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  • 1. Burén, Jonas
    et al.
    Eriksson, Jan W
    Is insulin resistance caused by defects in insulin's target cells or by a stressed mind?2005In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 21, no 6, p. 487-94Article in journal (Refereed)
    Abstract [en]

    The importance of understanding insulin action is emphasized by the increasing prevalence of insulin resistance in various populations and by the fact that it plays an important pathophysiological role in many common disorders, for example, diabetes, obesity, hypertension and dyslipidemia. The primary factors responsible for the development of insulin resistance are so far unknown, although both genetic and environmental factors are involved. The genetic defects responsible for the common forms of insulin resistance, for example, in type 2 diabetes, are largely unidentified. Some studies from our group as well as by other investigators suggest that cellular insulin resistance is reversible and that it may be secondary to factors in the in vivo environment. These may include insulin-antagonistic action of hormones like catecholamines, glucocorticoids, sex steroids and adipokines as well as dysregulation of autonomic nervous activity and they could contribute to the early development of insulin resistance. Some of these factors can directly impair glucose uptake capacity and this might be due to alterations in key proteins involved in insulin's intracellular signaling pathways. This article briefly summarizes proposed mechanisms behind cellular and whole-body insulin resistance. In particular, we question the role of intrinsic defects in insulin's target cells as primary mechanisms in the development of insulin resistance in type 2 diabetes and we suggest that metabolic and neurohormonal factors instead are the main culprits.

  • 2.
    Christensen, Michael
    et al.
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Schiffer, Tomas A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Håkan
    Linkoping Univ, Dept Radiol Norrkoping, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Krag, Sören Palmelund
    Aarhus Univ Hosp, Dept Pathol, Aarhus, Denmark.
    Nörregaard, Rikke
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-22019In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 35, no 2, article id e3091Article in journal (Refereed)
    Abstract [en]

    Background: The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis.

    Methods: Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg(-1)) and when stable started on metformin treatment (250 mg kg(-1)) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance.

    Results: Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats.

    Conclusions: Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.

  • 3.
    Coppieters, Ken T.
    et al.
    La Jolla Inst Allergy & Immunol, Type Diabet Ctr 1, La Jolla, CA 92037 USA.
    Wiberg, Anna
    La Jolla Inst Allergy & Immunol, Type Diabet Ctr 1, La Jolla, CA 92037 USA.
    Amirian, Natalie
    La Jolla Inst Allergy & Immunol, Type Diabet Ctr 1, La Jolla, CA 92037 USA.
    Kay, Thomas W.
    St Vincents Inst, Dept Immunol & Diabet, Melbourne, Vic 3065, Australia.
    von Herrath, Matthias G.
    La Jolla Inst Allergy & Immunol, Type Diabet Ctr 1, La Jolla, CA 92037 USA.
    Persistent glucose transporter expression on pancreatic beta cells from longstanding type 1 diabetic individuals2011In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, no 8, p. 746-754Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent reports have established the notion that many patients with longstanding type 1 diabetes (T1D) possess a remnant population of insulin-producing beta cells. It remains questionable, however, whether these surviving cells can physiologically sense and respond to glucose stimuli.

    METHODS: Frozen pancreatic sections from non-diabetic donors (n=8), type 2 diabetic patients (n=4), islet autoantibody-positive non-diabetic patients (n=3), type 1 diabetic patients (n=10) and one case of gestational diabetes were obtained via the network for Pancreatic Organ Donors. All longstanding T1D samples were selected based on the detection of insulin-producing beta cells in the pancreas by immunohistochemistry. RNA was isolated from all sections followed by cDNA preparation and quantitative real-time polymerase chain reaction for insulin, glucose transporter 1 (GLUT1), GLUT2 and GLUT3. Finally, immunofluorescent staining was performed on consecutive sections for all four of these markers and a comparison was made between the expression of GLUT2 in humans versus NOD mice.

    RESULTS: In contrast to islets from the most widely used T1D model, the NOD mouse, human islets predominantly express GLUT1 and, to a much lesser extent, GLUT3 on their surface instead of GLUT2. Relative expression levels of these receptors do not significantly change in the context of the various (pre-)diabetic conditions studied. Moreover, in both species preservation of GLUT expression was observed even under conditions of substantial leucocyte infiltration or decades of T1D duration.

    CONCLUSIONS: These data suggest that despite being subjected to multiple years of physiological stress, the remaining beta-cell population in longstanding T1D patients retains a capacity to sense glucose via its GLUTs.

  • 4.
    Edlund, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The roles of NADPH-oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 5, p. 349-356Article in journal (Refereed)
    Abstract [en]

    Background

    Sustained hyperglycaemia induces increased renal oxygen consumption resulting in reduced oxygen availability in the diabetic kidney. We investigated the roles of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and the neuronal nitric oxide synthase (nNOS) for the increased oxygen consumption in streptozotocin-diabetic rats.

    Methods

    Oxygen consumption was measured in isolated proximal tubular cells (PTC) from streptozotocin-induced diabetic rats (n = 7-9 per group) with and without chronic treatment with apocynin, a NADPH-oxidase inhibitor, or S-methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, or a combination of the two and the results were compared to normoglycaemic controls (n = 10). Oxidative stress was estimated from thiobarbituric acid reactive substances and protein expression measured by Western blot.

    Results

    Proximal tubular cells from untreated diabetic rats had increased oxygen consumption compared to controls (40.6 +/- 7.9 versus 10.9 +/- 2.0 nmol/mg protein/min). All treatments reduced the diabetes-induced increase in oxygen consumption (apocynin 10.5 +/- 1.7, SMTC 19.7 +/- 3.0 and apocynin +/- SMTC 21.6 +/- 3.6 nmol/mg protein/min). Neither apocynin nor SMTC had any effect on the oxygen consumption in cells pre-incubated with ouabain, an inhibitor of active electrolyte transport. Oxidative stress was elevated in the diabetic kidney and inhibited by all treatments. The increased oxygen consumption by diabetic proximal tubular cells correlated with increased protein expressions of p47phox and nNOS and the treatments prevented these increases.

    Conclusions

    Diabetes induces oxidative stress, which increases oxygen consumption in proximal tubular cells. Inhibition of either NADPH-oxidase or nNOS prevented the increased oxygen consumption. The effect of blocking both these enzymes was less than additive suggesting overlapping pathways which warrant further studies.

  • 5.
    Julin, Bettina
    et al.
    Ivbar Inst, Stockholm, Sweden.
    Willers, Carl
    Ivbar Inst, Stockholm, Sweden; Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Lindgren, Peter
    Karolinska Inst, Med Management Ctr, Stockholm, Sweden; Swedish Inst Hlth Econ, Lund, Sweden.
    Muth, Karin Looström
    Alingsås Hosp, Dept Internal Med, Alingsås, Sweden.
    Svensson, Ann-Marie
    Ctr Registers, Natl Diabet Register, Gothenburg, Sweden.
    Lilja, Mikael
    Umeå Univ, Dept Publ Hlth & Clin Med, Unit Res Educ & Dev Östersund, Umeå, Sweden.
    Dahlström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Association between sociodemographic determinants and health outcomes in individuals with type 2 diabetes in Sweden2018In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 34, no 4, article id e2984Article in journal (Refereed)
    Abstract [en]

    Background: Concurrent multifactorial treatment is needed to reduce consequent risks of diabetes, yet most studies investigating the relationship between sociodemographic factors and health outcomes have focused on only one risk factor at a time. Swedish health care is mainly tax‐funded, thus providing an environment that should facilitate equal health outcomes in patients, independent of background, socioeconomic status, or health profile. This study aimed at investigating the association between several sociodemographic factors and diabetes‐related health outcomes represented by HbA1c, systolic blood pressure, low‐density lipoprotein cholesterol, predicted 5‐year risk of cardiovascular disease, and statin use.

    Methods: This large retrospective registry study was based on patient‐level data from individuals diagnosed with type 2 diabetes during 2010 to 2011 (n = 416,228) in any of 7 Swedish regions (~65% of the Swedish population). Health equity in diabetes care analysed through multivariate regression analyses on intermediary outcomes (HbA1c, systolic blood pressure, and low‐density lipoprotein), predicted 5‐year risk of cardiovascular disease and process (i.e., statin use) after 1‐year follow‐up, adjusting for several sociodemographic factors.

    Results: We observed differences in intermediary risk measures, predicted 5‐year risk of cardiovascular disease, and process dependent on place of birth, sex, age, education, and social setting, despite Sweden's articulated vision of equal health care.

    Conclusions: Diabetes patients' health was associated with sociodemographic prerequisites. Furthermore, in addition to demographics (age and sex) and disease history, educational level, marital status, and region of birth are important factors to consider when benchmarking health outcomes, e.g., average HbA1c level, and evaluating the level of health equity between organizational units or between different administrative regions.

  • 6. Lindahl, Emma
    et al.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Müller, Patrick
    El Agha, Eli
    Friederich, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Dahlman-Wright, Karin
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Jörnvall, Hans
    Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells2011In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, no 7, p. 697-704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.

  • 7. Loseth, Sissel
    et al.
    Mellgren, Svein I.
    Jorde, Rolf
    Lindal, Sigurd
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 2, p. 100-106Article in journal (Refereed)
    Abstract [en]

    Background To evaluate possible differences in distal polyneuropathy (PN) characteristics and degree of abnormalities for various small and large fibre parameters in diabetes type 1 (DM1) and type 2 (DM2). Methods Sixty-six DM1 and 57 DM2 patients with or without PN symptoms were included. Nerve conduction studies (NCS), quantitative sensory testing (QST) and quantification of intraepidermal nerve fibres (IENFs) were performed. Z-scores were calculated from reference materials. Results In both groups, 42% had abnormal NCS classification, 42% (DM1) and 39% (DM2) abnormal QST, as well as 40% (DM1) and 32% (DM2) abnormal IENF density. Seventy percent (DM1) and 65% (DM2) had one of the three tests abnormal (differences not significant). Correlations were found between most Z-score parameters and disease duration and HbAlc in DM1, but fewer in DM2. In multivariate analysis, some NCS and QST Z-scores were more abnormal in DM2. Symptom scoring correlated better with NCS and QST parameters in DM1. Conclusions The differences could be referred to disease duration, glycaemic control and possibly patient age. The various parameters from NCS, QST and IENF analysis contribute differently in the assessment of polyneuropathy. Copyright (C) 2009 John Wiley & Sons, Ltd.

  • 8.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lai, En Yin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    C-peptide constricts pancreatic islet arterioles in diabetic, but not normoglycaemic mice2008In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 24, no 2, p. 165-168Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pancreatic islet blood flow is regulated separately from that of the exocrine pancreas, and a consistent finding during impaired glucose tolerance is an increased blood perfusion. The aim of the present study was to investigate whether C-peptide affects pancreatic islet arterioles in normal and diabetic mice.

    MATERIALS AND METHODS: Control and diabetic C57-Bl mice were studied after 2 weeks of alloxan-induced diabetes. Islet arterioles were dissected and microperfused with Dulbecco's modified Eagle medium (DMEM) solution. The effect of luminal application of mouse C-peptide was investigated.

    RESULTS: C-peptide reduced the diameter of islet arterioles from diabetic mice (-10+/-4%, P<0.05) compared to base-line values, whilst arterioles from normoglycaemic animals did not respond to C-peptide (P=0.2).

    CONCLUSION: These findings suggest a role for C-peptide in the regulation of islet blood flow, especially during conditions with impaired glucose tolerance.

  • 9.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Moe, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats2007In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 23, no 5, p. 400-405Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Initially, diabetes is commonly associated with an increased glomerular filtration rate (GFR), a potential mechanism involved in the progression of diabetic nephropathy. Several studies have reported reno-protective effects of C-peptide. C-peptide reduces diabetes-induced hyperfiltration, as well as renal hypertrophy and albuminuria. In order to gain further understanding of these effects, it is very important to localize the active sites within the C-peptide molecule. This study was designed to elucidate the effects of the C-peptide fragment EVARQ on kidney function, blood pressure and blood glucose levels in diabetic rats in vivo.

    METHODS

    The study was performed on adult inactin-anaesthetized male Sprague-Dawley rats. Two weeks prior to the experiment, diabetes was induced by a single intravenous injection of streptozotocin (55 mg/kg BW). After recovery and recording of baseline values, vehicle, C-peptide (50 pmol . kg BW(-1).h(-1)) or EVARQ (500 pmol.kg BW(-1).h(-1)) was continuously administered for a total of 100 min.

    RESULTS

    Before substance administration, all diabetic groups displayed a pronounced hyperfiltration as compared to the control rats. Continuous administration of both C-peptide and EVARQ reduced the diabetes-induced hyperfiltration within an hour. Furthermore, blood pressure was only reduced in diabetic rats that were given C-peptide, whereas the blood glucose decreased in the diabetic groups that were given either C-peptide or EVARQ.

    CONCLUSIONS

    The present study shows that administration of the C-peptide fragment EVARQ has similar effects on GFR and blood glucose levels as the intact C-peptide molecule, suggesting at least one active site within this region.

  • 10.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shimada, Kohei
    Ishii, Tatsuya
    Furuya, Daniela Tomie
    Kamikawa, Akihiro
    Kimura, Kazuhiro
    Proinsulin C-peptide prevents type-1 diabetes-induced decrease of renal Na(+)-K(+)-ATPase alpha1-subunit in rats2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 3, p. 193-199Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: C-peptide reduces renal damage in diabetic patients and experimental animal models. In vitro studies suggest that the renal effects of C-peptide may, in part, be explained by stimulation of Na(+)/K(+)-ATPase activity. However, the responses of Na(+)/K(+)-ATPase expression in the kidney of diabetic animals to C-peptide administration remain unclear. The aim of this study was to clarify the responses.

    METHODS: Type 1 diabetic rats were produced by injecting streptozotocin (STZ), and some of the rats were treated with either C-peptide or insulin by the aid of an osmotic pump for 1 week. The mRNA expression and immunohistochemical localization of Na(+)/K(+)-ATPase alpha1-, alpha2- and beta3-subunits were investigated in the kidney of these rats.

    RESULTS: Na(+)/K(+)-ATPase alpha1-subunit was abundantly expressed in the medullary collecting ducts of control animals, but the expression was markedly decreased in the diabetic state with concomitant decrease in its mRNA expression. Similar decreases were observed in the insulin-treated diabetic rats, whereas in the C-peptide-treated diabetic rats, there was no reduction in the alpha1-expression. The beta3-subunit was expressed in podocytes and parietal cells in the glomeruli, vascular endothelial cells, and cortical collecting ducts, but lesser signals were observed in the proximal and distal tubules. However, the beta3-subunit did not appear to be affected by the diabetic state.

    CONCLUSIONS: Diabetes selectively reduced Na(+)/K(+)-ATPase alpha1-subunit expression and abundance. Chronic administration of C-peptide prevented this decrease. This implies a role for C-peptide in the long-term regulation of Na(+)/K(+)-ATPase function.

  • 11.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ortsäter, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocin-diabetic rat model2004In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 20, no 6, p. 452-459Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The animal model with streptozotocin (STZ)-induced diabetes mellitus is associated with progressive renal disturbances. The aim of this study was to differentiate between toxic effects of STZ and the effect of hyperglycemia. Previous studies have been limited to investigating the influence of STZ on glomerular filtration rate (GFR), albuminuria and renal morphology. The present study presents a new approach when transplanting beta-cells to cure the STZ-treated animals and extends the evaluation to include both renal function and oxygen metabolism.

    METHODS:

    Animals were allocated to three groups: control animals, STZ-diabetic animals and animals rendered diabetic with an injection of STZ, followed by immediate syngeneic transplantation of approximately 1000 pancreatic islets into the splenic parenchyma. This latter procedure reversed the hyperglycemia induced by STZ. Renal function was evaluated from GFR and urinary albumin and protein leakage, while regional renal blood flow was determined using a laser-Doppler technique and oxygen tension measured with Clark-type electrodes.

    RESULTS:

    In diabetic animals, GFR increased, renal oxygen tension decreased and renal hypertrophy occurred, along with urinary leakage of protein, including albumin. Early transplantation of pancreatic islets to STZ-treated animals prevented the development of all these changes, except for proteinuria. However, an analysis of urinary protein content revealed that albuminuria was preventable by islet transplantation.

    CONCLUSIONS:

    We conclude that the urinary protein leakage in this animal model is at least partly due to direct toxic effects of STZ, whereas the other renal changes investigated in this study are due to the long-term diabetic condition.

  • 12.
    Sundsten, Tea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ostenson, Claes-Göran
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Serum protein patterns in newly diagnosed type 2 diabetes mellitus--influence of diabetic environment and family history of diabetes.2008In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 24, no 2, p. 148-154Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Individuals with normal glucose tolerance (NGT) and type 2 diabetes mellitus (T2DM) represent heterogeneous groups with differences in beta-cell function and genetic background. The aim of the present study was to compare serum protein profiles of NGT and T2DM individuals and determine the influence of the genetic background versus diabetic environment on differentially displayed proteins. METHODS: Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to compare serum protein profiles of NGT persons and T2DM patients. All participants were from the Stockholm Diabetes Prevention Program (SDPP) cohort. They were selected to have high or low beta-cell function (HOMA-beta) and family history of type 2 diabetes (FHD) or not. RESULTS: Eight proteins were found to be elevated and five lowered (p<0.05) in serum of T2DM patients. In a second comparison, the NGT and T2DM groups were divided into persons with FHD and low HOMA-beta and those without FHD and high HOMA-beta. Three proteins were rediscovered and interpreted to be different due to genetic background. Two of these were identified as apolipoprotein C3 (apoC3) and albumin. Ten proteins were interpreted to be not related to FHD, and one of these was identified as transthyretin. CONCLUSIONS: Using the SELDI-technique, serum protein profiles of NGT and T2DM persons with differences in beta-cell function and FHD were compared. The diabetic environment had a major influence on most of these proteins, while FHD was an important factor for apoC3 and albumin.

  • 13. Svensson, M K
    et al.
    Tyrberg, M
    Nyström, L
    Arnqvist, H J
    Bolinder, J
    Östman, J
    Gudbjörnsdottir, S
    Landin-Olsson, M
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    The risk for diabetic nephropathy is low in young adults in a 17-year follow-up from the Diabetes Incidence Study in Sweden (DISS). Older age and higher BMI at diabetes onset can be important risk factors.2015In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 31, no 2, p. 138-146Article in journal (Refereed)
    Abstract [en]

    AIMS: The main objective of this study was to estimate the occurrence of diabetic nephropathy in a population-based cohort of patients diagnosed with diabetes as young adults (15-34 years).

    METHODS: All 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19 years after diagnosis, and 468 (58%) participated. Analysis of islet antibodies was used to classify type of diabetes.

    RESULTS: After median 17 years of diabetes, 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with diabetic nephropathy. Ninety-one percent had microalbuminuria and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1 kg/m(2) ), a near-significant predictor of development of diabetic nephropathy. Age at onset of diabetes (p = 0.041), BMI (p = 0.012) and HbA1c (p < 0.001) were significant predictors of developing diabetic nephropathy between 9 and 17 years of diabetes. At 17 years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1 mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.05 1.12 per 1 mmHg increase) were associated with DN.

    CONCLUSIONS: Patients with T2DM diagnosed as young adults seem to have an increased risk to develop diabetic nephropathy compared with those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers for development of diabetic nephropathy. In addition, poor glycaemic control but not systolic blood pressure at 9 years of follow-up was a risk marker for later development of diabetic nephropathy. Copyright © 2014 John Wiley & Sons, Ltd.

  • 14. Svensson, Maria
    et al.
    Eriksson, Jan W
    Insulin resistance in diabetic nephropathy - cause or consequence?2006In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 22, no 5, p. 401-410Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) is associated with multiple risk factors for cardiovascular disease. Many studies have shown that IR is present in chronic renal failure (CRF), and recent evidence suggests that IR can also occur in the early stages of renal disease. Patients with diabetic nephropathy (DN) have an increase in cardiovascular mortality, and since IR may be a contributing factor, this emphasizes the importance of a detailed understanding of the mechanisms linking IR and renal dysfunction at different stages of DN. IR can be detected early on in DN, e.g. at the stage of microalbuminuria (MA) and this could indicate a common genetic trait for IR and DN. As DN progresses further, IR is aggravated and it may, in addition to other factors, possibly accelerate the decline in renal function toward end-stage renal disease (ESRD). Several potentially modifiable mechanisms including circulating hormones, neuroendocrine pathways and chronic inflammation, are said to contribute to the worsening of IR. In ESRD, uremic toxins are of major importance. In this review article, we address the association between different stages of DN and IR and attempt to summarize major findings on potential mechanisms linking DN and IR. We conclude that IR is a consequence, and potentially also a cause of DN. In addition, there are probably genetic and environmental background factors that predispose to both IR and DN.

  • 15.
    Tian, Geng
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Binzhou Med Univ, Yantai, Peoples R China..
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Prolonged exposure to palmitate deteriorates glucose-induced cAMP generation and pulsatile insulin secretion2015In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 31, p. 9-10Article in journal (Other academic)
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