaSglt1 protein was identified as a transmembrane protein with 14 α-helix structures locating plasma membrane by the methods of predicted tertiary structure and immunohistochemical staining. MaSglt1 protein has a hollow channel forms which could be specifically coupled with two Na+ ions to recognize glucose and carry out transmembrane transport. High sglt1 mRNA was found in the intestine and kidney. The mRNA levels of intestinal sglt1 had a positive correlation with dietary starch levels at 3 h after feeding, and the mRNA was significantly higher than that at 24 h, however, the mRNA levels of renal sglt1 presented results opposite to those of intestinal sglt1. The mRNA levels of renal sglt1 had a positive correlation with dietary starch levels at 24 h after feeding, and the expression was significantly higher than that at 3 h. These results confirmed that Masglt11 was mainly found in the intestine and kidney and was located in the cell membrane, playing a role in glucose homeostasis.

Intestinal SGLT1 as a therapeutic target in COVID-19-related diabetes: A "two-edged sword" hypothesis.

Emerging data are linking coronavirus disease 2019 (COVID‐19) with an increased risk of developing new‐onset diabetes. The gut has been so far out of the frame of the discussion on the pathophysiology of COVID‐19‐induced diabetes, with the pancreas, liver, and adipose tissue being under the spotlight of medical research. Sodium‐glucose co‐transporters (SGLT) 1 represent important regulators of glucose absorption, expressed in the small intestine where they mediate almost all sodium‐dependent glucose uptake. Similar to what happens in diabetes and other viral infections, SGLT1 upregulation could result in increased intestinal glucose absorption and subsequently promote the development of hyperglycaemia in COVID‐19. Considering the above, the question whether dual SGLT (1 and 2) inhibition could contribute to improved outcomes in such cases sounds challenging, deserving further evaluation. Future studies need to clarify whether putative benefits of dual SGLT inhibition in COVID‐19 outweigh potential risks, particularly with respect to drug‐induced euglycaemic diabetic ketoacidosis, gastrointestinal side effects, and compromised host response to pathogens.

Canagliflozin: A New Therapeutic Option in Patients That Present Postprandial Hyperinsulinemic Hypoglycemia after Roux-en-Y Gastric Bypass: A Pilot Study

Introduction: Roux-en-Y gastric bypass (RYGB) is the most common surgical procedure for morbid obesity. However, it can present serious late complications, like postprandial hyperinsulinemic hypoglycemia (PHH). Recent data suggested an increase in intestinal SGLT-1 after RYGB. However, there is no data on the inhibition of SGLT-1 to prevent PHH in patients with prior RYBG. On this basis, we aimed to evaluate (a) the effect of canagliflozin 300 mg on the response to 100 g glucose overload (oral glucose tolerance test [OGTT]); (b) the pancreatic response after intra-arterial calcium stimulation in the context of PHH after RYGB. Materials and Methods: This is a prospective pilot study including patients (n = 21) with PHH after RYGB, matched by age and gender with healthy controls (n = 5). Basal OGTT and after 2 weeks of daily 300 mg of canagliflozin was performed in all cases. In addition, venous sampling after intra-arterial calcium stimulation of the pancreas was performed in 10 cases. Results: OGTT after canagliflozin showed a significant reduction of plasma glucose levels (minute 30: 161.5 ± 36.22 vs. 215.9 ± 58.11 mg/dL; minute 60: 187.46 ± 65.88 vs. 225.9 ± 85.60 mg/dL, p < 0.01) and insulinemia (minute 30: 95.6 ± 27.31 vs. 216.35 ± 94.86 mg/dL, p = 0.03; minute 60: 120.85 ± 94.86 vs. 342.64 ± 113.32 mIU/L, p < 0.001). At minute 180, a significant reduction (85.7%) of the rate of hypoglycemia was observed after treatment with canagliflozin (p < 0.00001). All cases presented normal pancreatic response after intra-arterial calcium administration. Conclusion: Canagliflozin (300 mg) significantly decreased glucose absorption and prevented PHH after 100 g OGTT in patients with RYGB. Our results suggest that canagliflozin could be a new therapeutic option for patients that present PHH after RYGB.

Sleeve Gastrectomy Surgery Improves Glucose Metabolism by Downregulating the Intestinal Expression of Sodium–Glucose Cotransporter-3

Aims Sleeve gastrectomy (SG) has been proven effective in the treatment of obesity and type 2 diabetes. We hypothesized that SGLT3 may play an important role in the mechanism of glucose control and weight loss after SG. Materials and methods Daily body weight and food intake were measured in SG and sham-operated mice. Glucose tolerance test, SGLT3 agonist (αMG), and SGLT1 inhibitor (phlorizin) perfusion experiments were used to detect changes in intestinal SGLT3 and SGLT1 activity following SG. Expression of SGLT3a and SGLT1 was assessed at 2 weeks, 1 month after surgery by quantitative PCR and fluorescence immunoassay. Hematoxylin and eosin staining was used to detect morphological changes in the villi. SGLT3 and SGLT1 expression was measured after stimulation of human intestinal epithelial cells (HIEC). Results Both the body weight and daily food intake of the SG-treated mice decreased within 30 days after surgery. Oral glucose absorption was significantly reduced at 30 days. The intestinal stimulation proved that SG can improve glucose metabolism, which can be reversed by αMG and enhanced by phlorizin. Villus height and surface area of the intestine in SG mice decreased after surgery. mRNA expression of SGLT3a and SGLT1 decreased at 2 weeks and 1 month after SG, immunofluorescence also confirmed these changes. HIEC stimulation confirmed that αMG could increase the expression of SGLT3 and SGLT1, but the expression of SGLT1 was down regulated when phlorizin was added to the medium. Conclusion The results suggest that reducing SGLT3 expression might contribute to lowering blood glucose and controlling body weight after SG.

Inhibition of the facilitative sugar transporters (GLUTs) by tea extracts and catechins.

Tea polyphenolics have been suggested to possess blood glucose lowering properties by inhibiting sugar transporters in the small intestine and improving insulin sensitivity. In this report, we studied the effects of teas and tea catechins on the small intestinal sugar transporters, SGLT1 and GLUTs (GLUT1, 2 and 5). Green tea extract (GT), oolong tea extract (OT), and black tea extract (BT) inhibited glucose uptake into the intestinal Caco-2 cells with GT being the most potent inhibitor (IC50 : 0.077mg/mL), followed by OT (IC50 : 0.136mg/mL) and BT (IC50 : 0.56mg/mL). GT and OT inhibition of glucose uptake was partial non-competitive, with an inhibitor constant (Ki ) = 0.0317 and 0.0571mg/mL, respectively, whereas BT was pure non-competitive, Ki =0.36mg/mL. Oocytes injected to express small intestinal GLUTs were inhibited by teas, but SGLT1 was not. Furthermore, catechins present in teas were the predominant inhibitor of glucose uptake into Caco-2 cells, and gallated catechins the most potent: CG > ECG > EGCG≥GCG when compared to the non-gallated catechins (C, EC, GC, and EGC). In Caco-2 cells, individual tea catechins reduced the SGLT1 gene, but not protein expression levels. In contrast, GLUT2 gene and protein expression levels were reduced after 2hours exposure to catechins but increased after 24hours. These in vitro studies suggest teas containing catechins may be useful dietary supplements capable of blunting postprandial glycaemia in humans, including those with or at risk to Type 2 diabetes mellitus.

Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2.

Selective analogs of the natural glycoside phloridzin are marketed drugs that reduce hyperglycemia in diabetes by inhibiting the active sodium glucose cotransporter SGLT2 in the kidneys. In addition, intestinal SGLT1 is now recognized as a target for glycemic control. To expand available type 2 diabetes remedies, we aimed to find novel SGLT1 inhibitors beyond the chemical space of glycosides. We screened a bioactive compound library for SGLT1 inhibitors and tested primary hits and additional structurally similar molecules on SGLT1 and SGLT2 (SGLT1/2). Novel SGLT1/2 inhibitors were discovered in separate chemical clusters of natural and synthetic compounds. These have IC50‐values in the 10‐100 μmol/L range. The most potent identified novel inhibitors from different chemical clusters are (SGLT1‐IC50 Mean ± SD, SGLT2‐IC50 Mean ± SD): (+)‐pteryxin (12 ± 2 μmol/L, 9 ± 4 μmol/L), (+)‐ε‐viniferin (58 ± 18 μmol/L, 110 μmol/L), quinidine (62 μmol/L, 56 μmol/L), cloperastine (9 ± 3 μmol/L, 9 ± 7 μmol/L), bepridil (10 ± 5 μmol/L, 14 ± 12 μmol/L), trihexyphenidyl (12 ± 1 μmol/L, 20 ± 13 μmol/L) and bupivacaine (23 ± 14 μmol/L, 43 ± 29 μmol/L). The discovered natural inhibitors may be further investigated as new potential (prophylactic) agents for controlling dietary glucose uptake. The new diverse structure activity data can provide a starting point for the optimization of novel SGLT1/2 inhibitors and support the development of virtual SGLT1/2 inhibitor screening models.

Stimulation of constitutive nitric oxide uniquely and compensatorily regulates intestinal epithelial cell brush border membrane Na absorption.

In the mammalian small intestine, sodium is primarily absorbed by Na+/H+ exchange (NHE3) and Na‐glucose cotransport (SGLT1) in the brush border membrane (BBM) of villus cells. However, how enhanced cellular constitutive nitric oxide (cNO) may affect NHE3 and SGLT1 remains unclear. Both in vivo in rabbit intestinal villus cells and in vitro IEC‐18 cells, administration of NO donor, GSNAP, modestly increased cNO. GSNAP stimulated SGLT1 in villus and IEC‐18 cells. The mechanism of stimulation was secondary to an increase in the affinity of SGLT1 for glucose. The change in SGLT1 was not secondary to altered Na‐extruding capacity of the cell since Na+/K+‐ATPase was decreased by GSNAP treatment. In contrast, GSNAP inhibited NHE3 activity in villus cell BBM. The mechanism of NHE3 inhibition was secondary to reduced BBM transporter numbers. These studies demonstrated that the physiological increase in cNO uniquely regulates mammalian small intestinal NHE3 and SGLT1 to maintain Na homeostasis.

32 – Unique Regulation of Intestinal Epithelial Cell Na-Glucose Co-Transporter Sglt1 by Constitutive Nitric Oxide

32 – Unique Regulation of Intestinal Epithelial Cell Na-Glucose Co-Transporter Sglt1 by Constitutive Nitric Oxide

OR22-5 Sotagliflozin Decreases Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption

Sotagliflozin (Sota) inhibits sodium glucose cotransporter 2 (SGLT2; IC50=1.8 nM) and SGLT1 (IC50=36 nM). In humans, Sota improves glycemic control in part by increasing urinary glucose excretion via renal SGLT2 inhibition. Sota also lowers postprandial glucose (PPG), likely by inhibiting intestinal SGLT1 to delay the rate of appearance of oral glucose (RaO). To test the hypothesis that Sota delays SGLT1-mediated RaO, we performed a randomized, 3-period crossover study comparing effects of single doses of placebo (Pbo), Sota (400 mg) and canagliflozin (Cana, 300 mg), an SGLT2 inhibitor (IC50=4.2 nM) that inhibits SGLT1 (IC50=663 nM) with lower potency than Sota, on RaO using a dual-glucose tracer method in two cohorts of 12 healthy subjects each; plasma glucose, insulin and additional pharmacodynamic parameters were also evaluated. All subjects received a continuous [U-13C6] glucose infusion starting 5 hr before their first mixed meal (MM) test. Cohort 1 subjects had a MM breakfast containing [6,6-2H2] glucose starting 0.25 hr postdose and a MM lunch containing [1-2H1] glucose starting 5.25 hr postdose. Cohort 2 subjects had a MM breakfast containing no labeled glucose starting 0.25 hr postdose and a MM lunch containing [6,6-2H2] glucose starting 4.25 hr postdose. Plasma glucose, and labeled glucose as a fraction of plasma glucose, were measured frequently for 5 hr after any MM containing labeled glucose, while plasma levels of insulin, intestinal hormones and other analytes were measured frequently after any MM containing [6,6-2H2] glucose. For the Cohort 1 MM breakfast, Sota and Cana: 1) lowered RaO AUC[0-1 hr] and RaO AUC[0-2 hr], and also lowered AUC[0-4hr] for insulin, c-peptide and gastric inhibitory peptide (GIP), all p<0.05 vs Pbo; 2) showed trends toward lowering PPG AUC[0-4hr] vs Pbo; 3) increased AUC[0-4hr] for total glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), both p<0.05 vs Pbo; and 4) did not alter glucagon AUC[0-4hr] or the AUC[0-5hr] for RaO or endogenous glucose production (EGP). Results were similar for the Cohort 2 MM lunch starting 4.25 hr postdose, except: 1) RaO, insulin and c-peptide AUC[0-1hr] decreased more for Sota vs Cana, all p<0.05; and 2) Sota and Cana increased glucagon AUC[0-4hr] and EGP AUC[0-5hr], both p<0.05 vs Pbo. For the Cohort 1 MM lunch starting 5.25 hr postdose: 1) Sota lowered RaO AUC[0-1hr] vs Cana and Pbo, and lowered PPG AUC[0-5hr] vs Cana and Pbo, both p<0.05; and 2) Cana did not lower RaO AUC[0-1hr] or PPG AUC[0-5hr] vs Pbo. We conclude that Sota delayed RaO, resulting in lower postprandial levels of glucose and insulin. The mechanism was likely a prolonged local inhibition of intestinal SGLT1 that persisted, despite feeding, during at least the first 5 hours after oral Sota dosing. The Sota-mediated decrease in GIP levels and increases in GLP-1 and PYY levels after oral glucose challenge are consistent with local inhibition of intestinal SGLT1.

Consuming Genistein Improves Survival Rates in the Absence of Laxative in ΔF508-CF Female Mice.

Genistein is a naturally occurring isoflavone found in soy. Genistein has been shown to increase the open probability of the most common cystic fibrosis (CF) disease-associated mutation, ∆F508-CFTR. Mice homozygous for the ∆F508 mutation are characterized with severe intestinal disease and require constant laxative treatment for survival. This pathology mimics the intestinal obstruction (meconium ileus) seen in some cystic fibrosis patients. This study tested whether dietary supplementation with genistein would reduce the dependence of the ∆F508 CF mouse model on laxatives for survival, thereby improving mortality rates. At weaning (21 days), homozygous ∆F508 mice were maintained on one of three diet regimens for a period of up to 65 days: normal diet, normal diet plus colyte, or genistein diet. Survival rates for males were as follows: standard diet (38%, n = 21), standard diet plus colyte (83%, n = 42) and genistein diet (60%, n = 15). Survival rates for females were as follows: standard diet (47%, n = 19), standard diet plus colyte (71%, n = 38), and genistein diet (87%, n = 15). Average weight of male mice fed genistein diet increased by ~2.5 g more (p = 0.006) compared to those with colyte treatment. Genistein diet did not change final body weight of females. Expression of intestinal SGLT-1 increased 2-fold (p = 0.0005) with genistein diet in females (no change in males, p = 0.722). Expression of GLUT2 and GLUT5 was comparable between all diet groups. Genistein diet reduced the number of goblet cells per micrometer of crypt depth in female (p = 0.0483), yet was without effect in males (p = 0.7267). The results from this study demonstrate that supplementation of diet with genistein for ~45 days increases the survival rate of female ∆F508-CF mice (precluding the requirement for laxatives), and genistein only improves weight gain in males.

Altered pancreatic islet morphology and function in SGLT1 knockout mice on a glucose-deficient, fat-enriched diet

ObjectivesGlycemic control by medical treatment represents one therapeutic strategy for diabetic patients. The Na+-d-glucose cotransporter 1 (SGLT1) is currently of high interest in this context. SGLT1 is known to mediate glucose absorption and incretin secretion in the small intestine. Recently, inhibition of SGLT1 function was shown to improve postprandial hyperglycemia. In view of the lately demonstrated SGLT1 expression in pancreatic islets, we investigated if loss of SGLT1 affects islet morphology and function. MethodsEffects associated with the loss of SGLT1 on pancreatic islet (cyto) morphology and function were investigated by analyzing islets of a SGLT1 knockout mouse model, that were fed a glucose-deficient, fat-enriched diet (SGLT1−/−-GDFE) to circumvent the glucose-galactose malabsorption syndrome. To distinguish diet- and Sglt1−/−-dependent effects, wildtype mice on either standard chow (WT-SC) or the glucose-free, fat-enriched diet (WT-GDFE) were used as controls. Feeding a glucose-deficient, fat-enriched diet further required the analysis of intestinal SGLT1 expression and function under diet-conditions. ResultsConsistent with literature, our data provide evidence that small intestinal SGLT1 mRNA expression and function is regulated by nutrition. In contrast, pancreatic SGLT1 mRNA levels were not affected by the applied diet, suggesting different regulatory mechanisms for SGLT1 in diverse tissues. Morphological changes such as increased islet sizes and cell numbers associated with changes in proliferation and apoptosis and alterations of the β- and α-cell population are specifically observed for pancreatic islets of SGLT1−/−-GDFE mice. Glucose stimulation revealed no insulin response in SGLT1−/−-GDFE mice while WT-GDFE mice displayed only a minor increase of blood insulin. Irregular glucagon responses were observed for both, SGLT1−/−-GDFE and WT-GDFE mice. Further, both animal groups showed a sustained release of GLP-1 compared to WT-SC controls. ConclusionLoss or impairment of SGLT1 results in abnormal pancreatic islet (cyto)morphology and disturbed islet function regarding the insulin or glucagon release capacity from β- or α-cells, respectively. Consequently, our findings propose a new, additional role for SGLT1 maintaining proper islet structure and function.

Hypoglycemic Effects of Pyrodextrins with Different Molecular Weights and Digestibilities in Mice with Diet-Induced Obesity.

Pyrodextrin shares some properties of resistant starch, which is metabolically beneficial, and has potential applications as a functional food. In this study, we report that the oral administration of pyrodextrin (50 mg/kg/d for 7 weeks) decreased blood glucose (from 9.18 ± 1.47 to 7.67 ± 0.42 mmol/L), serum HbA1c, triglycerides, adipocyte size, and body weight (from 24.4 ± 1.2 to 22.5 ± 1.2 g) in mice with high-fat-diet-induced obesity. Western-blotting analysis suggested that pyrodextrins decreased intestinal SGLT-1 and GLUT-2 expression to ∼70 and ∼60% of the obese control, respectively, which slowed down glucose transportation from the gut into the blood and tentatively improved hepatic metabolism. Moreover, the pyrodextrin with a lower molecular weight of 44 kDa, a more branched structure, and increased nondigestible starch of 46.2 ± 0.3% showed stronger hypoglycemic activity. This work provides important information for developing pyrodextrins as a functional food and dietary supplement for the management of obesity and diabetes.

Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model.

Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.

Novel and Unexpected Functions of SGLTs.

It has been 30 years since the intestinal sodium glucose cotransporter SGLT1 was cloned, and, in the intervening years, there have been many advances that have influenced physiology and medicine. Among the first was that SGLT1 is the founding member of the human gene family SLC5, containing 11 diverse transporters and a glucose sensor. Equally surprising was that SGLTs are members of a structural family of cotransporters and exchangers in different gene families. This led to the conclusion that these proteins operate by a mechanism where transport involves the opening and closing of external and internal gates. The mechanism is shared by a wide variety of transporters in different structural families, e.g., the human facilitated glucose transporters (SLC2) in the huge major facilitator superfamily (MFS). Not surprising is the finding that mutations in Sglt genes cause the rare diseases glucose-galactose-malabsorption (GGM) and familial renal glucosuria (FRG). However, it was not envisaged that SGLT inhibitors would be used to treat diabetes mellitus, and these drugs may be able to treat cancer. Finally, in 2017, we have just learned that SGLT1 may be required to resist infection and to avoid recurrent pregnancy loss.