The once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide improves postprandial glucose levels in type 2 diabetes patients

Objective <a>In the LixiLan-G trial, switching to iGlarLixi, a once-daily titratable fixed-ratio combination of insulin glargine </a>100 units/mL and the glucagon-like peptide-1 receptor agonist (GLP-1 RA) lixisenatide, improved glucose control in type 2 diabetes (T2D) uncontrolled with GLP-1 RAs over 26 weeks versus continuing prior GLP-1 RA. A prespecified, 26-week, single-arm extension of LixiLan-G aimed to determine the durability of iGlarLixi efficacy and safety over 52 weeks. Research Design and Methods Participants with T2D uncontrolled by GLP-1 RAs (HbA1c 7–9 % [53–75 mmol/mol]) were initially randomized to switch to iGlarLixi or continue prior GLP-1 RA. Those randomized to iGlarLixi who completed the 26-week primary endpoint period could continue iGlarLixi open-label treatment over a 26-week extension to assess durability of efficacy and safety. Results Glycemic control achieved with iGlarLixi at week 26 (mean HbA1c 6.7 % [50 mmol/mol]) was maintained at week 52 (mean HbA1c 6.7 % [50 mmol/mol]; mean ± standard deviation change from baseline at week 52: −1.0 ± 0.9 % [11 ± 10 mmol/mol]). Proportions of participants reaching HbA1c <7 % (53 mmol/mol) with iGlarLixi were similar at week 26 (62%) and 52 (64%), as were those reaching this target without documented symptomatic (<3.0 mmol/L) hypoglycemia (57% and 58%). Safety of iGlarLixi was similar at weeks 26 and 52, with low rates of documented symptomatic hypoglycemia and gastrointestinal events. Conclusions The efficacy and safety of iGlarLixi at the end of the 26-week randomized treatment period was maintained over the 26-week extension period in the LixiLan-G trial.

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The once-daily human glucagon-like peptide-1 analog, liraglutide, improves β-cell function in Japanese patients with type 2 diabetes

Journal of Diabetes Investigation ◽

10.1111/j.2040-1124.2012.00193.x ◽

2012 ◽

Vol 3 (4) ◽

pp. 388-395 ◽

Cited By ~ 9

Author(s):

Yutaka Seino ◽

Mads Frederik Rasmussen ◽

Per Clauson ◽

Kohei Kaku

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Japanese Patients ◽

Β Cell ◽

Once Daily ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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

Canadian Journal of Chemistry ◽

10.1139/cjc-2015-0039 ◽

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00383.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. G301-G309 ◽

Cited By ~ 18

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.

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