| 1. |
- Avall, Karin, et al.
(författare)
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Apolipoprotein CIII links islet insulin resistance to beta-cell failure in diabetes
- 2015
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:20, s. E2611-E2619
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance and beta-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and beta-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of beta-cell cytoplasmic free Ca2+ concentration ([Ca2+](i)) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+](i) response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of beta-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.
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| 2. |
- Holmberg, Rebecka, et al.
(författare)
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Lowering apolipoprotein CIII delays onset of type 1 diabetes
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:26, s. 10685-10689
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Tidskriftsartikel (refereegranskat)abstract
- Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when β cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted β-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes.
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| 3. |
- Lindgren, Joel, 1982-, et al.
(författare)
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A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life
- 2014
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Ingår i: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 102:3, s. 252-259
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1) and related peptide agonists have been extensively investigated for glycaemic control in Type 2 diabetes, and may also have therapeutic applications for other diseases. Due to the short half-life (t1/2<2 min) of the endogenous peptide, caused by proteolytic degradation and renal clearance, different strategies for half-life extension and sustained release have been explored. In the present study, conjugates between a GLP-1 analogue and a 5 kDa albumin-binding domain (ABD) derived from streptococcal protein G have been chemically synthesized and evaluated. ABD binds with high affinity to human serum albumin, which is highly abundant in plasma and functions as a drug carrier in the circulation. Three different GLP-1-ABD conjugates, with the two peptides connected by linkers of two, four, and six PEG units, respectively, were synthesized and tested in mouse pancreatic islets at high (11 mM) and low (3 mM) glucose concentration. Insulin release upon stimulation was shown to be glucose-dependent, showing no significant difference between the three different GLP-1-ABD conjugates and unconjugated GLP-1 analogue. The biological activity, in combination with the high affinity binding to albumin, make the GLP-1-ABD conjugates promising GLP-1 receptor agonists expected to show extended in vivo half-life.
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| 4. |
- Refai, Essam
(författare)
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Bioactive peptides and proteins in disease
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Regulatory peptides and marker proteins are important to study in order to understand disease mechanisms. This applies of course also to our common diseases where all relationships are not yet known. Cancer and diabetes are two such complex diseases that affect hundreds of millions of people worldwide. This thesis addresses particular aspects of these two diseases, regarding one regulatory peptide (VIP, vasoactive intestinal polypeptide) that may be useful for tumor tracing and two proteins (apoCIII, apolipoprotein CIII, and TTR, transthyretin) that are altered in type 1 diabetes. VIP and functional VIP receptors are expressed in neuroblastomas, suggesting that the growth of these cells may be mediated in part by an autocrine action of VIP. VIP receptors are present in many epithelial cancers including breast, colon, non-small cell lung cancer, and pancreatic and prostate cancers. Due to the high density of VIP receptors on cancer cells, radiolabelled VIP may be used to image these tumours. It was therefore important for us to study in vivo distribution of the radiolabelled VIP prior to its usage as tumour tracer. We also studied the biological effects of VIP on tumours in an animal model, as there may be differences with respect to receptor expression between cultured tumour cells and tumour cells grown in vivo. Our studies could provide new insight into tumour imaging with respect to radiolabelled VIP. Type 1 diabetes serum was shown to increase intracellular Ca2+ and cause cell death. ApoCIII and TTR were isolated from sera of newly diagnosed type 1 diabetic patients based on a biological assay of increases of intracellular Ca2+. The exposure of the pancreatic beta-cell to apoCIII not only increases intracellular Ca2+, but also causes programmed cell death. Furthermore, the activity of apoCIII and type 1 diabetes serum was totally blocked when a polyclonal antibody against human apoCIII was added. TTR did not have any effect on cell death. When applying the patch clamp technique, both cells treated with apoCIII and those treated with TTR displayed larger Ca 2+ -channel currents than control cells. Research over the last 30 years has established that type 1 diabetes is an autoimmune disease, but the triggers of the initiation and progression of the disease are still not identified. Genetic, immunological and environmental factors are involved in the pathogenesis of type 1 diabetes and it is most likely that the events involved can differ between different patients. Further investigations are needed to elucidate all pathways and how they are related to the underlying autoimmunity, but our results show that there is at least a group of type 1 diabetes patients where apoCIII and TTR play a role.
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