Effects of long-term treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet endocrine cells in non-obese type 2 diabetic Goto-Kakizaki rats

Inaba, Wataru; Mizukami, Hiroki; Kamata, Kosuke; Takahashi, Kazunori; Tsuboi, Kentaro; Yagihashi, Soroku

doi:10.1016/j.ejphar.2012.07.030

Cited by 29 publications

(25 citation statements)

References 42 publications

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“…We and others have shown that DPP4 inhibition increases insulin secretion in experimental models using rats [19,20] and mice [6,21]. In this study we demonstrate that chronic treatment with the DPP4 inhibitor vildagliptin in an advanced-aged DIO mouse model improved insulin secretion and beta cell function throughout the course of the long study period of 11 months.…”

Section: Discussionmentioning

confidence: 55%

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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Section: Discussionmentioning

confidence: 55%

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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“…To evaluate proliferation rate of b-and a-cells, double immunostaining of Ki67 (MIB1; Dako) and insulin or glucagon was also performed. Choice of antibodies was determined by high specificity and reproducibility of staining results in the literature and our previous studies (5,18). For double immunostaining, sections were first incubated with TUNEL agents, or antibodies against Ki67, gH2AX, and C/EBP-b, and then antibody to insulin or glucagon.…”

Section: Immunostainingmentioning

confidence: 99%

Involvement of Oxidative Stress–Induced DNA Damage, Endoplasmic Reticulum Stress, and Autophagy Deficits in the Decline of β-Cell Mass in Japanese Type 2 Diabetic Patients

et al. 2014

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OBJECTIVEDeficits of b-cells characterize the islet pathology in type 2 diabetes. It is yet to be clear how the b-cell loss develops in type 2 diabetes. We explored the implication of oxidative stress, endoplasmic reticulum (ER)-induced stress, and autophagy deficit in the b-cell decline in Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODSPancreases from recent autopsy cases of 47 type 2 diabetic and 30 nondiabetic subjects were investigated on the islet structure with morphometric analysis. Volume densities of islet (Vi), b-cell (Vb), and a-cell (Va) were measured. To evaluate cell damage of endocrine cells, immunohistochemical expressions of oxidative stress-related DNA damage as expressed by gH2AX, ER stress-related cell damage as CCAAT/enhancer 1 binding protein-b (C/EBP-b), and autophagy deficit as P62 were semiquantified, and their correlations to islet changes were sought. RESULTSCompared with nondiabetic subjects, Vb was reduced in diabetic subjects. Contrariwise, there was an increase in Va. There was a significant link between reduced Vb and increased HbA 1c levels (P < 0.01) and a trend of inverse correlation between Vb and duration of diabetes (P = 0.06). Expressions of gH2AX, P62, and C/EBP-b were all enhanced in diabetic islets, and reduced Vb correlated with the intensity of gH2AX expression but not with C/EBP-b or P62 expressions. Combined expressions of gH2AX, P62, and C/EBP-b were associated with severe reduction of Vb. CONCLUSIONSb-Cell deficit in type 2 diabetes was associated with increased oxidative stress and may further be augmented by autophagic deficits and ER stress.

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“…Similarly, islets from Goto-Kakizaki rats, a model of T2D, have macrophage infiltration and an increased number of MHC-II-positive cells (46,47). Macrophage infiltration has also been observed in islets from human T2D subjects (41).…”

Section: Discussionmentioning

confidence: 85%

Insulin-like Growth Factor 2 Overexpression Induces β-Cell Dysfunction and Increases Beta-cell Susceptibility to Damage

Casellas

Mallol

Salavert

et al. 2015

Journal of Biological Chemistry

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Background: Human and animal studies have shown associations between insulin growth factor 2 (IGF2) and diabetes. Results: Overexpression of insulin growth factor 2 in ␤-cells leads to ␤-cell dysfunction and makes islets more vulnerable to ␤-cell damage and immune attack. Conclusion: IGF2 may play an important role in the predisposition and development of diabetes. Significance: This study unravels an unprecedented role of IGF2 on physiology of ␤-cells.

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Effects of long-term treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet endocrine cells in non-obese type 2 diabetic Goto-Kakizaki rats

Cited by 29 publications

References 42 publications

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

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

Involvement of Oxidative Stress–Induced DNA Damage, Endoplasmic Reticulum Stress, and Autophagy Deficits in the Decline of β-Cell Mass in Japanese Type 2 Diabetic Patients

Insulin-like Growth Factor 2 Overexpression Induces β-Cell Dysfunction and Increases Beta-cell Susceptibility to Damage

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