Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice

Moriya, Ryuichi; Saito, Takashi; Itô, Junko; Mashiko, Satoshi; Seo, Toru

doi:10.1152/ajpendo.00412.2009

Cited by 145 publications

(152 citation statements)

References 24 publications

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“…Although our finding might be partially due to the measurement of active (but not total) GIP, we speculate that the effect of canagliflozin on GIP may be milder when compared with that on GLP-1 in patients with type 2 diabetes but not in healthy subjects. We speculate that the possible decrease of glucose-stimulated GIP secretion due to SGLT1 inhibition of K cells (GIP secretory-cells located mainly in the mucosal membrane of the upper small intestine) [22] may not be fully realized because of the increased glucose-absorption in patients with type 2 diabetes as compared with that in healthy subjects [12]. On the other hand, the increased glucose in the intestinal lumen due to SGLT1 inhibition is probably responsible for the increase of GLP-1 secretion by L cells in the lower small intestine.…”

Section: Discussionmentioning

confidence: 98%

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: Discussionmentioning

confidence: 98%

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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“…Indeed, it has been estimated that almost half the daily uptake of water from the small intestine occurs via SGLT 1 dependent pathways [Meinild et al 1998]. Moreover, SGLT 1 also serves as the intestinal glucose sensor for glucose-induced incretin secretion [Moriya et al 2009], a key component in glycaemic control. These characteristics potentially make SGLT 1 a less acceptable clinical target, and selectivity for SGLT 2 a desirable property.…”

Section: What Does Dapagliflozin Do To the Kidney?mentioning

confidence: 99%

Renal effects of dapagliflozin in patients with type 2 diabetes

Thomas

2014

Therapeutic Advances in Endocrinology

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Diabetes mellitus was originally conceived as a renal disorder. In the last decade, however, there has been renewed interest in role of the kidney in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodium glucose transporter-2 (SGLT 2 ) as a means to better control glucose levels and at the same time augment calorie wasting and lower insulin, blood pressure and uric acid levels. Such actions, indirectly, may also have benefits for the prevention of diabetic complications including renal disease. However, there are also data to support the potential for direct renoprotective actions arising from inhibition of SGLT 2 , including actions to attenuate diabetes-associated hyperfiltration and tubular hypertrophy, as well as reduce the tubular toxicity of glucose. Some studies have demonstrated significant reductions in albumin excretion in various experimental models, independent of its effects on blood pressure or glucose control. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress. This article reviews the clinical and experimental data pertaining to the renal effects of SGLT 2 inhibition with a particular focus on dapaglifozin.

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“…Interestingly, intestinal transporters may also provide a nutrient-sensing role in the enteroendocrine cell. The sodium-coupled glucose cotransporter SGLT1 (26,30,33) and its related protein SGLT3 (10) are increasingly being acknowledged for their role in luminal glucose sensing by enteroendocrine cells. However, the precise mechanism for protein detection by gut enteroendocrine cells remains unclear.…”

mentioning

confidence: 99%

Protein hydrolysate-induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter PepT1

Liou

Chavez

Espero

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Dietary protein is a major stimulant for cholecystokinin (CCK) secretion by the intestinal I cell, however, the mechanism by which protein is detected is unknown. Indirect functional evidence suggests that PepT1 may play a role in CCK-mediated changes in gastric motor function. However, it is unclear whether this oligopeptide transporter directly or indirectly activates the I cell. Using both the CCK-expressing enteroendocrine STC-1 cell and acutely isolated native I cells from CCK-enhanced green fluorescent protein (eGFP) mice, we aimed to determine whether PepT1 directly activates the enteroendocrine cell to elicit CCK secretion in response to oligopeptides. Both STC-1 cells and isolated CCK-eGFP cells expressed PepT1 transcripts. STC-1 cells were activated, as measured by ERK1/2 phosphorylation, by both peptone and the PepT1 substrate Cefaclor; however, the PepT1 inhibitor 4-aminomethyl benzoic acid (AMBA) had no effect on STC-1 cell activity. The PepT1-transportable substrate glycyl-sarcosine dose-dependently decreased gastric motility in anesthetized rats but had no affect on activation of STC-1 cells or on CCK secretion by CCK-eGFP cells. CCK secretion was significantly increased in response to peptone but not to Cefaclor, cephalexin, or Phe-Ala in CCK-eGFP cells. Taken together, the data suggest that PepT1 does not directly mediate CCK secretion in response to PepT1 specific substrates. PepT1, instead, may have an indirect role in protein sensing in the intestine.

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Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice

Cited by 145 publications

References 24 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

Renal effects of dapagliflozin in patients with type 2 diabetes

Protein hydrolysate-induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter PepT1

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