1,721,046 research outputs found
Autophagy and the pancreatic beta-cell in human type 2 diabetes
No full textPancreatic beta-cell dysfunction is central to the development and worsening of type 2 diabetes. Whereas beta-cell apoptosis plays a major role in reducing beta-cell mass in diabetes, alterations of autophagy can also lead to beta-cell death, as recently demonstrated in type 2 diabetic subjects. In addition, several studies with cell lines and rodent models have shown the importance of autophagy in regulating beta-cell survival and function. Although most of the underlying molecular mechanisms remain to be elucidated, this growing evidence raises interest in the role of autophagy in beta-cell pathophysiology and suggests the possibility of exploring autophagic processes to develop tools for protection of the pancreatic beta-cell in type 2 diabetes
The pancreatic beta cells in human type 2 diabetes
No full textBell-cell (beta-cell) impairment is central to the development and progression of human diabetes, as a result of the combined effects of genetic and acquired factors. Reduced islet number and/or reduced beta cells amount in the pancreas of individuals with Type 2 diabetes have been consistently reported. This is mainly due to increased beta cell death, not adequately compensated for by regeneration. In addition, several quantitative and/or qualitative defects of insulin secretion have been observed in Type 2 diabetes, both in vivo and ex vivo with isolated islets. All this is associated with modifications of islet cell gene and protein expression. With the identification of several susceptible Type 2 diabetes loci, the role of genotype in affecting beta-cell function and survival has been addressed in a few studies and the relationships between genotype and beta-cell phenotype investigated. Among acquired factors, the importance of metabolic insults (in particular glucotoxicity and lipotoxicity) in the natural history of beta-cell damage has been widely underlined. Continuous improvements in our knowledge of the beta cells in human Type 2 diabetes will lead to more targeted and effective strategies for the prevention and treatment of the disease
Ultrastructural Localization of Histidine-rich Glycoprotein in Skeletal Muscle Fibers: Colocalization With AMP Deaminase
Full text linkHistidine-rich glycoprotein (HRG) is a plasma protein synthesized by the liver. We have given the first evidence of a tissue localization of HRG demonstrating its presence in skeletal muscle, associated with the zinc enzyme AMP deaminase (AMPD1). Moreover, we have shown that muscle cells do not synthesize HRG, but they can internalize it from plasma. We have recently demonstrated by confocal laser scanning microscopy that in human skeletal muscle, HRG is mainly localized in the myofibrils, preferentially at the I-band of the sarcomere, in the sarcoplasm, and in the nuclei. Using transmission electron microscopy and immunogold analysis, we carried out this study on human and rat normal skeletal muscles with the purpose to deepen the ultrastructural localization of HRG in skeletal muscle fibers. The immunogold analysis evidenced the presence of HRG in the sarcomeres, mainly in the I-band and to a less extent in the A-band, in the heterochromatin of nuclei, and in the sarcoplasmic reticulum. The colocalization of HRG and skeletal muscle AMPD1 was also analyzed. A colabeling of HRG and AMPD1 was evident at sarcomeric, sarcoplasmic reticulum, and nuclear levels. The significance of these interesting and new results is discussed in this article
A NEW METHOD FOR THE INVESTIGATION OF ENDOCRINE-REGULATED AUTOPHAGY AND PROTEIN-DEGRADATION IN RAT-LIVER
No full textIn vivo effect of an antilipolytic drug (3,5'-dimethilylpyrazole) on autophagic proteolysis and autophagy-related gene expression in rat liver
No full textAutophagy is an intracellular pathway induced by starvation, inhibited by
nutrients, that is responsible for degradation of long-lived proteins and altered
cell organelles. This process is involved in cell maintenance could be induced by
antilipolytic drugs and may have anti-aging effects [A. Donati, The involvement
of macroautophagy in aging and anti-aging interventions, Mol. Aspects Med. 27
(2006) 455-470]. We analyzed the effect of an intraperitoneal injection of an
antilipolytic agent (3,5'-dimethylpyrazole, DMP, 12mg/kg b.w.), that mimics
nutrient shortage on autophagy and expression of autophagic genes in the liver of
male 3-month-old Sprague-Dawley albino rats. Autophagy was evaluated by observing
electron micrographs of the liver autophagosomal compartment and by monitoring
protein degradation assessed by the release of valine into the bloodstream. LC3
gene expression, whose product is one of the best known markers of autophagy, was
also monitored. As expected, DMP decreased the plasma levels of free fatty acids,
glucose, and insulin and increased autophagic vacuoles and proteolysis. DMP
treatment caused an increase in the expression of the LC3 gene although this
occurred later than the induction of authophagic proteolysis caused by DMP.
Glucose treatment rescued the effects caused by DMP on glucose and insulin plasma
levels and negatively affected the rate of autophagic proteolysis, but did not
suppress the positive regulatory effect on LC3 mRNA levels. In conclusion,
antilipolytic drugs may induce both autophagic proteolysis and higher expression
of an autophagy-related gene and the effect on autophagy gene expression might
not be secondary to the stimulation of autophagic proteolysis
Dehydroascorbate protection against dioxin-induced toxicity in the beta cell line INS-1E
No full textThe aryl receptor inhibitor epigallocatechin-3-gallate protects INS-1E beta-cell line against acute dioxin toxicity.
No full textThe aim of this research was to investigate the mechanism(s) underlying the acute toxicity of dioxin in pancreatic beta cells and to evaluate the protective effects of epigallocatechin-3-gallate (EGCG), the most abundant of the green tea's catechins and a powerful inhibitor of the aryl hydrocarbon receptor (AhR). Using the insulin-secreting INS-1E cell line we have explored the effect of 1h exposure to different concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alone or in the presence of EGCG, on: (a) cell survival; (b) cellular ultrastructure; (c) intracellular calcium levels; (d) mitochondrial membrane potential; (e) glucose-stimulated insulin secretion and (f) activation of MAP kinases. Our results demonstrate that TCDD is highly toxic for INS-1E cells, suggesting that pancreatic beta cells should be considered a relevant and sensitive target for dioxin acute toxicity. EGCG significantly protects INS-1E cells against TCDD-induced toxicity in terms of both cell survival and preservation of cellular ultrastructure. The mechanism of this protective effect seems to be related to: (a) the ability of EGCG to preserve the mitochondrial function and thus to prevent the TCDD-induced inhibition of glucose-stimulated insulin secretion and (b) the ability of EGCG to inhibit the TCDD-induced activation of selected kinases, such as e.g. ERK 1/2 and JNK. Our results clearly show that EGCG is able to protect pancreatic beta cells against dioxin acute toxicity and indicate the mitochondrion as the most likely target for this beneficial effect
A role for autophagy in ß-cell life and death
No full textAutophagy is a vacuolar, self-digesting mechanism responsible for the removal of organelles and defined regions of the cytoplams. This process has, in general, a beneficial role for the cell, since it regulates the turnover of aged proteins and eliminates damaged structures. However, cells that undergo altered autophagy may be triggered to die in a non-apoptotic manner. As a matter of fact, in recent years it has become clear that dysregulated autophagy may be implicated in several disorders, such as cancer, neurodegenerative diseases and hepatic encephalopathy. We have recently shown that beta-cells of type 2 diabetic subjects show signs of autophagy associated death, which may contribute to the overall loss of beta-cell mass in type 2 diabetes. In addition, studies with cell lines and rodent models have demonstrated the importance of autophagy in beta-cell function and survival. Altogether, the available evidence supports the view that autophagy is implicated in beta-cell pathophysiology, and suggests that addressing the molecular mechanisms involved in autophagic regulation might provide clues for preventing or treating beta-cell damage in diabetes
Ultrastructural morphometric analysis of insulin secretory granules in human type 2 diabetes.
Full text linkWe performed an ultrastructural morphometric analysis of insulin secretory
granules in pancreatic beta cells from control and type 2 diabetic multiorgan
donors. The volume density of insulin granules significantly (p < 0.05) reduced
in beta cells from type 2 diabetic patients with respect to non-diabetic
subjects, and this reduction was mainly attributable to a decrease in mature
granules. On the contrary, no significant difference was observed in the volume
density of docked granules between controls and type 2 diabetic patients. In
addition, there was a significant positive correlation between the density volume
of total insulin granules and stimulated insulin secretion in non-diabetic
islets. In conclusion, we detected significant changes in the intracellular
distribution of insulin secretory granules within the beta cell that might be
related with the alterations in insulin secretion observed in type 2 diabetes
patients
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