Targeting the gastrointestinal tract to treat type 2 diabetes

in Journal of Endocrinology
View More View Less
  • 1 Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON, Canada
  • 2 Department of Physiology, University of Toronto, Toronto, ON, Canada

The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.

Abstract

The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.

Introduction

The incidence of type 2 diabetes has more than doubled since 1980, with over 382 million affected individuals worldwide, in conjunction with an increase in obesity rates and the spread of a western lifestyle (Scully 2012). Given that type 2 diabetes has many comorbidities, such as hypertension, dyslipidaemia and cardiovascular disease, which contribute to the ever-rising economic burden, it is of utmost importance to develop successful therapeutic options. Chronic hyperglycaemia is a hallmark characteristic of type 2 diabetes and is, therefore, a main target for diabetes treatment. As such, metformin remains the most prescribed drug for type 2 diabetes due to its potent antihyperglycaemic effect, largely from a reduction in hepatic glucose production (Rojas & Gomes 2013). Although its mechanism of action still remains largely debated, recent evidence suggests a major role of the gastrointestinal tract in mediating metformin’s glucose-lowering effect (Duca et al. 2015, Buse et al. 2016). Interestingly, this is not the only evidence for a therapeutic role of the gut in diabetes treatment. Over the past decade, incretin-based therapies including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-IV (DPP-IV) inhibitors have demonstrated powerful glucose-lowering efficacy, and are now commonly prescribed, usually in conjunction with metformin (Deacon & Lebovitz 2016, Madsbad 2016). Furthermore, despite being prescribed for the treatment of morbid obesity, metabolic/bariatric surgery results in rapid and sustained remission of diabetes, and is potentially more effective than conventional therapy (Mingrone et al. 2012, Mingrone et al. 2015).

The success of these treatments has expanded the classical view of the gastrointestinal (GI) tract from a ‘digestion and absorption’ organ to a major contributor to metabolic homeostasis. The GI tract exhibits crucial negative feedback signals, of both hormonal and neural origin, in response to incoming nutrients, preventing nutrient excess by suppressing food intake and endogenous nutrient production (Cote et al. 2014). The current review aims to highlight the current and potential therapeutic role of the GI tract in treating type 2 diabetes.

Gut peptide signalling in regulating glucose metabolism

Ingestion of nutrients leads to complex and integrative negative feedback mechanisms, which originate from the gut and contribute to the control of food intake, glucose metabolism, energy expenditure and thermogenesis, among other potential metabolic pathways (Bauer et al. 2016). In the case of glucose metabolism, postprandial gut-derived signals can lower hepatic glucose production, increase insulin production and secretion, reduce glucagon levels and alter glucose uptake. These signals are thought to originate from preasbsorptive nutrients being sensed on the apical surface of enteroendocrine cells (EECs) (Reimann et al. 2008), given the ‘open-type’ structure of these specialized epithelial endocrine cells. However, it is still unclear whether nutrient sensors of EECs are predominantly located on the apical side, with the possibility of basolateral nutrient sensing having been recently proposed (Christensen et al. 2015). Nonetheless, EECs can secrete gut peptides on their basolateral side in response to direct nutrient stimulation via binding to nutrient receptors localized on EECs, by intracellular metabolism and through neuroendocrine mechanisms (see Psichas et al. 2015a for extensive review). For example, fatty acids are potent secretogogues for both GLP-1 and CCK, potentially via activation of free fatty acid receptors (FFAR, FFAR1, FFAR4, activated by medium- to long-chain free fatty acids (Briscoe et al. 2003, Hirasawa et al. 2005), and FFAR2 and FFAR3, activated by short-chain fatty acids (Tolhurst et al. 2012, Psichas et al. 2015b)) localized on EECs, although the mechanisms of action appear to be more complex than originally thought. In the case of lipids, while Ffar knockout (KO) animals have severely impaired release of both GLP-1 (Edfalk et al. 2008) and CCK (Liou et al. 2011b) in response to a triglyceride challenge, it was recently demonstrated that LCFAs activate the FFAR1-Gq signalling pathway to induce only a modest release of GLP-1 (Hauge et al. 2015). However, both oleoylethanolamide and 2-monoacylglycerols, which are derived from triglycerides, activate a GPR119-Gs signalling cascade (Overton et al. 2006, Hansen et al. 2012b), leading to the hypothesis that triglyceride-induced gut peptide signalling is likely due to a combined effect of direct LCFA-FFAR1-Gq signalling and activation of the Gs signalling pathway in EECs (Hauge et al. 2015). In addition to a direct action on FFARs, fatty acids are also taken up by the intestine, and mice lacking absorptive proteins such as CD36 or FAT4 results in impaired gut peptide release (Poreba et al. 2012, Sundaresan et al. 2013). This may be due to intracellular metabolism and activation of PKC-ζ or PKC-δ to induce GLP-1 or CCK release, respectively (Iakoubov et al. 2007, Breen et al. 2011), or via alteration of cellular respiration and stimulation of glycolysis (Clara et al. 2016). The same complexity in nutrient-induced gut peptide stimulation is observed for carbohydrates. For example, carbohydrates can be sensed by the T1R2/T1R3 sweet taste receptor found in the gut (Jang et al. 2007), although the physiological relevance of sweet taste receptor activation on gut peptide signalling in humans remains debated (Parker et al. 2009). Conversely, recent work suggests that GLP-1 release occurs via uptake of glucose coupled with Na+ through the sodium/glucose cotransporter member 1 (SGLT1), inducing small currents triggered by increased Na+ which leads to membrane depolarization and voltage-gated Ca2+ entry, ultimately resulting in GLP-1 secretion (Gribble et al. 2003, Kuhre et al. 2015). Less is known about intestinal protein sensing, with GPR93, CaSR and PepT1 all being suggested to mediate protein-induced gut peptide release (Nemoz-Gaillard et al. 1998, Darcel et al. 2005, Liou et al. 2011a,c).

In the traditional view, the proximal intestine contains I-cells, which secrete CCK, and GIP-releasing K-cells, while L-cells cosecrete PYY and GLP-1 and are located mainly in the distal intestine (Little et al. 2006). However, recent work has challenged these classical views, as individual enteroendocrine cells have been shown to express a variety of gut peptides (Egerod et al. 2012, Habib et al. 2012, Svendsen et al. 2015, Grunddal et al. 2016), while the proximal small intestine has been shown to secrete significant amounts of GLP-1 (Theodorakis et al. 2006). Once released, gut peptides can act locally on afferent neurons innervating the GI tract that signal to the caudal brainstem or enteric neurons, and/or they can enter the circulation to act centrally, or on peripheral targets, to regulate glucose metabolism (Cote et al. 2014). For example, GLP-1 receptors (GLP-1Rs) are located on vagal afferents that innervate the gut in close proximity to L-cells (Richards et al. 2014), indicating a possible paracrine gut–brain axis for mediating its glycaemic effects. However, GLP-1Rs are also located on neurons innervating the portal vein (Vahl et al. 2007), on β cells of the pancreas (Pyke et al. 2014), and in the central nervous system (Shimizu et al. 1987, Heppner et al. 2015), all possible targets for GLP-1 action (described in more detail below). Nonetheless, most studies demonstrate that vagal neural transmission is necessary for nutrient-induced gut feedback as anaesthetics, neurotoxins or vagotomy abolishes nutrient-induced reductions in food intake (Schwartz 2011), and in the case of lipid-induced CCK release, the lowering of hepatic glucose production (Wang et al. 2008a).

In response to lipids, CCK is released from EECs in a process dependent on intracellular esterification of long-chain fatty acids to long-chain fatty acyl-CoA via acyl-CoA synthase-3 (Sundaresan et al. 2013) and upon PKC-δ stimulation (Breen et al. 2011, Kokorovic et al. 2011). Released CCK activates the CCK receptor (CCK1-R) on vagal afferents innervating the small intestine (Raybould et al. 1988), which leads to PKA activation and vagal afferent firing (Rasmussen et al. 2012). Vagal afferent activation enhances N-Methyl-d-aspartate (NMDA) receptor-mediated neuronal transmission in the nucleus of the solitary tract (NTS) to lower glucose production via the hepatic vagal branch (Rasmussen et al. 2012). Interestingly, the ability of intestinal lipids and CCK to reduce glucose production is diminished in rats fed a 3-day high-fat diet (Wang et al. 2008a, Cheung et al. 2009), highlighting the pathophysiological relevance of this pathway. Although preliminary studies demonstrate that preabsorptive lipids may not potently inhibit hepatic glucose production in humans (Xiao et al. 2015), this lipid-CCK pathway requires much more extensive and thorough testing. Furthermore, 8weeks of treatment with the bile acid sequestrant, colesevelam, improves glycaemic control in humans with impaired glucose tolerance through a mechanism dependent on prevention of bile acid absorption and increased local CCK secretion (Marina et al. 2012), suggesting this aforementioned CCK gut–brain–liver axis could be of therapeutic relevance. Additionally, cotreatment of a CCK receptor agonist with a GLP-1R agonist has demonstrated initial therapeutic promise (Irwin et al. 2015; see section below).

GLP-1 has been widely studied for its incretin effect, where it stimulates an increase in insulin secretion at the level of the pancreas (Kreymann et al. 1987, Mojsov et al. 1987). Interestingly, recent evidence suggests that GLP-1 may additionally exert its effect via activation of visceral afferent neurons (Yamamoto et al. 2003), challenging the conventional model of GLP-1 action. GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) in the portal vein and liver, leaving only 10–15% of secreted GLP-1 for entry into the systemic circulation (Holst & Deacon 2005). As a result, studies hypothesize that effects on insulin release, as well as other glucoregulatory effects of GLP-1, such as decreased glucose production, increased glucose utilization and regulation of counter-regulatory hormones, are mediated at least in part by a gut–brain–periphery axis (Burcelin et al. 2001). Complicating this model further, GLP-1 can also act centrally to regulate food intake (Tang-Christensen et al. 1996), energy expenditure (Lockie et al. 2012), GI function (Seeley et al. 2000) and importantly, glucose homeostasis (Knauf et al. 2005, Gustavson et al. 2008). However, in contrast to these studies, others suggest that the glucoregulatory effects of GLP-1 are primarily mediated by pancreatic GLP-1R activation (Lamont et al. 2012, Smith et al. 2014). Nonetheless, GLP-1 plays an important role in the regulation of metabolism and glucose homeostasis, and as a result, some of the latest drugs to come onto the market have aimed to exploit the GLP-1R signalling pathway. Two main drug classes have emerged, degradation-resistant GLP-1R agonists and DPP-IV inhibitors.

Incretin-based drug

GLP-1R agonists

GLP-1R agonists commonly fall into two categories based on their duration of receptor activation: short-acting compounds, which deliver short-lived GLP-1R activation, and long-acting compounds, which activate their receptor continuously at their recommended dose (Madsbad 2016). Short-acting compounds include exenatide (Byetta), which was the first GLP-1R agonist approved for clinical use, and lixisenatide (Lyxumia), which has subsequently been approved for use in Europe, but not in the USA. Exenatide exhibits approximately 50% amino acid identity with human GLP-1 and has an affinity for the GLP-1R that is equivalent to native GLP-1. It contains a glycine residue at position 2, which provides resistance to degradation by DPP-IV and an increased circulating half-life (Furman 2012). Exenatide is the most widely studied of the GLP-1R agonists, with over 7years of continuous clinical follow-up data. Early clinical trials examining the efficacy of exenatide showed that twice-daily 10μg injections effectively lowered both fasting and postprandial glucose concentrations in diabetic individuals after 30weeks of treatment (Buse et al. 2004, DeFronzo et al. 2005, Kendall et al. 2005).

The success of exenatide led to the development of new long-acting GLP-1R agonists with pharmacokinetic properties designed for once-daily or once-weekly administration. Liraglutide (marketed as Victoza) is a modified form of GLP-1 that contains a Ser34Arg substitution and has a C16 palmitoyl fatty acid side chain at Lys26, which allow binding to serum albumin and provide resistance to DPP-IV degradation (Lovshin & Drucker 2009). Liraglutide thus exhibits a prolonged half-life with stable plasma levels for up to 13h after subcutaneous injection. Liraglutide administration (1.8mg once daily) results in 24-h glucose control when prescribed as monotherapy or in combination therapy with oral glucose-lowering agents (Buse et al. 2009, Garber et al. 2009, Marre et al. 2009, Nauck et al. 2009, Russell-Jones et al. 2009). Other long-acting GLP-1R agonists include the once-weekly formulations of exenatide (Bydureon), albiglutide (Eperzan and Tanzeum) and dulaglutide (Trulicity) (Madsbad 2016). Differences in the duration of action largely account for differences in glucose control between GLP-1R agonists. For example, delayed gastric emptying is more strongly associated with short-acting GLP-1R agonists, resulting in greater effects on postprandial plasma glucose when compared with long-acting agonists (Drucker et al. 2008, Ji et al. 2013, Kapitza et al. 2013, Meier et al. 2015). On the other hand, the longer half-lives of long-acting GLP-1R agonists allow a greater improvement in 24-h glucose control, including fasting plasma glucose, when compared with short-acting agonists (Drucker et al. 2008, Buse et al. 2009, Blevins et al. 2011, Kapitza et al. 2013).

Despite the popularity of GLP-1R agonists, considerable mystery surrounds the main site of action for GLP-1R agonist antidiabetic effects. Exenatide readily crosses the blood–brain barrier, even more efficiently than native GLP-1 (Kastin & Akerstrom 2003), and it has been shown to activate brain regions involved in food reward and glucose homeostasis when administered subcutaneously (Daniele et al. 2015). The effects of exenatide on food intake may be mediated by its central action, as exenatide-induced reductions in energy intake in humans have been associated with increased hypothalamic connectivity (Schlogl et al. 2013), and intracerebroventricular injection of the GLP-1R antagonist, exendin-9, blocks the inhibitory effects of exenatide on energy intake in rodents (Kanoski et al. 2011). However, the effects of exenatide on glucose regulation do not appear to be dependent on central GLP-1R activation (Lamont et al. 2012), and evidence suggests that exenatide may exert its effects on glycaemia through direct action on the pancreas (Smith et al. 2014). There has also been evidence that the anorexic effects of exenatide are mediated, at least in part, by the activation of GLP-1R expressed on peripheral vagal afferents. However, studies suggest that although the early effects of exenatide require vagal afferent signalling, the later effects do not (Kanoski et al. 2011, Labouesse et al. 2012). Similar to exenatide, the main site of action of liraglutide remains unknown. Interestingly, liraglutide has been shown to improve insulin sensitivity in humans, as assessed by the hyperinsulinaemic euglycaemic clamp (Jinnouchi et al. 2015), indicating that in addition to its effects on insulin secretion, liraglutide also exhibits beneficial extrapancreatic effects on glycaemia. Liraglutide also passes the blood–brain barrier and it has been shown to bind to neurons within the arcuate nucleus and other sites within the hypothalamus (Secher et al. 2014). Evidence suggests that the anorectic effects of liraglutide are mediated via GLP-1Rs expressed both centrally and on vagal afferent neurons (Kanoski et al. 2011, Secher et al. 2014). However, whether liraglutide mediates its glucose-lowering effects through a manner similar to its anorectic effects requires attention. Some studies suggest that liraglutide-induced improvements in glucose tolerance do not require central or vagal GLP-1R (Sisley et al. 2014) and that its effects on glycaemia are via direct action on the pancreas (Smith et al. 2014). Thus, although the effects of liraglutide on glycaemia appear to be primarily dependent on the activation of pancreatic GLP-1R, central and vagal GLP-1R signalling should not be overlooked given their importance in lowering food intake and body weight, which is a primary treatment strategy for type 2 diabetes. A better understanding of the exact mechanisms for the glucose-lowering effects of GLP-1R agonists could result in more targeted drug designs to exploit the specific pathways.

DPP-IV inhibitors

DPP-IV inhibitors, also referred to as ‘incretin enhancers’, lower blood glucose levels through a prolongation of the action of GLP-1, and to a lower extent, GIP (a second incretin hormone produced in the small intestine) (Hansotia et al. 2004). Typically, DPP-IV inhibitors reduce DPP-IV activity by about 80%, which corresponds to a twofold increase in biologically active GLP-1 (Heine et al. 2005). This is associated with an increase in insulin and decrease in glucagon secretion and reduced fasting and postprandial glucose levels in individuals with diabetes (Heine et al. 2005).

Sitagliptin was the first DPP-IV inhibitor approved for use in 2006. It is a nonpeptide heterocyclic compound with rapid onset and a long duration of action, which facilitates once-daily dosing (Lovshin & Drucker 2009). Vildagliptin and saxagliptin were approved for use soon after sitagliptin; these compounds are cyanopyrrolidines with a slow onset and prolonged action upon binding to DPP-IV (Lovshin & Drucker 2009). The shorter half-life of vildagliptin requires twice-daily dosing (Lovshin & Drucker 2009). However, saxagliptin is suitable for once-daily dosing as a result of the presence of the active metabolite BMS-510849, which also inhibits DPP-IV (Trujillo & Nuffer 2014). The most recent DPP-IV inhibitors to reach the market are linagliptin (a methylxanthine) and alogliptin (a heterocyclic aminopiperidine), which are also administered once daily due to their relatively longer half-lives (Trujillo & Nuffer 2014, Handelsman et al. 2015). Each DPP-IV inhibitor elevates GLP-1 and improves glycaemia to a similar degree (Trujillo & Nuffer 2014, Handelsman et al. 2015). Once DPP-IV is maximally inhibited, glycated haemoglobin (HbA1c) reductions plateau; therefore, improvements are consistent across this drug class and there is no basis for differentiation regarding efficacy (Lovshin & Drucker 2009).

Despite the success of DPP-IV inhibitors, the cellular site that is responsible for their glucoregulatory effects has yet to be determined. Indeed, it is likely that increased endogenous GLP-1 could reach the pancreas and brain to exert the aforementioned effects. Studies in rodents indicate that a dose of sitagliptin that is sufficient to inhibit intestinal, but not systemic, DPP-IV activity is sufficient for improving glucose tolerance and insulin levels. This effect is associated with increased activity of the vagal nerve, suggesting that DPP-IV inhibitors may regulate glycaemia predominantly through local inhibition of intestinal DPP-IV activity and activation of neuronal GLP-1Rs (Waget et al. 2011).

Cocktail therapy

Despite the early beneficial effects of gut peptide-based therapies, the signalling pathways involved are redundant and the body can adjust. Therefore, it follows that the design of multitarget peptides capable of modulating more than one hormonal pathway could have distinct therapeutic benefits for the treatment of type 2 diabetes. Combination therapy with long-acting GIP and GLP-1 mimetics has been considered in preclinical studies with some success (Irwin & Flatt 2009); however, issues of separate drug formulation and dosing limits the therapeutic success. As such, a single hybrid peptide, MAR701, has been developed that can directly activate both GIP receptor and GLP-1R and appears to have beneficial effects in rodents (Finan et al. 2013). Further studies have investigated the effects of GLP-1R agonism combined with either glucagon receptor agonism (Pan et al. 2006, Day et al. 2009, 2012) or antagonism (Pocai et al. 2009). Although contradictory in nature, these contrasting regimens utilize both the beneficial glucose-lowering effects of GLP-1, combined with either inhibition of glucagon-mediated gluconeogenesis and glycogenolysis (Sinclair & Drucker 2005), and activation of glucagon pathways involved in energy turnover and weight loss (Pocai et al. 2009). Another modified hybrid peptide, ZP3022, involves a combined GLP-1-gastrin agonist (Fosgerau et al. 2013), which activates GLP-1R and CCK2-R and improves glycaemic control in db/db mice through enhancement of β cell mass (Fosgerau et al. 2013). Perhaps a more appealing peptide would be one that targets the GLP-1R and CCK1-R given the involvement of the CCK1-R in the activation of the gut–brain–liver axis. Indeed, combined administration of long-acting GLP-1R and CCK1-R agonists has shown pronounced synergistic metabolic benefits in rodent models of type 2 diabetes, including improved glycaemic control and loss of body weight (Irwin et al. 2013, Trevaskis et al. 2015). As such, a novel CCK/GLP-1 hybrid peptide based on the chemical structures of the CCK1-R agonist, (pGlu-Gln)-CCK-8, and exenatide has recently been described and shown to have significant therapeutic potential in high-fat-fed mice (Irwin et al. 2015). This molecule clearly warrants further study as a potential new treatment option for type 2 diabetes.

Considering the evident therapeutic efficacy of dual target peptide therapies, single compounds with the ability to activate three or more regulatory peptides could potentially provide even greater metabolic benefits. As a result, modified peptides with the ability to activate glucagon, GLP-1 and GIP receptors have been developed and have been shown to produce dramatic improvements in glucose homeostasis and overall metabolic control in high-fat-fed mice (Bhat et al. 2013a,b, Finan et al. 2015). Despite the clear potential of these tri-agonists, issues regarding the ratio of GIP, GLP-1 and glucagon receptor activation still requires investigation. As such, a recent study has reported the distinct beneficial effects of a balanced glucagon, GLP-1 and GIP receptor tri-agonist for the correction of obesity and diabetes in high-fat-fed mice (Finan et al. 2015). There is, therefore, a clear and attractive rationale for further testing of multitarget peptides for the treatment of type 2 diabetes in humans. In addition, given the recent findings that EECs coexpress a variety of gut peptides (Egerod et al. 2012, Habib et al. 2012, Svendsen et al. 2015, Grunddal et al. 2016), it may be possible to develop a drug that promotes the cosecretion of multiple gut peptides from EECs. For example, infusion of bombesin, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, or peptone stimulates the cosecretion of GLP-1, PYY, neurotensin and CCK (Svendsen et al. 2015), and interestingly, neurotensin acts synergistically with GLP-1 to regulate metabolism (Grunddal et al. 2016). This suggests that stimulating the release of an endogenous gut peptide ‘cocktail’, similar to engineering poly-agonists that mimic these peptides (Day et al. 2009, 2012, Finan et al. 2013, 2015), could be a useful alternative approach for improving metabolic control in type 2 diabetes.

The potential treatment of diabetes via mimicry of gut peptide signalling is bolstered by the success of bariatric surgery. Indeed, bariatric surgery has demonstrated great efficacy in normalizing blood glucose levels and ameliorating diabetes in obese populations, which has been suggested to be due in part to improvements in intestinal nutrient sensing and subsequent modulation of the secretion and biological action of numerous gut-derived peptides (see below). The following section aims to not only describe the various surgical procedures demonstrated to improve glucose regulation, but to introduce some of the major hypothesized mechanisms, in addition to intestinal nutrient sensing, underlying the success of bariatric surgery and to highlight the current therapeutic strategies directly targeting these mechanisms.

Bariatric surgery

The long-term success of bariatric surgery to reverse diabetes in obese patients underscores the need for identifying the mechanisms of action. Bariatric surgery encompasses many surgical procedures that are either restrictive in nature, by altering the stomach size or nutrient flux into the stomach, or involve the rerouting of the intestinal tract (Fig. 1). Roux-en-y gastric bypass surgery (RYGB) is one of the most commonly performed bariatric surgical procedures and involves a reduction in the size of the stomach, by creating a gastric pouch out of the upper portion of the stomach, and rerouting the intestinal tract by connecting the proximal jejunum to the stomach and thus excluding the duodenum (Ward & Prachand 2009). RYGB induces substantial effects on diabetes remission (Buchwald et al. 2004) and produces metabolic benefits that are maintained for over 10years (Karlsson et al. 2007). However, the biliopancreatic diversion with duodenal switch (BPD-DS) procedure, which involves a pylorus-preserving vertical sleeve gastrectomy (VSG) (as opposed to the original BPD procedure, which involved a distal gastrectomy sacrificing the pylorus (Scopinaro et al. 1979)) and creation of a Roux limb, a long biliopancreatic limb and a short common channel, achieves diabetes resolution rates that are significantly better than RYGB (90% vs 70%) (Buchwald et al. 2004, 2009). However, despite its long-term metabolic success (Buchwald et al. 2004, 2009), the technical difficulty and meticulous patient surveillance have limited the use of this surgical technique to about 17% of all bariatric surgeries (Buchwald et al. 2009), although it is the metabolic surgery of choice for some surgeons (Marceau et al. 2015). Interestingly, VSG alone has substantial weight loss effects and appears to induce rapid and long-term diabetes resolution in obese type 2 diabetics (Bayham et al. 2012, Madsbad et al. 2014), which has been attributed to much more than simply restriction (see below or Seeley et al. 2015 for review).

Figure 1
Figure 1

Effectiveness of bariatric surgery yields possible ‘gut-centered’ treatment options for type 2 diabetes. Bariatric surgery, in the form of vertical sleeve gastrectomy, roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, duodenal-jejunal bypass or ileal transposition, have all been demonstrated to exert beneficial effects on glucose homeostasis, hypothesized to be due to changes in nutrient sensing, gut peptide signalling, gut microbiota and/or bile acids. Current gastrointestinal-based therapeutic options for type 2 diabetes involve drugs or treatments targeting these pathways.

Citation: Journal of Endocrinology 230, 3; 10.1530/JOE-16-0056

To evaluate the relative contribution of gastric restriction vs rearrangement of the intestinal tract to the antidiabetic effects of bariatric surgery, an experimental procedure entitled duodenal-jejunal bypass (DJB) was developed. This procedure involves repositioning the intestinal tract without restriction or exclusion of the stomach. Although DJB does not elicit the same weight loss effects as RYGB or BPD, this procedure has been shown to produce glucose-lowering effects in nonobese rodents (Rubino et al. 2004), and in a small subset of nonobese or mild-obese humans with type 2 diabetes, independent of weight loss (Cohen et al. 2007, 2012, Lee et al. 2010, Geloneze et al. 2012). Moreover, in Asia, a novel surgery similar to a BPD-DS has been developed that involves a DJB with VSG, and has demonstrated initial success in the treatment of diabetes (Kasama et al. 2009, Lee et al. 2014). Lastly, another experimental metabolic surgery still in early human trials is ileal interposition (with or without VSG), which involves resection of 10–20cm of the distal ileum and its transposition into the proximal jejunum. This procedure results in weight loss, reduced food intake and improved glycaemic regulation in both rodents and humans (Wang et al. 2008b, Gagner 2011, Zhang et al. 2011, Grueneberger et al. 2013, Grueneberger et al. 2014, Ramzy et al. 2014).

Surgical intervention remains one of the most successful treatment options for the remission of diabetes. However, it is important that the best metabolic procedure is selected with benefits vs risks assessed for each individual patient (Castagneto Gissey et al. 2016). Despite the relative risks associated with procedures like RYGB and BPD-DS, a better understanding of these surgeries may continue to lead to less invasive and risky surgical procedures that equal in effectiveness. Moreover, noninvasive devices mimicking bariatric surgery could provide substantial benefits, such as the duodenal endoluminal sleeve, which involves inserting a flexible tube that inhibits the interaction of nutrients with the duodenum and has been shown to improve glucose regulation (Habegger et al. 2014). Ultimately, elucidation of the mechanisms underpinning the resolution of diabetes following bariatric surgery could lead to the discovery of novel pharmacological bariatric mimetics that could one day replace the need for bariatric surgery altogether. Therefore, the following sections describe some of the more developed hypotheses regarding the success of bariatric surgery, mainly the role of intestinal gut peptide signalling, gut microbiota and bile acids, and highlight the therapeutic potential of directly targeting these pathways.

Gut peptide and nutrient sensing

Given that many patients have exhibited postsurgical changes in gut hormone secretion (Rodieux et al. 2008), many studies have investigated whether changes in nutrient sensing mediate the weight loss and glucose-lowering effects of this procedure. One of the leading candidates for the success of bariatric surgery is altered gut peptide signalling, mainly GLP-1 (Salehi et al. 2011, Jimenez et al. 2013). Indeed, after RYGB, there is an increase in the number of gut peptide-expressing EECs (Mumphrey et al. 2013) and consequently, increased postprandial gut peptide secretion (Madsbad et al. 2014). In the case of GLP-1, many studies have shown an increase in circulating GLP-1 levels following RYGB and VSG (Rodieux et al. 2008, Chambers et al. 2011, Salehi et al. 2011, Jimenez et al. 2013), and postprandial GLP-1 levels are increased as early as 2days postsurgery (le Roux et al. 2007) and have persisted as long as 10years postsurgery (Dar et al. 2012). Improvements in glucose tolerance following RYGB or VSG in rats are abolished with exendin-9 administration (Chambers et al. 2011), all suggesting a role for GLP-1 in the glucose-lowering success of RYGB. Some studies argue against this (Clements et al. 2004, Rubino et al. 2004, le Roux et al. 2007), whereas some have shown that GLP-1 levels do not rise accordingly (Salinari et al. 2014), inhibition of GLP-1 signalling has no effect on glycaemia following RYGB (Jimenez et al. 2013, Shah et al. 2014) and GLP-1R deficient mice still exhibit improved glycaemia following RYGB and VSG (Wilson-Perez et al. 2013, Mokadem et al. 2014). As such, other gut peptides have been implicated as potential contributors to improved glycaemia following bariatric surgery.

Plasma PYY levels are increased following RYGB (le Roux et al. 2006, 2007, Rodieux et al. 2008) and DJB (Zhang et al. 2011, Liu et al. 2012, Imoto et al. 2014), and a causal link between PYY signalling and weight loss has been suggested for both humans (le Roux et al. 2007, Morinigo et al. 2008) and rodents (Chandarana et al. 2011), although studies investigating the role of PYY in the antidiabetic effects of these bariatric procedures are lacking. Interestingly, PYY action has been correlated with increased sensitivity to GLP-1 and improved glucose tolerance following bariatric surgery (Chandarana et al. 2013), suggesting that studies investigating the role of PYY in the glucoregulatory effects of bariatric surgery are warranted. Another gut peptide identified as a possible mediator of the beneficial effects of bariatric surgery is ghrelin. Plasma ghrelin levels are substantially reduced following VSG (Chambers et al. 2013); however, VSG is equally effective in improving glucose tolerance and lowering food intake and body weight in ghrelin-deficient and wild-type mice (Chambers et al. 2013), indicating that the beneficial effects of VSG are not dependent on reduced ghrelin signalling. Other factors have been shown to be altered following one or more of these procedures such as CCK, GIP and glucagon (Jacobsen et al. 2012, Rhee et al. 2015). Therefore, improvements in glycaemia following bariatric surgery may not be dependent on changes in the action of a single gut peptide, and it is very possible that an adaptive shift increases postingestive feedback, contributing to the rapid lowering of glucose levels.

Given that the rearrangement of the intestinal tract results in an increased flux of nutrients into the jejunum, it was hypothesized that increased jejunal nutrient sensing could mediate the improvements in glucose regulation. Indeed, intrajejunal nutrients lower hepatic glucose production via a gut–brain–liver neuronal axis, independent of changes in circulating insulin levels, while inhibition of these jejunal nutrient sensing pathways altered the rapid glucose-lowering effect of DJB in streptozotocin (STZ)-induced uncontrolled diabetic rats during refeeding (Breen et al. 2012). While lowering of glucose in STZ-induced uncontrolled diabetic rats following DJB was associated with increased circulating GLP-1 levels, this was not the case following DJB in BBdp rats (Breen et al. 2012), Zucker diabetic fatty rats (Patel et al. 2014) or Goto-Kakizaki rats (Salinari et al. 2014), further arguing against the importance of GLP-1 in DJB. Interestingly, in a follow-up study, it was shown that direct leptin infusion into the jejunum activates jejunal leptin receptor-phosphoinositide-3-kinase signalling to lower endogenous glucose production through a neuronal network, while blocking jejunal leptin receptor signalling abolished the improvements in glucose homeostasis of DJB-diabetic rodents during refeeding (Rasmussen et al. 2014). However, it is important to note that for these studies, the testing period was only 2weeks following DJB, and while this demonstrates that the rapid remission of diabetes following GBP may be due in part to nutrient- and hormonal-jejunal sensing mechanisms, the long-term potential of these sensing mechanisms remains unknown. The cell-type mediating the effect of jejunal leptin following DJB has not been characterized, the nodose ganglia contains leptin receptors (Li et al. 2011b) and studies suggest that leptin receptors on vagal afferents, rather than intestinal epithelial cells, play a role in the development of obesity and hyperglycaemia (de Lartigue et al. 2014). Thus, it is likely that leptin is acting on vagal afferents innervating the gut to regulate glucose homeostasis. However, whether this pathway can be exploited to treat hyperglycaemia remains to be explored. Interestingly, while leptin treatment in obesity is generally unsuccessful due to leptin resistance, cotreatment of leptin with peptides that promote weight loss and leptin sensitivity, such as amylin and CCK, has been shown to be effective in improving glucose homeostasis in rodents (Sadry & Drucker 2013, Trevaskis et al. 2015). Furthermore, human analogues of amylin and leptin were successful in lowering body weight in clinical trials (Ravussin et al. 2009); however, safety concerns lead to the discontinuation of development. Nonetheless, future studies investigating not just leptin receptor activation, but rather vagal signalling in general, may hold promise for the development of novel antidiabetic therapies.

Bile acids

In addition to distal intestinal nutrient sensing and gut peptide changes, rearranging the intestinal tract during bariatric surgery profoundly alters bile acid levels and composition, which has been suggested as key contributor to its success (Seeley et al. 2015). Bile acids have been implicated in the regulation of glucose homeostasis through their effects on glucose production and glucose-induced insulin secretion (Thomas et al. 2008, 2009). Beyond acting as detergent for luminal fat digestion and absorption, bile acids act as endocrine factors, activating the G protein-coupled receptor TGR5, and a ligand-activated transcription factor farnesoid X receptor (FXR) (Fiorucci et al. 2009). In RYGB, bile acids flow undiluted through the biliopancreatic limb and do not mix with food until reaching the common channel of the distal jejunum. As such, increased presence of bile acids in this region could activate TGR5, which is localized on EECs, and can stimulate the release of gut peptides such as GLP-1 and PYY (Katsuma et al. 2005, Pournaras et al. 2012). However, increased gut peptide levels following RYGB have been shown to be independent of changes in bile acids (Bhutta et al. 2014, Jorgensen et al. 2015), and recent evidence shows that increased GLP-1 levels following VSG do not require TGR5 signalling, although TGR5 was shown to contribute to the glucoregulatory benefits of VSG in this study (McGavigan et al. 2015). Interestingly, the effects of VSG on body weight and glucose levels were abolished in Fxr knockout mice, suggesting a role for FXR in the metabolic effects of this procedure (Ryan et al. 2014). Indeed, FXR is essential for normal glucose homeostasis (Ma et al. 2006), and bile acid activation of FXR induces FGF19 (in humans and its mouse orthologue FGF15) release from the ileal intestinal epithelium (Zhang et al. 2013). Improvements in glucose homeostasis following RYGB are associated with changes in FGF 19/15 (Pournaras et al. 2012, Sachdev et al. 2015), possibly via inhibitory effects on hepatic glucose production and lipogenesis through reductions in bile acid secretion (Gerhard et al. 2013). More recently, it has been shown that central FGF 19 improves glucose tolerance, suggesting a central role for the glucoregulatory action of FGF 19 (Morton et al. 2013, Ryan et al. 2013, Marcelin et al. 2014). These studies, therefore, suggest that synthetic FXR agonists could act as potential diabetic treatments. Indeed, obeticholic acid, a semisynthetic FXR agonist, improves insulin sensitivity in type 2 diabetic patients (Mudaliar et al. 2013), while GW4064 has been shown to prevent insulin resistance in rodents (Ma et al. 2013). Furthermore, treatment with a gut-specific FXR agonist, fexaramine, reduces diet-induced increases in hepatic glucose production in mice, likely due to a robust increase in FGF 15 (Fang et al. 2015). In contrast, some studies suggest that intestinal inhibition of FXR may in fact be beneficial via a reduction in intestinally derived ceramides (Li et al. 2013, Jiang et al. 2015), or via increased GLP-1 signalling (Trabelsi et al. 2015), warranting further research into FXR agonism/antagonism for the treatment of diabetes. Interestingly, it has also been proposed that FXR-mediated metabolic improvements are due to alterations of the gut microbiota (Ryan et al. 2014).

Gut microbiota

The gut microbiota, which contains an estimated 100 trillion cells consisting of over 1000 different species of known bacteria, has a major influence on host energy homeostasis, and diabetes is associated with changes in both the bacterial composition and genetic make-up (see for review on gut microbiota and diabetes (Duca & Lam 2014, Tilg & Moschen 2014)). Meanwhile bariatric surgery drastically alters the composition and diversity of the gut microbiota in humans, rats and mice (Zhang et al. 2009, Furet et al. 2010, Li et al. 2011a, Liou et al. 2013, Osto et al. 2013, Ryan et al. 2014, Tremaroli et al. 2015, Yang et al. 2015). Interestingly, germ-free (GF) mice colonized with the microbiota derived from humans, who had underwent RYGB or vertical banded gastroplasty exhibited reduced fat deposition when compared with GF mice colonized with the microbiota of obese controls (Tremaroli et al. 2015). This is in line with the fact that GF animals inoculated with the gut microbiota of RYGB-treated mice gained less weight and have a trend towards improved insulin sensitivity when compared with GF mice receiving sham microbiota (Liou et al. 2013).

Although the mechanisms for gut microbiota-mediated improvements in glucose homeostasis are still not completely understood (Duca & Lam 2014, Tilg & Moschen 2014), alterations in short-chain fatty acid (SCFA) production via fermentation of nondigestible polysaccharides has been hypothesized (Vrieze et al. 2012, Liou et al. 2013). For example, in the RYGB microbiota transplant study described above, levels of propionate were increased in both the RYGB-treated donor and the recipient mice (Liou et al. 2013). Indeed, supplementation with propionate or fermentable fibre is known to reduce appetite and improve glucose tolerance, possibly from inducing distal intestinal gut peptide secretion (Everard et al. 2011, Lin et al. 2012, Chambers et al. 2015, Psichas et al. 2015b). Ileal propionate activates mucosal FFAR2 to lower hepatic glucose production through a GLP-1-dependent neuronal pathway (Zadeh-Tahmasebi et al. 2016), while increased concentrations of SCFA in the large intestine have been shown to increase circulating levels of GLP-1 and PYY and reduce postprandial insulin and glucose levels (Tolhurst et al. 2012, Psichas et al. 2015b). As such, it is possible that improvements in glucose homeostasis following RYGB are due, at least in part, to changes in the production of SCFA in the ileum and large intestine. Although treatment with SCFAs is not feasible, as they are very unpalatable and do not reach the distal small and large intestine where they are endogenously produced, prebiotic treatment (nondigestible fibre) effectively increases distal intestinal SCFA production and improves glucose homeostasis in rodents (Cani et al. 2006b, Everard et al. 2011), which is thought to be mediated through an increase in gut peptide release (Cani et al. 2004, 2005, Everard et al. 2011, Neyrinck et al. 2012). While some evidence exists for the beneficial effects of fermentable dietary fibre in humans (Archer et al. 2004, Cani et al. 2006a, 2009, Parnell & Reimer 2009), intake of dietary fibre is generally low (Howarth et al. 2003), and prebiotic treatment may not readily increase propionate production (Chambers et al. 2015). As such, a novel carrier molecule was developed to selectively increase colonic propionate levels. Treatment with this inulin-propionate ester for 24weeks reduced weight gain and adipose distribution, and prevented the decrease in glucose tolerance and insulin sensitivity exhibited by the control group (Chambers et al. 2015). In addition, faecal microbiota transfer (FMT) represents another potential mechanism to increase SCFA levels and improve glucose homeostasis, as duodenal transfer of microbiota from lean humans into those with metabolic syndrome results in an increase in butyrate-producing bacteria and insulin sensitivity 6weeks after the transfer (Vrieze et al. 2012). However, FMT is still experimental, and a more selective change in distal bacterial composition through pre- or probiotics may prove a safer and more efficacious option.

One of the more recently studied bacteria, Akkermansia muciniphila, might hold promise as a probiotic treatment for diabetes. A. muciniphila is a mucin-degrading, Gram-negative bacterium that resides in the mucus layer, and represents 3–5% of the microbial community (Derrien et al. 2004). Levels of A. muciniphila are inversely correlated with body weight, glucose tolerance and type 1 diabetes, while RYGB increases A. muciniphila abundance (Zhang et al. 2009, Hansen et al. 2012a, Everard et al. 2013, Liou et al. 2013, Shin et al. 2014, Schneeberger et al. 2015, Dao et al. 2016). Furthermore, reduced A. muciniphila levels in diet-induced obesity are normalized following prebiotic feeding, which is associated with improvements in metabolic dysregulation (Everard et al. 2013). In humans, A. muciniphila abundance is inversely related to fasting glucose and patients with increased A. muciniphila abundance and gene richness exhibited improved fasting plasma glucose levels and greater improvements in insulin sensitivity following caloric restriction (Dao et al. 2016). Direct chronic treatment in diet-induced obese mice with alive, but not heat-killed A. muciniphila reversed weight and fat mass gain, as well as insulin resistance (Everard et al. 2013). Further, chronic treatment with dietary phenols from grapes, or cranberry extract, improved glucose tolerance and insulin sensitivity which was hypothesized to be due to A. muciniphila abundance (Anhe et al. 2015, Roopchand et al. 2015). Although A. muciniphila remains to be tested in humans, this is one example in an ever-expanding list of potential probiotics that could help lower glucose levels in type 2 diabetes (Le Barz et al. 2015, Stenman et al. 2015a). It is interesting to note that metformin treatment has been shown to alter the gut microbiota, with chronic treatment resulting in A. muciniphila abundance, as well as changes in bile acid levels, suggesting a gut microbiota-mediated role for metformin treatment (Lien et al. 2014, Napolitano et al. 2014, Shin et al. 2014).

Metformin

As mentioned above, metformin is the first-line medication for the treatment of type 2 diabetes, as it potently reduces hyperglycaemia via a reduction in hepatic glucose production (Foretz et al. 2014). Although the main action of metformin was originally hypothesized to be due to activation of hepatic AMP-activated kinase (AMPK) (Shaw et al. 2005), an intracellular energy sensor, via increased AMP levels resultant from inhibition of the mitochondrial respiratory chain complex 1 (Owen et al. 2000), recent work has readily challenged that. Recent studies have demonstrated that metformin can lower HGP by: suppressing glycolytic enzymes in an AMPK-independent fashion (Foretz et al. 2010), antagonizing hepatic glucagon action (Miller et al. 2013), and via an alteration in mitochondrial and cytosolic redox states (Madiraju et al. 2014). Furthermore, the action of metformin in the gut has recently been identified to play a role in its glucose-lowering ability (Fig. 2). Indeed, oral/intestinal treatment of metformin results in a greater drop of blood glucose than IV or even portal treatment (Stepensky et al. 2002). Interestingly, delayed-release metformin, which is formulated to avoid absorption and target the lower bowel, was more effective at lowering fasting plasma glucose than currently available metformin (Buse et al. 2016). One possible mechanism may be in the ability of metformin to activate a gut–brain–liver axis to lower hepatic glucose production. Specifically, preabsorptive metformin activates small intestinal mucosal AMPK, triggering a GLP-1R-protein kinase A-dependent pathway to lower glucose production (Duca et al. 2015). This is in line with the fact that metformin can increase both acute and chronic levels of GLP-1 (Foretz et al. 2014). Interestingly, when small intestinal AMPK was virally knocked-down in diabetic rodents, the glucose-lowering ability of acute metformin treatment was diminished by about 50%, indicating a potent and sustained contribution of intestinal AMPK activation to metformin’s effect (Duca et al. 2015). Additionally, this study highlights the potential for more direct targeting of intestinal energy sensors to treat diabetes. For example, in addition to AMPK, the NAD+-dependent deacetylase sirtuin 1 (SIRT1) is expressed in the small intestinal mucosa. Activation of small intestinal SIRT1, via intraintestinal resveratrol infusion, triggers a vagal gut–brain neuronal axis to improve hypothalamic insulin sensitivity to lower hepatic glucose production in high-fat-fed and diabetic rodents (Cote et al. 2015). Interestingly, this effect was also dependent on AMPK (Cote et al. 2015), indicating a possible interactive dependency between these two molecules, although it remains to be tested whether SIRT1 is required for intraintestinal metformin in the gut. Nonetheless, it may be efficacious to develop a ‘gut-targeted’ metformin-like molecule that could activate intestinal mucosal AMPK and/or other energy sensors to potently lower glucose levels in diabetic individuals, given that intestinal AMPK is reduced in diabetes (Harmel et al. 2014).

Figure 2
Figure 2

Intestinal actions of metformin potentially regulating glucose homeostasis. Metformin can act in the gut to alter gut microbiota and bile acids, which have been shown to contribute to glucose homeostasis. Furthermore, metformin increases GLP-1 release and can activate intestinal AMPK to lower glucose production possibly via increased GLP-1 signalling.

Citation: Journal of Endocrinology 230, 3; 10.1530/JOE-16-0056

Conclusion

The metabolic potential of the GI tract is becoming increasingly recognized. Drugs aimed at mimicking gut-derived molecules, like GLP-1 receptor agonists, are readily being tested and used for diabetic treatment. As of now, most GLP-1R agonists are administered as a complimentary therapeutic option to metformin, but perhaps in the future, more specialized ‘cocktail’ treatments will be developed to provide a more complete action on complex signalling pathways that often compensate and limit long-term drug potential. Perhaps an even better approach will be to alter endogenous levels of gut-derived hormones, as is done with manipulation of bile acids and gut microbiota following bariatric surgery. Instead of surgery, drugs are also being developed to directly influence the gut milieu, like bile acid sequestrants and pre/probiotics. Although manipulation of a stable gut microbiota has proven difficult, with more research into how to effectively and favourably alter the microbiota in the long-term, pre/probiotics could be a valuable tool in treating diabetes, possibly as a combination with frontline treatments (Stenman et al. 2015b). Even more intriguing is the possibility that future treatments may involve genetically modified bacteria that contain therapeutic factors to help treat metabolic disease (Chen et al. 2014). Overall, the GI tract represents a promising avenue for the development of successful targeted therapeutic options for the treatment of diabetes.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

P V B is supported by an Ontario Graduate Scholarship and a Banting and Best Diabetes Centre graduate studentship. F A D is a Banting Fellow.

References

  • Anhe FF, Roy D, Pilon G, Dudonne S, Matamoros S, Varin TV, Garofalo C, Moine Q, Desjardins Y & Levy E et al. 2015 A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 64 872883. (doi:10.1136/gutjnl-2014-307142)

    • Search Google Scholar
    • Export Citation
  • Archer BJ, Johnson SK, Devereux HM & Baxter AL 2004 Effect of fat replacement by inulin or lupin-kernel fibre on sausage patty acceptability, post-meal perceptions of satiety and food intake in men. British Journal of Nutrition 91 591599. (doi:10.1079/BJN20031088)

    • Search Google Scholar
    • Export Citation
  • Bauer PV, Hamr SC & Duca FA 2016 Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota. Cellular and Molecular Life Sciences 73 737755. (doi:10.1007/s00018-015-2083-z)

    • Search Google Scholar
    • Export Citation
  • Bayham BE, Greenway FL, Bellanger DE & O’Neil CE 2012 Early resolution of type 2 diabetes seen after Roux-en-Y gastric bypass and vertical sleeve gastrectomy. Diabetes Technology & Therapeutics 14 3034. (doi:10.1089/dia.2011.0151)

    • Search Google Scholar
    • Export Citation
  • Bhat VK, Kerr BD, Flatt PR & Gault VA 2013a A novel GIP-oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties. Biochemical Pharmacology 85 16551662. (doi:10.1016/j.bcp.2013.03.009)

    • Search Google Scholar
    • Export Citation
  • Bhat VK, Kerr BD, Vasu S, Flatt PR & Gault VA 2013b A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice. Diabetologia 56 14171424. (doi:10.1007/s00125-013-2892-2)

    • Search Google Scholar
    • Export Citation
  • Bhutta HY, Deelman TE, le Roux CW, Ashley SW, Rhoads DB & Tavakkoli A 2014 Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery. American Journal of Physiology: Gastrointestinal and Liver Physiology 307 G588G593. (doi:10.1152/ajpgi.00405.2013)

    • Search Google Scholar
    • Export Citation
  • Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, Trautmann M & Porter L 2011 DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 96 13011310. (doi:10.1210/jc.2010-2081)

    • Search Google Scholar
    • Export Citation
  • Breen DM, Yue JT, Rasmussen BA, Kokorovic A, Cheung GW & Lam TK 2011 Duodenal PKC-delta and cholecystokinin signaling axis regulates glucose production. Diabetes 60 31483153. (doi:10.2337/db11-0852)

    • Search Google Scholar
    • Export Citation
  • Breen DM, Rasmussen BA, Kokorovic A, Wang R, Cheung GW & Lam TK 2012 Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nature Medicine 18 950955. (doi:10.1038/nm.2745)

    • Search Google Scholar
    • Export Citation
  • Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS & Minnick DT et al. 2003 The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. Journal of Biological Chemistry 278 1130311311. (doi:10.1074/jbc.M211495200)

    • Search Google Scholar
    • Export Citation
  • Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K & Schoelles K 2004 Bariatric surgery: a systematic review and meta-analysis. JAMA 292 17241737. (doi:10.1001/jama.292.14.1724)

    • Search Google Scholar
    • Export Citation
  • Buchwald H, Estok R, Fahrbach K, Banel D, Jensen MD, Pories WJ, Bantle JP & Sledge I 2009 Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. American Journal of Medicine 122 248256.e5. (doi:10.1016/j.amjmed.2008.09.041)

    • Search Google Scholar
    • Export Citation
  • Burcelin R, Da Costa A, Drucker D & Thorens B 2001 Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes 50 17201728. (doi:10.2337/diabetes.50.8.1720)

    • Search Google Scholar
    • Export Citation
  • Buse JB, Henry RR, Han J, Kim DD, Fineman MS & Baron ADExenatide-113 Clinical Study Group 2004 Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27 26282635. (doi:10.2337/diacare.27.11.2628)

    • Search Google Scholar
    • Export Citation
  • Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L & Group L-S 2009 Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374 3947. (doi:10.1016/S0140-6736(09)60659-0)

    • Search Google Scholar
    • Export Citation
  • Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A & Fineman M 2016 The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 39 198205.

    • Search Google Scholar
    • Export Citation
  • Cani PD, Dewever C & Delzenne NM 2004 Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. British Journal of Nutrition 92 521526. (doi:10.1079/BJN20041225)

    • Search Google Scholar
    • Export Citation
  • Cani PD, Neyrinck AM, Maton N & Delzenne NM 2005 Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obesity Research 13 10001007. (doi:10.1038/oby.2005.117)

    • Search Google Scholar
    • Export Citation
  • Cani PD, Joly E, Horsmans Y & Delzenne NM 2006a Oligofructose promotes satiety in healthy human: a pilot study. European Journal of Clinical Nutrition 60 567572. (doi:10.1038/sj.ejcn.1602350)

    • Search Google Scholar
    • Export Citation
  • Cani PD, Knauf C, Iglesias MA, Drucker DJ, Delzenne NM & Burcelin R 2006b Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. Diabetes 55 14841490. (doi:10.2337/db05-1360)

    • Search Google Scholar
    • Export Citation
  • Cani PD, Lecourt E, Dewulf EM, Sohet FM, Pachikian BD, Naslain D, De Backer F, Neyrinck AM & Delzenne NM 2009 Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. American Journal of Clinical Nutrition 90 12361243. (doi:10.3945/ajcn.2009.28095)

    • Search Google Scholar
    • Export Citation
  • Castagneto Gissey L, Casella Mariolo JR & Mingrone G 2016 How to choose the best metabolic procedure? Current Atherosclerosis Reports 18 43. (doi:10.1007/s11883-016-0590-5)

    • Search Google Scholar
    • Export Citation
  • Chambers AP, Jessen L, Ryan KK, Sisley S, Wilson-Perez HE, Stefater MA, Gaitonde SG, Sorrell JE, Toure M & Berger J et al. 2011 Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 141 950958. (doi:10.1053/j.gastro.2011.05.050)

    • Search Google Scholar
    • Export Citation
  • Chambers AP, Kirchner H, Wilson-Perez HE, Willency JA, Hale JE, Gaylinn BD, Thorner MO, Pfluger PT, Gutierrez JA & Tschop MH et al. 2013 The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology 144 5052.e5. (doi:10.1053/j.gastro.2012.09.009)

    • Search Google Scholar
    • Export Citation
  • Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SE, MacDougall K, Preston T, Tedford C & Finlayson GS et al. 2015 Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64 17441754. (doi:10.1136/gutjnl-2014-307913)

    • Search Google Scholar
    • Export Citation
  • Chandarana K, Gelegen C, Karra E, Choudhury AI, Drew ME, Fauveau V, Viollet B, Andreelli F, Withers DJ & Batterham RL 2011 Diet and gastrointestinal bypass-induced weight loss: the roles of ghrelin and peptide YY. Diabetes 60 810818. (doi:10.2337/db10-0566)

    • Search Google Scholar
    • Export Citation
  • Chandarana K, Gelegen C, Irvine EE, Choudhury AI, Amouyal C, Andreelli F, Withers DJ & Batterham RL 2013 Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance. Molecular Metabolism 2 142152. (doi:10.1016/j.molmet.2013.03.001)

    • Search Google Scholar
    • Export Citation
  • Chen Z, Guo L, Zhang Y, Walzem RL, Pendergast JS, Printz RL, Morris LC, Matafonova E, Stien X & Kang L et al. 2014 Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. Journal of Clinical Investigation 124 33913406. (doi:10.1172/JCI72517)

    • Search Google Scholar
    • Export Citation
  • Cheung GW, Kokorovic A, Lam CK, Chari M & Lam TK 2009 Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metabolism 10 99109. (doi:10.1016/j.cmet.2009.07.005)

    • Search Google Scholar
    • Export Citation
  • Christensen LW, Kuhre RE, Janus C, Svendsen B & Holst JJ 2015 Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. Physiological Reports 3 e12551. (doi:10.14814/phy2.12551)

    • Search Google Scholar
    • Export Citation
  • Clara R, Langhans W & Mansouri A 2016 Oleic acid stimulates glucagon-like peptide-1 release from enteroendocrine cells by modulating cell respiration and glycolysis. Metabolism: Clinical and Experimental 65 817. (doi:10.1016/j.metabol.2015.10.003)

    • Search Google Scholar
    • Export Citation
  • Clements RH, Gonzalez QH, Long CI, Wittert G & Laws HL 2004 Hormonal changes after Roux-en Y gastric bypass for morbid obesity and the control of type-II diabetes mellitus. American Surgeon 70 14.

    • Search Google Scholar
    • Export Citation
  • Cohen RV, Schiavon CA, Pinheiro JS, Correa JL & Rubino F 2007 Duodenal-jejunal bypass for the treatment of type 2 diabetes in patients with body mass index of 22–34 kg/m2: a report of 2 cases. Surgery for Obesity and Related Diseases 3 195197. (doi:10.1016/j.soard.2007.01.009)

    • Search Google Scholar
    • Export Citation
  • Cohen RV, Rubino F, Schiavon C & Cummings DE 2012 Diabetes remission without weight loss after duodenal bypass surgery. Surgery for Obesity and Related Diseases 8 e66e68. (doi:10.1016/j.soard.2011.07.007)

    • Search Google Scholar
    • Export Citation
  • Cote CD, Zadeh-Tahmasebi M, Rasmussen BA, Duca FA & Lam TK 2014 Hormonal signaling in the gut. Journal of Biological Chemistry 289 1164211649. (doi:10.1074/jbc.O114.556068)

    • Search Google Scholar
    • Export Citation
  • Cote CD, Rasmussen BA, Duca FA, Zadeh-Tahmasebi M, Baur JA, Daljeet M, Breen DM, Filippi BM & Lam TK 2015 Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network. Nature Medicine 21 498505. (doi:10.1038/nm.3821)

    • Search Google Scholar
    • Export Citation
  • Daniele G, Iozzo P, Molina-Carrion M, Lancaster J, Ciociaro D, Cersosimo E, Tripathy D, Triplitt C, Fox P & Musi N et al. 2015 Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system. Diabetes 64 34063412. (doi:10.2337/db14-1718)

    • Search Google Scholar
    • Export Citation
  • Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J & Hoyles L et al. 2016 Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65 426436. (doi:10.1136/gutjnl-2014-308778)

    • Search Google Scholar
    • Export Citation
  • Dar MS, Chapman WH 3rd, Pender JR, Drake AJ 3rd, O’Brien K, Tanenberg RJ, Dohm GL & Pories WJ 2012 GLP-1 response to a mixed meal: what happens 10 years after Roux-en-Y gastric bypass (RYGB)? Obesity Surgery 22 10771083. (doi:10.1007/s11695-012-0624-1)

    • Search Google Scholar
    • Export Citation
  • Darcel NP, Liou AP, Tome D & Raybould HE 2005 Activation of vagal afferents in the rat duodenum by protein digests requires PepT1. Journal of Nutrition 135 14911495.

    • Search Google Scholar
    • Export Citation
  • Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, Findeisen H, Bruemmer D, Drucker DJ & Chaudhary N et al. 2009 A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nature Chemical Biology 5 749757. (doi:10.1038/nchembio.209)

    • Search Google Scholar
    • Export Citation
  • Day JW, Gelfanov V, Smiley D, Carrington PE, Eiermann G, Chicchi G, Erion MD, Gidda J, Thornberry NA & Tschop MH et al. 2012 Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents. Biopolymers 98 443450. (doi:10.1002/bip.22072)

    • Search Google Scholar
    • Export Citation
  • de Lartigue G, Ronveaux CC & Raybould HE 2014 Deletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity. Molecular Metabolism 3 595607. (doi:10.1016/j.molmet.2014.06.003)

    • Search Google Scholar
    • Export Citation
  • Deacon CF & Lebovitz HE 2016 A comparative review of DPP-4 inhibitors and sulphonylureas. Diabetes, Obesity and Metabolism 18 333347. (doi:10.1111/dom.12610)

    • Search Google Scholar
    • Export Citation
  • DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS & Baron AD 2005 Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28 10921100. (doi:10.2337/diacare.28.5.1092)

    • Search Google Scholar
    • Export Citation
  • Derrien M, Vaughan EE, Plugge CM & de Vos WM 2004 Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. International Journal of Systematic and Evolutionary Microbiology 54 14691476. (doi:10.1099/ijs.0.02873-0)

    • Search Google Scholar
    • Export Citation
  • Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L & Group D-S 2008 Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372 12401250. (doi:10.1016/S0140-6736(08)61206-4)

    • Search Google Scholar
    • Export Citation
  • Duca FA & Lam TK 2014 Gut microbiota, nutrient sensing and energy balance. Diabetes, Obesity and Metabolism 16 (Supplement 1) 6876. (doi:10.1111/dom.12340)

    • Search Google Scholar
    • Export Citation
  • Duca FA, Cote CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM & Lam TK 2015 Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nature Medicine 21 506511. (doi:10.1038/nm.3787)

    • Search Google Scholar
    • Export Citation
  • Edfalk S, Steneberg P & Edlund H 2008 Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57 22802287. (doi:10.2337/db08-0307)

    • Search Google Scholar
    • Export Citation
  • Egerod KL, Engelstoft MS, Grunddal KV, Nohr MK, Secher A, Sakata I, Pedersen J, Windelov JA, Fuchtbauer EM & Olsen J et al. 2012 A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology 153 57825795. (doi:10.1210/en.2012-1595)

    • Search Google Scholar
    • Export Citation
  • Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, Possemiers S, Van Holle A, Francois P & de Vos WM et al. 2011 Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60 27752786. (doi:10.2337/db11-0227)

    • Search Google Scholar
    • Export Citation
  • Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG & Delzenne NM et al. 2013 Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. PNAS 110 90669071. (doi:10.1073/pnas.1219451110)

    • Search Google Scholar
    • Export Citation
  • Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S & Lukasheva Y et al. 2015 Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nature Medicine 21 159165. (doi:10.1038/nm.3760)

    • Search Google Scholar
    • Export Citation
  • Finan B, Ma T, Ottaway N, Muller TD, Habegger KM, Heppner KM, Kirchner H, Holland J, Hembree J & Raver C et al. 2013 Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Science Translational Medicine 5 209ra151. (doi:10.1126/scitranslmed.3007218)

    • Search Google Scholar
    • Export Citation
  • Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, Zhang L, Habegger KM & Fischer K et al. 2015 A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nature Medicine 21 2736.

    • Search Google Scholar
    • Export Citation
  • Fiorucci S, Mencarelli A, Palladino G & Cipriani S 2009 Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends in Pharmacological Sciences 30 570580. (doi:10.1016/j.tips.2009.08.001)

    • Search Google Scholar
    • Export Citation
  • Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F & Viollet B 2010 Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. Journal of Clinical Investigation 120 23552369. (doi:10.1172/JCI40671)

    • Search Google Scholar
    • Export Citation
  • Foretz M, Guigas B, Bertrand L, Pollak M & Viollet B 2014 Metformin: from mechanisms of action to therapies. Cell Metabolism 20 953966. (doi:10.1016/j.cmet.2014.09.018)

    • Search Google Scholar
    • Export Citation
  • Fosgerau K, Jessen L, Lind Tolborg J, Osterlund T, Schaeffer Larsen K, Rolsted K, Brorson M, Jelsing J & Skovlund Ryge Neerup T 2013 The novel GLP-1-gastrin dual agonist, ZP3022, increases beta-cell mass and prevents diabetes in db/db mice. Diabetes, Obesity and Metabolism 15 6271. (doi:10.1111/j.1463-1326.2012.01676.x)

    • Search Google Scholar
    • Export Citation
  • Furet JP, Kong LC, Tap J, Poitou C, Basdevant A, Bouillot JL, Mariat D, Corthier G, Dore J & Henegar C et al. 2010 Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59 30493057. (doi:10.2337/db10-0253)

    • Search Google Scholar
    • Export Citation
  • Furman BL 2012 The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. Toxicon 59 464471. (doi:10.1016/j.toxicon.2010.12.016)

    • Search Google Scholar
    • Export Citation
  • Gagner M 2011 Surgical treatment of nonseverely obese patients with type 2 diabetes mellitus: sleeve gastrectomy with ileal transposition (SGIT) is the same as the neuroendocrine brake (NEB) procedure or ileal interposition associated with sleeve gastrectomy (II-SG), but ileal interposition with diverted sleeve gastrectomy (II-DSG) is the same as duodenal switch. Surgical Endoscopy 25 655656. (doi:10.1007/s00464-010-1221-9)

    • Search Google Scholar
    • Export Citation
  • Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, Hale PM, Zdravkovic M, Bode B & Group L-S 2009 Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 373 473481. (doi:10.1016/S0140-6736(08)61246-5)

    • Search Google Scholar
    • Export Citation
  • Geloneze B, Geloneze SR, Chaim E, Hirsch FF, Felici AC, Lambert G, Tambascia MA & Pareja JC 2012 Metabolic surgery for non-obese type 2 diabetes: incretins, adipocytokines, and insulin secretion/resistance changes in a 1-year interventional clinical controlled study. Annals of Surgery 256 7278. (doi:10.1097/SLA.0b013e3182592c62)

    • Search Google Scholar
    • Export Citation
  • Gerhard GS, Styer AM, Wood GC, Roesch SL, Petrick AT, Gabrielsen J, Strodel WE, Still CD & Argyropoulos G 2013 A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care 36 18591864. (doi:10.2337/dc12-2255)

    • Search Google Scholar
    • Export Citation
  • Gribble FM, Williams L, Simpson AK & Reimann F 2003 A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line. Diabetes 52 11471154. (doi:10.2337/diabetes.52.5.1147)

    • Search Google Scholar
    • Export Citation
  • Grueneberger JM, Fritz T, Zhou C, Meyer S, Karcz-Socha I, Sawczyn T, Stygar D, Goos M, Hopt UT & Kusters S 2013 Long segment ileal transposition leads to early amelioration of glucose control in the diabetic obese Zucker rat. Wideochir Inne Tech Maloinwazyjne 8 130138. (doi:10.5114/wiitm.2011.32925)

    • Search Google Scholar
    • Export Citation
  • Grueneberger JM, Karcz-Socha I, Sawczyn T, Kosmowski J, Stygar D, Goos M, Kusters S, Zwirska-Korczala K, Marjanovic G & Keck T et al. 2014 Systematic ileal transposition in Zucker rats shows advantage for long segment distal transposition. Surgery 155 165172. (doi:10.1016/j.surg.2013.05.033)

    • Search Google Scholar
    • Export Citation
  • Grunddal KV, Ratner CF, Svendsen B, Sommer F, Engelstoft MS, Madsen AN, Pedersen J, Nohr MK, Egerod KL & Nawrocki AR et al. 2016 Neurotensin is coexpressed, coreleased, and acts together with GLP-1 and PYY in enteroendocrine control of metabolism. Endocrinology 157 176194. (doi:10.1210/en.2015-1600)

    • Search Google Scholar
    • Export Citation
  • Gustavson SM, Sandoval DA, Ertl AC, Bao S, Raj SR & Davis SN 2008 Stimulation of both type I and type II corticosteroid receptors blunts counterregulatory responses to subsequent hypoglycemia in healthy man. American Journal of Physiology: Endocrinology and Metabolism 294 E506E512. (doi:10.1152/ajpendo.00589.2007)

    • Search Google Scholar
    • Export Citation
  • Habegger KM, Al-Massadi O, Heppner KM, Myronovych A, Holland J, Berger J, Yi CX, Gao Y, Lehti M & Ottaway N et al. 2014 Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia. Gut 63 12381246. (doi:10.1136/gutjnl-2013-304583)

    • Search Google Scholar
    • Export Citation
  • Habib AM, Richards P, Cairns LS, Rogers GJ, Bannon CA, Parker HE, Morley TC, Yeo GS, Reimann F & Gribble FM 2012 Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153 30543065. (doi:10.1210/en.2011-2170)

    • Search Google Scholar
    • Export Citation
  • Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, Blonde L, Bray GA, Cohen AJ & Dagogo-Jack S et al. 2015 American association of clinical endocrinologists and american college of endocrinology – clinical practice guidelines for developing a diabetes mellitus comprehensive care plan – 2015. Endocrine Practice 21 (Supplement 1) 187. (doi:10.4158/EP15672.GLSUPPL)

    • Search Google Scholar
    • Export Citation
  • Hansen CH, Krych L, Nielsen DS, Vogensen FK, Hansen LH, Sorensen SJ, Buschard K & Hansen AK 2012a Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 55 22852294. (doi:10.1007/s00125-012-2564-7)

    • Search Google Scholar
    • Export Citation
  • Hansen HS, Rosenkilde MM, Holst JJ & Schwartz TW 2012b GPR119 as a fat sensor. Trends in Pharmacological Sciences 33 374381. (doi:10.1016/j.tips.2012.03.014)

    • Search Google Scholar
    • Export Citation
  • Hansotia T, Baggio LL, Delmeire D, Hinke SA, Yamada Y, Tsukiyama K, Seino Y, Holst JJ, Schuit F & Drucker DJ 2004 Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 53 13261335. (doi:10.2337/diabetes.53.5.1326)

    • Search Google Scholar
    • Export Citation
  • Harmel E, Grenier E, Bendjoudi Ouadda A, El Chebly M, Ziv E, Beaulieu JF, Sane A, Spahis S, Laville M & Levy E 2014 AMPK in the small intestine in normal and pathophysiological conditions. Endocrinology 155 873888. (doi:10.1210/en.2013-1750)

    • Search Google Scholar
    • Export Citation
  • Hauge M, Vestmar MA, Husted AS, Ekberg JP, Wright MJ, Di Salvo J, Weinglass AB, Engelstoft MS, Madsen AN & Luckmann M et al. 2015 GPR40 (FFAR1) – combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo. Molecular Metabolism 4 314. (doi:10.1016/j.molmet.2014.10.002)

    • Search Google Scholar
    • Export Citation
  • Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG & Group GS 2005 Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Annals of Internal Medicine 143 559569. (doi:10.7326/0003-4819-143-8-200510180-00006)

    • Search Google Scholar
    • Export Citation
  • Heppner KM, Kirigiti M, Secher A, Paulsen SJ, Buckingham R, Pyke C, Knudsen LB, Vrang N & Grove KL 2015 Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. Endocrinology 156 255267. (doi:10.1210/en.2014-1675)

    • Search Google Scholar
    • Export Citation
  • Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S & Tsujimoto G 2005 Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nature Medicine 11 9094. (doi:10.1038/nm1168)

    • Search Google Scholar
    • Export Citation
  • Holst JJ & Deacon CF 2005 Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors. Diabetologia 48 612615. (doi:10.1007/s00125-005-1705-7)

    • Search Google Scholar
    • Export Citation
  • Howarth NC, Saltzman E, McCrory MA, Greenberg AS, Dwyer J, Ausman L, Kramer DG & Roberts SB 2003 Fermentable and nonfermentable fiber supplements did not alter hunger, satiety or body weight in a pilot study of men and women consuming self-selected diets. Journal of Nutrition 133 31413144.

    • Search Google Scholar
    • Export Citation
  • Iakoubov R, Izzo A, Yeung A, Whiteside CI & Brubaker PL 2007 Protein kinase Czeta is required for oleic acid-induced secretion of glucagon-like peptide-1 by intestinal endocrine L cells. Endocrinology 148 10891098. (doi:10.1210/en.2006-1403)

    • Search Google Scholar
    • Export Citation
  • Imoto H, Shibata C, Ikezawa F, Kikuchi D, Someya S, Miura K, Naitoh T & Unno M 2014 Effects of duodeno-jejunal bypass on glucose metabolism in obese rats with type 2 diabetes. Surgery Today 44 340348. (doi:10.1007/s00595-013-0638-x)

    • Search Google Scholar
    • Export Citation
  • Irwin N & Flatt PR 2009 Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications. Diabetologia 52 17241731. (doi:10.1007/s00125-009-1422-8)

    • Search Google Scholar
    • Export Citation
  • Irwin N, Hunter K, Montgomery IA & Flatt PR 2013 Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat-fed mice. Diabetes, Obesity and Metabolism 15 650659. (doi:10.1111/dom.12079)

    • Search Google Scholar
    • Export Citation
  • Irwin N, Pathak V & Flatt PR 2015 A novel CCK-8/GLP-1 hybrid peptide exhibiting prominent insulinotropic, glucose-lowering, and satiety actions with significant therapeutic potential in high-fat-fed mice. Diabetes 64 29963009. (doi:10.2337/db15-0220)

    • Search Google Scholar
    • Export Citation
  • Jacobsen SH, Olesen SC, Dirksen C, Jorgensen NB, Bojsen-Moller KN, Kielgast U, Worm D, Almdal T, Naver LS & Hvolris LE et al. 2012 Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obesity Surgery 22 10841096. (doi:10.1007/s11695-012-0621-4)

    • Search Google Scholar
    • Export Citation
  • Jang HJ, Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim BJ, Zhou J, Kim HH, Xu X, Chan SL & Juhaszova M et al. 2007 Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. PNAS 104 1506915074. (doi:10.1073/pnas.0706890104)

    • Search Google Scholar
    • Export Citation
  • Ji L, Onishi Y, Ahn CW, Agarwal P, Chou CW, Haber H, Guerrettaz K & Boardman MK 2013 Efficacy and safety of exenatide once-weekly vs exenatide twice-daily in Asian patients with type 2 diabetes mellitus. Journal of Diabetes Investigation 4 5361. (doi:10.1111/j.2040-1124.2012.00238.x)

    • Search Google Scholar
    • Export Citation
  • Jiang C, Xie C, Lv Y, Li J, Krausz KW, Shi J, Brocker CN, Desai D, Amin SG & Bisson WH et al. 2015 Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nature Communications 6 10166. (doi:10.1038/ncomms10166)

    • Search Google Scholar
    • Export Citation
  • Jimenez A, Casamitjana R, Viaplana-Masclans J, Lacy A & Vidal J 2013 GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. Diabetes Care 36 20622069. (doi:10.2337/dc12-1535)

    • Search Google Scholar
    • Export Citation
  • Jinnouchi H, Sugiyama S, Yoshida A, Hieshima K, Kurinami N, Suzuki T, Miyamoto F, Kajiwara K, Matsui K & Jinnouchi T 2015 Liraglutide, a glucagon-like peptide-1 analog, increased insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp examination in patients with uncontrolled type 2 diabetes mellitus. Journal of Diabetes Research 2015 706416. (doi:10.1155/2015/706416)

    • Search Google Scholar
    • Export Citation
  • Jorgensen NB, Dirksen C, Bojsen-Moller KN, Kristiansen VB, Wulff BS, Rainteau D, Humbert L, Rehfeld JF, Holst JJ & Madsbad S et al. 2015 Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations. Journal of Clinical Endocrinology and Metabolism 100 E396E406. (doi:10.1210/jc.2014-1658)

    • Search Google Scholar
    • Export Citation
  • Kanoski SE, Fortin SM, Arnold M, Grill HJ & Hayes MR 2011 Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 152 31033112. (doi:10.1210/en.2011-0174)

    • Search Google Scholar
    • Export Citation
  • Kapitza C, Forst T, Coester HV, Poitiers F, Ruus P & Hincelin-Mery A 2013 Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes, Obesity and Metabolism 15 642649. (doi:10.1111/dom.12076)

    • Search Google Scholar
    • Export Citation
  • Karlsson J, Taft C, Ryden A, Sjostrom L & Sullivan M 2007 Ten-year trends in health-related quality of life after surgical and conventional treatment for severe obesity: the SOS intervention study. International Journal of Obesity 31 12481261. (doi:10.1038/sj.ijo.0803573)

    • Search Google Scholar
    • Export Citation
  • Kasama K, Tagaya N, Kanehira E, Oshiro T, Seki Y, Kinouchi M, Umezawa A, Negishi Y & Kurokawa Y 2009 Laparoscopic sleeve gastrectomy with duodenojejunal bypass: technique and preliminary results. Obesity Surgery 19 13411345. (doi:10.1007/s11695-009-9873-z)

    • Search Google Scholar
    • Export Citation
  • Kastin AJ & Akerstrom V 2003 Entry of exendin-4 into brain is rapid but may be limited at high doses. International Journal of Obesity and Related Metabolic Disorders 27 313318. (doi:10.1038/sj.ijo.0802206)

    • Search Google Scholar
    • Export Citation
  • Katsuma S, Hirasawa A & Tsujimoto G 2005 Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochemical and Biophysical Research Communications 329 386390. (doi:10.1016/j.bbrc.2005.01.139)

    • Search Google Scholar
    • Export Citation
  • Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS & Baron AD 2005 Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28 10831091. (doi:10.2337/diacare.28.5.1083)

    • Search Google Scholar
    • Export Citation
  • Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Gremeaux T, Drucker DJ & Kahn CR et al. 2005 Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. Journal of Clinical Investigation 115 35543563. (doi:10.1172/JCI25764)

    • Search Google Scholar
    • Export Citation
  • Kokorovic A, Cheung GW, Breen DM, Chari M, Lam CK & Lam TK 2011 Duodenal mucosal protein kinase C-delta regulates glucose production in rats. Gastroenterology 141 17201727. (doi:10.1053/j.gastro.2011.06.042)

    • Search Google Scholar
    • Export Citation
  • Kreymann B, Williams G, Ghatei MA & Bloom SR 1987 Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet 2 13001304. (doi:10.1016/S0140-6736(87)91194-9)

    • Search Google Scholar
    • Export Citation
  • Kuhre RE, Frost CR, Svendsen B & Holst JJ 2015 Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine. Diabetes 64 370382. (doi:10.2337/db14-0807)

    • Search Google Scholar
    • Export Citation
  • Labouesse MA, Stadlbauer U, Weber E, Arnold M, Langhans W & Pacheco-Lopez G 2012 Vagal afferents mediate early satiation and prevent flavour avoidance learning in response to intraperitoneally infused exendin-4. Journal of Neuroendocrinology 24 15051516. (doi:10.1111/j.1365-2826.2012.02364.x)

    • Search Google Scholar
    • Export Citation
  • Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H & Drucker DJ 2012 Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. Journal of Clinical Investigation 122 388402. (doi:10.1172/JCI42497)

    • Search Google Scholar
    • Export Citation
  • Le Barz M, Anhe FF, Varin TV, Desjardins Y, Levy E, Roy D, Urdaci MC & Marette A 2015 Probiotics as complementary treatment for metabolic disorders. Diabetes and Metabolism Journal 39 291303. (doi:10.4093/dmj.2015.39.4.291)

    • Search Google Scholar
    • Export Citation
  • le Roux CW, Aylwin SJ, Batterham RL, Borg CM, Coyle F, Prasad V, Shurey S, Ghatei MA, Patel AG & Bloom SR 2006 Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Annals of Surgery 243 108114. (doi:10.1097/01.sla.0000183349.16877.84)

    • Search Google Scholar
    • Export Citation
  • le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos A, Laurenius A, Lonroth H, Fandriks L, Ghatei MA & Bloom SR et al. 2007 Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Annals of Surgery 246 780785. (doi:10.1097/SLA.0b013e3180caa3e3)

    • Search Google Scholar
    • Export Citation
  • Lee HC, Kim MK, Kwon HS, Kim E & Song KH 2010 Early changes in incretin secretion after laparoscopic duodenal-jejunal bypass surgery in type 2 diabetic patients. Obesity Surgery 20 15301535. (doi:10.1007/s11695-010-0248-2)

    • Search Google Scholar
    • Export Citation
  • Lee WJ, Lee KT, Kasama K, Seiki Y, Ser KH, Chun SC, Chen JC & Lee YC 2014 Laparoscopic single-anastomosis duodenal-jejunal bypass with sleeve gastrectomy (SADJB-SG): short-term result and comparison with gastric bypass. Obesity Surgery 24 109113. (doi:10.1007/s11695-013-1067-z)

    • Search Google Scholar
    • Export Citation
  • Li JV, Ashrafian H, Bueter M, Kinross J, Sands C, le Roux CW, Bloom SR, Darzi A, Athanasiou T & Marchesi JR et al. 2011a Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut 60 12141223. (doi:10.1136/gut.2010.234708)

    • Search Google Scholar
    • Export Citation
  • Li Y, Wu X, Zhou S & Owyang C 2011b Low-affinity CCK-A receptors are coexpressed with leptin receptors in rat nodose ganglia: implications for leptin as a regulator of short-term satiety. American Journal of Physiology: Gastrointestinal and Liver Physiology 300 G217G227. (doi:10.1152/ajpgi.00356.2010)

    • Search Google Scholar
    • Export Citation
  • Li F, Jiang C, Krausz KW, Li Y, Albert I, Hao H, Fabre KM, Mitchell JB, Patterson AD & Gonzalez FJ 2013 Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nature Communications 4 2384.

    • Search Google Scholar
    • Export Citation
  • Lien F, Berthier A, Bouchaert E, Gheeraert C, Alexandre J, Porez G, Prawitt J, Dehondt H, Ploton M & Colin S et al. 2014 Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. Journal of Clinical Investigation 124 10371051. (doi:10.1172/JCI68815)

    • Search Google Scholar
    • Export Citation
  • Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X & Forrest G et al. 2012 Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS ONE 7 e35240. (doi:10.1371/journal.pone.0035240)

    • Search Google Scholar
    • Export Citation
  • Liou AP, Chavez DI, Espero E, Hao S, Wank SA & Raybould HE 2011a Protein hydrolysate-induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter PepT1. American Journal of Physiology: Gastrointestinal and Liver Physiology 300 G895G902. (doi:10.1152/ajpgi.00521.2010)

    • Search Google Scholar
    • Export Citation
  • Liou AP, Lu X, Sei Y, Zhao X, Pechhold S, Carrero RJ, Raybould HE & Wank S 2011b The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 140 903912. (doi:10.1053/j.gastro.2010.10.012)

    • Search Google Scholar
    • Export Citation
  • Liou AP, Sei Y, Zhao X, Feng J, Lu X, Thomas C, Pechhold S, Raybould HE & Wank SA 2011c The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. American Journal of Physiology: Gastrointestinal and Liver Physiology 300 G538G546. (doi:10.1152/ajpgi.00342.2010)

    • Search Google Scholar
    • Export Citation
  • Liou AP, Paziuk M, Luevano JM Jr, Machineni S, Turnbaugh PJ & Kaplan LM 2013 Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Science Translational Medicine 5 178ra141. (doi:10.1126/scitranslmed.3005687)

    • Search Google Scholar
    • Export Citation
  • Little TJ, Doran S, Meyer JH, Smout AJ, O’Donovan DG, Wu KL, Jones KL, Wishart J, Rayner CK & Horowitz M et al. 2006 The release of GLP-1 and ghrelin, but not GIP and CCK, by glucose is dependent upon the length of small intestine exposed. American Journal of Physiology: Endocrinology and Metabolism 291 E647E655. (doi:10.1152/ajpendo.00099.2006)

    • Search Google Scholar
    • Export Citation
  • Liu S, Zhang G, Wang L, Sun D, Chen W, Yan Z, Sun Y & Hu S 2012 The entire small intestine mediates the changes in glucose homeostasis after intestinal surgery in Goto-Kakizaki rats. Annals of Surgery 256 10491058. (doi:10.1097/SLA.0b013e31826c3866)

    • Search Google Scholar
    • Export Citation
  • Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C, Ananthakrishnan G, Rohner-Jeanrenaud F, Drucker DJ & DiMarchi R et al. 2012 Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 61 27532762. (doi:10.2337/db11-1556)

    • Search Google Scholar
    • Export Citation
  • Lovshin JA & Drucker DJ 2009 Incretin-based therapies for type 2 diabetes mellitus. Nature Reviews: Endocrinology 5 262269. (doi:10.1038/nrendo.2009.48)

    • Search Google Scholar
    • Export Citation
  • Ma K, Saha PK, Chan L & Moore DD 2006 Farnesoid X receptor is essential for normal glucose homeostasis. Journal of Clinical Investigation 116 11021109. (doi:10.1172/JCI25604)

    • Search Google Scholar
    • Export Citation
  • Ma Y, Huang Y, Yan L, Gao M & Liu D 2013 Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharmaceutical Research 30 14471457. (doi:10.1007/s11095-013-0986-7)

    • Search Google Scholar
    • Export Citation
  • Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S & MacDonald MJ et al. 2014 Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510 542546. (doi:10.1038/nature13270)

    • Search Google Scholar
    • Export Citation
  • Madsbad S 2016 A review of head-to-head comparisons of GLP-1 receptor agonists. Diabetes, Obesity and Metabolism 18 317332. (doi:10.1111/dom.12596)

    • Search Google Scholar
    • Export Citation
  • Madsbad S, Dirksen C & Holst JJ 2014 Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes and Endocrinology 2 152164. (doi:10.1016/S2213-8587(13)70218-3)

    • Search Google Scholar
    • Export Citation
  • Marceau P, Biron S, Marceau S, Hould FS, Lebel S, Lescelleur O, Biertho L, Simard S & Kral JG 2015 Long-term metabolic outcomes 5 to 20 years after biliopancreatic diversion. Obesity Surgery 25 15841593. (doi:10.1007/s11695-015-1599-5)

    • Search Google Scholar
    • Export Citation
  • Marcelin G, Jo YH, Li X, Schwartz GJ, Zhang Y, Dun NJ, Lyu RM, Blouet C, Chang JK & Chua S Jr 2014 Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Molecular Metabolism 3 1928. (doi:10.1016/j.molmet.2013.10.002)

    • Search Google Scholar
    • Export Citation
  • Marina AL, Utzschneider KM, Wright LA, Montgomery BK, Marcovina SM & Kahn SE 2012 Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and beta-cell function. Diabetes Care 35 11191125. (doi:10.2337/dc11-2050)

    • Search Google Scholar
    • Export Citation
  • Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, Le Thi TD, Colagiuri S & LEAD-1 SU Study Group 2009 Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabetic Medicine 26 268278. (doi:10.1111/j.1464-5491.2009.02666.x)

    • Search Google Scholar
    • Export Citation
  • McGavigan AK, Garibay D, Henseler ZM, Chen J, Bettaieb A, Haj FG, Ley RE, Chouinard ML & Cummings BP 2015 TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut. (doi:10.1136/gutjnl-2015-309871)

    • Search Google Scholar
    • Export Citation
  • Meier JJ, Rosenstock J, Hincelin-Mery A, Roy-Duval C, Delfolie A, Coester HV, Menge BA, Forst T & Kapitza C 2015 Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care 38 12631273. (doi:10.2337/dc14-1984)

    • Search Google Scholar
    • Export Citation
  • Miller RA, Chu Q, Xie J, Foretz M, Viollet B & Birnbaum MJ 2013 Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494 256260. (doi:10.1038/nature11808)

    • Search Google Scholar
    • Export Citation
  • Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, Nanni G, Pomp A, Castagneto M & Ghirlanda G et al. 2012 Bariatric surgery versus conventional medical therapy for type 2 diabetes. New England Journal of Medicine 366 15771585. (doi:10.1056/NEJMoa1200111)

    • Search Google Scholar
    • Export Citation
  • Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Nanni G, Castagneto M, Bornstein S & Rubino F 2015 Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 386 964973. (doi:10.1016/S0140-6736(15)00075-6)

    • Search Google Scholar
    • Export Citation
  • Mojsov S, Weir GC & Habener JF 1987 Insulinotropin: glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. Journal of Clinical Investigation 79 616619. (doi:10.1172/JCI112855)

    • Search Google Scholar
    • Export Citation
  • Mokadem M, Zechner JF, Margolskee RF, Drucker DJ & Aguirre V 2014 Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency. Molecular Metabolism 3 191201. (doi:10.1016/j.molmet.2013.11.010)

    • Search Google Scholar
    • Export Citation
  • Morinigo R, Vidal J, Lacy AM, Delgado S, Casamitjana R & Gomis R 2008 Circulating peptide YY, weight loss, and glucose homeostasis after gastric bypass surgery in morbidly obese subjects. Annals of Surgery 247 270275. (doi:10.1097/SLA.0b013e31815f6e77)

    • Search Google Scholar
    • Export Citation
  • Morton GJ, Matsen ME, Bracy DP, Meek TH, Nguyen HT, Stefanovski D, Bergman RN, Wasserman DH & Schwartz MW 2013 FGF19 action in the brain induces insulin-independent glucose lowering. Journal of Clinical Investigation 123 47994808. (doi:10.1172/JCI70710)

    • Search Google Scholar
    • Export Citation
  • Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P & Castelloe E et al. 2013 Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145 574582.e1. (doi:10.1053/j.gastro.2013.05.042)

    • Search Google Scholar
    • Export Citation
  • Mumphrey MB, Patterson LM, Zheng H & Berthoud HR 2013 Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats. Neurogastroenterology and Motility 25 e70e79. (doi:10.1111/nmo.12034)

    • Search Google Scholar
    • Export Citation
  • Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, Rajpal D, Spivak A, Brown JR & Nunez DJ 2014 Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE 9 e100778. (doi:10.1371/journal.pone.0100778)

    • Search Google Scholar
    • Export Citation
  • Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, During M, Matthews DR & Group L-S 2009 Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 32 8490. (doi:10.2337/dbib8-1355)

    • Search Google Scholar
    • Export Citation
  • Nemoz-Gaillard E, Bernard C, Abello J, Cordier-Bussat M, Chayvialle JA & Cuber JC 1998 Regulation of cholecystokinin secretion by peptones and peptidomimetic antibiotics in STC-1 cells. Endocrinology 139 932938. (doi:10.1210/endo.139.3.5802)

    • Search Google Scholar
    • Export Citation
  • Neyrinck AM, Van Hee VF, Piront N, De Backer F, Toussaint O, Cani PD & Delzenne NM 2012 Wheat-derived arabinoxylan oligosaccharides with prebiotic effect increase satietogenic gut peptides and reduce metabolic endotoxemia in diet-induced obese mice. Nutrition and Diabetes 2 e28. (doi:10.1038/nutd.2011.24)

    • Search Google Scholar
    • Export Citation
  • Osto M, Abegg K, Bueter M, le Roux CW, Cani PD & Lutz TA 2013 Roux-en-Y gastric bypass surgery in rats alters gut microbiota profile along the intestine. Physiology and Behavior 119 9296. (doi:10.1016/j.physbeh.2013.06.008)

    • Search Google Scholar
    • Export Citation
  • Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM & Tang-Christensen M et al. 2006 Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metabolism 3 167175. (doi:10.1016/j.cmet.2006.02.004)

    • Search Google Scholar
    • Export Citation
  • Owen MR, Doran E & Halestrap AP 2000 Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal 348 607614. (doi:10.1042/bj3480607)

    • Search Google Scholar
    • Export Citation
  • Pan CQ, Buxton JM, Yung SL, Tom I, Yang L, Chen H, MacDougall M, Bell A, Claus TH & Clairmont KB et al. 2006 Design of a long acting peptide functioning as both a glucagon-like peptide-1 receptor agonist and a glucagon receptor antagonist. Journal of Biological Chemistry 281 1250612515. (doi:10.1074/jbc.M600127200)

    • Search Google Scholar
    • Export Citation
  • Parker HE, Habib AM, Rogers GJ, Gribble FM & Reimann F 2009 Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 52 289298. (doi:10.1007/s00125-008-1202-x)

    • Search Google Scholar
    • Export Citation
  • Parnell JA & Reimer RA 2009 Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. American Journal of Clinical Nutrition 89 17511759. (doi:10.3945/ajcn.2009.27465)

    • Search Google Scholar
    • Export Citation
  • Patel RT, Shukla AP, Ahn SM, Moreira M & Rubino F 2014 Surgical control of obesity and diabetes: the role of intestinal vs. gastric mechanisms in the regulation of body weight and glucose homeostasis. Obesity 22 159169. (doi:10.1002/oby.20441)

    • Search Google Scholar
    • Export Citation
  • Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME & Jiang G et al. 2009 Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58 22582266. (doi:10.2337/db09-0278)

    • Search Google Scholar
    • Export Citation
  • Poreba MA, Dong CX, Li SK, Stahl A, Miner JH & Brubaker PL 2012 Role of fatty acid transport protein 4 in oleic acid-induced glucagon-like peptide-1 secretion from murine intestinal L cells. American Journal of Physiology: Endocrinology and Metabolism 303 E899E907. (doi:10.1152/ajpendo.00116.2012)

    • Search Google Scholar
    • Export Citation
  • Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, Bekker JH, Ghatei MA, Bloom SR & Walters JR et al. 2012 The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 153 36133619. (doi:10.1210/en.2011-2145)

    • Search Google Scholar
    • Export Citation
  • Psichas A, Reimann F & Gribble FM 2015a Gut chemosensing mechanisms. Journal of Clinical Investigation 125 908917. (doi:10.1172/jci76309)

  • Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR & Frost G 2015b The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. International Journal of Obesity 39 424429. (doi:10.1038/ijo.2014.153)

    • Search Google Scholar
    • Export Citation
  • Pyke C, Heller RS, Kirk RK, Orskov C, Reedtz-Runge S, Kaastrup P, Hvelplund A, Bardram L, Calatayud D & Knudsen LB 2014 GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155 12801290. (doi:10.1210/en.2013-1934)

    • Search Google Scholar
    • Export Citation
  • Ramzy AR, Nausheen S & Chelikani PK 2014 Ileal transposition surgery produces ileal length-dependent changes in food intake, body weight, gut hormones and glucose metabolism in rats. International Journal of Obesity 38 379387. (doi:10.1038/ijo.2013.201)

    • Search Google Scholar
    • Export Citation
  • Rasmussen BA, Breen DM, Luo P, Cheung GW, Yang CS, Sun B, Kokorovic A, Rong W & Lam TK 2012 Duodenal activation of cAMP-dependent protein kinase induces vagal afferent firing and lowers glucose production in rats. Gastroenterology 142 834843.e3. (doi:10.1053/j.gastro.2011.12.053)

    • Search Google Scholar
    • Export Citation
  • Rasmussen BA, Breen DM, Duca FA, Cote CD, Zadeh-Tahmasebi M, Filippi BM & Lam TK 2014 Jejunal leptin-PI3K signaling lowers glucose production. Cell Metabolism 19 155161. (doi:10.1016/j.cmet.2013.11.014)

    • Search Google Scholar
    • Export Citation
  • Ravussin E, Smith SR, Mitchell JA, Shringarpure R, Shan K, Maier H, Koda JE & Weyer C 2009 Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity 17 17361743. (doi:10.1038/oby.2009.184)

    • Search Google Scholar
    • Export Citation
  • Raybould HE, Gayton RJ & Dockray GJ 1988 Mechanisms of action of peripherally administered cholecystokinin octapeptide on brain stem neurons in the rat. Journal of Neuroscience 8 30183024.

    • Search Google Scholar
    • Export Citation
  • Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ & Gribble FM 2008 Glucose sensing in L cells: a primary cell study. Cell Metabolism 8 532539. (doi:10.1016/j.cmet.2008.11.002)

    • Search Google Scholar
    • Export Citation
  • Rhee NA, Wahlgren CD, Pedersen J, Mortensen B, Langholz E, Wandall EP, Friis SU, Vilmann P, Paulsen SJ & Kristiansen VB et al. 2015 Effect of Roux-en-Y gastric bypass on the distribution and hormone expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes. Diabetologia 58 22542258. (doi:10.1007/s00125-015-3696-3)

    • Search Google Scholar
    • Export Citation
  • Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, Gribble FM & Reimann F 2014 Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63 12241233. (doi:10.2337/db13-1440)

    • Search Google Scholar
    • Export Citation
  • Rodieux F, Giusti V, D’Alessio DA, Suter M & Tappy L 2008 Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release. Obesity 16 298305. (doi:10.1038/oby.2007.83)

    • Search Google Scholar
    • Export Citation
  • Rojas LB & Gomes MB 2013 Metformin: an old but still the best treatment for type 2 diabetes. Diabetology & Metabolic Syndrome 5 6. (doi:10.1186/1758-5996-5-6)

    • Search Google Scholar
    • Export Citation
  • Roopchand DE, Carmody RN, Kuhn P, Moskal K, Rojas-Silva P, Turnbaugh PJ & Raskin I 2015 Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Diabetes 64 28472858. (doi:10.2337/db14-1916)

    • Search Google Scholar
    • Export Citation
  • Rubino F, Gagner M, Gentileschi P, Kini S, Fukuyama S, Feng J & Diamond E 2004 The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Annals of Surgery 240 236242. (doi:10.1097/01.sla.0000133117.12646.48)

    • Search Google Scholar
    • Export Citation
  • Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, Zdravkovic M, Ravn GM, Simo R & Liraglutide E et al. 2009 Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 52 20462055. (doi:10.1007/s00125-009-1472-y)

    • Search Google Scholar
    • Export Citation
  • Ryan KK, Kohli R, Gutierrez-Aguilar R, Gaitonde SG, Woods SC & Seeley RJ 2013 Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154 915. (doi:10.1210/en.2012-1891)

    • Search Google Scholar
    • Export Citation
  • Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Perez HE, Sandoval DA, Kohli R & Backhed F et al. 2014 FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509 183188. (doi:10.1038/nature13135)

    • Search Google Scholar
    • Export Citation
  • Sachdev S, Wang Q, Billington C, Connett J, Ahmed L, Inabnet W, Chua S, Ikramuddin S & Korner J 2015 FGF 19 and bile acids increase following Roux-en-Y gastric bypass but not after medical management in patients with type 2 diabetes. Obesity Surgery 26 957965. (doi:10.1007/s11695-015-1834-0)

    • Search Google Scholar
    • Export Citation
  • Sadry SA & Drucker DJ 2013 Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nature Reviews: Endocrinology 9 425433. (doi:10.1038/nrendo.2013.47)

    • Search Google Scholar
    • Export Citation
  • Salehi M, Prigeon RL & D’Alessio DA 2011 Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes 60 23082314. (doi:10.2337/db11-0203)

    • Search Google Scholar
    • Export Citation
  • Salinari S, le Roux CW, Bertuzzi A, Rubino F & Mingrone G 2014 Duodenal-jejunal bypass and jejunectomy improve insulin sensitivity in Goto-Kakizaki diabetic rats without changes in incretins or insulin secretion. Diabetes 63 10691078. (doi:10.2337/db13-0856)

    • Search Google Scholar
    • Export Citation
  • Schlogl H, Kabisch S, Horstmann A, Lohmann G, Muller K, Lepsien J, Busse-Voigt F, Kratzsch J, Pleger B & Villringer A et al. 2013 Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. Diabetes Care 36 19331940. (doi:10.2337/dc12-1925)

    • Search Google Scholar
    • Export Citation
  • Schneeberger M, Everard A, Gomez-Valades AG, Matamoros S, Ramirez S, Delzenne NM, Gomis R, Claret M & Cani PD 2015 Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Scientific Reports 5 16643. (doi:10.1038/srep16643)

    • Search Google Scholar
    • Export Citation
  • Schwartz GJ 2011 Gut fat sensing in the negative feedback control of energy balance – recent advances. Physiology and Behavior 104 621623. (doi:10.1016/j.physbeh.2011.05.003)

    • Search Google Scholar
    • Export Citation
  • Scopinaro N, Gianetta E, Civalleri D, Bonalumi U & Bachi V 1979 Bilio-pancreatic bypass for obesity: II. Initial experience in man. British Journal of Surgery 66 618620. (doi:10.1002/bjs.1800660906)

    • Search Google Scholar
    • Export Citation
  • Scully T 2012 Diabetes in numbers. Nature 485 S2S3. (doi:10.1038/485S2a)

  • Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS, Hansen G, Grove KL, Pyke C & Raun K et al. 2014 The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. Journal of Clinical Investigation 124 44734488. (doi:10.1172/JCI75276)

    • Search Google Scholar
    • Export Citation
  • Seeley RJ, Blake K, Rushing PA, Benoit S, Eng J, Woods SC & D’Alessio D 2000 The role of CNS glucagon-like peptide-1 (7–36) amide receptors in mediating the visceral illness effects of lithium chloride. Journal of Neuroscience 20 16161621.

    • Search Google Scholar
    • Export Citation
  • Seeley RJ, Chambers AP & Sandoval DA 2015 The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes. Cell Metabolism 21 369378. (doi:10.1016/j.cmet.2015.01.001)

    • Search Google Scholar
    • Export Citation
  • Shah M, Law JH, Micheletto F, Sathananthan M, Dalla Man C, Cobelli C, Rizza RA, Camilleri M, Zinsmeister AR & Vella A 2014 Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass. Diabetes 63 483493. (doi:10.2337/db13-0954)