Effects of streptozotocin on pancreatic islet β-cell apoptosis and glucose metabolism in zebrafish larvae

Abstract Aims Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets. Methods Streptozotocin-treated diabetic mice expressing a fluorescent reporter specifically in pancreatic islet α-cells were administered the biguanide metformin (100 mg/kg), thiazolidinedione rosiglitazone (10 mg/kg), or sulfonylurea tolbutamide (20 mg/kg) for 10 days. We assessed the impact of the treatment on metabolic status of the animals as well as on the morphology, proliferative potential and transdifferentiation of pancreatic islet cells, using immunofluorescence. Results The effect of the therapy on the islet cells varied depending on the drug and included enhanced pancreatic islet β-cell proliferation, in case of metformin and rosiglitazone; de-differentiation of α-cells and β-cell apoptosis with tolbutamide; increased relative number of β-cells and bi-hormonal insulin + glucagon + cells with metformin. These effects were accompanied by normalisation of food and fluid intake with only minor effects on glycaemia at the low doses of the agents employed. Conclusions Our data suggest that metformin and rosiglitazone attenuate the depletion of the β-cell pool in the streptozotocin-induced diabetes, whereas tolbutamide exacerbates the β-cell apoptosis, but is likely to protect β-cells from chronic hyperglycaemia by directly elevating insulin secretion.

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Maternal high-fat diet regulates glucose metabolism and pancreatic β cell phenotype in mouse offspring at weaning

PeerJ ◽

10.7717/peerj.9407 ◽

2020 ◽

Vol 8 ◽

pp. e9407

Author(s):

Jia Zheng ◽

Ling Zhang ◽

Ziwei Wang ◽

Junqing Zhang

Keyword(s):

Glucose Metabolism ◽

Cell Apoptosis ◽

High Fat Diet ◽

Cell Mass ◽

Male Offspring ◽

Cell Phenotype ◽

Chow Diet ◽

High Fat ◽

Β Cell ◽

Weaning Age

Background Maternal malnutrition is a critical factor in determining the risk of obesity and glucose intolerance in offspring. However, little is known about the effects of a maternal high-fat diet (HFD) on the β cell phenotype in offspring, which is a major factor in glucose homeostasis, especially during the early life of offspring. Methods Dams were randomly fed a HFD (60% kcal from fat) or a chow diet before pregnancy and during gestation and lactation. Glucose metabolism and the β cell phenotype were assessed in male offspring at weaning. Results Dams fed a HFD showed impaired glucose tolerance. A HFD predisposed the offspring to increased impairment of metabolic health, including obesity, glucose intolerance and insulin resistance, compared with offspring from chow diet-fed dams. Furthermore, increased islet sizes and islet densities were observed in male offspring from HFD-fed dams at weaning. There were increases in the insulin-positive area, β cell mass and β cell proliferation in male offspring from HFD-fed dams at weaning age. Next, we further determined whether a maternal HFD could affect β cell apoptosis in mouse offspring and found that there was no significant change in β cell apoptosis between the HFD and control groups. Conclusion Our study is novel in showing that a maternal HFD predisposes offspring to impaired glucose metabolism and has a profound effect on β cell mass and proliferation in offspring mice, which is observed in mice as early as at weaning age. However, further study to clarify the underlying mechanisms is warranted.

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Role of nucleolar protein NOM1 in pancreatic islet β cell apoptosis in diabetes

Experimental and Therapeutic Medicine ◽

10.3892/etm.2016.3576 ◽

2016 ◽

Vol 12 (4) ◽

pp. 2275-2280 ◽

Cited By ~ 1

Author(s):

Leilei Yu ◽

Huifeng Wang ◽

Zhongxiu Guo ◽

Fenghua Li ◽

Hong Cui

Keyword(s):

Pancreatic Islet ◽

Cell Apoptosis ◽

Nucleolar Protein ◽

Β Cell

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Protease inhibitors used in the treatment of HIV+ induce β-cell apoptosis via the mitochondrial pathway and compromise insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90445.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. E925-E935 ◽

Cited By ~ 16

Author(s):

Sheng Zhang ◽

Michael J. Carper ◽

Xiaoyong Lei ◽

W. Todd Cade ◽

Kevin E. Yarasheski ◽

...

Keyword(s):

Cell Death ◽

Protease Inhibitors ◽

Pancreatic Islet ◽

Cell Apoptosis ◽

Cell Function ◽

People Living With Hiv ◽

Β Cell ◽

Apoptotic Pathway ◽

Insulinoma Cells ◽

Factor C

Inclusion of HIV protease inhibitors (PIs) in the treatment of people living with HIV+ has markedly decreased mortality but also increased the incidence of metabolic abnormalities, causes of which are not well understood. Here, we report that insulinopenia is exacerbated when Zucker fa/fa rats are exposed to a PI for 7 wk, suggesting that chronic PI exposure adversely affects pancreatic islet β-cell function. In support of this possibility, we find increased apoptosis, as reflected by TUNEL fluorescence analyses, and reduced insulin-secretory capacity in insulinoma cells and human pancreatic islet cells after in vitro exposures (48–96 h) to clinically relevant PIs (ritonavir, lopinavir, atazanavir, or tipranavir). Furthermore, pancreatic islets isolated from rats administered an HIV-PI for 3 wk exhibit greater cell death than islets isolated from vehicle-administered rats. The higher incidence of HIV-PI-induced cell death was associated with cleavage and, hence, activation of caspase-3 and poly(ADP)-ribose polymerase but not with activation of phospho-pancreatic endoplasmic reticulum (ER) kinase or induction of ER stress apoptotic factor C/EBP homologous protein. Exposure to the HIV-PIs, however, led to activation of mitochondria-associated caspase-9, caused a loss in mitochondrial membrane potential, and promoted the release of cytochrome c, suggesting that HIV-PIs currently in clinically use can induce β-cell apoptosis by activating the mitochondrial apoptotic pathway. These findings therefore highlight the importance of considering β-cell viability and function when assessing loss of glycemic control and the course of development of diabetes in HIV+ subjects receiving a protease inhibitor.

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Glucose Metabolism Disorder Induces Spermatogenic Dysfunction in Northern Pig-Tailed Macaques (Macaca leonina) With Long-Term SIVmac239 Infection

Frontiers in Endocrinology ◽

10.3389/fendo.2021.745984 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tian-Zhang Song ◽

Ming-Xu Zhang ◽

Han-Dan Zhang ◽

Xue-Hui Wang ◽

Wei Pang ◽

...

Keyword(s):

Glucose Metabolism ◽

Pancreatic Islet ◽

Lactate Production ◽

Whole Body ◽

Β Cell ◽

Metabolism Disorder ◽

Immunodeficiency Virus ◽

Glucose Metabolism Disorder ◽

Sivmac239 Infection

Although spermatogenic dysfunction is widely found in patients with human immunodeficiency virus (HIV), the underlying reasons remain unclear. Thus far, potential hypotheses involving viral reservoirs, testicular inflammation, hormone imbalance, and cachexia show inconsistent correlation with spermatogenic dysfunction. Here, northern pig-tailed macaques (NPMs) exhibited marked spermatogenic dysfunction after long-term infection with simian immunodeficiency virus (SIVmac239), with significant decreases in Johnsen scores, differentiated spermatogonial stem cells, and testicular proliferating cells. The above hypotheses were also evaluated. Results showed no differences between SIV− and SIV+ NPMs, except for an increase in follicle stimulating hormone (FSH) during SIV infection, which had no direct effect on the testes. However, long-term SIVmac239 infection undermined pancreatic islet β cell function, partly represented by significant reductions in cellular counts and autophagy levels. Pancreatic islet β cell dysfunction led to glucose metabolism disorder at the whole-body level, which inhibited lactate production by Sertoli cells in testicular tissue. As lactate is the main energy substrate for developing germ cells, its decrease was strongly correlated with spermatogenic dysfunction. Therefore, glucose metabolism disorder appears to be a primary cause of spermatogenic dysfunction in NPMs with long-term SIVmac239 infection.

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ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.0c06456 ◽

2020 ◽

Author(s):

Yanqi Li ◽

Yanchao Wang ◽

Lei Zhang ◽

Ziyi Yan ◽

Jingjing Shen ◽

...

Keyword(s):

Cell Apoptosis ◽

Mitochondrial Apoptosis ◽

Β Cell ◽

Apoptosis Pathway ◽

Mitochondrial Apoptosis Pathway

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Dihydroartemisinin prevents palmitate-induced β-cell apoptosis

APOPTOSIS ◽

10.1007/s10495-021-01660-6 ◽

2021 ◽

Author(s):

Zhiyong Wang ◽

·Yan Hao ◽

·Haibing Yu ◽

Pei Wei

Keyword(s):

Cell Apoptosis ◽

Β Cell

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The Role of High Fat Diets and Liver Peptidase Activity in the Development of Obesity and Insulin Resistance in Wistar Rats

Nutrients ◽

10.3390/nu12030636 ◽

2020 ◽

Vol 12 (3) ◽

pp. 636

Author(s):

Germán Domínguez-Vías ◽

Ana Belén Segarra ◽

Manuel Ramírez-Sánchez ◽

Isabel Prieto

Keyword(s):

Glucose Metabolism ◽

Wistar Rats ◽

Metabolic Disorders ◽

Peptidase Activity ◽

High Fat ◽

Β Cell ◽

High Fat Diets ◽

Glutamyl Transferase ◽

Fat Diets

High-fat diets (HFD) have been widely associated with an increased risk of metabolic disorders and overweight. However, a high intake of sources that are rich in monounsaturated fatty acids has been suggested as a dietary agent that is able to positively influence energy metabolism and vascular function. The main objective of this study was to analyze the role of dietary fats on hepatic peptidases activities and metabolic disorders. Three diets: standard (S), HFD supplemented with virgin olive oil (VOO), and HFD supplemented with butter plus cholesterol (Bch), were administered over six months to male Wistar rats. Plasma and liver samples were collected for clinical biochemistry and aminopeptidase activities (AP) analysis. The expression of inducible nitric oxide synthase (iNOS) was also determined by Western blot in liver samples. The diet supplement with VOO did not induce obesity, in contrast to the Bch group. Though the VOO diet increased the time that was needed to return to the basal levels of plasma glucose, the fasting insulin/glucose ratio and HOMA2-%B index (a homeostasis model index of insulin secretion and valuation of β-cell usefulness (% β-cell secretion)) were improved. An increase of hepatic membrane-bound dipeptidyl-peptidase 4 (DPP4) activity was found only in VOO rats, even if no differences in fasting plasma glucagon-like peptide 1 (GLP-1) were obtained. Both HFDs induced changes in hepatic pyroglutamyl-AP in the soluble fraction, but only the Bch diet increased the soluble tyrosyl-AP. Angiotensinase activities that are implicated in the metabolism of angiotensin II (AngII) to AngIV increased in the VOO diet, which was in agreement with the higher activity of insulin-regulated-AP (IRAP) in this group. Otherwise, the diet that was enriched with butter increased soluble gamma-glutamyl transferase (GGT) and Leucyl-AP, iNOS expression in the liver, and plasma NO. In summary, VOO increased the hepatic activity of AP that were related to glucose metabolism (DPP4, angiotensinases, and IRAP). However, the Bch diet increased activities that are implicated in the control of food intake (Tyrosine-AP), the index of hepatic damage (Leucine-AP and GGT), and the expression of hepatic iNOS and plasma NO. Taken together, these results support that the source of fat in the diet affects several peptidases activities in the liver, which could be related to alterations in feeding behavior and glucose metabolism.

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