| 1. |
- Bergman, Hilde-Marlene, et al.
(författare)
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Metabolite aberrations in early diabetes detected in rat kidney using mass spectrometry imaging
- 2019
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Ingår i: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 411:13, s. 2809-2816
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease is a serious complication of diabetes that can ultimately lead to end-stage renal disease. The pathogenesis of diabetic kidney disease is complex, and fundamental research is still required to provide a better understanding of the driving forces behind it. We report regional metabolic aberrations from an untargeted mass spectrometry imaging study of kidney tissue using an insulinopenic rat model of diabetes. Diabetes was induced by intravenous injection of streptozotocin, and kidneys were harvested 2weeks thereafter. Imaging was performed using nanospray desorption electrospray ionization connected to a high-mass-resolving mass spectrometer. No histopathological changes were observed in the kidney sections; however, mass spectrometry imaging revealed a significant increase in several 18-carbon unsaturated non-esterified fatty acid species and monoacylglycerols. Notably, these 18-carbon acyl chains were also constituents of several increased diacylglycerol species. In addition, a number of short- and long-chain acylcarnitines were found to be accumulated while several amino acids were depleted. This study presents unique regional metabolic data indicating a dysregulated energy metabolism in renal mitochondria as an early response to streptozotocin-induced type I diabetes.
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| 2. |
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| 3. |
- Lindfors, Lina, et al.
(författare)
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Is GPR146 really the receptor for proinsulin C-peptide?
- 2020
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 30:13
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Tidskriftsartikel (refereegranskat)abstract
- Proinsulin C-peptide has previously been proposed to interact with a G-protein coupled receptor (GPCR), specifically the orphan receptor GPR146. To investigate the potential of C-peptide in treating complications of diabetes, such as kidney damage, it is necessary to understand its mode of action. We used CHO-K1 cells expressing human GPR146 to study human and murine C-peptide in dynamic mass redistribution and GPCR beta-arrestin assays, as well as with fluorescence confocal microscopy. Neither assay revealed any significant intracellular response to C-peptide at concentrations of up to 33 mu M. We observed no internalisation of C-peptide by fluorescence microscopy. Our results do not support GPR146 as the receptor for C-peptide, but suggest that further investigations of the mode of action of C-peptide should be undertaken.
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| 4. |
- Lindfors, Lina
(författare)
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Molecular Imaging of Diabetic Kidney Tissue and Binding Studies of Proinsulin C-peptide
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetic kidney disease is a serious complication of diabetes with a complex and incompletely understood pathology. In this work, the molecular changes in diabetic rat kidneys at a very early disease stage were studied using nanospray desorption electrospray ionisation mass spectrometry imaging. Our results demonstrate how disease-relevant metabolites and lipids can be conveniently analysed on intact kidney tissue sections. A number of significantly increased metabolites were identified in the diabetic kidney, revealing disturbances in energy metabolism detectable before histological changes.Proinsulin C-peptide is produced in the pancreas along with insulin and has shown beneficial effects in diabetes, but its mode of action is not yet known. 125I radiolabelled C-peptide was used to study its tissue distribution in healthy and diabetic rats after intravenous injection. The majority of C-peptide accumulated in renal tissues, with lower levels in the diabetic animals, showing that there are significant changes in kidney – C-peptide interactions in early stage diabetes.The interactions of C-peptide with the orphan receptor GPR146, which has been proposed as its receptor, were also investigated using Chinese hamster ovary cells overexpressing human GPR146. Neither dynamic mass redistribution nor β-arrestin recruitment assays showed any significant response to human or murine C-peptides in the GPR146 overexpressing cells compared to controls. Fluorescence confocal microscopy revealed no surface binding or cellular uptake of C-peptides by GPR146 overexpressing cells compared to controls. These combined results refute the suggestion that GPR146 is the C-peptide receptor.To further probe the function of C-peptide, 15N-labelled residues were incorporated into the peptide in preparation for nanoscale secondary ion mass spectrometry imaging of cells and intact kidney tissue sections. A number of crosslinking C-peptides were also designed and synthesised for experiments aimed at identifying its binding target. These studies have not yet been completed. Finally, to investigate the structure-activity relationship of C-peptide, a library of modified pentapeptide analogues was created for medium-throughput testing in a cell assay.
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| 5. |
- Lundgren, Markus, et al.
(författare)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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