Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

Oguma, Takahiro; Nakayama, Keiko; Kuriyama, Chiaki; Matsushita, Yasuyuki; Yoshida, Kumiko; Hikida, Kumiko; Obokata, Naoyuki; Tsuda-Tsukimoto, Minoru; Saito, Akira; Akita, Keiichi; Ueta, Kiichiro; Shiotani, Masaharu

doi:10.1124/jpet.115.225508

Cited by 64 publications

(70 citation statements)

References 55 publications

(59 reference statements)

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“…Finally, an effect independent of SGLT1 inhibition might have also partially influenced the results as described above. In the current study, further elevation of plasma active GLP-1 levels was observed by addition of teneligliptin, a DPP4 inhibitor, supporting the results of previous animal studies [10,11]. This finding appears to suggest a benefit of co-treatment of canagliflozin with DPP4 inhibitors for elevating circulating GLP-1 levels.…”

Section: Discussionsupporting

confidence: 80%

“…Four patients in the control group and 2 in the canagliflozin-treated group retracted their written agreement on participation at least before initiation of the study (i.e., the Meal test). One patient cells located mainly in the mucosal membrane of the lower small intestine [10]. The remarkable elevation of plasma active GLP-1 levels was noted especially with co-administration of dipeptidyl peptidase 4 (DPP4) inhibitors, which block GLP-1 degradation [11].…”

Section: Originalmentioning

confidence: 99%

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Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial

et al. 2017

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SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. SGLT2 is expressed in the S1 segment of the proximal renal tubules, and inhibition of this molecule results in a remarkable increase in urinary glucose excretion [1][2][3][4] Abstract. Canagliflozin has a robust inhibitory effect on sodium glucose transporter (SGLT)-2 and a mild inhibitory effect on SGLT1. The main purpose of this study was to investigate the effect of canagliflozin on circulating active glucagon-like peptide 1 (GLP-1) levels in patients with type 2 diabetes. Patients were randomly divided into a control group (n =15) and a canagliflozin-treated group (n =15). After hospitalization, the canagliflozin-treated group took 100 mg/day canagliflozin for the entire study, and after 3 days both groups took 20 mg/day teneligliptin for an additional 3 days. In a meal test, canagliflozin significantly decreased the area under curve (AUC) (0-120 min) for plasma glucose (PG) after 3 days when compared with that at baseline, and addition of teneligliptin to the canagliflozin-treated group further decreased it. A significant decrease in the AUC (0-120 min) for serum insulin by canagliflozin was obtained, but the addition of teneligliptin elevated the AUC, and thus abolished the significant difference from baseline. A significant increase in the AUC (0-120 min) of plasma active GLP-1 by canagliflozin-treatment compared with that at baseline was observed, and the addition of teneligliptin resulted in a further increase. However, canagliflozin-treatment did not change the AUC (0-120 min) of plasma active glucose-dependent insulinotropic peptide (GIP). In conclusions, canagliflozin-administration before meals decreased PG and serum insulin, and increased plasma active GLP-1 levels in patients with type 2 diabetes. Canagliflozin did not greatly influence plasma active GIP levels. Key words: Canagliflozin, GLP-1, GIP, SGLT1is located in a more distal region from the glomerulus compared with the location of S1. SGLT1 is responsible for approximately 10% of the glucose absorption in the kidney [2]. Among the SGLT2 inhibitors, canagliflozin also possesses a mild SGLT1 inhibitory effect [5,6]. Because SGLT1 is also expressed in the small intestine [7,8], inhibition of SGLT1 appears to cause the inhibition of glucose absorption in this location as well. In fact, it is reported that administration of canagliflozin can transiently repress the increase of postprandial plasma glucose (PG) levels probably via SGLT1 inhibition in the small intestine by a maximum of 30 % in healthy subjects [9].Interestingly, recent animal studies showed that administration of canagliflozin not only caused an increase in the glucose concentration in the lower small intestinal lumen probably by SGLT1 inhibition, but also resulted in a tendency toward an increase in the levels of plasma glucagon-like peptide (GLP)-1 (a hormone that increases insulin secr...

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Section: Discussionsupporting

confidence: 80%

Section: Originalmentioning

confidence: 99%

Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial

et al. 2017

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“…It has been previously determined that SGLT1 and GLUT2 expressions are upregulated in rats with STZ-induced diabetes. 20) Consistent with this, our DC group showed increased SGLT1 and GLUT2 gene and protein expression in the intestine, which contributes to the development of hyperglycemia. SGLT1 is transcriptionally regulated by recruiting HNF-1α and HNF-1β to the cis-regulatory element of its promoter.…”

Section: Discussionsupporting

confidence: 70%

Germinated Waxy Black Rice Ameliorates Hyperglycemia and Dyslipidemia in Streptozotocin-Induced Diabetic Rats

Kang

Lim

Lee

et al. 2017

Biological & Pharmaceutical Bulletin

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This study aimed to examine the anti-diabetic effect of germinated waxy black rice (GWBR) using streptozotocin (STZ)-induced diabetic rats. In the diabetic rats, GWBR supplementation for 8 weeks reduced plasma blood glucose concentrations, improved glucose clearance and prevented diabetes-induced weight loss. Rats with STZ-induced diabetes who received GWBR supplementation exhibited decreased expression of sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter (GLUT) 2 genes and proteins in the small intestine via decreases in hepatocyte nuclear factor (HNF)-1α, HNF-1β, and HNF-4α, transcriptional factors that are involved in the regulation of SGLT1 and GLUT2, compared with the rats with STZ-induced diabetes that did not receive GWBR supplements. GWBR supplementation also enhanced the expression of GLUT4 and the genes and proteins involved in GLUT4 translocation, such as insulin receptor (IR) and insulin receptor substrate 1 (IRS1), and increased the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, Akt) proteins in skeletal muscle. GWBR further increased glycogen synthase (GS) 1 by decreasing glycogen synthase kinase (GSK)-3β in skeletal muscle. Interestingly, GWBR recovered STZ-impaired pancreatic β-cells, resulting in increased insulin synthesis and secretion. In addition, GWBR reduced serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, aspartate transferase and alanine transferase concentrations and increased high-density lipoprotein cholesterol concentrations. Taken together, these findings suggest that GWBR could be a candidate for improving the diabetic condition by regulating glucose uptake in the intestine and muscle and regulating the secretion of insulin from the pancreas.

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“…The SGK1 inhibitor may also transiently inhibit SGLT1 and thereby defer and delay glucose absorption along the distal intestine (Oguma et al 2015). This effect in itself would help reduce the prandial glucose excursion and might increase GLP1 and peptide YY secretion from intestinal L cells (Oguma et al 2015). Further study is needed to investigate the effect of SGK1 inhibitors on the secretion of incretin.…”

Section: Discussionmentioning

confidence: 99%

“…This effect may be one of the mechanisms by which the SGK1 inhibitor reverses hyperglycemia in db/db mice. The SGK1 inhibitor may also transiently inhibit SGLT1 and thereby defer and delay glucose absorption along the distal intestine (Oguma et al 2015). This effect in itself would help reduce the prandial glucose excursion and might increase GLP1 and peptide YY secretion from intestinal L cells (Oguma et al 2015).…”

Section: Discussionmentioning

confidence: 99%

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

Hao

Pan

et al. 2016

Journal of Molecular Endocrinology

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This study investigates the effectiveness and mechanisms of a serum-and glucocorticoidinducible kinase 1 (SGK1) inhibitor in counteracting hyperglycemia. In an in vivo experiment, we demonstrated that after an 8-week treatment with an SGK1 inhibitor, the fasting blood glucose and HbA1c level significantly decreased in db/db mice. RT-PCR and western blot analyses revealed that intestinal SGK1 and sodium glucose co-transporter 1 (SGLT1) expression were enhanced in db/db mice. Treatment with an SGK1 inhibitor decreased excessive SGLT1 expression in the intestine of db/db mice. In vitro experiments with intestinal IEC-6 cells showed that the co-administration of an SGK1 inhibitor partly reversed the SGLT1 expression and glucose absorption that were induced by dexamethasone. In conclusion, this study revealed that the favorable effect of an SGK1 inhibitor on hyperglycemia is partly due to decreased glucose absorption through SGLT1 in the small intestine. These data collectively suggest that SGK1 may be a potent target for the treatment of diabetes and other metabolic disorders.

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Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

Cited by 64 publications

References 55 publications

Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial

Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial

Germinated Waxy Black Rice Ameliorates Hyperglycemia and Dyslipidemia in Streptozotocin-Induced Diabetic Rats

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

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