Intestinal SGLT1 in metabolic health and disease

The Na+-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na+ gradient created by Na+-K+-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na+ homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases.

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Incretin-based therapy for treating patients with type 2 diabetes

Orvosi Hetilap ◽

10.1556/oh.2011.29238 ◽

2011 ◽

Vol 152 (48) ◽

pp. 1931-1940 ◽

Cited By ~ 1

Author(s):

György Jermendy

Keyword(s):

Type 2 Diabetes ◽

Clinical Practice ◽

New Drugs ◽

Clinical Experiences ◽

Dipeptidyl Peptidase 4 ◽

New Class ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Near Future

In the last couple of years, a new class of antidiabetic drugs became available for the clinical practice. Due to the intensive research, several new drugs reached the market. Among the incretinmimetics both the GLP-1 (glucagon like peptide-1)-receptor agonist exenatide and the GLP-1-analogue liraglutide can be used for treatment. As for incretin enhancers (dipeptidyl-peptidase-4 [DPP-4]-inhibitors), sitagliptin, vildagliptin and saxagliptin are available in Hungary, linagliptin will be introduced to the market in the near future. In clinical practice, any incretin-based new drugs can be used for treating patients with type 2 diabetes, preferably in combination with metformin. The clinical experiences with these new drugs are reviewed focusing on both the benefits and the potential side-effects of the particular compounds. Orv. Hetil., 2011, 152, 1931–1940.

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Glucagon-Like Peptide-1: The Basis of a New Class of Treatment for Type 2 Diabetes.

ChemInform ◽

10.1002/chin.200442239 ◽

2004 ◽

Vol 35 (42) ◽

Author(s):

Lotte Bjerre Knudsen

Keyword(s):

Type 2 Diabetes ◽

New Class ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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The effects of yam gruel on lowering fasted blood glucose in T2DM rats

Open Life Sciences ◽

10.1515/biol-2020-0096 ◽

2020 ◽

Vol 15 (1) ◽

pp. 763-773

Author(s):

Xinjun Lin ◽

Zongting Luo ◽

Shuqin Pang ◽

Carol Chunfeng Wang ◽

Li Ge ◽

...

Keyword(s):

Blood Glucose ◽

Gut Microbiota ◽

Peptide Yy ◽

Short Chain Fatty Acids ◽

Scientific Basis ◽

Probiotic Bacteria ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled

AbstractThere is increasing evidence of the linkage between type 2 diabetes mellitus (T2DM) and gut microbiota. Based on our previous studies, we investigated the hypoglycemic mechanisms of yam gruel to provide a scientific basis for its popularization and application. Wistar rats were randomly divided into control and T2DM model groups. Rats in the model group were stimulated by a high-sugar/high-fat diet combined with an intraperitoneal injection of streptozotocin to induce T2DM. The T2DM rats were further subdivided randomly into three groups: (1) DM, (2) DM + yam gruel, and (3) DM + metformin. After 4 weeks of intervention, the changes in gut microbiota, short-chain fatty acids (SCFAs) (acetic acid, propionic acid, and butyric acid), the expression of G protein-coupled receptor 43 (GPR43), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and fasted blood glucose (FBG) levels were observed. Yam gruel intervention elevated the abundance of probiotic bacteria and increased the expression of SCFAs, GPR43 receptor, GLP-1, and PYY. It also reduced FBG levels. We conclude that yam gruel can lower FBG by promoting the growth of probiotic bacteria, increasing the content of SCFAs, and enhancing the expression of GPR43 receptor to increase the content of GLP-1 and PYY in serum.

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orlistat improves release of gut hormones increasing satiety in obese women

Obesity and metabolism ◽

10.14341/omet2014464 ◽

2014 ◽

Vol 11 (4) ◽

pp. 64

Author(s):

Teona Albertovna Shvangiradze

Keyword(s):

Impact Analysis ◽

Peptide Yy ◽

Gut Hormones ◽

Metabolic Effects ◽

Obese Women ◽

Fat Absorption ◽

Intestinal Hormones ◽

Glucose And Lipid Metabolism ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Orlistat, which reduces fat absorption by inhibiting intestinal lipase is a registered drug for obesity pharmacotherapy. Meta-analyzes indicate various positive metabolic effects of orlistat, including improvements in glucose and lipid metabolism, lowering both systolic and diastolic blood pressure. It is assumed that orlistat can reduce postprandial satiety by inhibiting the release of intestinal hormones (incretins), especially glucagon-like peptide-1 (GLP-1). Impact analysis of the secretion of incretins, with prolonged use of orlistat was conducted. The aim of the study M.Olszanecka-Glinianowicz et al. was to evaluate the effect of 8 weeks of treatment with orlistat as part of a weight loss program for preprandialnye levels of peptide YY and GLP-1.

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Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00029.2005 ◽

2005 ◽

Vol 289 (3) ◽

pp. R729-R737 ◽

Cited By ~ 61

Author(s):

Karine Proulx ◽

Daniela Cota ◽

Tamara R. Castañeda ◽

Matthias H. Tschöp ◽

David A. D'Alessio ◽

...

Keyword(s):

Food Intake ◽

Motor Activity ◽

Peptide Yy ◽

Metabolic Effects ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Apolipoprotein A ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Induced Changes

Oleoylethanolamide (OEA), a lipid synthesized in the intestine, reduces food intake and stimulates lipolysis through peroxisome proliferator-activated receptor-α. OEA also activates transient receptor potential vanilloid type 1 (TRPV1) in vitro. Because the anorexigenic effect of OEA is associated with delayed feeding onset and reduced locomotion, we examined whether intraperitoneal administration of OEA results in nonspecific behavioral effects that contribute to the anorexia in rats. Moreover, we determined whether circulating levels of other gut hormones are modulated by OEA and whether CCK is involved in OEA-induced anorexia. Our results indicate that OEA reduces food intake without causing a conditioned taste aversion or reducing sodium appetite. It also failed to induce a conditioned place aversion. However, OEA induced changes in posture and reduced spontaneous activity in the open field. This likely underlies the reduced heat expenditure and sodium consumption observed after OEA injection, which disappeared within 1 h. The effects of OEA on motor activity were similar to those of the TRPV1 agonist capsaicin and were also observed with the peroxisome proliferator-activated receptor-α agonist Wy-14643. Plasma levels of ghrelin, peptide YY, glucagon-like peptide 1, and apolipoprotein A-IV were not changed by OEA. Finally, antagonism of CCK-1 receptors did not affect OEA-induced anorexia. These results suggest that OEA suppresses feeding without causing visceral illness and that neither ghrelin, peptide YY, glucagon-like peptide 1, apolipoprotein A-IV, nor CCK plays a critical role in this effect. Despite that OEA-induced anorexia is unlikely to be due to impaired motor activity, our data raise a cautionary note in how specific behavioral and metabolic effects of OEA should be interpreted.

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Glucagon-like Peptide-1: The Basis of a New Class of Treatment for Type 2 Diabetes

Journal of Medicinal Chemistry ◽

10.1021/jm030630m ◽

2004 ◽

Vol 47 (17) ◽

pp. 4128-4134 ◽

Cited By ~ 120

Author(s):

Lotte Bjerre Knudsen

Keyword(s):

Type 2 Diabetes ◽

New Class ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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The Interplay of Glucagon-Like Peptide-1 Receptor Trafficking and Signalling in Pancreatic Beta Cells

Frontiers in Endocrinology ◽

10.3389/fendo.2021.678055 ◽

2021 ◽

Vol 12 ◽

Author(s):

Amaara Marzook ◽

Alejandra Tomas ◽

Ben Jones

Keyword(s):

Pancreatic Beta Cells ◽

Metabolic Effects ◽

Physiological Importance ◽

Intracellular Signals ◽

Class B ◽

The Central Nervous System ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) which mediates the effects of GLP-1, an incretin hormone secreted primarily from L-cells in the intestine and within the central nervous system. The GLP-1R, upon activation, exerts several metabolic effects including the release of insulin and suppression of appetite, and has, accordingly, become an important target for the treatment for type 2 diabetes (T2D). Recently, there has been heightened interest in how the activated GLP-1R is trafficked between different endomembrane compartments, controlling the spatial origin and duration of intracellular signals. The discovery of “biased” GLP-1R agonists that show altered trafficking profiles and selective engagement with different intracellular effectors has added to the tools available to study the mechanisms and physiological importance of these processes. In this review we survey early and recent work that has shed light on the interplay between GLP-1R signalling and trafficking, and how it might be therapeutically tractable for T2D and related diseases.

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Distribution and function of glucagon-like peptide 1 (GLP-1) in the digestive tract of mammals and the clinical use of its analogues

Medycyna Weterynaryjna ◽

10.21521/mw.6374 ◽

2023 ◽

Vol 76 (07) ◽

pp. 6374-2023 ◽

Cited By ~ 1

Author(s):

ALEKSANDRA GÓRSKA ◽

MARCIN B. ARCISZEWSKI

Keyword(s):

Type 2 Diabetes ◽

Food Intake ◽

Metabolic Diseases ◽

Biological Effects ◽

Glucagon Secretion ◽

The Body ◽

Reactive Hypoglycemia ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Recently, interest in glucagon-like peptide-1 (GLP-1) and other peptides derived from preproglucagon has increased significantly. GLP-1 is a 30-amino acid peptide hormone produced in L-type enteroendocrine cells as a response to food intake. GLP-1 is rapidly metabolized and inactivated by the dipeptidyl peptidase IV enzyme before the hormone leaves the intestine, which increases the likelihood that GLP-1 action is transmitted through sensory neurons in the intestine and liver through the GLP-1 receptor. The main actions of GLP-1 are to stimulate insulin secretion (i.e. act as incretin hormone) and inhibit glucagon secretion, thus contributing to the reduction of postprandial glucose spikes. GLP-1 also inhibits motility and gastrointestinal secretion, and therefore acts as part of the „small bowel brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these effects, GLP-1 or GLP-1 receptor agonists are now increasingly used to treat type 2 diabetes. Reduced GLP-1 secretion may contribute to the development of obesity, and excessive secretion may be responsible for postprandial reactive hypoglycemia. The use of GLP-1 agonists opens up new possibilities for the treatment of type 2 diabetes and other metabolic diseases. In the last two decades, many interesting studies covering both the physiological and pathophysiological role of GLP-1 have been published, and our understanding of GLP-1 has broadened significantly. In this review article, we have tried to describe our current understanding of how GLP-1 works as both a peripheral hormone and as a central neurotransmitter in health and disease. We focused on its biological effects on the body and the potential clinical application in relation to current research.

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