| 1. |
- Fransson, Liselotte, et al.
(författare)
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beta-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome
- 2013
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Ingår i: Journal of Endocrinology. - : BioScientifica. - 0022-0795 .- 1479-6805. ; 219:3, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 mu g/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into beta-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.
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| 2. |
- Fransson, Liselotte, et al.
(författare)
-
β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome
- 2013
-
Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 219:3, s. 231-241
-
Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 μg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into β-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.
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| 3. |
- Miller, Victoria, et al.
(författare)
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Associations of the glycaemic index and the glycaemic load with risk of type 2 diabetes in 127594 people from 20 countries (PURE): a prospective cohort study
- 2024
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Ingår i: The Lancet Diabetes and Endocrinology. - 2213-8587 .- 2213-8595. ; 12, s. 330-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between the glycaemic index and the glycaemic load with type 2 diabetes incidence is controversial. We aimed to evaluate this association in an international cohort with diverse glycaemic index and glycaemic load diets. Methods: The PURE study is a prospective cohort study of 127 594 adults aged 35–70 years from 20 high-income, middle-income, and low-income countries. Diet was assessed at baseline using country-specific validated food frequency questionnaires. The glycaemic index and the glycaemic load were estimated on the basis of the intake of seven categories of carbohydrate-containing foods. Participants were categorised into quintiles of glycaemic index and glycaemic load. The primary outcome was incident type 2 diabetes. Multivariable Cox Frailty models with random intercepts for study centre were used to calculate hazard ratios (HRs). Findings: During a median follow-up of 11·8 years (IQR 9·0–13·0), 7326 (5·7%) incident cases of type 2 diabetes occurred. In multivariable adjusted analyses, a diet with a higher glycaemic index was significantly associated with a higher risk of diabetes (quintile 5 vs quintile 1; HR 1·15 [95% CI 1·03–1·29]). Participants in the highest quintile of the glycaemic load had a higher risk of incident type 2 diabetes compared with those in the lowest quintile (HR 1·21, 95% CI 1·06–1·37). The glycaemic index was more strongly associated with diabetes among individuals with a higher BMI (quintile 5 vs quintile 1; HR 1·23 [95% CI 1·08–1·41]) than those with a lower BMI (quintile 5 vs quintile 1; 1·10 [0·87–1·39]; p interaction=0·030). Interpretation: Diets with a high glycaemic index and a high glycaemic load were associated with a higher risk of incident type 2 diabetes in a multinational cohort spanning five continents. Our findings suggest that consuming low glycaemic index and low glycaemic load diets might prevent the development of type 2 diabetes. Funding: Full funding sources are listed at the end of the Article.
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| 4. |
- Rosengren, Victoria
(författare)
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Protein expression analysis of insulin producing cells exposed to endoplasmic reticulum stress
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly as a result of the obesity epidemic. T2DM develops in individuals who fails to compensate for increased demand of insulin. Obese individuals display alterations in the circulating lipid profile and there is evidence that the elevated levels of fatty acids are detrimental to pancreatic β-cells which may contribute to the progression of β-cell failure via both impaired function and a reduction of the β-cell mass seen in T2DM patients, but the mechanism is not completely known. There is evidence that saturated fatty acids can induce apoptosis, as well as endoplasmic reticulum (ER) stress. As a secretory cell, the pancreatic β-cell is equipped with a highly developed ER to assist in the folding process of newly synthesized proteins, but this cell organelle is sensitive to alteration in homeostasis, and an imbalance between protein load and folding capacity can result in ER stress. This thesis aimed to investigate the protein expression in insulin producing cells exposed to ER stress by the use of proteomics and Western blot. In paper I, cells were exposed to the ER stress inducer thapsigargin. By the use of proteomic methodology we found decreased levels of the ER localized proteins GRP78/BiP, PDIA3 and PDIA6 following thapsigargin treatment. The decreased protein levels of GRP78/BiP was not a consequence of reduced mRNA expression. Instead the decrease involved a combination of reduced protein synthesis and enhanced degradation by both proteasome and autophagy. The data in paper I provides an explanation to why INS-1E cells are vulnerable to conditions of ER stress. In paper II, cells were exposed to thapsigargin and the saturated fatty acid palmitate. By proteomic investigation we identified 7,786 proteins, of which 6,117 were overlapping in two data sets. 1,000 proteins were regulated by thapsigargin and 227 by palmitate. With bioinformatic analysis we found a set of transcription factors predicted to be regulated in the same manner by the thapsigargin and palmitate. This paper shows that the treatments not only share the induction of ER stress but also share an effect on the lipid handling in the cell by affecting several metabolic master transcription factors involved in lipid and cholesterol biosynthesis. In paper III we investigated pathways involved in the cytotoxic action of glucocorticoids (GCs). Excess of GCs is associated with glucose intolerance and diabetes. The data show that GC activates p38 MAPK and JNK in β-cells, which work in opposite to regulate the cytotoxic effects induced by GCs. The data also suggests that protein phosphatase 5 play a protective role, since reduced PP5 levels in MIN6 cells and islets makes the cells sensitized to the toxic effects induced by GCs. Furthermore, our result indicate that GC exposure 2 compromises the cellular response to ER stress in insulin producing cells which may lead to an impaired capacity to restore the homeostasis in the ER. A deeper understanding of the mechanisms and the mediators of the ER and apoptotic pathways will hopefully provide tools to preserve the β-cell mass and delay the progression to T2DM.
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