The Glycemic Index, Postprandial Hypotension and Cardiovascular Disease

High glycemic index diets have been associated with an increased risk of cardiovascular disease events and all-cause mortality. We suggest that part of the reason for this association is through the effect of the rapidly digested high glycemic index carbohydrate diets in promoting the effects of postprandial hypotension in vulnerable individuals. Postprandial hypotension has been recognized as a problem especially affecting the frail elderly. The phenomenon occurs earlier in the day and includes syncope and falls acutely and more serious cardiovascular events and increased all-cause mortality in the longer-term. The mechanism appears to relate to the rapid digestion of carbohydrates foods. Strategies that reduce the amount of meal carbohydrates and their rate of absorption by enzyme inhibition or by delaying gastric emptying and have proved helpful as has increased fluid intake, presumably due to dilution of small intestinal contents and a reduction in the tonicity, so reducing the need for intestinal fluid secretion to dilute osmotically active sugars and products of digestion. In this way the need for increased blood flow to the gut can be reduced, that would otherwise steal blood from the systemic circulation resulting in a drop in blood pressure and an increase in heart rate. Slowly absorbed or low glycemic index carbohydrates would therefore appear potentially useful as part of the dietary strategy for the treatment of postprandial hypotension and conversely postprandial hypotension could be one of the reasons why high glycemic index diets have been associated with increased CVD risk.

Characterisation of proguanylin expressing cells in the intestine – evidence for constitutive luminal secretion

Guanylin, a peptide implicated in regulation of intestinal fluid secretion, is expressed in the mucosa, but the exact cellular origin remains controversial. In a new transgenic mouse model fluorescent reporter protein expression driven by the proguanylin promoter was observed throughout the small intestine and colon in goblet and Paneth(-like) cells and, except in duodenum, in mature enterocytes. In Ussing chamber experiments employing both human and mouse intestinal tissue, proguanylin was released predominantly in the luminal direction. Measurements of proguanylin expression and secretion in cell lines and organoids indicated that secretion is largely constitutive and requires ER to Golgi transport but was not acutely regulated by salt or other stimuli. Using a newly-developed proguanylin assay, we found plasma levels to be raised in humans after total gastrectomy or intestinal transplantation, but largely unresponsive to nutrient ingestion. By LC-MS/MS we identified processed forms in tissue and luminal extracts, but in plasma we only detected full-length proguanylin. Our transgenic approach provides information about the cellular origins of proguanylin, complementing previous immunohistochemical and in-situ hybridisation results. The identification of processed forms of proguanylin in the intestinal lumen but not in plasma supports the notion that the primary site of action is the gut itself.

A novel role of intestine epithelial GABAergic signaling in regulating intestinal fluid secretion

γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system, and it is produced via the enzymatic activity of glutamic acid decarboxylase (GAD). GABA generates fast biological signaling through type A receptors (GABAAR), an anionic channel. Intriguingly, GABA is found in the jejunum epithelium of rats. The present study intended to determine whether a functional GABA signaling system exists in the intestinal epithelium and if so whether the GABA signaling regulates intestinal epithelial functions. RT-PCR, Western blot, and immunohistochemical assays of small intestinal tissues of various species were performed to determine the expression of GABA-signaling proteins in intestinal epithelial cells. Perforated patch-clamp recording was used to measure GABA-induced transmembrane current in the small intestine epithelial cell line IEC-18. The fluid weight-to-intestine length ratio was measured in mice that were treated with GABAAR agonist and antagonist. The effect of GABAAR antagonist on allergic diarrhea was examined using a mouse model. GABA, GAD, and GABAAR subunits were identified in small intestine epithelial cells of mice, rats, pigs, and humans. GABAAR agonist induced an inward current and depolarized IEC-18. Both GABA and the GABAAR agonist muscimol increased intestinal fluid secretion of rats. The increased intestinal secretion was largely decreased by the GABAAR antagonist picrotoxin or gabazine, but not by tetrodotoxin. The expression levels of GABA-signaling proteins were increased in the intestinal epithelium of mice that were sensitized and challenged with ovalbumin (OVA). The OVA-treated mice exhibited diarrhea, which was alleviated by oral administration of gabazine or picrotoxin. An endogenous autocrine GABAergic signaling exists in the mammalian intestinal epithelium, which upregulates intestinal fluid secretion. The intestinal GABAergic signaling becomes intensified in allergic diarrhea, and inhibition of this GABA-signal system alleviates the allergic diarrhea.