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Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. Potential mechanisms of insulin resistance in muscle cells The importance of fatty acids in the development of type 2 diabetes. Fatty Acid Signalling and insulin secretion in the ? -cell Fatty Acid Signalling in the ? -cell and insulin secretion. Summary ^ Fat Storage (especially visceral adipose tissue) ^ FFA ^ Adipokines ^ FFA ^ Adipokines v Adiponectin ? cell failure Insulin Resistance Impaired Glucose Tolerance Diabetes Positive Energy Balance Modified from: The importance of fatty acids in the development of type 2 diabetes. Clipping is a handy way to collect and organize the most important slides from a presentation. Prof John Betteridge reviews the impact of various diabetic drugs on glycemic control, vascular prevention and Beta cell function. Prof John Betteridge, London, discusses the evolution of diabetes therapy, the epidemic rise in diabetes, current and emerging diabetes therapies. This meta-analysis of all prospective CV outcome trials with DPP-4 inhibitors provided more reliable data regarding the overall CV safety and the effect of DPP-4 inhibitors on specific CV and important non-CV endpoints. In the TECOS-trial (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) with the DPP-4 inhibitor sitagliptin, the primary endpoint of non-inferiority for the composite cardiovascular endpoint was met. Linagliptin was well tolerated including in the elderly with normal renal function to severe renal impairment; overall incidence of adverse events was similar for linagliptin compared to placebo. Lancet, Jan 2013, The DURATION-6 trial compared the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes.
In high-risk patients with type 2 diabetes and previous stroke, pioglitazone significantly reduced the occurrence of recurrent fatal and nonfatal stroke. Will pioglitazone stabilize carotid artery vulnerable plaque in patients with acute coronary syndromes (ACS) and type 2 diabetes? Treatment with pioglitazone to improve insulin sensitivity, reduced stroke and MI in patients with insulin resistance but without diabetes and who have experienced ischaemic stroke or TIA.
In patients with type 2 diabetes and angiographic coronary artery disease, treatment with pioglitazone resulted in larger LDL particle size and decreasing concentrations, associated with less plaque progression. A 10-year post-marketing study in patients with type 2 diabetes demonstrated no statistically significant increased risk of bladder cancer to patients exposed to pioglitazone.
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Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors.
In 2013, 382 million people worldwide were characterized as diabetic patients with around 90% of patients diagnosed with type 2 diabetes (T2D), a metabolic disorder intrinsically linked with obesity (1). Acute FFA-mediated insulin secretion from isolated human and rodent islets involves amplification of the second phase of GSIS (5, 6, 15, 20). Although there are currently no FFA1 agonists approved for clinical use, considerable interest developed around Fasiglifam (designated TAK-875 in pre-clinical studies, Figure 2), an orally available FFA1 agonist developed by Takeda (30–32) (Table 1).
The ability of synthetic FFA1 agonists to induce significant incretin release was recently shown to depend upon whether the compound was a partial or full agonist (8, 10, 40) (Figure 1). Although no issues were raised regarding safety and tolerability during Phase I and II trials, Fasiglifam was recently withdrawn from phase III trials due to potential liver toxicity (43) (Table 1).
A recent study indicated that, in addition to the previously described insulin-sensitizing effects associated with GLP-1 release, improved systemic insulin sensitivity may also be associated with FFA4-mediated anti-inflammatory effects on macrophages (56) (Figure 1). Initial synthetic FFA4 agonists, including GW9508, NCG21 (Figure 2), and NCG46 (Table 1), showed significant dual agonism at FFA1 (70).
High fiber intake protects against obesity and T2D via SCFA production, particularly butyrate, acetate, and propionate, from bacterial fermentation of dietary fiber in the large intestine (74).
Complete elucidation of the metabolic effects of FFA2 and FFA3 has, however, been complicated by conflicting results using FFA2 and FFA3 null mice.
This molecule of glycerol and one fatty acid is now called 2-monoacylglycerol (2-monoglyceride, old name).
A model for the pathogenesis of type 2 diabetes involving adipose tissue, the pancreas and NLRP3. Figure 1: A model for the pathogenesis of type 2 diabetes involving adipose tissue, the pancreas and NLRP3. Department of Microbiology and Immunology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Center for Translational Immunology and Institute of Inflammatory Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. Neither the service provider nor the domain owner maintain any relationship with the advertisers. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience.
Selective synthetic ligands for free fatty acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). T2D is defined by insulin resistance in peripheral tissues, such as the liver and muscle, and a loss of pancreatic beta-cell function, resulting in insufficient insulin secretion (2), and constitutes a risk factor for health issues including cardiovascular disease, impaired wound healing, blindness, and renal failure (1).
FFA1 is also expressed by various enteroendocrine cells where it regulates the release of incretin hormones such as glucagon-like peptide-1 (GLP-1), an insulinotropic, anorectic peptide that reduces gastric emptying and motility, as well as cholecystokinin (CCK), shown to regulate pancreatic secretion, inhibit gastric motility, and reduce energy intake (7–10) (Figure 1).
This is reduced by approximately 50% in FFA1-null mice, with the remaining effect attributed to intracellular metabolism of FFAs (5, 6, 15, 20). Similarly, Amgen and Eli Lilly removed AMG-837 and LY2881835 (Table 1; Figure 2), respectively from Phase I clinical trials due to concerns over toxicity (43).
Within adipose tissue, FFA4 gene expression is upregulated following a HFD and FFA4 activation in adipocytes is associated with increased adipogenesis and glucose uptake (54–56), suggesting that FFA4 activation may promote adiposity and obesity (Figure 1). In this study, FFA4 expression in macrophages was elevated in response to obesity and FFA4 activation decreased pro-inflammatory gene expression in M1 macrophages and increased expression of M2 anti-inflammatory genes with reduced macrophage infiltration of adipose tissues also observed in FFA4 null mice due to decreased chemotaxis (56).
However, our groups have recently reported on TUG-891, a potent and selective FFA4 agonist (55, 71) (Table 1, Figure 2), although TUG-891 is significantly less selective for murine FFA4 compared to murine FFA1, potentially limiting its use in pre-clinical in vivo studies in mice (71).
Moreover, modulation of gut microbiota using pre- and probiotics in both mice and humans regulates body weight, appetite, and glucose homeostasis (74).


For example, in one study, HFD-fed FFA2 null mice display lower body fat mass and improved glucose control compared to wild-type mice, indicating a role for FFA2 antagonists in the treatment of T2D (84). The accumulation of dysfunctional mitochondria then enhances mitochondrial generation of ROS and the release of mitochondrial DNA into the cytosol, both of which promote activation of the NLRP3 inflammasome and release of IL-1β (p17 subunit).
In case of trademark issues please contact the domain owner directly (contact information can be found in whois). In particular, clinical studies show that Fasiglifam, an agonist of the long-chain FFA receptor, FFA1, improved glycemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. Although T2D can sometimes be controlled through strict diet regulation, a large number of patients require clinical therapies.
FFA1 is also present within the central nervous system (CNS) (11, 12) although whether neuronal FFA1 contributes to the regulation of glucose homeostasis remains to be fully determined (Figure 1). Dietary FFAs, such as ω-3 fatty acids from fish oils and SCFAs derived from the fermentation of dietary fiber, have profound effects on metabolic and inflammatory processes associated with obesity and T2D.
In contrast, transgenic overexpression of FFA1 under the control of the mouse insulin II promoter prevents development of hyperglycemia and improves insulin secretion and glucose tolerance in diabetic mouse models (21). Crucially, although these effects were comparable to current sulfonylurea treatments, Fasiglifam was associated with markedly less side effects, with no significant increases in body weight and a reduced concomitant incidence of hypoglycemia (32–36). A number of academic and industrial drug programs are aimed at developing FFA receptor agonists for the treatment of T2D.
In contrast, Amgen described AM-1638 and AM-5262 (Table 1; Figure 2) as full FFA1 agonists that directly stimulate insulin secretion and promote incretin release from enteroendocrine cells (39, 41, 42) (Figure 1).
However, the pre-clinical and clinical data generated using Fasiglifam provides a strong rationale and validation for further studies into the potential use of FFA1 agonism as a novel treatment for T2D.
However, mutation of FFA4 (p.R270H variant) is associated with an increased risk of obesity in European populations (although this variant is almost absent in a Japanese population), and young FFA4 null mice fed a HFD gained significantly more fat mass than their wild-type littermates, suggesting that FFA4 protects against diet-induced obesity (57).
These anti-inflammatory effects are largely associated with FFA4-mediated recruitment of β-arrestin 2, a scaffold protein typically associated with receptor desensitization and internalization that is also implicated in the regulation of distinct signaling pathways (56, 66, 67). Recent modeling and mutational efforts have, however, clearly defined how TUG-891 interacts with FFA4 (72), information that will be invaluable in developing novel ligands with improved pharmacological properties for this receptor. Contrastingly, FFA2 null mice were also shown to be obese on a normal diet, with reduced insulin sensitivity and marked insulin resistance whereas adipocyte-specific overexpression of FFA2 resulted in lower body weight in a HFD study (85). The majority of portal supply to hepatic free fatty acids derives from dietary fat and the rest from visceral fat. A high concentration of glucose has been shown to promote the production of IL-1β by pancreatic beta cells but not by macrophages. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Current treatments, such as metformin, sulfonylureas, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors, are deployed primarily to either improve insulin secretion, peripheral insulin sensitivity, or both (3). FFA1 expression has also been reported in glucagon-producing alpha cells within the pancreas, although this remains controversial (13–17).
These effects have, at least in part, been attributed to the activation of free fatty acid receptors (FFA1–4), leading to a great deal of interest in the development of synthetic FFA receptor agonists for the treatment of metabolic disease. As anticipated from this, GW9508, a synthetic FFA1 agonist (Table 1) stimulated GSIS in pancreatic MIN6 cells (22).
This is consistent with pre-clinical data demonstrating that Fasiglifam improved fasting hyperglycemia and glucose tolerance and augmented GSIS in diabetic rat models, with no hypoglycemia observed in normoglycemic rats (31).
A representative selection of the current range of synthetic agonists that have so far been developed for these receptors are shown. This incretin-stimulating effect was abolished in FFA1 knockout mice and the effect of AM-1638 on glucose homeostasis was attenuated by the GLP-1R antagonist, Ex(9–39)NH2, indicating a particularly key role for GLP-1 (39). Currently, Japan Tobacco are conducting Phase II clinical trials with their FFA1 agonist candidate, JTT-851 and Piramal have begun Phase I clinical trials on their FFA1 agonist, P11187 (43) (Table 1). FFA4 agonism is also commonly associated with improved insulin sensitivity, with FFA4 null mice reported to have increased fasting glucose and impaired responses to insulin and glucose tolerance testing (56, 57) (Figure 1).
In the case of FFA4, β-arrestin 2 interacts with TAB1 that, in turn, inhibits lipopolysaccharide (LPS)- and tumor necrosis factor (TNF)-alpha-induced TAK1 stimulation, thereby blocking toll-like receptor 4 (TLR4) and the TNF-alpha inflammatory pathways (56, 66, 67).
To date, no FFA4 agonists have entered clinical trials although a number of FFA4 agonist programs are ongoing. Similarly, the loss of FFA3 either resulted in weight loss, obesity, or had no effect in different studies (86–88). Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss, and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. However, there remains a demand for distinct, safe, and effective treatments for T2D, with the current therapies often associated with side effects including hypoglycemia and weight gain. FFA1 expression has also been well characterized in taste buds where it mediates, in part, taste preference for fatty acids, although the significance of this, and possible effects of pharmacological activation or blockade, remains to be fully elucidated (18, 19) (Figure 1).
Agonism of the long-chain FFA receptor FFA1, the most fully characterized of these receptors, improves glucose-stimulated insulin secretion from the pancreas. FFA1 gene expression is also reduced under glucolipotoxic conditions in rats and in islets from T2D patients while a rare mutation in the human FFA1 gene is associated with attenuated lipid-mediated enhancement of GSIS (23–25). No changes in insulin resistance have been reported in response to Fasiglifam treatment (37, 38) and Fasiglifam had no effect on glucagon secretion in isolated human islets and did not alter glucagon levels in T2D patients (39). Similarly, LY2881835, a full FFA1 agonist from Eli Lilly (Table 1), increased GSIS, lowered blood glucose levels, and increased GLP-1 secretion in animal models (43).
Daiichi Sanyko also recently described 3-aryl-3-ethoxypropanoic acids as orally active FFA1 agonists that improve insulin secretion and glucose homeostasis in rats (44). A number of these metabolic effects, such as increased insulin secretion, satiety, and improved glycemic control, have been attributed, at least in part, to FFA4-dependent incretin release from enteroendocrine cells, particularly GLP-1 (4, 54, 55, 58) (Figure 1).
Interestingly, recent studies have also reported FFA4-mediated anti-inflammatory effects within the brain. However, the relative potency and preference for various SCFAs appears to vary significantly across species (81, 82). Hence, the development of more potent and selective FFA2 and FFA3 agonists will hopefully facilitate the elucidation of the metabolic effects of FFA2 and FFA3 and ultimately provide future treatments for T2D. In the pancreas, the accumulation of IAPP activates the NLRP3 inflammasome and promotes the release IL-1β from macrophages, which causes beta-cell dysfunction and death.
In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programs within industry and academia aimed at improving the safety and effectiveness of these potential treatments.


Naturally occurring free fatty acids (FFAs) found in the diet, including ω-3 fatty acids, have profound effects on metabolic and inflammatory processes associated with T2D, although the molecular basis for these effects are complex and incompletely understood (4).
Additionally, full agonists of this receptor increase incretin release from the gut, thereby indirectly increasing pancreatic insulin secretion, as well as improving systemic insulin sensitivity and promoting satiety. The effects of FFA1 on pancreatic beta cell viability, however, has been controversial, with pancreatic-specific FFA1 overexpression associated with disrupted islet morphology and impaired beta cell function whereas FFA1 disruption is linked with increased beta cell viability in mice fed on a high-fat diet (HFD) (26). Importantly, prolonged Fasiglifam exposure was also not associated with beta cell dysfunction or apoptosis (31). Amgen demonstrated that multiple ligand binding pockets exist on FFA1, comprising of up to two allosteric sites as well as the FFA binding orthosteric site (40). Additionally, FFA1 agonists developed by Astellas are reported to have beneficial effects on glucose homeostasis in diabetic mouse models (45, 46). SCFA-triggered secretion of GLP-1 was almost completely abolished in primary colonic cultures from FFA2 null mice and reduced, to a lesser extent, in mice lacking FFA3 (76). Agonism of another long-chain FFA receptor, FFA4, is associated with incretin release from the gut, as well as an anti-inflammatory effect on macrophages that, in turn, may improve systemic insulin sensitivity.
These observations promoted the concept that, at least in the longer term, FFA1 antagonism could be beneficial in the treatment of diabetes. One allosteric site is targeted by compounds such as AM-837 and TAK-875 while the second allosteric site is a target for receptor agonists such as AM-1638 that act as full agonists. Sanofi and Boehringer-Ingelheim are also reported to have FFA1 agonist programs under development (43). Similarly, TUG-891 (Figure 2), a potent FFA4 agonist (see below), also increased GLP-1 secretion from STC-1 and GLUTag enteroendocrine cells (55).
Similarly, GSK has recently described a series of diarylsulfonamides as FFA4 agonists (73) and Metabolex has reported that their series of dihydrobenzofuran-based FFA4 agonists improved glucose homeostasis in mice, with moderate glucose-lowering effects in mice shown with a separate series of FFA4 agonists (66). FFA2 is expressed in adipose tissue, intestine, islet cells, enteroendocrine cells, and immune cells while FFA3 is highly expressed in the small intestine, colon, and pancreas (4).
Small carboxylic acids derived from the natural SCFA ligands have shown appreciable and predictable selectivity but have low potency (80). Many of the biological effects of FFAs have now been attributed, at least in part, to FFAs interacting with a group of G protein-coupled receptors (GPCRs) designated the FFA receptors. In the pancreas, FFA4 is associated with reduced cell apoptosis and FFA4 has recently been detected in alpha and delta cells and regulates glucagon and somatostatin release, respectively. However, most subsequent pre-clinical studies contradict these findings, indicating that FFA1 agonism has no detrimental effects on beta cell viability (16, 20, 21), or even protects beta cells (27–29). Consequently, positive co-operativity was shown between either AMG-837 or AM-1638 in conjunction with natural FFA ligands in cell based assays measuring second-messenger generation, as well as primary cell based assays, with positive co-operativity also reported between AMG-837 and AM-1638 during an oral glucose tolerance test in a diabetic rodent model (40).
In an academic context, the University of Southern Denmark have developed 4-(benzylamine)hydrocinnamic acid FFA1 agonists such as TUG-469 (47, 48) and 4-alkyne hydrocinnamic acid FFA1 agonists, including TUG-424 and TUG-770 (49–51) (Table 1). However, a recent study has questioned the significance of FFA4-mediated GLP-1 release (59). Additionally, Kindex Therapeutics described beneficial effects in the treatment of obesity, inflammation, and metabolic disorders with alpha acids that were reported to act both as FFA4 agonists and also as partial PPARγ agonists (66). FFA2 expression levels are also elevated in the skeletal muscle, liver, and adipose tissue of HFD-fed rodents, with FFA2 shown to regulate adipogenesis and adipocyte differentiation and inhibit lipolysis (83) (Figure 1). The most well-characterized FFA receptors are the two LCFA-specific receptors, FFA1 and FFA4, and the SCFA-specific receptors FFA2 and FFA3. Both FFA1 and FFA4 have been detected in taste buds although the full implications of this in relation to obesity remain to be determined. Within these programs, several strategies have been followed to reduce compound lipophilicity (48, 52, 53).
FFA4 also co-localizes with the orexigenic peptide, ghrelin, in duodenal cells in vivo, with recent studies showing that FFA4 activation inhibits ghrelin secretion (60, 61).
However, the clinical use of these drugs was deemed to be limited due to low solubility and poor pharmacokinetics (90).
The relationship of Body Mass Index to Diabetes Mellitus, Hypertension and Dyslipidaemia: Comparison of data from two national surveys. FFA receptor agonism, particularly of the FFA1 receptor, has subsequently been shown to have beneficial metabolic effects (4).
Consequently, TUG-770 (Figure 2) has recently been described as a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties, improving glucose tolerance in diet-induced obese mice. Orthosteric FFA2 agonists and antagonists have also now been reported (82, 91) and used to demonstrate a role for this receptor in improved glucose uptake, decreased colon motility and contractility, increased GLP-1 secretion, and inhibiting leukocyte activation (81, 82, 89, 92). Consequently, a number of ongoing industrial and academic programs are focused upon developing potent and selective synthetic agonists of FFA1.
Both receptors have been linked with incretin release from enteroendocrine cells, as well as both systemic anti- and pro-inflammatory effects. This effect did not desensitize, being fully maintained after 29 days of chronic dosing (49). FFA4 expression has also recently been detected in delta cells and alpha cells within the pancreas and was consequently linked with the inhibition of glucose-dependent somatostatin release and the regulation of glucagon secretion, respectively (63, 64) (Figure 1).
FFA3 agonists are even less developed although Arena Pharmaceuticals has reported a series of FFA3-selective compounds (89) (Table 1). Although currently less developed, activation of each of FFA2, FFA3, and FFA4 has also been suggested to have potential benefits for metabolic function. However, due to conflicting results using receptor-specific knockout models and a limited selection of pharmacological tools, more work is required to elucidate the physiological effects of FFA2 and FFA3 agonism. Similar to FFA1, FFA4 is also expressed in taste buds and is linked with the regulation of taste preference although, again, the significance of this in relation to obesity and T2D remains to be clarified (65) (Figure 1). In this review, we will therefore discuss the potential of FFA receptor agonists as novel clinical treatments for T2D.
Hence, although recent microbiota studies highlight quite elegantly the role that gut-derived SCFAs can play in the regulation of metabolism, there still remains a great demand for improved FFA2 and FFA3 agonists to fully unravel and define the consequences of activation of these receptors for metabolic health.
Fasting plasma free fatty acids and risk of type 2 diabetes: the atherosclerosis risk in communities study.



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