Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

Marchand, Kelly; Arany, Edith; Hill, David J.

doi:10.1152/ajpendo.00132.2010

Cited by 15 publications

(9 citation statements)

References 56 publications

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“…We and others have shown that young rodents retain the capacity to partially regenerate β-cell mass after STZ ablation, but this regenerative potential is mitigated in adulthood (Bonner-Weir et al 1981, Portha et al 1989, Wang et al 1996, Thyssen et al 2006, Tschen et al 2009, Chamson-Reig et al 2010, Cox et al 2010, Marchand et al 2010, Nicholson et al 2010. This loss of regenerative capacity coincides with the decline seen here in both Ins + Glut2 LO cell abundance, and a change in their anatomical location.…”

Section: :3supporting

confidence: 59%

Decrease in Ins+Glut2LO β-cells with advancing age in mouse and human pancreas

Beamish

Mehta

Strutt

et al. 2017

Journal of Endocrinology

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The presence and location of resident pancreatic β-cell progenitors is controversial. A subpopulation of insulin-expressing but glucose transporter-2-low (InsGlut2) cells may represent multipotent pancreatic progenitors in adult mouse and in human islets, and they are enriched in small, extra-islet β-cell clusters (<5 β cells) in mice. Here, we sought to identify and compare the ontogeny of these cells in mouse and human pancreata throughout life. Mouse pancreata were collected at postnatal days 7, 14, 21, 28, and at 3, 6, 12, and 18 months of age, and in the first 28 days after β-cell mass depletion following streptozotocin (STZ) administration. Samples of human pancreas were examined during fetal life (22-30 weeks gestation), infancy (0-1 year), childhood (2-9), adolescence (10-17), and adulthood (18-80). Tissues were analyzed by immunohistochemistry for the expression and location of insulin, GLUT2 and Ki67. The proportion of β cells within clusters relative to that in islets was higher in pancreas of human than of mouse at all ages examined, and decreased significantly at adolescence. In mice, the total number of InsGlut2 cells decreased after 7 days concurrent with the proportion of clusters. These cells were more abundant in clusters than in islets in both species. A positive association existed between the appearance of new β cells after the STZ treatment of young mice, particularly in clusters and smaller islets, and an increased proportional presence of InsGlut2 cells during early β-cell regeneration. These data suggest that InsGlut2 cells are preferentially located within β-cell clusters throughout life in pancreas of mouse and human, and may represent a source of β-cell plasticity.

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Section: :3supporting

confidence: 59%

Decrease in Ins+Glut2LO β-cells with advancing age in mouse and human pancreas

Beamish

Mehta

Strutt

et al. 2017

Journal of Endocrinology

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“…Endothelium function may therefore be improved. Atorvastatin was reported to improve the regeneration of β-cell mass due to increase of intro-islet endothelial cells [8]. …”

Section: Discussionmentioning

confidence: 99%

“…On the one hand, recent studies showed that beneficial effect of atorvastatin on insulin resistance were due to decrease of inflammation [7]. On the other hand, functional β-cell mass was expanded with atorvastatin in the neonatal rodent [8]. However, whether the β-cell function will be affected is a concern.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin helps preserve pancreatic β cell function in obese C57BL/6 J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress

Chen

Liu

et al. 2014

Lipids Health Dis

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Background3-Hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Currently, statins are used as first-line therapy in the treatment of diabetic dyslipidemia. However, effects of statins on β cell function remains unclear. This study aims to examine effects of atorvastatin treatment on pancreatic β cell function in obese C57BL/6 J mice and the possible mechanisms.MethodsDiet-induced obesity (DIO) C57BL/6 J mice were treated with atorvastatin (30 mg/kg/day) for 58 days. β cell function was assessed by hyperglycemic clamp and the area of insulin-positive β cells was examined by immunofluorescence. Gene expression was assessed by RT-PCR, and endoplasmic reticulum (ER) stress related proteins were examined by Western blot. Additionally, cell viability and apoptosis of the cholesterol-loaded NIT-1 cells were investigated after atorvastatin treatment.ResultsHyperglycemic clamp study revealed that glucose infusion rate (GIR) and insulin stimulation ratio in atorvastatin-treated DIO mice were markedly higher than control mice (P < 0.05, P < 0.01 vs. con), indicating preserved β-cell sensitivity to glucose. Lipid profiles of plasma triglyceride (TG), pancreas TG and plasma cholesterol (CHO) were improved. Pancreas weight and weight index were improved significantly after atorvastatin treatment (P < 0.05 vs. con). Immunofluorescence results showed that atorvastatin-treated mice had significantly larger insulin-positive β cell area (P < 0.05 vs. con). Furthermore, RT-PCR and western blot showed that the mRNA and protein expression of pancreatic and duodenal homeobox 1 (Pdx1) in the pancreas were upregulated (P < 0.001, P < 0.01 vs. con). Moreover, the expression level of ER stress markers of activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2α (eIF2α) were downregulated in the pancreas of atorvastatin-treated mice (P < 0.001, P < 0.01, P < 0.01 vs. con). Besides, atorvastatin protected the pancreatic β cell line of NIT-1 from cholesterol-induced apoptosis. Western blot showed increased expression of anti-apoptotic protein of B-cell lymphoma 2 (Bcl-2).ConclusionPancreatic β cell function of obese C57BL/6 J mice was preserved after atorvastatin treatment, and this improvement may be attributed to enhanced pancreas proliferation and amelioration of pancreatic ER stress.

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“…After 8 weeks of treatment, an oral glucose tolerance test (OGTT) was performed under short ether narcosis. Blood glucose and plasma insulin were measured after overnight fasting and 120 minutes after an oral glucose load of 0.3 g/100 g body weight given through a gauge (15,16 …”

Section: Animalsmentioning

confidence: 99%

Arteriolar insulin resistance in a rat model of polycystic ovary syndrome

Sára

Péter

Masszi

et al. 2012

Fertility and Sterility

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Objective: To investigate the vascular dysfunction caused by insulin resistance in polycystic ovary syndrome (PCOS) and the effectiveness of vitamin D in an animal model. Design: Controlled experimental animal study. Setting: Animal laboratory at a university research institute. Animal(s): Thirty female Wistar rats. Intervention(s): Rats were divided into groups at age 21-28 weeks. Twenty of them were subjected to dihydrotestosterone (DHT) treatment (83 mg/d); ten of them also received parallel vitamin D treatment (120 ng/100 g/wk). Oral glucose tolerance tests with insulin level measurements were performed. Gracilis arterioles were tested for their contractility as well as their nitric oxide (NO)-dependent and insulin-induced dilation using pressure arteriography. Main Outcome Measure(s): Several physiologic parameters, glucose metabolism, and pressure arteriography. Result(s): DHT treatment increased the passive diameter of resistance arterioles, lowered norepinephrine-induced contraction (30.1 AE 4.7% vs. 8.7 AE 3.6%) and reduced acetylcholine-induced (122.0 AE 2.9% vs. 48.0 AE 1.4%) and insulin-induced (at 30 mU/mL: 21.7 AE 5.3 vs. 9.8 AE 5.6%) dilation. Vitamin D treatment restored insulin relaxation and norepinephrine-induced contractility; in contrast, it failed to alter NO-dependent relaxation.

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Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

Cited by 15 publications

References 56 publications

Decrease in Ins+Glut2LO β-cells with advancing age in mouse and human pancreas

Decrease in Ins+Glut2LO β-cells with advancing age in mouse and human pancreas

Atorvastatin helps preserve pancreatic β cell function in obese C57BL/6 J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress

Arteriolar insulin resistance in a rat model of polycystic ovary syndrome

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