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fatty acids and insulin-secreting cells

Shlomo Sasson
Activated peroxisome proliferator-activated receptor-δ (PPARδ) induces the expression of genes encoding enzymes that metabolize fatty acids and carbohydrate. Attempts to identify cellular activators of PPARδ produced large lists of various fatty acids and their metabolic derivatives; however, there is no consensus on specific and selective binding interactions of natural ligands with PPARδ. Most models on binding interactions within the ligand binding domain (LBD) of PPARδ have been derived from analyses of PPARδ-LBD crystals formed with synthetic low molecular weight ligands...
October 18, 2016: Biochimie
Christoph Nowak, Samira Salihovic, Andrea Ganna, Stefan Brandmaier, Taru Tukiainen, Corey D Broeckling, Patrik K Magnusson, Jessica E Prenni, Rui Wang-Sattler, Annette Peters, Konstantin Strauch, Thomas Meitinger, Vilmantas Giedraitis, Johan Ärnlöv, Christian Berne, Christian Gieger, Samuli Ripatti, Lars Lind, Nancy L Pedersen, Johan Sundström, Erik Ingelsson, Tove Fall
Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test...
October 2016: PLoS Genetics
Attilio Pingitore, Edward S Chambers, Thomas Hill, Inmaculada Ruz Maldonado, Bo Liu, Gavin Bewick, Douglas J Morrison, Tom Preston, Gareth A Wallis, Catriona Tedford, Ramón Castañera González, Guo Cai Huang, Pratik Choudhary, Gary Frost, Shanta J Persaud
AIMS: Diet-derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the effects of increasing colonic delivery of the SCFA propionate on β-cell function in humans and the direct effects of propionate on isolated human islets in vitro. MATERIALS AND METHODS: For 24 weeks human subjects ingested an inulin-propionate ester that delivers propionate to the colon...
October 20, 2016: Diabetes, Obesity & Metabolism
Takafumi Hara
FFA1 is a G protein-coupled receptor activated by medium- to long-chain fatty acids. FFA1 plays important roles in various physiological processes such as insulin secretion and energy metabolism. FFA1 expressed on pancreatic β-cells and intestine contributes to insulin and incretin secretion, respectively. These physiological functions of FFA1 are interesting as an attractive drug target for type II diabetes and metabolic disorders. A number of synthetic FFA1 ligands have been developed and they have contributed to our current understanding of the physiological and pathophysiological functions of FFA1 both in in vitro and in vivo studies...
October 19, 2016: Handbook of Experimental Pharmacology
Chafiq Hamdouchi, Steven D Kahl, Anjana Patel Lewis, Guemalli R Cardona, Richard W Zink, Keyue Chen, Thomas E Eessalu, James V Ficorilli, Marialuisa C Marcelo, Keith A Otto, Kelly L Wilbur, Jayana P Lineswala, Jared L Piper, D Scott Coffey, Stephanie A Sweetana, Joseph V Haas, Dawn A Brooks, Edward J Pratt, Ruth M Belin, Mark A Deeg, Xiaosu Ma, Ellen A Cannady, Jason T Johnson, Nathan P Yumibe, Qi Chen, Pranab Maiti, Chahrzad Montrose-Rafizadeh, Yanyun Chen, Anne Reifel Miller
The G protein-coupled receptor 40 (GPR40) also known as Free Fatty Acid Receptor 1 (FFAR1) is highly expressed in pancreatic, islet cells and responds to endogenous fatty acids resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity and pharmacokinetic properties...
October 17, 2016: Journal of Medicinal Chemistry
Valérie Bergeron, Julien Ghislain, Vincent Poitout
Free fatty acid receptor 1 (FFA1/GPR40) plays a key role in the potentiation of glucose-stimulated insulin secretion by fatty acids in pancreatic beta cells. We previously demonstrated that GPR40 signaling leads to cortical actin remodeling and potentiates the second phase of insulin secretion. In this study, we examined the role of p21 activated kinase 4 (PAK4), a known regulator of cytoskeletal dynamics, in GPR40-dependent potentiation of insulin secretion. The fatty acid oleate induced PAK4 phosphorylation in human islets, in isolated mouse islets and in the insulin secreting cell line INS832/13...
October 4, 2016: Islets
U Smith, B B Kahn
Obesity, the major cause of the current global epidemic of type 2 diabetes (T2D), induces insulin resistance in peripheral insulin target tissues. Several mechanisms have been identified related to cross-talk between adipose tissue, skeletal muscle and liver. These mechanisms involve both increased free fatty acid release and altered secretion of adipokines from adipose tissue. A major determinant of metabolic health is the ability of subcutaneous adipose tissue (SAT) to store excess fat rather than allowing it to accumulate in ectopic depots including liver (i...
October 3, 2016: Journal of Internal Medicine
Mahmoud El Azzouny, Melissa J Longacre, Israr-Ul H Ansari, Robert T Kennedy, Charles F Burant, Michael J MacDonald
OBJECTIVE: Glucose-stimulated insulin secretion in pancreatic beta cells requires metabolic signals including the generation of glucose-derived short chain acyl-CoAs in the cytosol from mitochondrially-derived metabolites. One concept of insulin secretion is that ATP citrate lyase generates short chain acyl-CoAs in the cytosol from mitochondrially-derived citrate. Of these, malonyl-CoA, is believed to be an important signal in insulin secretion. Malonyl-CoA is also a precursor for lipids...
October 2016: Molecular Metabolism
B Hayward, J C Molero, K Windmill, A Sanigorski, J Weir, N L McRae, K Aston-Mourney, B Osborne, B Liao, K R Walder, P J Meikle, N Konstantopoulos, C Schmitz-Peiffer
The pathways through which fatty acids induce insulin resistance have been the subject of much research. We hypothesise that by focussing on the reversal of insulin resistance, novel insights can be made regarding the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered during the prevention of palmitate-induced glucose production in hepatocytes using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0...
September 29, 2016: Experimental and Clinical Endocrinology & Diabetes
Y J Deng, S L Zhang, P M Liu, L F Mai, J Y Tang, L Yan
Objective: To compare the incidence of metabolic disorders and uric acid (UA) levels between patients with primary aldosteronism (PA) and essential hypertension (EH), and to explore factors associated with UA levels in these patients. Methods: A total of 117 PA and 117 EH patients individually matched by sex, age, blood pressure and duration of hypertension were recruited from in-hospital patients who were hospitalized in our department because of suspicion of secondary hypertension from January 2008 to December 2014...
September 24, 2016: Zhonghua Xin Xue Guan Bing za Zhi
Sadeesh K Ramakrishnan, Lucia Russo, Simona S Ghanem, Payal R Patel, Ana Maria Oyarce, Garrett Heinrich, Sonia M Najjar
High-fat diet reduces the expression of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane glycoprotein that promotes insulin clearance and downregulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptoralpha (PPARalpha) transcriptionally suppresses CEACAM1 expression, we herein examined whether high-fat downregulates CEACAM1 expression in a PPARalpha;-dependent mechanism. By activating PPARalpha, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation...
September 23, 2016: Journal of Biological Chemistry
Jun Sung Moon, Udayakumar Karunakaran, Suma Elumalai, In-Kyu Lee, Hyoung Woo Lee, Yong-Woon Kim, Kyu Chang Won
AIM/HYPOTHESIS: Cluster determinant 36 (CD36), a fatty acid transporter, was reported to have a pivotal role in glucotoxicity-induced beta cell dysfunction. However, little is known about how glucotoxicity influences CD36 expression, and it is unknown whether this action can be counteracted by metformin. In the present study, we showed that metformin counteracts glucotoxicity by alleviating oxidative and endoplasmic reticulum (ER) stress-induced CD36 expression. METHODS: We used primary rat islets as well as INS-1 cells for 72h to 24h with 30mM glucose, respectively...
September 9, 2016: Journal of Diabetes and its Complications
Kyung-Ah Cho, Minhwa Park, Yu-Hee Kim, So-Youn Woo, Kyung-Ha Ryu
Saturated free fatty acids (FFAs) act as lipid mediators and induce insulin resistance in skeletal muscle. Specifically, in obesity-related diseases such as type 2 diabetes, FFAs directly reduce insulin sensitivity and glucose uptake in skeletal muscle. However, the knowledge of how FFAs mediate inflammation and subsequent tissue disorders, including fibrosis in skeletal muscle, is limited. FFAs are a natural ligand for toll-like receptor 2 (TLR2) and TLR4, and induce chronic low-grade inflammation that directly stimulates skeletal muscle tissue...
September 13, 2016: Journal of Cellular and Molecular Medicine
A Motterle, C Sanchez-Parra, R Regazzi
Pancreatic β-cells are highly specialized cells committed to secrete insulin in response to changes in the level of nutrients, hormones and neurotransmitters. Chronic exposure to elevated concentrations of glucose, fatty acids or inflammatory mediators can result in modifications in β-cell gene expression that alter their functional properties. This can lead to the release of insufficient amount of insulin to cover the organism's needs, and thus to the development of diabetes mellitus. Although most of the studies carried out in the last decades to elucidate the causes of β-cell dysfunction under disease conditions have focused on protein-coding genes, we now know that insulin-secreting cells also contain thousands of molecules of RNA that do not encode polypeptides but play key roles in the acquisition and maintenance of a highly differentiated state...
September 2016: Diabetes, Obesity & Metabolism
Xiwen Xiong, Xupeng Sun, Qingzhi Wang, Xinlai Qian, Yang Zhang, Xiaoyan Pan, Xiaocheng Charlie Dong
Chronic exposure of pancreatic β-cells to abnormally elevated levels of free fatty acids can lead to β-cell dysfunction and even apoptosis, contributing to type 2 diabetes pathogenesis. In pancreatic β-cells, SIRT6 has been shown to regulate insulin secretion in response to glucose stimulation. However, what roles SIRT6 play in β-cells in response to lipotoxicity remain poorly understood. Our data indicated that SIRT6 protein and mRNA levels were reduced in islets from diabetic and aged mice. High concentrations of palmitate also led to a decrease in SIRT6 expression in MIN6 β-cells and resulted in cell dysfunction and apoptosis...
September 6, 2016: Journal of Endocrinology
Agata Mierzwicka, Marek Bolanowski
Among new peptides responsible for the pathogenesis of metabolic disorders and carbohydrate metabolism, adipokines are of great importance. Adipokines are substances of hormonal character, secreted by adipose tissue. Apart from the well-known adipokines, adropin and preptin are relatively newly discovered, hence their function is not fully understood. They are peptides not secreted by adipose tissue but their role in the metabolic regulations seems to be significant. Preptin is a 34-amino acid peptide, a derivative of proinsulin growth factor II (pro-IGF-II), secreted by pancreatic β cells, considered to be a physiological enhancer of insulin secretion...
2016: Postȩpy Higieny i Medycyny Doświadczalnej
Julia M Houthuijzen
Increased energy intake can lead to obesity, which increases the risk for the development of diabetes and cancer. Free fatty acids regulate numerous cellular processes like insulin secretion, inflammation, proliferation and cell migration. Dysregulation of these cellular functions by increased lipid intake plays a significant role in the development of diseases like diabetes and cancer. FFAR1 and FFAR4 are two free fatty acid receptors that are under increasing investigation for their roles in diabetes and more recently also cancer...
August 31, 2016: Molecular Pharmacology
Steven K Malin, Sangeeta R Kashyap
Bariatric surgery is a gastrointestinal procedure that has emerged as the most effective treatment for weight loss. Roux-en-Y gastric bypass and sleeve gastrectomy are the main procedures currently performed. However, the benefits of bariatric surgery extend beyond weight loss. In fact, improvements in β-cell function occur before clinically meaningful weight loss and contribute to type 2 diabetes mellitus (T2D) remission. Herein, we discuss evidence supporting the efficacy of bariatric surgery for weight loss and improved insulin secretion in patients with and without T2D...
July 2016: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
Anna Veprik, Dana Laufer, Sara Weiss, Nir Rubins, Michael D Walker
Insulin secretion by pancreatic β-cells is primarily regulated by glucose; however, hormones and additional nutrients, such as long-chain fatty acids, also play an important role in adjusting insulin output to physiologic needs. To examine the role of short-chain fatty acids (SCFAs) in β-cell function, we analyzed mouse models of gain and loss of function of GPR41 (FFAR3), a receptor for SCFAs, vs. wild-type control mice. GPR41 gain of function (41 Tg) and GPR41 loss of function (KO 41) resulted in complementary changes in glucose tolerance, without significant effects on insulin sensitivity...
August 22, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Reza Nemati, Jun Lu, Andrea Tura, Greg Smith, Rinki Murphy
BACKGROUND: The purpose of this study was to compare acute changes of non-esterified fatty acids (NEFA) in relation to beta cell function (BCF) and insulin resistance in obese patients with type 2 diabetes (T2D) who underwent laparoscopic gastric bypass (GBP), laparoscopic sleeve gastrectomy (SG) or very low calorie diet (VLCD). METHODS: In a non-randomised study, fasting plasma samples were collected from 38 obese patients with T2D, matched for age, body mass index (BMI) and glycaemic control, who underwent GBP (11) or SG (14) or VLCD (13)...
August 16, 2016: Obesity Surgery
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