Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes

Drucker, D. J.

doi:10.1517/13543784.12.1.87

Cited by 219 publications

(57 citation statements)

References 138 publications

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“…Hence, one recent glucose-lowering strategic approach is to enhance active incretin hormone levels and activity through the development of selective DPP-IV inhibitors [6], [7]. The approach in both preclinical animal models of type 2 diabetes and in clinical studies of patients with type 2 diabetes has shown to increase levels of intact GLP-1 and GIP, ultimately leading to meaningful improvements in overall glucose homeostasis [8]–[10].…”

Section: Introductionmentioning

confidence: 99%

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

et al. 2012

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BackgroundRecently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms.Methods and FindingsOtsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs.ConclusionsSitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes.

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Section: Introductionmentioning

confidence: 99%

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

et al. 2012

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“…Another way to increase circulating GLP-1 is to inhibit the cleavage enzyme, DPP-4. In fact, DPP-4 inhibitors that raise endogenous concentrations of active GLP-1 [42] and have been shown to be effective in lowering fasting and postprandial glucose concentrations [43]. In contrast to GLP-1 based therapy, DPP-4 inhibitors have been shown to be weight neutral [5].…”

Section: Review Of Clinical Data On Glp-1 and Energy Homeostasismentioning

confidence: 99%

Is the GLP-1 system a viable therapeutic target for weight reduction?

Tong

Sandoval

2011

Rev Endocr Metab Disord

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Incretin hormones are intestinally derived peptides that are known to augment glucose-stimulated insulin secretion and suppress glucagon levels. Incretin mimetics are attractive adjunctive therapy for type 2 diabetes due to its efficacy on reducing hyperglycemia with a minimal risk of hypoglycemia. In contrast to most available hypoglycemia agents that cause weight gain, incretin mimetics are associated with moderate weight loss. In this review, we focused our discussion on the actions of glucagon-like peptide 1 (GLP-1) in the brain regulation of energy expenditure and food intake. Furthermore, we reviewed the data from preclinical and clinical studies in humans and discussed the actions of GLP-1, GLP-1 analogs, dipeptidyl pepidase 4 (DPP-4) inhibitors on body weight regulation as well as mechanism by which these effects may occur. The gastrointestinal side effects common to GLP-1 based therapeutics such as nausea hamper its wide spread use. Here, we discussed theoretical possibilities for maximizing weight loss and minimizing nausea with of incretin-based therapy.

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“…However, GLP-1 is degraded rapidly by the action of dipeptidyl peptidase 4 (DPP4; Kim et al, 2005a). Thus, stabilization of GLP-1 via DPP4 inhibition is a new therapeutic approach for type 2 diabetes (Drucker, 2003;Holst, 2004;Nielsen, 2005;Smalley et al, 2006). Sitagliptin is a first drug approved by FDA in 2006 as an inhibitor for DPP4.…”

Section: Research Articlementioning

confidence: 99%

In vitrometabolism and transport of the new dipeptidyl peptidase 4 inhibitors, KR66222 and KR66223

Ahn¹,

Kim²,

Liu³

et al. 2011

Xenobiotica

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We investigated the in vitro metabolism and transport of KR66222 and KR66223, new inhibitors of dipeptidyl peptidase (DPP) 4, using human liver microsomes (HLMs) and a Caco-2 cell monolayer. Human liver microsomal incubation of KR66222 in the presence of the NADPH-generating system resulted in the formation of two metabolites, identified as S-oxidation (KR68334) and hydrolysis (KR66223) products using liquid chromatography/tandem mass spectrometry. The formation of KR66223 via an esterase and the formation of KR68334 via CYP3A5 and CYP3A4 seem to be major factors in the in vitro metabolism of KR66222 using HLMs. Additionally, KR66222 had a significantly greater basal to apical transport rate (2.5-fold) than apical to basal transport in the Caco-2 cell monolayer, suggesting the involvement of an efflux transport system. Further studies using inhibitors of efflux transporters and P-glycoprotein (P-gp) overexpressed cells revealed that P-gp was involved in the basal to apical transport of KR66222. These findings suggest that KR66222 undergoes a significant first pass effect, which may serve to decrease the bioavailability of KR66222. The active metabolite, KR66223, was stable for 1 h at 37°C in pooled HLMs (98.9 ± 2.6% of control) and did not undergo P-gp-mediated efflux in Caco-2 cells. Apparent permeability of KR66223 (4.96 × 10(-6) cm/s) was comparable to that of KR66222 (4.08 × 10(-6) cm/s). In conclusion, considering pharmacokinetic variability and the intestinal first-pass effect caused by the involvement of CYP3A and P-gp, KR66223 seems to have better in vitro metabolism and permeability characteristics than KR66222.

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Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes

Cited by 219 publications

References 138 publications

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

Is the GLP-1 system a viable therapeutic target for weight reduction?

In vitrometabolism and transport of the new dipeptidyl peptidase 4 inhibitors, KR66222 and KR66223

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