Aims/hypothesis Beta cell failure is a crucial component in the pathogenesis of type 2 diabetes. One of the proposed mechanisms of beta cell failure is local inflammation, but the presence of ...pancreatic islet inflammation in type 2 diabetes and the mechanisms involved remain under debate. Methods Chemokine and cytokine expression was studied by microarray analysis of laser-capture microdissected islets from pancreases obtained from ten non-diabetic and ten type 2 diabetic donors, and by real-time PCR of human islets exposed to oleate or palmitate at 6 or 28 mmol/l glucose. The cellular source of the chemokines was analysed by immunofluorescence of pancreatic sections from individuals without diabetes and with type 2 diabetes. Results Microarray analysis of laser-capture microdissected beta cells showed increased chemokine and cytokine expression in type 2 diabetes compared with non-diabetic controls. The inflammatory response in type 2 diabetes was mimicked by exposure of non-diabetic human islets to palmitate, but not to oleate or high glucose, leading to the induction of IL-1β, TNF-α, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-C motif) ligand 2 (CCL2). Interference with IL-1β signalling abolished palmitate-induced cytokine and chemokine expression but failed to prevent lipotoxic human islet cell death. Palmitate activated nuclear factor κB (NF-κB) in human pancreatic beta and non-beta cells, and chemically induced endoplasmic reticulum stress caused cytokine expression and NF-κB activation similar to that occurring with palmitate. Conclusions/interpretation Saturated-fatty-acid-induced NF-κB activation and endoplasmic reticulum stress may contribute to IL-1β production and mild islet inflammation in type 2 diabetes. This inflammatory process does not contribute to lipotoxicity ex vivo, but may lead to local chemokine release.
Pancreatic β-cell dysfunction is central to the pathogenesis of type 2 diabetes, and the loss of functional β-cell mass in type 2 diabetes is at least in part secondary to increased β-cell apoptosis. ...Accumulating evidence suggests that endoplasmic reticulum (ER) stress is present in β-cells in type 2 diabetes. Free fatty acids (FFAs) cause ER stress and are putative mediators of β-cell dysfunction and death. In this review, we discuss the molecular mechanisms underlying ER stress induced by saturated and unsaturated FFAs. Oleate and palmitate trigger ER stress through ER Ca²⁺ depletion and build-up of unfolded proteins in the secretory pathway. Saturated and unsaturated FFAs elicit a differential signal transduction in the three branches of the ER stress response, resulting in different survival/apoptosis outcomes. The protection of β-cells against FFAs through the interference with ER stress signalling has opened novel therapeutic perspectives for type 2 diabetes. Chemical chaperones, salubrinal and glucagon-like peptide-1 (GLP-1) analogues have been used to protect β-cells from lipotoxic ER stress. Importantly, the pro- and antiapoptotic effects of these compounds are cell and context dependent.
Lactate is released in large quantity from sites of sepsis and inflammation. We asked whether the increased lactate production found in sepsis can be explained by the augmented glycolysis of ...inflammatory cells. The glycolytic metabolism of rat peritoneal leukocytes was measured following cecal ligation and perforation (CLP) or sham laparotomy. CLP augmented glucose uptake, the pentose phosphate pathway, and glucose oxidation. Lactate output increased from 1.03 ± 0.05 to 1.20 ± 0.05 fmol · cell
−1 · min
−1 (
P < .001). Total lactate output of peritoneal lavage fluid increased from 7.94 ± 2.59 to 28.12 ± 5.60 nmol L · min
−1 (
P < .005). The effect of lipopolysaccharide (LPS) on the lactate output of whole blood from 31 critically ill patients was measured. Leukocyte lactate production was calculated by multiple linear regression analysis. Following exposure to LPS, human leukocyte lactate output increased from 0.20 ± 0.09 to 1.22 ± 0.14 fmol · cell
−1, min
−1 (
P < .001). This rate of production is so high that it suggests that the lactate output of different tissue beds in sepsis may be affected by their different cell populations and state of activation. This study supports the hypothesis that lactate may be more a product of inflammation than a marker of tissue hypoxia in sepsis.
D-mannoheptulose was recently proposed to be transported into cells mainly at the intervention of GLUT2. In the present study, it was investigated whether advantage could be taken from such a ...situation to assess the contribution of insulin-producing B-cells to the total mass of isolated rat pancreatic islets. After 60 min incubation at 37 degrees C in the presence of 8.3 mM D-glucose, the intracellular distribution space of D-3Hmannoheptulose (0.1 mM) averaged, in islets from control and streptozotocin-induced diabetic rats, respectively 49.0+/-2.3 and 6.2+/-1.5% of the corresponding intracellular 3HOH space, all values being corrected for extracellular contamination as judged from the distribution space of U-14Csucrose (1.0 mM). These findings indicate that the present approach indeed allows to assess the relative contribution of B-cells to total islet mass for purpose of comparison between animals with different metabolic and/or hormonal status.
Pancreatic uptake of [2-(14)C]alloxan Malaisse, W J; Doherty, M; Ladrière, L ...
International journal of molecular medicine,
03/2001, Letnik:
7, Številka:
3
Journal Article
Recenzirano
The uptake of 2-(14)Calloxan by the pancreatic gland was investigated in control and streptozotocin-induced diabetic (STZ) rats, using both in vitro and in vivo techniques. Whether after 10 to 60 min ...incubation of pieces of pancreas in the presence of 2-(14)Calloxan or 60 min to 24 h after intravenous injection of 2-(14)Calloxan to control and insulin-treated STZ rats, the radioactive content of the pancreas (dpm/mg wet weight) only represented, in the STZ rats, about two thirds of the reference value found in control animals. These findings indicate that insulin-producing islet B-cells participate to a sizeable extent to the overall uptake of 2-(14)C- alloxan by the whole pancreatic gland, despite the fact that they account for no more than about one percent of the total pancreas mass. Hence, it should be possible to preferentially label the endocrine moiety of the pancreas, in the perspective of its imaging and quantification by a non-invasive procedure, by use of a suitable radiolabelled molecule selectively taken up by islet, as distinct from acinar, pancreatic cells.
Apoptosis is probably the main form of β-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to β-cell destruction through nuclear factor-κB (NF-κB) activation. ...Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are β-cell toxic also via NF-κB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced β-cell apoptosis and determine whether TNFα, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-κB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified β-cells by oleate, palmitate, and/or cytokines (IL-1β, interferon-γ, TNFα). Palmitate and IL-1β induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFα did not potentiate FFA toxicity in primary β-cells. The NF-κB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1β but not by FFAs. Cytokines activated NF-κB in INS-1E and β-cells, but FFAs did not. Moreover, FFAs did not enhance NF-κB activation by TNFα. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced β-cell death but the mechanisms involved are different. Whereas cytokines induce NF-κB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-κB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of β-cell death in T1DM and T2DM.
The role currently ascribed to the accumulation of L-arginine in the pancreatic islet B-cell as a determinant of its insulinotropic action was reevaluated by comparing the uptake and the metabolic, ...ionic, electric, and secretory effects of the cationic amino acid with those of its more positively charged methyl ester in rat pancreatic islets. The response to L-arginine methyl ester differed from that evoked by the unesterified amino acid by a lower uptake and oxidation, lack of inhibitory action on D-glucose metabolism, more severe inhibition of the catabolism of endogenous L-glutamine, inhibition of 45Ca net uptake, decrease in both 86Rb outflow from prelabeled islets perifused at normal extracellular Ca2+ concentration and 45Ca efflux from prelabeled islets perifused in the absence of extracellular Ca2+, and delayed and lesser insulinotropic action. These findings reinforce the view that the carrier-mediated entry of L-arginine into the islet B-cells, with resulting depolarization of the plasma membrane, represents the essential mechanism for stimulation of insulin release by this cationic amino acid.
Moment biographique important, le passage à la retraite intervient à un âge où les recours aux médicaments psychotropes sont plus élevés, surtout chez les femmes, qu’aux âges inférieurs.
Nous avons ...procédé à une extraction de la base des prescriptions présentées au remboursement du Régime social des indépendants (RSI) en France métropolitaine sur une période de 12 mois avant le jour de leur retraite et 12 mois après, en vue de calculer des taux de recours – généraux et par classe de médicaments psychotropes – et de rechercher l’influence du sexe, de l’âge, de la dernière profession, d’une affection psychiatrique, de la région de résidence et de la période (avant/après le départ en retraite).
Le taux de recours aux psychotropes des indépendants à l’âge de la retraite s’élève à 35 % (33 % pour les hommes et 42 % pour les femmes). Les benzodiazépines constituent le premier groupe prescrit (42,5 % des volumes pour 24,8 % des personnes) ; suivent des antidépresseurs (32,1 % des volumes pour 15,3 % des personnes), des somnifères (21,0 % des volumes pour 12,9 % des personnes), des antipsychotiques (3,5 % des volumes pour 2,1 % des personnes) et des traitements de la dépendance alcoolique (1,0 % des volumes pour 0,8 % des personnes). Les groupes qui présentent les plus forts recours sont les personnes présentant une affection psychiatrique de longue durée (ALD 23 – 93,1 %), les bénéficiaires de la couverture maladie universelle (CMU – 48,8 %), les femmes (42,0 %) et les personnes de 60
ans (37,9 %), alors que les anciens artisans (33,2 %) présentent un taux de recours plus faible que les autres professions.
Les variables ci-dessus, ainsi que la résidence dans le Nord-Pas-de-Calais et le Limousin, sont plus reliées à de forts taux de recours que le départ en retraite ; ce dernier n’induit qu’une très faible diminution du recours aux médicaments psychotropes.
Retiring is an important life event and occurs at an age when psychotropic medicines are used more, particularly in women, compared to younger ages. This use is liable to fall after exposure to occupational stress ends although the loss of professional recognition and ageing may cause episodes of anxiety and depression.
We have conducted an extraction from the database of the social payments system for self-employed people (craftsmen, shopkeepers and self-employed professions) of prescriptions of psychotropic drugs presented for reimbursement in mainland France over a period of 12
months before and 12
months after retirement, i.e. a period of two years for each of the 28,293 people in the sample in order to calculate levels of use – both general and by class of psychotropic drug – and to examine the influence of sex, age, last occupation, psychiatric disease, low income, region of residence and period (before/after beginning retirement) using bivariate analysis and logistic regression.
Psychotropic drugs were used in self-employed people at the time of retirement by 33% of men and 42% of women (34.9% both sexes combined). 28.1% of recipients were given one prescription, 46.1% between two and five, 17.2% between six and ten and 8.7% more than ten prescriptions during the two years of the study (mean
=
4.4 prescriptions per person). The leading group prescribed was benzodiazepines (42.5% of volume – 24.8% of people), followed by antidepressants (32.1% of volume – 15.3% of people), hypnotics (21% of volume – 12.9% of people), antipsychotics (3.5% of volume – 2.1% of people) and treatments for alcohol dependency (1% of volume – 0.8% of people). The greatest users were people with long-term psychiatric disorders (LTD23 – 93.1%; OR
=
22.1;
P
<
0.001), those with low incomes (48.8%; OR
=
1.7;
P
<
0.001), women (42%; OR
=
1.4;
P
<
0.001) and those of 60
years old (37.9%; OR
=
1.1 compared to those under 60
years old;
P
<
0,001), whereas former craftsmen (33.2%) had lower use than other professions. Rates of use were significantly higher in six regions in men, including Nord-Pas-de-Calais and Limousin, which were the only two regions in which rates were also significantly higher in women. Of those who took psychotropic drugs during the observation period, 53.7% continued to take them after they had retired; 21.2% stopped using them once they had retired and a similar proportion (21.5%) began to use them after retiring. The number of prescriptions (21,741 during the year before retirement and 21,337 during the year after retirement) fell very slightly (−2%).
More than a third of self-employed people in mainland France use psychotropic drugs at retirement age. The end of occupational stress which may be the reason for taking some of these drugs results in few changes in use, possibly because use has become more habitual than necessary. Documented psychiatric disease, low income, living in Limousin, female sex and living in Nord-Pas-de-Calais, emerge in decreasing order of importance in our study as factors most closely related to frequent use.
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