Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

08:00 EDT 12th July 2019 | BioPortfolio

Summary of "Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A."

Interstitial cells of Cajal, which express the calcium-activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid -tolylamide (TM-23) with 30 nM half-maximal inhibitory concentration. Here, we tested the efficacy of TM-23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TM-23 strongly inhibited spontaneous and carbachol-stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TM-23 for at least 4 h following a single oral or intraperitoneal dose at 10 mg/kg. Gastric emptying, as assessed following an oral bolus of phenol red or independently by [Tc]-diethylenetriamine pentaacetic acid scintigraphy, was reduced by TM-23 by ∼60% at 20 min. Interestingly, there was little effect of TM-23 on baseline whole-gut transit time or time to diarrhea induced by castor oil. Consequent to the delay in gastric emptying, TM-23 administration significantly reduced the elevation in blood sugar in mice following an oral but not intraperitoneal glucose load. These results provide pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric emptying, such as dumping syndrome, and potentially for improving glucose tolerance in diabetes mellitus/metabolic syndrome and enhancing satiety in obesity.-Cil, O., Anderson, M. O., Yen, R., Kelleher, B., Huynh, T. L., Seo, Y., Nilsen, S. P., Turner, J. R., Verkman, A. S. Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.


Journal Details

This article was published in the following journal.

Name: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Pages: fj201900858R


DeepDyve research library

PubMed Articles [17219 Associated PubMed Articles listed on BioPortfolio]

Metformin attenuates the postprandial fall in blood pressure in type 2 diabetes.

Metformin has been shown to modulate the cardiovascular response to intraduodenal glucose in patients with type 2 diabetes (T2DM), and may have the capacity to regulate postprandial blood pressure (BP...

Gastric Emptying Improved Significantly After PRG Compared to Billroth-I Reconstruction: Assessment of Gastric Emptying With a C-Breath Test.

We advocated the usefulness of pylorus-reconstruction gastrectomy (PRG) to improve quality of life following surgery for gastric cancer. The current study assessed gastric emptying following PRG in co...

The incretin system in healthy humans: the role of GIP and GLP-1.

The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohy...

Gastric emptying in patients with well-controlled type 2 diabetes compared to non-diabetic young and older controls.

Gastric emptying is a major determinant of postprandial glycaemia, and is often delayed in longstanding, complicated type 2 diabetes (T2DM). There is, however, little information about gastric emptyin...

The Effect of the Intra-gastric Balloon on Gastric Emptying and the DeMeester Score.

The mechanism of weight loss with the intra-gastric balloon (IGB) is thought to be a decrease in gastric emptying (GE); however the evidence is conflicting. Nausea, abdominal pain, and gastroesophagea...

Clinical Trials [12316 Associated Clinical Trials listed on BioPortfolio]

Gastric Emptying During the Labour

Current recommendations permit the ingestion of all clear fluids (water, apple juice, black coffee..) during labour. However, regarding food during labour, the recommendations vary. Britis...

Effect of Smoking on Postprandial Gastric Emptying, Glucose Tolerance and Secretion of Gut and Pancreatic Hormones

The study aims to evaluate the effect of smoking on postprandial responses such as plasma glucose, secretion of gut - and pancreatic hormones and gastric emptying in healthy, heavy smoking...

The Effect of an Acute Increase in Plasma IL-6 on Glucose Tolerance When a Meal is Administered Intraduodenally

The aim of the study is to investigate and clarify whether the effect of IL-6 on glucose tolerance and insulin secretion are secondary to the changes in gastric emptying. The literature p...

Gastric Emptying in Elderly With Hip Fracture

The gastric emptying of 400 ml 12.6% carbohydrate rich drink is investigated in elderly women, age 75-100, with acute hip fracture. The emptying time will be assessed by the paracetamol ab...

Gastric Emptying - Implications for the Pathogenesis of Type 2 Diabetes

People of black African and Caribbean descent have a greater risk of developing type 2 diabetes than white Europeans. The aim of this study is to increase our knowledge of how the conditio...

Medical and Biotech [MESH] Definitions

A peptide of 36 or 37 amino acids that is derived from PROGLUCAGON and mainly produced by the INTESTINAL L CELLS. GLP-1(1-37 or 1-36) is further N-terminally truncated resulting in GLP-1(7-37) or GLP-1-(7-36) which can be amidated. These GLP-1 peptides are known to enhance glucose-dependent INSULIN release, suppress GLUCAGON release and gastric emptying, lower BLOOD GLUCOSE, and reduce food intake.

A test to determine the ability of an individual to maintain HOMEOSTASIS of BLOOD GLUCOSE. It includes measuring blood glucose levels in a fasting state, and at prescribed intervals before and after oral glucose intake (75 or 100 g) or intravenous infusion (0.5 g/kg).

A 37-amino acid peptide derived from the C-terminal of GLICENTIN. It is mainly produced by the INTESTINAL L CELLS. Oxyntomodulin can reduce digestive secretions, delay gastric emptying, and reduced food intake.

A pathological state in which BLOOD GLUCOSE level is less than approximately 140 mg/100 ml of PLASMA at fasting, and above approximately 200 mg/100 ml plasma at 30-, 60-, or 90-minute during a GLUCOSE TOLERANCE TEST. This condition is seen frequently in DIABETES MELLITUS, but also occurs with other diseases and MALNUTRITION.

An enzyme of the oxidoreductase class that catalyzes the conversion of beta-D-glucose and oxygen to D-glucono-1,5-lactone and peroxide. It is a flavoprotein, highly specific for beta-D-glucose. The enzyme is produced by Penicillium notatum and other fungi and has antibacterial activity in the presence of glucose and oxygen. It is used to estimate glucose concentration in blood or urine samples through the formation of colored dyes by the hydrogen peroxide produced in the reaction. (From Enzyme Nomenclature, 1992) EC

Quick Search

DeepDyve research library

Relevant Topics

Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Diabetes is a lifelong condition that causes a person's blood sugar level to become too high. The two main types of diabetes are: type 1 diabetes type 2 diabetes In the UK, diabetes affects approximately 2.9 million people. There are a...

Searches Linking to this Article