| 1. |
- Ahrén, Bo, et al.
(författare)
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Disturbed alpha-cell function in mice with beta-cell specific overexpression of human islet amyloid polypeptide.
- 2008
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008
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Tidskriftsartikel (refereegranskat)abstract
- Exogenous administration of islet amyloid polypeptide (IAPP) has been shown to inhibit both insulin and glucagon secretion. This study examined alpha-cell function in mice with beta-cell specific overexpression of human IAPP (hIAPP) after an oral protein gavage (75 mg whey protein/mouse). Baseline glucagon levels were higher in transgenic mice (41 +/- 4.0 pg/mL, n = 6) than in wildtype animals (19 +/- 5.1 pg/mL, n = 5, P = .015). In contrast, the glucagon response to protein was impaired in transgenic animals (21 +/- 2.7 pg/mL in transgenic mice versus 38 +/- 5.7 pg/mL in wildtype mice at 15 minutes; P = .027). Baseline insulin levels did not differ between the groups, while the insulin response, as the glucagon response, was impaired after protein challenge (P = .018). Glucose levels were not different between the groups and did not change significantly after protein gavage. Acetaminophen was given through gavage to the animals (2 mg/mouse) to estimate gastric emptying. The plasma acetaminophen profile was similar in the two groups of mice. We conclude that disturbances in glucagon secretion exist in mice with beta-cell specific overexpression of human IAPP, which are not secondary to changes in gastric emptying. The reduced glucagon response to protein challenge may reflect a direct inhibitory influence of hIAPP on glucagon secretion.
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| 2. |
- Andersson, Arne, et al.
(författare)
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Amyloid Deposition in Transplanted Human Pancreatic Islets : A Conceivable Cause of Their Long-Term Failure
- 2008
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Ingår i: EXPERIMENTAL DIABETES RESEARCH. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008:562985
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Tidskriftsartikel (refereegranskat)abstract
- Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.
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| 3. |
- Dahlfors, Gunilla, et al.
(författare)
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Inhibitory effect of diabetes on proliferation of vascular smooth muscle after balloon injury in rat aorta
- 2000
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Ingår i: Experimental Diabetes Research. - 1687-5214 .- 1687-5303. ; 1:2, s. 101-109
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Tidskriftsartikel (refereegranskat)abstract
- The effect of streptozotocin-induced diabetes on cell proliferation in rat aortic intima-media, as well as on local gene expression of transforming growth factor-β1 (TGF-β1) was studied. TGF-β1 mRNA was measured by solution hybridization and TGF-β1 protein by ELISA. Proliferation was measured by bromodeoxyuridine incorporation into DNA two days after balloon injury. All BrdU-labelled cells observed were smooth muscle cells. After a diabetes duration of 2 and 4 weeks, labelled cells were significantly fewer compared with controls. Circulating levels of total TGF-β1 were lowered in rats with 2 weeks diabetes. Although the balloon injury procedure by itself stimulated the gene expression of TGF-β1, no significant difference in TGF-β1 mRNA content between diabetic and control rats after injury was found. In conclusion: vascular smooth muscle proliferation in vivo is inhibited by the diabetic state in this model of insulin deficient diabetes and this inhibition is not related to an impaired local expression of TGF-β1.
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| 4. |
- Ekberg, K, et al.
(författare)
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Effect of C-peptide on diabetic neuropathy in patients with type 1 diabetes
- 2008
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Ingår i: Experimental diabetes research. - : Hindawi Limited. - 1687-5303 .- 1687-5214. ; 2008, s. 457912-
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Tidskriftsartikel (refereegranskat)abstract
- Recent results indicate that proinsulin C-peptide, contrary to previous views, exerts important physiological effects and shows the characteristics of a bioactive peptide. Studies in type 1 diabetes, involving animal models as well as patients, demonstrate that C-peptide in replacement doses has the ability to improve peripheral nerve function and prevent or reverse the development of nerve structural abnormalities. Peripheral nerve function, as evaluated by determination of sensory nerve conduction velocity and quantitative sensory testing, is improved by C-peptide replacement in diabetes type 1 patients with early stage neuropathy. Similarly, autonomic nerve dysfunction is ameliorated following administration of C peptide for up to 3 months. As evaluated in animal models of type 1 diabetes, the improved nerve function is accompanied by reversal or prevention of nerve structural changes, and the mechanisms of action are related to the ability of C-peptide to correct diabetes-induced reductions in endoneurial blood flow and in -ATPase activity and modulation of neurotrophic factors. Combining the results demonstrates that C-peptide may be a possible new treatment of neuropathy in type 1 diabetes.
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| 5. |
- Elfving, Maria, et al.
(författare)
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Maternal enterovirus infection during pregnancy as a risk factor in Offspring Diagnosed with Type 1 Diabetes between 15 and 30 years of age
- 2008
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; , s. 271958-
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Tidskriftsartikel (refereegranskat)abstract
- Maternal enterovirus infections during pregnancy may increase the risk of offspring developing type 1 diabetes during childhood. The aim of this study was to investigate whether gestational enterovirus infections increase the offspring's risk of type 1 diabetes later in life. Serum samples from 30 mothers without diabetes whose offspring developed type 1 diabetes between 15 and 25 years of age were analyzed for enterovirus-specific immunoglobulin M (IgM) antibodies and enterovirus genome (RNA), and compared to a control group. Among the index mothers, 9/30 (30%) were enterovirus IgM-positive, and none was positive for enterovirus RNA. In the control group, 14/90 (16%) were enterovirus IgM-positive, and 4/90 (4%) were positive for enterovirus RNA (n.s.). Boys of enterovirus IgM-positive mothers had approximately 5 times greater risk of developing diabetes (OR 4.63; 95% CI 1.22-17.6), as compared to boys of IgM-negative mothers (P < .025). These results suggest that gestational enterovirus infections may be related to the risk of offspring developing type 1 diabetes in adolescence and young adulthood.
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| 6. |
- Engelbertsen, Daniel, et al.
(författare)
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Increased Inflammation in Atherosclerotic Lesions of Diabetic Akita-LDLr(-/-) Mice Compared to Nondiabetic LDLr(-/-) Mice.
- 2012
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2012:Nov.,28
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Tidskriftsartikel (refereegranskat)abstract
- Background. Diabetes is associated with increased cardiovascular disease, but the underlying cellular and molecular mechanisms are poorly understood. One proposed mechanism is that diabetes aggravates atherosclerosis by enhancing plaque inflammation. The Akita mouse has recently been adopted as a relevant model for microvascular complications of diabetes. Here we investigate the development of atherosclerosis and inflammation in vessels of Akita mice on LDLr(-/-) background. Methods and Results. Akita-LDLr(-/-) and LDLr(-/-) mice were fed high-fat diet from 6 to 24 weeks of age. Blood glucose levels were higher in both male and female Akita-LDLr(-/-) mice (137% and 70%, resp.). Male Akita-LDLr(-/-) mice had markedly increased plasma cholesterol and triglyceride levels, a three-fold increase in atherosclerosis, and enhanced accumulation of macrophages and T-cells in plaques. In contrast, female Akita-LDLr(-/-) mice demonstrated a modest 29% increase in plasma cholesterol and no significant increase in triglycerides, atherosclerosis, or inflammatory cells in lesions. Male Akita-LDLr(-/-) mice had increased levels of plasma IL-1β compared to nondiabetic mice, whereas no such difference was seen between female diabetic and nondiabetic mice. Conclusion. Akita-LDLr(-/-) mice display considerable gender differences in the development of diabetic atherosclerosis. In addition, the increased atherosclerosis in male Akita-LDLr(-/-) mice is associated with an increase in inflammatory cells in lesions.
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| 7. |
- Forst, T, et al.
(författare)
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New tricks by an old dog
- 2008
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Ingår i: Experimental diabetes research. - : Hindawi Limited. - 1687-5303 .- 1687-5214. ; 2008, s. 384219-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Hach, T, et al.
(författare)
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C-peptide and its C-terminal fragments improve erythrocyte deformability in type 1 diabetes patients
- 2008
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Ingår i: Experimental diabetes research. - : Hindawi Limited. - 1687-5303 .- 1687-5214. ; 2008, s. 730594-
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis. Data now indicate that proinsulin C-peptide exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. This study aimed to investigate the influence of C-peptide and fragments thereof on erythrocyte deformability and to elucidate the relevant signal transduction pathway.Methods. Blood samples from 23 patients with type 1 diabetes and 15 matched healthy controls were incubated with 6.6 nM of either human C-peptide, C-terminal hexapeptide, C-terminal pentapeptide, a middle fragment comprising residues 11–19 of C-peptide, or randomly scrambled C-peptide. Furthermore, red blood cells from 7 patients were incubated with C-peptide, penta- and hexapeptides with/without addition of ouabain, EDTA, or pertussis toxin. Erythrocyte deformability was measured using a laser diffractoscope in the shear stress range 0.3–60 Pa.Results. Erythrocyte deformability was impaired by 18–25% in type 1 diabetic patients compared to matched controls in the physiological shear stress range 0.6–12 Pa(P<.01–.001). C-peptide, penta- and hexapeptide all significantly improved the impaired erythrocyte deformability of type 1 diabetic patients, while the middle fragment and scrambled C-peptide had no detectable effect. Treatment of erythrocytes with ouabain or EDTA completely abolished the C-peptide, penta- and hexapeptide effects. Pertussis toxin in itself significantly increased erythrocyte deformability.Conclusion/interpretation. C-peptide and its C-terminal fragments are equally effective in improving erythrocyte deformability in type 1 diabetes. The C-terminal residues of C-peptide are causally involved in this effect. The signal transduction pathway isCa2+-dependent and involves activation of red blood cellNa+,K+-ATPase.
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| 9. |
- Hoppener, J. W. M., et al.
(författare)
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Human Islet Amyloid Polypeptide Transgenic Mice: In Vivo and Ex Vivo Models for the Role of hIAPP in Type 2 Diabetes Mellitus
- 2008
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303.
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Tidskriftsartikel (refereegranskat)abstract
- Human islet amyloid polypeptide (hIAPP), a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2). To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process. Copyright (C) 2008 J. W. M. Hoppener et al.
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| 10. |
- Ludvigsen, Eva, et al.
(författare)
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Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo
- 2011
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2011, s. 623472-
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Tidskriftsartikel (refereegranskat)abstract
- Somatostatin acts via five receptors (sst1-5). We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.
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| 11. |
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| 12. |
- Pan, ML, et al.
(författare)
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Subthreshold α₂-adrenergic activation counteracts glucagon-like peptide-1 potentiation of glucose-stimulated insulin secretion
- 2011
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Ingår i: Experimental diabetes research. - : Hindawi Limited. - 1687-5303 .- 1687-5214. ; 2011, s. 604989-
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Tidskriftsartikel (refereegranskat)abstract
- The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1) receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX-) sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.
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| 13. |
- Paulsson, Johan F, et al.
(författare)
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Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation
- 2008
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008:865850
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET) using the contstruct pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and the fluoorescence was measured at 440 nm excitation and 535 nm (EYFP) and 480 nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (rec prolAPP) or the processing metabolites of prolAPP; the N-terminal flanking peptide withIAPP (recN+IAPP); IAPP with the C-terminal flanking peptied (recIAPP+C) and lslet Amyloid Polypeptide (recIAPP). Peptides were added in solubilized from (50 mu M) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of FRET and apoptosis was determined to occurein cells incubated with recproIAPP (49%), recN+IAPP (46%), recIAPP (72%) and recIAPP+C (59%). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.
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| 14. |
- Persson, Anders, et al.
(författare)
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Comparison of measurements of autoantibodies to glutamic acid decarboxylase and islet antigen-2 in whole blood eluates from dried blood spots using the RSR-enzyme linked immunosorbent assay kits and in-house radioimmunoassays.
- 2010
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2010
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the performance of dried blood spots (DBSs) with subsequent analyses of glutamic acid decarboxylase (GADA) and islet antigen-2 (IA-2A) with the RSR-ELISAs, we selected 80 children newly diagnosed with type 1 diabetes and 120 healthy women. DBSs from patients and controls were used for RSR-ELISAs while patients samples were analysed also with in-house RIAs. The RSR-ELISA-GADA performed well with a specificity of 100%, albeit sensitivity (46%) was lower compared to in RIA (56%; P = .008). No prozone effect was observed after dilution of discrepant samples. RSR-ELISA-IA-2A achieved specificity of 69% and sensitivity was lower (59%) compared with RIA (66%; P < .001). Negative or low positive patients and control samples in the RSR-ELISA-IA-2A increased after dilution. Eluates from DBS can readily be used to analyse GADA with the RSR-ELISA, even if low levels of autoantibodies were not detected. Some factor could disturb RSR-ELISA-IA-2A analyses.
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| 15. |
- Roeske-Nielsen, A, et al.
(författare)
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A variation in the cerebroside sulfotransferase gene is linked to exercise-modified insulin resistance and to type 2 diabetes.
- 2009
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Ingår i: Experimental diabetes research. - : Hindawi Limited. - 1687-5303 .- 1687-5214. ; 2009
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The glycosphingolipid beta-galactosylceramide-3-O-sulfate (sulfatide) is present in the secretory granules of the insulin producing beta-cells and may act as a molecular chaperone of insulin. The final step in sulfatide synthesis is performed by cerebroside sulfotransferase (CST) (EC 2.8.2.11). The aim of this study was to investigate whether two single nucleotide polymorphisms (SNP), rs2267161 located in an exon or rs42929 located in an intron, in the gene encoding CST are linked to type 2 diabetes (T2D). METHODS: As a population survey, 265 male and female patients suffering from T2D and 291 gender matched controls were examined. RESULTS: A higher proportion of T2D patients were heterozygous at SNP rs2267161 with both T (methionine) and C (valine) alleles present (49.8% versus 41.3%, P = .04). The calculated odd risk for T2D was 1.47 (1.01-2.15, P = .047). Among female controls, the homozygous CC individuals displayed lower insulin resistance measured by HOMA-IR (P = .05) than the C/T or TT persons; this was particularly prevalent in individuals who exercise (P = .03). CONCLUSION: Heterozygosity at SNP rs2267161 in the gene encoding the CST enzyme confers increased risk of T2D. Females with the CC allele showed lower insulin resistance.
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| 16. |
- Rutledge, Elizabeth A., et al.
(författare)
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Sequence Variation and Expression of the Gimap Gene Family in the BB Rat
- 2009
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303.
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Tidskriftsartikel (refereegranskat)abstract
- Positional cloning of lymphopenia (lyp) in the BB rat revealed a frameshift mutation in Gimap5, a member of at least seven related GTPase Immune Associated Protein genes located on rat chromosome 4q24. Our aim was to clone and sequence the cDNA of the BB diabetes prone (DP) and diabetes resistant (DR) alleles of all seven Gimap genes in the congenic DR.lyp rat line with 2 Mb of BB DP DNA introgressed onto the DR genetic background. All (100%) DR.(lyp/lyp) rats are lymphopenic and develop type 1 diabetes (T1D) by 84 days of age while DR.(+/+) rats remain T1D and lyp resistant. Among the seven Gimap genes, the Gimap5 frameshift mutation, a mutant allele that produces no protein, had the greatest impact on lymphopenia in the DR.(lyp/lyp) rat. Gimap4 and Gimap1 each had one amino acid substitution of unlikely significance for lymphopenia. Quantitative RT-PCR analysis showed a reduction in expression of all seven Gimap genes in DR.lyp/lyp spleen and mesenteric lymph nodes when compared to DR.+/+. Only four; Gimap1, Gimap4, Gimap5, and Gimap9 were reduced in thymus. Our data substantiates the Gimap5 frameshift mutation as the primary defect with only limited contributions to lymphopenia from the remaining Gimap genes. Copyright (C) 2009 Elizabeth A. Rutledge et al.
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| 17. |
- Sentinelli, Federica, et al.
(författare)
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Association of FTO polymorphisms with early age of obesity in obese Italian subjects
- 2012
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is recognized as a major health problem worldwide. Genetic factors play a major role in obesity, and genomewide association studies have provided evidence that several common variants within the fat mass- and obesity-associated (FTO) gene are significantly associated with obesity. Very limited data is available on FTO in the Italian population. Aims of our study are to investigate: (1) the association of FTO gene SNPs rs9939609 and rs9930506 with body mass index (BMI) and obesity-related parameters in a large cohort (n=752) of Italian obese subjects; (2) the association between the two FTO SNPs and age of onset of obesity. Our results demonstrate a strong association between FTO SNPs rs9939609 (P<0.043) and rs9930506 (P<0.029) with BMI in the Italian population. FTO rs9930506 was significantly associated with higher BMI in a G allele dose-dependent manner (BMI+1.4kg/m2per G allele). We also observed that the association with BMI of the two FTO variants varied with age, with the carriers of the risk alleles developing an increase in body weight earlier in life. In conclusion, our study further demonstrates a role of the genetic variability in FTO on BMI in a large Italian population. Copyright © 2012 Federica Sentinelli et al.
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| 18. |
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| 19. |
- Westermark, Gunilla, et al.
(författare)
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Transthyretin and Amyloid in the Islets of Langerhans in Type-2 Diabetes
- 2008
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Ingår i: EXPERIMENTAL DIABETES RESEARCH. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008:429274
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Tidskriftsartikel (refereegranskat)abstract
- Transthyretin (TTR) is a major amyloid fibril protein in certain systemic forms of amyloidosis. It is a plasma protein, mainly synthesized by the liver but expression occurs also at certain minor locations, including the endocrine cells in the islets of Langerhans. With the use of immunohistochemistry and in situ hybridization, we have studied the distribution of transthyretincontaining cells in islets of Langerhans in type-2 diabetic and nondiabetic individuals. TTR expression was particularly seen in alpha (glucagon) cells. Islets from type-2 diabetic patients had proportionally more transthyretin-reactive islet cells, including beta cells. A weak transthyretin immunoreaction in IAPP-derived amyloid occurred in some specimens. In seeding experiments in vitro, we found that TTR fibrils did not seed IAPP while IAPP fibrils seeded TTR. It is suggested that islet expression of transthyretin may be altered in type-2 diabetes.
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