The short chain fatty acid (SCFA) receptor (free fatty acid receptor-3; FFAR3) is expressed in pancreatic β cells; however, its role in insulin secretion is not clearly defined. Here, we examined the role of FFAR3 in insulin secretion. Using islets from global knockout FFAR3 (Ffar3−/−) mice, we explored the role of FFAR3 and ligand-induced FFAR3 signaling on glucose stimulated insulin secretion. RNA sequencing was also performed to gain greater insight into the impact of FFAR3 deletion on the islet transcriptome. First exploring insulin secretion, it was determined that Ffar3−/− islets secrete more insulin in a glucose-dependent manner as compared to wildtype (WT) islets. Next, exploring its primary endogenous ligand, propionate, and a specific agonist for FFAR3, signaling by FFAR3 inhibited glucose-dependent insulin secretion, which occurred through a Gαi/o pathway. To help understand these results, transcriptome analyses by RNA-sequencing of Ffar3−/− and WT islets observed multiple genes with well-known roles in islet biology to be altered by genetic knockout of FFAR3. Our data shows that FFAR3 signaling mediates glucose stimulated insulin secretion through Gαi/o sensitive pathway. Future studies are needed to more rigorously define the role of FFAR3 by in vivo approaches.
Abstract Background and aims Normal gestation involves reprogramming of maternal gut microbiome (GM) that may contribute to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM – maternal metabolism interaction. Methods The GM and plasma metabolome of CD1, NIH-Swiss and C57BL/6J mice were analyzed using 16S rRNA sequencing and untargeted LC-MS throughout gestation and postpartum. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM in the process was studied using fecal microbial transplants (FMT). Results Significant variation in gut microbial alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time-point specific, with species enriched at gestation day 15/19 (G15/19), a point of heightened IR, distinct from those enriched pre- or post- pregnancy. Untargeted and targeted metabolomics revealed elevated plasma kynurenine at G15/19 in all three mouse strains. IDO1, the rate limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine levels effects on IR derive from the GM in both mouse and human pregnancy. Conclusions GM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1.
Background Studies suggest that short chain fatty acids (SCFAs), which are primarily produced from fermentation of fiber, regulate insulin secretion through free fatty acid receptors 2 and 3 (FFA2 and FFA3). As these are G-protein coupled receptors (GPCRs), they have potential therapeutic value as targets for treating type 2 diabetes (T2D). The exact mechanism by which these receptors regulate insulin secretion and other aspects of pancreatic β cell function is unclear. It has been reported that glucose-dependent release of acetate from pancreatic β cells negatively regulates glucose stimulated insulin secretion. While these data raise the possibility of acetate's potential autocrine action on these receptors, these findings have not been independently confirmed, and multiple concerns exist with this observation, particularly the lack of specificity and precision of the acetate detection methodology used.
Today cancer is a leading cause of death among the developed countries. Its highly complex nature makes it difficult to understand as it entails multiple cellular physiological systems such as cell signaling and apoptosis. The biggest challenges faced by cancer chemoprevention/chemotherapy is maintaining drug circulation and avoiding multidrug resistance. Overall there is modest evidence regarding the protective effects of nutrients from supplements against a number of cancers. Numerous scientific literatures available advocate the use of polyphenols for chemoprevention. Some groups have also suggested use of combination of nutrients in cancer prevention. However, we have yet to obtain the desired results in the line of cancer chemotherapy research. Nanotechnology can play a pivotal role in cancer treatment and prevention. Moreover, nanoparticles can be modified in various ways to prolong circulation, enhance drug localization, increase drug efficacy, and potentially decrease the chances of multidrug resistance. In this communication, we will cover the use of various polyphenols and nutrients in cancer chemoprevention. The application of nanotechnology in this regard will also be included. In view of available reports on the potential of nanoparticles, we suggest their usage along with different combination of nutrients as cancer chemotherapeutic agents.
Cysteine proteinase inhibitors are of prime physiologic importance inside the cells, controlling the activities of lysosomal cysteine proteases. The present work aimed to realize the effects of nitric oxide on the structure and function of goat lung cystatin (GLC) and to evaluate antinitrostative efficacy of curcumin and quercetin. Nitric oxide induced structural modifications were followed by fluorescence spectroscopy and PAGE and functional inactivation by monitoring the inhibition of caseinolytic activity of papain. Ten millimolar sodium nitroprusside (SNP) caused time dependent inactivation of GLC-I with complete functional loss precipitating at 180 min. Curcumin (50 μM) and quercetin (250 μM) opposed such loss in papain inhibitory activity of GLC-I. Loss in tertiary structure of GLC-I (fluorescence quenching and 15 nm red shift) was observed on SNP treatment. Inhibition of functional and structural SNP mediated damage of GLC-I by curcumin (50 μM) and quercetin (250 μM) reaffirms their NO scavenging potency.
Background: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control the pupillary light reflex (PLR) and synchronize sleep-wake cycles, melatonin secretion, and metabolic processes to the 24-h day. PLR abnormalities in diabetic retinopathy (DR) suggest ipRGC dysfunction. We explored whether ipRGC dysfunction in DR is associated with impaired sleep, circadian rhythms and metabolic functioning. Methods: Healthy controls (n=6), type 2 diabetes (T2D) without DR (n=8), or T2D with at least moderate DR (n=11) participated. PLR inferred ipRGC function, HbA1c, and nocturnal urinary 6-sulfatoxymelatonin (aMT6s/creatinine ratio) were measured. Sleep was recorded by 7-day actigraphy. Dim light melatonin onset (DLMO) was assessed by sampling saliva in the 7 hours before self-reported bedtime. Results: Mean age was 54.6±5.4 yr. The relative PLR was significantly smaller in T2D-DR (control vs. T2D-noDR vs. T2D-DR: 0.32(0.10) vs. 0.26 (0.09) vs. 0.13 (0.11), p=0.003). Nocturnal aMT6s [8.3 (3.1) vs. 14.6 (14.3) vs. 1.9 (2.1) ng/mg, p=0.001] was significantly lower in T2D-DR. Sleep was more disturbed in T2D-DR than others as reflected by higher wake time after sleep onset (p=0.024), higher fragmentation index (p=0.007) and lower sleep efficiency (p=0.030). HbA1c was similar between T2D groups. T2D-DR were more likely to have no detectable rise of salivary melatonin in the evening (normal 16% vs. DM-noDR 14% vs. DM-DR 67%, p=0.049). Smaller PLRs correlated with lower aMT6s (r=0.652, p=0.001). Among T2D, lower aMT6s and smaller PLR associated with lower sleep efficiency (p=0.029-0.046) and more fragmented sleep (p=0.028-0.066). There was no relationship between PLR or aMT6s with HbA1c in T2D. PLR was smaller in those without vs. with DMLO [0.11 (0.09) vs. 0.29 (0.09), p<0.001]. Conclusion: T2D with DR had dysregulated melatonin rhythm and disrupted sleep, which significantly correlated with the degree of ipRGC dysfunction. Disclosure S. Reutrakul: None. J.C. Park: None. F. Chau: None. T. Baynard: None. M. Priyadarshini: None. S. Crowley: None. J. McAnany: None. Funding University of Illinois at Chicago
Background: Gut microbiota is increasingly recognized as a powerful regulator of host physiology. Most of its effects are mediated through metabolites acting as energy sources, signaling receptor ligands and substrates for host enzymes. Owing to the meta-stability and high amenability of the gut microbiota to modification by diet and environment predicting specific gut microbes or its metabolites responsible for different host metabolic states is often confounded. Keywords: Cardiovascular disease, carnitine, choline, gut microbiota, trimethylamine, trimethylamine-N-oxide.
G protein-coupled receptors have been well described to contribute to the regulation of glucose-stimulated insulin secretion (GSIS). The short-chain fatty acid-sensing G protein-coupled receptor, free fatty acid receptor 2 (FFAR2), is expressed in pancreatic β-cells, and in rodents, its expression is altered during insulin resistance. Thus, we explored the role of FFAR2 in regulating GSIS. First, assessing the phenotype of wild-type and Ffar2(-/-) mice in vivo, we observed no differences with regard to glucose homeostasis on normal or high-fat diet, with a marginally significant defect in insulin secretion in Ffar2(-/-) mice during hyperglycemic clamps. In ex vivo insulin secretion studies, we observed diminished GSIS from Ffar2(-/-) islets relative to wild-type islets under high-glucose conditions. Further, in the presence of acetate, the primary endogenous ligand for FFAR2, we observed FFAR2-dependent potentiation of GSIS, whereas FFAR2-specific agonists resulted in either potentiation or inhibition of GSIS, which we found to result from selective signaling through either Gαq/11 or Gαi/o, respectively. Lastly, in ex vivo insulin secretion studies of human islets, we observed that acetate and FFAR2 agonists elicited different signaling properties at human FFAR2 than at mouse FFAR2. Taken together, our studies reveal that FFAR2 signaling occurs by divergent G protein pathways that can selectively potentiate or inhibit GSIS in mouse islets. Further, we have identified important differences in the response of mouse and human FFAR2 to selective agonists, and we suggest that these differences warrant consideration in the continued investigation of FFAR2 as a novel type 2 diabetes target.
The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut microbiome. We, along with other laboratories, have explored how SCFAs and their cognate receptors affect various metabolic conditions, including obesity, type 2 diabetes, and metabolic syndrome. Though gut microbiome and SCFA-level changes have been reported in T1D and in mouse models of the disease, the role of SCFA receptors in T1D remains under explored. In this review article, we will highlight the existing and possible roles of these receptors in T1D pathology. We conclude with a discussion of SCFA receptors as therapeutic targets for T1D, exploring an exciting new potential for novel treatments of glucometabolic disorders.
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