scholarly journals Targeting the gastrointestinal tract to treat type 2 diabetes

2016 ◽  
Vol 230 (3) ◽  
pp. R95-R113 ◽  
Author(s):  
Paige V Bauer ◽  
Frank A Duca
Keyword(s):  
Type 2 Diabetes ◽  
Gastrointestinal Tract ◽  
Nutrient Sensing ◽  
Gut Peptides ◽  
Glucose Levels ◽  
Social Burden ◽  
Lower Glucose ◽  
Glucagon Like Peptide 1 ◽  
Diabetes And Obesity

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.

Pharmacophore modeling and molecular docking studies of acridines as potential DPP-IV inhibitors

2015 ◽  
Vol 93 (7) ◽  
pp. 721-729
Author(s):  
R. Abu Khalaf ◽  
Z. Jarekji ◽  
T. Al-Qirim ◽  
D. Sabbah ◽  
G. Shattat
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Inhibitory Polypeptide ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Glucose Levels ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Circulating Levels

Inhibition of dipeptidyl peptidase-IV (DPP-IV) prevents the inactivation of gastric inhibitory polypeptide (GIP) and glucagon-like peptide–1 (GLP-1). This increases circulating levels of active GLP-1 and GIP and stimulates insulin secretion, which results in lowering of glucose levels and improvement of the glycemic control in patients with type 2 diabetes. In this study, pharmacophore modeling and docking experiments were carried out and a series of eight novel 2-ethoxy-6,9-disubstituted acridines (13, 15, and 17a–17f) have been designed and synthesized. Then, these compounds were evaluated for their ability to inhibit DPP-IV. Most of the synthesized compounds were proven to have anti-DPP-IV activity where compound 17b displayed the best activity of 43.8% inhibition at 30 μmol/L concentration. Results of this work might be helpful for further optimization to develop more potent DPP-IV inhibitors.

scholarly journals Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without Type 2 diabetes

2014 ◽  
Vol 306 (4) ◽  
pp. G301-G309 ◽  
Author(s):  
Sara Chowdhury ◽  
Dominic N. Reeds ◽  
Dan L. Crimmins ◽  
Bruce W. Patterson ◽  
Erin Laciny ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Gastric Emptying ◽  
Postprandial Glucose ◽  
Nerve Fibers ◽  
Intense Staining ◽  
Glucose Levels ◽  
Healthy Humans ◽  
Glucagon Like Peptide 1

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10–14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol·kg−1·min−1 was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

scholarly journals Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Olof Eriksson ◽  
Torsten Haack ◽  
Youssef Hijazi ◽  
Lenore Teichert ◽  
Veronique Tavernier ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Receptor Occupancy ◽  
Strong Interactions ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Positron Emission ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [68Ga]Ga-DO3A-Tuna-2 and [68Ga]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 ± 14.4% (SD) in N = 5 patients and a GLP1R occupancy of 49.9 ± 13.3%. Fasting Plasma Glucose levels (− 3.30 ± 1.14 mmol/L) and body weight (− 3.87 ± 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.

scholarly journals Off-Label Use of Liraglutide in the Management of a Pediatric Patient with Type 2 Diabetes Mellitus

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Sara J. Micale ◽  
Michael P. Kane ◽  
Eileen Hogan
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Pediatric Population ◽  
Off Label Use ◽  
Off Label ◽  
Glucose Levels ◽  
Glucagon Like Peptide 1 ◽  
Label Use

Liraglutide is a glucagon-like peptide 1 (GLP-1) analog indicated for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise in adults. Liraglutide lowers blood glucose levels by stimulating insulin secretion and decreasing glucagon release in glucose-dependent manners, increases satiety, and delays gastric emptying. Liraglutide, unlike metformin and insulin, is not approved for use in the pediatric population. We report the successful off-label use of liraglutide in an obese, 16 year old Caucasian female with type 2 diabetes mellitus.

scholarly journals Pathogenetic substantiation and effectiveness of vildagliptin use inpatients with diabetes mellitus type 2

2009 ◽  
Vol 6 (3) ◽  
pp. 16-26 ◽  
Author(s):  
T I Romantsova
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Control Of Diabetes ◽  
Glucagon Like Peptide 1

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. Now it isrecognized that the β-cell failure occurs much earlier and is more severe than previously thought. As a result, earlier and more aggressive new therapy is needed to achiev e better control of diabetes and to prev ent/slow the progressive B-cell failure that already is w ell established in IGT subjects. One approach is to target the incretin mimetic hormone glucagon-like peptide-1 (GLP-1). When blood glucose levels are elevated, GrP-1 stimulates insulin secretion, decreases glucagon secretion, impro ves β-cell function, and slows gastric emptying. GrP-1 production is reduced in patients with type 2 diabetes. Furthermore, GrP-1 is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme. Trials have showed, that new inhibitor DPP-4 vildagliptin (Galvus) hav e been demonstrated to significantly reduce HbA lc, fasting and prandial glucose levels when used as monotherapy and in соmbination with traditional agents. Advantages of vildagliptin include few adverse events, low risk of hypoglycemia, neutral effect on body weight, and a once-daily oral dosing regimen. Inaddition, vildagliptin may preserve the decline in β-cell function. Hence, vildagliptin may modify the natural progressive course of diabetes; this however, must be confirmed with longer-term controlled studies

Diabetes breakthroughs: Thornberry and Weber

2020 ◽  
pp. 153-186
Author(s):  
Eugene H. Cordes
Keyword(s):  
Type 2 Diabetes ◽  
Specific Inhibitor ◽  
Diabetic Patients ◽  
Clinical Use ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Functional Equivalent ◽  
Glucagon Like Peptide 1

Januvia and Janumet are important additions to the array of drugs that are employed to treat type 2 diabetes. Januvia (sitagliptin) works by an entirely novel mechanism: it is a potent and specific inhibitor of an enzyme known as DPP-4 (dipeptidyl peptidase-4). DPP-4 promotes the destruction of a peptide known as GLP-1 (glucagon-like-peptide-1), an incretin. Incretins are agents that stimulate the secretion of insulin and repress the secretion of glucagon. Both actions tend to normalize glucose levels. Indeed, clinical trials with GLP-1 have shown that this peptide normalizes blood glucose levels in both the fed and fasted states. GLP-1 must be given by injection and is not suitable for routine use by diabetic patients. However, an inhibitor of the enzyme that degrades GLP-1 is the functional equivalent of administration of GLP-1. Januvia acts in exactly this way. Janumet is a combination product in which Januvia is combined with metformin, an effective anti-diabetes agent that has been employed for many years. There are now a number of gliptins (DPP-4 inhibitors) in clinical use for type 2 diabetes.

scholarly journals GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists

2020 ◽  
Vol 105 (8) ◽  
pp. e2710-e2716 ◽  
Author(s):  
Jens Juul Holst ◽  
Mette Marie Rosenkilde
Keyword(s):  
Gut Peptides ◽  
Glucose Lowering ◽  
Cellular Processes ◽  
Reduce Weight Gain ◽  
Glucagon Like Peptide 1 ◽  
Nutrient Administration ◽  
Chimeric Peptides ◽  
Diabetes And Obesity ◽  
Gip Receptor

Abstract The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.

scholarly journals Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers

2001 ◽  
Vol 281 (1) ◽  
pp. E155-E161 ◽  
Author(s):  
C. Mark B. Edwards ◽  
Sarah A. Stanley ◽  
Rachel Davis ◽  
Audrey E. Brynes ◽  
Gary S. Frost ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Emptying ◽  
Healthy Volunteers ◽  
Plasma Glucose ◽  
Postprandial Glucose ◽  
Calorie Intake ◽  
Glucose Levels ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Exendin-4 is a long-acting potent agonist of the glucagon-like peptide 1 (GLP-1) receptor and may be useful in the treatment of type 2 diabetes and obesity. We examined the effects of an intravenous infusion of exendin-4 (0.05 pmol · kg−1 · min−1) compared with a control saline infusion in healthy volunteers. Exendin-4 reduced fasting plasma glucose levels and reduced the peak change of postprandial glucose from baseline (exendin-4, 1.5 ± 0.3 vs. saline, 2.2 ± 0.3 mmol/l, P < 0.05). Gastric emptying was delayed, as measured by the paracetamol absorption method. Volunteers consumed 19% fewer calories at a free-choice buffet lunch with exendin-4 (exendin-4, 867 ± 79 vs. saline 1,075 ± 93 kcal, P = 0.012), without reported side effects. Thus our results are in accord with the possibility that exendin-4 may be a potential treatment for type 2 diabetes, particularly for obese patients, because it acts to reduce plasma glucose at least partly by a delay in gastric emptying, as well as by reducing calorie intake.

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