The DPP-4 inhibitor vildagliptin increases pancreatic beta cell mass in neonatal rats

Duttaroy, Alokesh; Voelker, F. A.; Merriam, Kimberley; Zhang, Xia; Ren, Xianglin; Kala, S; Hughes, Thomas E.; Burkey, Bryan F.

doi:10.1016/j.ejphar.2010.10.062

Cited by 67 publications

(45 citation statements)

References 24 publications

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“…Furthermore, GLP1 and its analogs have been shown to enhance b-cell mass by increasing the proliferation and decreasing the apoptosis of b cells in animal models (Xu et al 1999, Wang & Brubaker 2002, Li et al 2003, Stoffers 2004. By contrast, despite clear evidence of the effects of GLP1 and its analogs, only a small number of reports to date have examined whether DPP4 inhibitors also enhance b-cell mass (Mu et al 2009, Cho et al 2011, Duttaroy et al 2011 or whether the increase in GLP1 levels elicited by DPP4 inhibition leads to the suppression of serum glucagon concentrations (Balas et al 2007, Ahren et al 2010.…”

Section: Introductionmentioning

confidence: 99%

DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

Shimizu¹,

Hosooka²,

Matsuda³

et al. 2012

Journal of Molecular Endocrinology

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The development of type 2 diabetes is accompanied by a progressive decline in b-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on b cells was studied in diabetic mice. Diabetic pancreatic b cell-specific C/EBPB transgenic (TG) mice exhibit decreased b-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on b cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased b-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in b cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in b cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic b cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

Shimizu¹,

Hosooka²,

Matsuda³

et al. 2012

Journal of Molecular Endocrinology

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“…Thus, both glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors, which increase the amount of active GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in the circulation, improve insulin secretion and lower blood glucose levels in both type 2 diabetic patients and experimental animal models of diabetes [2]. In rodent models of diabetes, it has also been demonstrated that DPP4 inhibitors can preserve beta cell mass [3], mainly through increasing beta cell proliferation and protecting beta cells from apoptosis [4,5]. The models used to show improved beta cell function and increased beta cell mass by incretin-based therapy have been genetically deficient rodents, rodents given an exogenous beta cell toxin, and animals with diet-induced obesity (DIO) subsequent to dietary changes introduced at a young age.…”

Section: Introductionmentioning

confidence: 99%

Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model

et al. 2013

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Aims/hypothesis Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). Methods After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. Results Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. Conclusions/interpretation In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.

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“…przekształcenie epitelium egzokrynnych przewodów trzustkowych w komórki "insulin positive" czy małych kępek hormonopozytywnych komórek parenchymy pod wpływem czynników wzrostowych i cytokin [48,49]. Uwzględnia się rolę róż-nych czynników stymulujących przekształcanie się komórek macierzystych trzustki w komórki beta [50][51][52]. Miyatsuka i German [53] podkreślają np.…”

Section: Neogenezaunclassified

Restrain of beta-cell destruction and stimulation of beta-cell regeneration in type 1 diabetes

Szewczyk¹,

Bury²,

Pierpoint³

2015

Pediatr. Endocrinol.

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The contemporary date on the microenvironment of pancreatic beta cells have been presented. Attention was drawn to successful attempts to inhibition of beta cells destruction after the diagnosis of type 1 diabetes. The attractive attempts of stimulation of beta cells regeneration by their proliferation, neogenesis from other non-endocrine elements or conversion of alfa to beta cells has been traced, also the role of the autonomic nervous system in these processes has been underlined. Pediatr. Endocrinol. 2015.14.3.52.35-40. © Copyright by PTEiDD 2015 Słowa kluczowe cukrzyca typu 1, mikro-środowisko komórek beta, hamowanie destrukcji komórek beta, regeneracja komórek beta Streszczenie W pracy zaprezentowano współczesne dane dotyczące funkcjonowania mikrośrodowiska komórek beta trzustki. Zwrócono uwagę na udane próby hamowania destrukcji komórek beta po rozpoznaniu cukrzycy typu 1. Prześledzono atrakcyjne próby mające na celu pobudzenie regeneracji komórek beta poprzez ich proliferację, neogenezę z innych elementów nieendokrynnych czy konwersję komórek alfa do beta. Podkreślono także rolę autonomicznego układu nerwowego w tych procesach.

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The DPP-4 inhibitor vildagliptin increases pancreatic beta cell mass in neonatal rats

Cited by 67 publications

References 24 publications

DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model

Restrain of beta-cell destruction and stimulation of beta-cell regeneration in type 1 diabetes

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