Type 2 diabetes pathophysiology concept map javascript,diabetes and dogs treatment antibiotics,high blood sugar with type 2 diabetes genetic,normal blood glucose level for type 2 diabetes uk - Plans On 2016

Metabolism is a sum of the physical and chemical changes that take place in human organism. A myriad of factors determine a person's rate of metabolism including: gender, age, body composition (fat vs.
Science, Technology and Medicine open access publisher.Publish, read and share novel research. GPR119 Agonists: A Novel Strategy for Type 2 Diabetes TreatmentXiaoyun Zhu1, Wenglong Huang1 and Hai Qian1[1] Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China1.
Rayburn WF1997Diagnosis and classification of diabetes mellitus: highlights from the American Diabetes Association. Collins FM2002Current treatment approaches to type 2 diabetes mellitus: successes and shortcomings. Fyfe2008GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity. Jones RM2004trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycaemia.
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These changes include both synthesis (anabolism) and breakdown (catabolism) of body constituents. A person may be genetically predisposed to having a greater number of adipose cells, which store fat. If you burn more calories than you consume, the body is forced to burn excess fat storage for energy. While at first these changes may seem difficult, their long-term results are definitely worth the effort. IntroductionType 2 diabetes (T2DM), also known as non-insulin-dependent diabetes mellitus (NIDDM), manifests with an inability to adequately regulate blood-glucose levels. Ahren, 2009Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes.
Davey, 2004G-protein-coupled receptors: new approaches to maximise the impact of GPCRS in drug discovery. In a narrower sense, the physical and chemical changes that take place in a given chemical substance within an organism.
But the exact reason why some people have faster metabolic rates than others is still not clearly understood. Likewise, the speedy metabolism of infants, growing children, and teenagers is due in part to growth hormone.
The amount of these fat-storing cells can increase with weight gain, but they never decrease. To do this, Doctor Barry Sears, the creator of the Zone eating program, suggests, "to begin, lower your caloric intake by 500 calories and when you hit a plateau lower your intake again by 200 calories." Of course, you can only lower your intake so far. By eating the proper foods and maintaining a good exercise program you should be able to speed up your fat-burning furnace. GPR119 is expressed on certain enteroendocrine cells (L and K cells) in the small intestine and by ?-cells within the islets of Langerhans of the pancreas.
A: The best pharmacophore model Hypo1 where H and HBA are illustrated in cyan and green, respectively. T2DM may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from T2DM have too little insulin or cannot use insulin effectively. It includes the uptake and distribution within the body of chemical compounds, the changes (biotransformations) undergone by such substances, and the elimination of the compounds and their metabolites. These cells are related to the set point - the theoretical weight range in which the body tends to stay and will fight to maintain. The last thing you want to do is restrict your calories to a point that once again your body thinks that it is starving.
Incorporate walking, swimming, cycling, or any other exercise that sustains an elevated heart rate for 30 to 40 minutes at least three times a week. In all three cell types, ligation of GPR119 by an agonist leads to the activation of adenylate cyclase and a rise in cAMP. Kowalski, 2010GPR119 agonists for the potential treatment of type 2 diabetes and related metabolic disorders.
Another approach, according to trainer Jacob Wilson, is caloric cycling, a process that tricks the body into believing you're not dieting by fluctuating caloric intake daily. This triggers the release of glucagon-like peptide 1 (GLP-1), and glucose-dependent isulinotropic peptide (GIP) or insulin from L, K and ?-cells, respectively. There are, however, deficiencies associated with currently available treatments, including hypoglycemicepisodes, weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema[2].
Pt experiences normal fluidDM, HPN, Glomerulonephritis, Polycystic decreased urine output balance as evidenced by stable Kidney Disease, Obstrution, Infection, Confusion, weakness, 2. Addtitionally, GLP-1 and GIP can both interact with their cognate receptors on the ?-cell to elicit insulin secretion. Glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors are also widely used in clinical therapy for T2DM. Portha, 2001Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Mitaku, 2002Identification of G protein-coupled receptor genes from the human genome sequence.
Eat four to six small meals, two to three hours apart throughout the day, rather than three widely spaced big meals.
GLP-1 analogs, which require parenteral administration, appear not to be associated with hypoglycemia but cause a relatively high frequency of gastrointestinal side effects[3].
Timing is essential: carbohydrates should be eaten at breakfast and post workout because of insulin's anabolic effects, but for the rest of the day control your insulin by eating only leafy green, fibrous vegetables and proteins. Since GLP-1 (and probably GIP) also promotes ?-cell viability, it is possible that orally acting GPR119 agonists may influence both the secretory activity and the viability of ?-cells, leading to improved glucose homeosetasis in patients with T2DM.
Small molecule DPP-4 inhibitors enhance glucose-dependent insulin release by inhibiting the degradation of endogenous GLP-1[4]. Several nonpeptide, except DPP-4 inhibitors, binding G protein-coupled receptors (GPCRs) have been deorphanized recently and are currently being evaluated as candidate GLP-1 secretagogues for T2DM[5, 6].

Among these, the G protein-coupled receptor 119 (GPR119) has received considerable attention from the pharmaceutical industry in recent years. Schioth, 2003Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. GPR119 may present an attractive drug target for treating T2DM, and its agonists may therefore represent potential new insulin secretagogues free of the risk of causing hypoglycemia.GPR119 has been described as a class A (rhodopsin-type) orphan GPCR without close primary sequence relative in the human genome[7]. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion from pancreatic ?-cells and increased release of the gut peptides GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY)[8]. Preclinical and clinical studies with GPR119 agonists in type 2 diabetes support that GPR119 agonists have been proposed as a novel therapeutic strategy for diabetes.
This review provides an overview of the recent progress made in the discovery of orally active GPR119 agonists[9], and outlines the current clinical trial landscape and paints a detailed illustration of the key structural information realized from GPR119 agonist campaigns.2. Assess contributing nutritional intake as evidenced nausea, mouth vomiting factors t activity by being free of signs of ulceration, bleeding intolerance. Discovery and characteristics of GPR119After the discovery of GPR119 in 1999 using data afforded by the Human Genome Project, it was subsequently described in the peer-reviewed literature as a Class A receptor with no close relatives. Independently, this receptor has been studied and described in the literature under various synonyms, including SNORF25 [10, 11], RUP3 [12], GPCR2 [13], 19AJ [14], OSGPR116 [15], MGC119957, HGPCR2 and glucose-dependent insulinotropic receptor (GDIR) [9].
GPR119 homologs have been identified in several vertebrate species, including the rat, mice, hamster, chimpanzee, rhesus monkey, cattle and dog[14].
Assist in coping with normal HR, BP during activity loss of tone, discomforts resulting from and absence of SOB, Decreased GFR decreased ROM fluid restriction. Encourage high-calorie,abnormalities toxins disorders dry flaky skin, pruritus, low-protein, low-sodium,(hperkalemia) (pericarditis, (HPN, purpura, thin brittle low-potassium snacks. Clusters of serine (S) and threonine (T) residues are highlighted in blue orange circles in the third intracellular loop and the C-terminus domain, and could represent potential sites of phosphorylation.In situ reveals that pancreatic ? cells are the main site of GPR119 expression in pancreatic islets[19]. Promote intake of high effusion, metastatic hair biologic volume protein pericardial calcification, HPN, generalized edema.
High expression levels in pancreatic ? cell lines NIT-1, MIN6 and RIN5 supports this observation[18, 20, 21].
Consistent with its expression in gut tissues, GPR119 mRNA was strongly expressed in several rodent GLP-1 secreting L-cell lines-including STC-1, FRIC, Hnci-h716 and GLUTag line[21, 22].
GPR119 signaling and de-orphanizationHigh-level expression of GPR119 in transfected HEK293 cells led to an increase in intracellular cAMP levels via activation of adenylate cyclase [10, 11, 19], indicating that this receptor couples efficiently to G?s.
In support of these data, potential endogenous ligands and synthetic small molecule agonists of GPR119 have been shown to increase cAMP levels (Figure 2). Lysophosphatidylcholine (LPC, Figure 3, 1) was the first proposed endogenous ligand for GPR119, based on its ability to stimulate glucose-dependent insulin release and increase cAMP in GPR119-transfected cells. The endovanilloid compounds N-oleoyl dopamine (OLDA, Figure 3, 3) and olvanil have recently been described as GPR119 agonists with in vitro potencies similar to that of OEA.
These fatty acid amides, OEA and OLDA, represent the best candidates for endogenous ligands, although they are less potent and selective than the natural ligands identified for many other GPCRs.
GPR119 regulation of insulin secretionBased on the expression profile and coupling properties of GPR119, it stands to reason that activation of the receptor in pancreatic ? cells might lead to enhanced glucose-dependent insulin release. Although the mechanism by which insulin secretion is increase following the activation of GPR119 involves a rise in cAMP, Ning et al.
The potent, selective GPR119 agonist discovered at Arena Pharmaceuticals, Inc., AR231453 (Figure 3, 4), significantly increased insulin release in HIT-T15 cells (a hamster insulinoma-derived line with robust GPR119 expression) and in rodent islets. GPR119 regulation of incretin secretionGPR119 stimulates the release of GIP, GLP-1 and at least one other L-cell peptide, peptide YY (3-36) (PYY)[30]. GPR119 mRNA was found to be expressed at significant levels in intestinal sub-regions that produce GIP and GLP-1. Cellular expression studies have extended these observations by showing that most GLP-1 producing L cells in the ileum and colon also contain GPR119 [30]. This is consistent with data showing high GPR119 expression in most in vitro L-cell models[30, 31]. GIP, the other major insulinotropic hormone of the gut, is produced primarily in the duodenal K cells (Figure 2).
In considering the actions of GPR119 agonists as pontential mediators of GLP-1 and GIP secretion, and the potential beneficial actions that derive from this, it should not be overlooked that the enteroendocrine cells from which these incretins are released, also secrete a range of additional products, including GLP-2, oxyntomodulin (OXM), cholecystokinin, and PYY from L cells, as well as xenin from K cells. So far, very little attention has been paid to these additional intestinal peptides during analysis of GPR119-mediated responses in vivo, but it is clear that their actions may be important in determining of the overall profile of metabolic responses following administration of GPR119 agonists. The role of these additional hormonal agents will required to clarify in the further study[23].4. Clinical trial status and future prospectsIt is hardly surprising that, based on the strong biological proof of concept generated using the potent, selective agonist molecule 4[19, 30, 32]. The following sections provide an overview of the multiple classes of GPR119 agonists, along with the available biological data, reported by various pharmaceutical organizations. Arena pharmaceuticalsArena Pharmaceuticals has been actively pursuing two GPR119 modulators, derived from 4 that were both considered for progression into human clinical, studies as potential drug candidates after the discovery and validation of this receptor as a viable target for the treatment of metabolic disorders.
In addition to delaying the onset of hyperglycemia, APD668 delayed elevation of HbA1c and also decreased the levels of triglycerides and free fatty acids. Therefore, they were encouraged that switching to this scaffold may also be the best approach to try to increase the range of possible sites of metabolism, without greatly increasing clearance.
Then APD597 (JNJ-38431055, Figure 5, 10) was then developed, which described the second generation trisubstituted pyrimidine agonists with improved solubility, pharmacokinetic and metabolism characteristics and excellent in vivo activity. Preliminary safety studies in rat (14-day) and dog (7-day) revealed no obvious liabilities that would prevent further development[34].
AstellasCompounds effective in stimulating insulin secretion and inhibiting the increase of blood sugar levels have been reported by Astellas. Detailed pharmacological data on two disclosed GPR119 agonists from Astellas have been presented.
The first generation analog, AS1535907 (Figure 6, 11), increased intracellular cAMP levels in GPR119 transfected HEK293 cells (EC50 = 1.5 ?M) and enhanced insulin secretion in the mouse NIT-1 pancreatic ?-cell line and rat perfused pancreas. BiovitrumBiovitrum has several published patent applications identifying GPR119 agonists which differ in the nature of the central aromatic ring (compounds 13–15)[8, 32]. Bristol-Myers squibbThe first series of GPR119 agonists reported by Bristol–Myers Squibb featured a [6,5], [6,6], or [6,7] bicyclic central core[41, 42]. Representative examples containing pyrimidine-fused pyrrazole, triazole, and morpholine ring systems are shown in Figure 8.
The two initial filings, from July 2006, describe agonists that retain a 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine core unit (Figure 9).

The prototypical compound 21 (Figure 9) demonstrated an EC50 of 40 nM in a CHO6CRE reporter assay.
In addition, hyperinsulinemic clamp experiments in normal rats showed that compound 21 enhances whole body insulin sensitivity[8].
The safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of GSK-1292263 were evaluated in a completed randomized, placebo-controlled clinical trial in healthy volunteers (ClinicalTrials.gov Identifier NCT00783549). A total of 69 subjects received single escalating doses of GSK-1292263 (10-400 mg) prior to administration of a 250mg dose given once daily for 2 and 5 days, which was also evaluated in combination with sitagliptin (100 mg). Treatment with GSK-1292263 at all doses was described as well tolerated, with the most common drug-related effects being mild headache, dizziness, hyperhidrosis, flushing and post-oGTT hypoglycemia. Coadministration with sitagliptin increased plasma active GLP-1 concentrations and lowered total GLP-1, GIP and PYY levels; no effects on gastric emptying were observed with GSK1292263. MerckMerck has two published patent applications describing GPR119 agonists which retain a 4,4’-bipiperidine scaffold (Figure 10; 25 and 26)[49, 50]. Although the data for specific Merck analogs are not available, several compounds have been claimed to exhibit an EC50 < 10 nM in the cAMP homogeneous time-resolved fluorescence (HTRF) assay[8].
In 2006, Schering–Plough filed several patents describing spiro-azetidine and spiro-azetidinone derivatives, which are described as T-calcium channels blockers, GPR119 receptor agonists and Niemann-Pick C1-like protein-1 antagonists, with utility for the treatment of pain, diabetes and disorders of metabolism (Figure 10, 27) [32, 51, 52]. The patent application pertaining to 30 discloses a series of 6-substituted 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-ones and the patent application associated with 31 describes a closely related chemical series of 7-substituted 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-ones[54]. MetabolexGPR119 agonists from Metabolex are based on a five-membered central heterocyclic core that is linked directly to the piperidine motif at its C4 position and to the aryl motif through an oxymethylene spacer[55-58] (Figure 11). Most examples in this application showed agonist activity at 10 ?M in the fluorescence resonance energy transfer (FRET) assay corresponding to increased intracellular cAMP levels.
Glucose stimulated insulin secretion experiments using isolated rat islets are described and compound 32 showed 1.78-fold stimulation of insulin secretion at 16 mM glucose. In preclinical studies, MBX-2982 was shown to increase cAMP levels in CHO cells expressing human GPR119 (EC50 = 3.9 nM) and to stimulate GSIS from isolated islets.
Metabolex has recently completed two additional Phase 1 studies of MBX-2982 in subjects with pre-diabetes.
In both studies, subjects with either impaired fasting glucose or impaired glucose tolerance were enrolled.
In addition, the effect of MBX-2982 on insulin secretion during a graded glucose infusion was examined. MBX-2982 was rapidly absorbed and its exposure at both doses approximately doubled on day four compared to day one, consistent with a terminal half-life of ~18 hr and supporting once daily dosing.
The glucose excursions (area under the curve) following a mixed meal were reduced relative to baseline by 26% and 37%, respectively, for the 100 and 300 mg cohorts. During the graded glucose infusions, the exposure to glucose was reduced relative to baseline by 11% and 18% for the 100 and 300 mg cohorts, respectively. Once daily dosing provided markedly enhanced exposures and improved dose proportionality, giving sustained levels of MBX-2982 predicted to be maximally effective. The effect of each dose on the glucose excursions following a mixed meal and an oral glucose challenge was investigated. All four doses of MBX-2982 produced statistically significant decreases in the glucose excursion following a mixed meal ranging from 34% to 51%. In both studies, MBX-2982 was safe and generally well tolerated with no serious adverse events, adverse event trends or dose-limiting toxicities.
These results provide continued clinical validation of the potential therapeutic benefits of MBX-2982 in the treatment of type 2 diabetes. Compounds of this patent application are defined in part by the terminal tetrahydroisoquinoline depicted in 34 (Figure 12)in February 2007.
Compound 35 is representative of IRM’s second chemical series of GPR119 modulators which was filed later in 2007[32, 64]. Compound 39 was the initial hit[66] (Figure 13), which demonstrated good potency (EC50 = 0.5 ?M) but poor efficacy (Emax = 33%).
In several rodent models of obesity and type 2 diabetes, PSN119-1 reduced food intake and improved oral glucose tolerance, giving credence to the premise that GPR119 agonists have the makings of effective oral antidiabesic agents. When administered orally to rats, this compound achieved high plasma concentrations, as did its active sulfone metabolite PSN119-1M (EC50 = 0.2 ?M, Emax = 392%)[67] (Figure 13).
More recently, the Prosidion group described GPR119 agonists in which the potentially labile tert-butylcarbamate functionality was replaced with bioisosteric heteroaryl groups, in particular with an oxadiazole similar to Arena’s AR231453.
Several azetidine-based GPR119 agonists (Figure 14) have also been disclosed by Prosidion [8, 68, 69].
In pre-clinical studies, PSN821 has demonstrated pronounced glucose lowering in rodent models of type 2 diabetes with no loss of efficacy on repeated administration, and substantial reductions of body weight in rodent models of obesity.
In male diabetic ZDF rats, both acute and chronic oral administration of PSN821, significantly and dose-dependently reduced glucose excursions in an oral glucose tolerance test.
In prediabetic male ZDF rats, weeks significantly lowered nonfasting blood glucose concentrations and HbA1c levels compared to vehicle.
In the double-blind, placebo-controlled, ascending single dose first-in-human study, PSN821 was generally well tolerated at doses up to 3000mg in healthy volunteers and 1000mg (the top dose tested) in patients with type 2 diabetes, with no clinically important adverse effects on laboratory tests, 12-lead ECGs or vital signs.
In patients with type 2 diabetes, PSN821 showed substantial and statistically significant reductions in glucose responses to a standard nutrient challenge of approximately 30% at 250mg and 500mg. Introduction of the cyanopyrrolidine pharmacophore of known DPP-4 inhibitors on the aryl motif of their GPR119 agonists provided compounds, which displayed dual activity as agonists of GPR119 and inhibitors of DPP-IV (Figure 14, 44 and 45). The validated pharmacophore generated can be used to evaluate how well any newly designed compound maps on the pharmacophore before undertaking any further study including synthesis, and also used as a three-dimensional query in database searches to identify compounds with diverse structures that can potentially agonist GPR119[73]. Figure 15.The first pharmacophore model for potent G protein-coupled receptor 119 agonist[73]. Future directions and concluding remarksIn summary, GPR119 agonists seem to provide a completely novel and previously unexplored approach to incretin therapy in patients with T2DM, increasing glucose-dependent insulin secretion through two complementary mechanisms: directly, through actions on the ? cell, and indirectly, through enhancement of GLP-1 and GIP release from the GI tract. It is also worth pointing out the obvious potential advantages that could theoretically be obtained by the co-administration of a GPR119 agonist (with a mechanism as a GLP-1 secretagogue) and a DPP-4 inhibitor (with a mechanism to protect secreted GLP-1), and some preliminary and recent published data support this attractive concept. Such a strategy may not only provide improved glycemic control, but also induce weight loss, a feature observed with GLP-1 mimetics but not with DPP-4 inhibitors. Following the recent entry of the GPR119 agonists MBX-2982, GSK-1292263 and PSN821 into clinical development, the value of these compounds as a new class of therapeutics for type 2 diabetes and associated obesity is likely to be determined within the next few years.AcknowledgementThis study was supported by the National Natural Science Foundation of China (No.

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