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  • 1.
    Boersma, Greta J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Johansson, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Heurling, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Wallenberg Centre for Molecular and Translational Medicine and the Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden.
    Skrtic, Stanko
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Panagiotou, Grigorios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical, Mölndal, Sweden.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical, Mölndal, Sweden.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study2018In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 50, no 8, p. 627-639Article in journal (Refereed)
    Abstract [en]

    We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

  • 2.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece.
    Alexandraki, Krystallenia I.
    Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece.
    Angelousi, Anna
    Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece.
    Chatzellis, Eleftherios
    Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece.
    Tsolakis, Apostolos V.
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Univ Hosp, CCK, Stockholm, Sweden.
    Karoumpalis, Ioannis
    G Gennimatas Gen Hosp, Dept Gastroenterol, Athens, Greece.
    Kolomodi, Denise
    Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece.
    Kassi, Evanthia
    Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece;Natl & Kapodistrian Nivers Athens, Med Sch, Dept Biol Chem, Athens, Greece.
    Kaltsas, Gregory
    Univ Athens, Laiko Hosp, Endocrine Oncol Unit, Dept Propauped Internal Med 1, Athens, Greece;Univ Warwick, Univ Hosp, Warwick Med Sch, Clin Sci Res Labs, Coventry, W Midlands, England;Coventry Univ, Fac Hlth & Life Sci, Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, England.
    Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1?2019In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 51, no 9, p. 580-585Article in journal (Refereed)
    Abstract [en]

    Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean +/- SD: 2 mm/year +/- 3.4 mm vs. 1.9 mm/year +/- 3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs.

  • 3.
    Delgado, Alberto Verdugo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Exome Sequencing and CNV Analysis on Chromosome 18 in Small Intestinal Neuroendocrine Tumors: Ruling Out a Suspect?2015In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 47, no 6, p. 452-455Article in journal (Refereed)
    Abstract [en]

    The genetic background in small intestinal neuroendocrine tumors is poorly understood, but several studies have revealed numerical imbalances. Loss of one copy of chromosome 18 is the most frequent genetic aberration in this tumor type, which indirectly suggests that a driver mutation may be present in the remaining allele. The aim of this study was to evaluate the mutation status on chromosome 18 in small intestinal neuroendocrine tumors. DNAs from 7 small intestinal neuroendocrine tumors were subjected to whole exome capture, followed by next generation sequencing and high resolution SNP array followed by copy number variation analysis. Exome capture sequencing generated an average coverage of 50.6-138.2. Only 19 genes were covered less than 8X. No tumor-specific somatic mutation was identified. Genomic profiling revealed loss of chromosome 18 in 5 out of 7 small intestinal neuroendocrine tumors and a number of other aberrancies. Loss of chromosome 18 is the most frequent genetic aberration in small intestinal neuroendocrine tumors, but no evidence for eventual mutations in the remaining allele. This suggests involvement of other mechanisms than point mutations in small intestinal neuroendocrine tumors tumorigenesis.

  • 4.
    Essand, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leja, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Öberg, Kjell E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oncolytic Viruses for the Treatment of Neuroendocrine Tumors2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 12, p. 877-883Article, review/survey (Refereed)
    Abstract [en]

    Oncolytic viruses are emerging as anticancer agents, and they have also shown great promise for use against neuroendocrine tumors. Many viruses have a natural tropism for replication in tumor cells. Others can be genetically engineered to selectively kill tumor cells. Viruses have some advantages as therapeutic agents over current cytotoxic drugs and small molecules. They replicate in tumor cells and thereby increase in number over time leading to increased dosage. They are immunogenic and can alter the immunosuppressive tumor microenvironment and activate immune effector cells. They have also been shown to be able to kill drug-resistant cancer stem cells. This article reviews the recent literature on oncolytic viruses used so far for neuroendocrine tumors and indicates important issues to focus on in the future.

  • 5.
    Johansson, T
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekeblad, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lack of Nuclear Expression of Hairy and Enhancer of Split-1 (HES1) in Pancreatic Endocrine Tumors2008In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 40, no 5, p. 354-359Article in journal (Refereed)
    Abstract [en]

    The Notch signaling cascade plays a vital role in the proliferation and differentiation of cells during pancreatic development. Cell line experiments have suggested the involvement of Notch signaling in pancreatic endocrine tumorigenesis. We investigated the expression of NOTCH1, HES1, HEY1 and ASCL1 in pancreatic endocrine tumors and compared the data to tumor phenotype including hormone production, heredity, and WHO classification. Real-time quantitative PCR and immunohistochemistry were performed on samples of 26 pancreatic endocrine tumors. For comparison, 10 specimens of macroscopically normal pancreas were analyzed using immunohistochemistry. The subcellular localization of proteins was determined. Neither hormone production, nor heredity, or WHO classification was found to be associated with the expression of these proteins. There were discrepancies between mRNA and protein expression levels. All tumors displayed ASCL1 immunoreactivity. HES1 immunoreactivity was lacking altogether in 46% of the tumors, and in the remaining lesions its expression was weak and confined to the cytoplasm. In the nontumorous pancreatic endocrine cells, weak nuclear expression of HES1 as well as of HEY1 and NOTCH1 was observed. There was a significant positive correlation between NOTCH1 and HES1 mRNA levels, but no indication that HES1 was inhibiting ASCL1 transcription was found. No nuclear expression of HES1 was found in the tumors. This lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas.

  • 6.
    Lindhe, Örjan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Mitotane Effects in a H295R Xenograft Model of Adjuvant Treatment of Adrenocortical Cancer2010In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 42, no 10, p. 725-730Article in journal (Refereed)
    Abstract [en]

    Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, o,p′-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. o,p′-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [11C]methionine (MET), [11C] metomidate (MTO), 2-deoxy-2-[18F]fluoro-d-glucose (FDG), and [18F]-l-tyrosine (FLT) in the aggregates were assessed ± drug treatment in vitro. Tumor growth was significantly inhibited when o,p′-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with o,p′-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 μM o,p′-DDD (p<0.01) in vitro. MeSO2-DDE (15 μM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with o,p′-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with o,p′-DDD. Further studies in humans are needed to investigate this.

  • 7.
    Lindholm, Daniel P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 12, p. 832-837Article, review/survey (Refereed)
    Abstract [en]

    Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.

  • 8. Lundgren, M
    et al.
    Burén, J
    Lindgren, P
    Myrnäs, T
    Ruge, T
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sex- and depot-specific lipolysis regulation in human adipocytes: interplay between adrenergic stimulation and glucocorticoids2008In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 40, no 12, p. 854-860Article in journal (Refereed)
    Abstract [en]

    The purpose of this investigation was to explore interactions between adrenergic stimulation, glucocorticoids, and insulin on the lipolytic rate in isolated human adipocytes from subcutaneous and omental fat depots, and to address possible sex differences. Fat biopsies were obtained from 48 nondiabetic subjects undergoing elective abdominal surgery. Lipolysis rate was measured as glycerol release from isolated cells and proteins involved in lipolysis regulation were assessed by immunoblots. Fasting blood samples were obtained and metabolic and inflammatory variables were analyzed. In women, the rate of 8-bromo-cAMP- and isoprenaline-stimulated lipolysis was approximately 2- and 1.5-fold higher, respectively, in subcutaneous compared to omental adipocytes, whereas there was no difference between the two depots in men. Dexamethasone treatment increased the ability of 8-bromo-cAMP to stimulate lipolysis in the subcutaneous depot in women, but had no consistent effects in fat cells from men. Protein kinase A, Perilipin A, and hormone sensitive lipase content in adipocytes was not affected by adipose depot, sex, or glucocorticoid treatment. In conclusion, catecholamine and glucocorticoid regulation of lipolysis in isolated human adipocytes differs between adipose tissue depots and also between sexes. These findings may be of relevance for the interaction between endogenous stress hormones and adipose tissue function in visceral adiposity and the metabolic syndrome.

  • 9. Lundgren, M
    et al.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    No in vitro effects of fatty acids on glucose uptake, lipolysis or insulin signaling in rat adipocytes.2004In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 36, no 4, p. 203-9Article in journal (Refereed)
    Abstract [en]

    Elevated plasma levels of free fatty acids (FFA) can produce insulin resistance in skeletal muscle tissue and liver and, together with alterations in beta-cell function, this has been referred to as lipotoxicity. This study explores the effects of FFAs on insulin action in rat adipocytes. Cells were incubated 4 or 24 h with or without an unsaturated FFA, oleate or a saturated FFA, palmitate (0.6 and 1.5 mM, respectively). After the culture period, cells were washed and insulin effects on glucose uptake and lipolysis as well as cellular content of insulin signaling proteins (IRS-1, PI3-kinase, PKB and phosphorylated PKB) and the insulin regulated glucose transporter GLUT4 were measured. No significant differences were found in basal or insulin-stimulated glucose uptake in FFA-treated cells compared to control cells, regardless of fatty acid concentration or incubation period. Moreover, there were no significant alterations in the expression of IRS-1, PI3-kinase, PKB and GLUT4 following FFA exposure. Insulin's ability to stimulate PKB phosphorylation was also left intact. Nor did we find any alterations following FFA exposure in basal or cAMP-stimulated lipolysis or in the ability of insulin to inhibit lipolysis. The results indicate that oleate or palmitate does not directly influence insulin action to stimulate glucose uptake and inhibit lipolysis in rat fat cells. Thus, lipotoxicity does not seem to occur in the fat tissue itself.

  • 10. Palming, J.
    et al.
    Jansson, P-A
    Renström, F.
    Johansson, A.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Karlsson, C.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Jan W.
    Hydrochlorothiazide Compared to Candesartan Treatment Increases Adipose Tissue Gene Expression and Circulating Levels of Serum Amyloid A in Hypertensive Patients2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 5, p. 319-324Article in journal (Refereed)
    Abstract [en]

    Treatment of hypertension with angiotensin receptor blockers has been shown to reduce the risk of developing type 2 diabetes in comparison to thiazide diuretics and beta adrenergic blockers. Therefore, we wanted to study the effect of antihypertensive drugs on adipose tissue with respect to insulin resistance. In the MEDICA (MEchanisms for the DIabetes preventing effects of CAndesartan) study, 22 hypertensive, nondiabetic patients with abdominal obesity (10 men, 12 women) were randomized into 12-week treatment periods with candesartan, hydrochlorothiazide, and placebo according to a 3-way cross-over design. Subcutaneous adipose tissue biopsies were taken after 8 weeks treatment to analyze gene expression, glucose uptake capacity, insulin-signaling, and adipocyte size. Adipose tissue gene expression of serum amyloid A (SAA) was higher after hydrochlorothiazide treatment compared to candesartan (p = 0.036), and this was in accordance with our previous finding on circulating SAA levels. Serum levels of E selectin were increased after hydrochlorothiazide compared to candesartan treatment (p = 0.002) and lower after candesartan compared to placebo (p = 0.002). In adipocytes, there were no significant differences between the treatments with respect to cell size, glucose uptake capacity, or insulin-signaling. In comparison to candesartan, hydrochlorothiazide raised the adipose tissue gene expression of SAA and the serum level of SAA as well as E selectin in hypertensive patients. Less adipose and systemic inflammation may be one explanation why candesartan is favorable in comparison to thiazide diuretics with respect to development of insulin resistance and type 2 diabetes.

  • 11. Renström, F
    et al.
    Burén, J
    Svensson, M K
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Factors in serum from type 2 diabetes patients can cause cellular insulin resistance2009In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 41, no 10, p. 767-772Article in journal (Refereed)
    Abstract [en]

    This pilot study was aimed to investigate whether there are humoral factors in serum from type 2 diabetic subjects that, in addition to glucose, insulin and free fatty acids are able to induce or contribute to peripheral insulin resistance with respect to glucose transport. Isolated subcutaneous adipocytes from 11 type 2 diabetic subjects and 10 nondiabetic controls were incubated for 24-h in medium supplemented with 25 % serum from a control or a type 2 diabetic donor, in the presence of a low (5 mM) or a high (15 mM) glucose concentration, respectively. After the incubation period glucose uptake capacity was assessed. Serum from type 2 diabetic donors, compared to serum from controls, significantly reduced the maximal insulin eff ect to stimulate glucose uptake (approximately 40 %, p < 0.05) in adipocytes from control subjects, independent of surrounding glucose concentrations. Glucose uptake capacity in adipocytes isolated from type 2 diabetic subjects was similar regardless of culture condition. No significant alterations were found in cellular content of key proteins in the insulin signaling cascade (insulin receptor substrate-1 and -2, and glucose transporter 4) that could explain the impaired insulin-stimulated glucose transport in control adipocytes incubated with serum from type 2 diabetic donors. The present findings indicate the presence of biomolecules in the circulation of type 2 diabetic subjects, apart from glucose, insulin, and free fatty acids with the ability to induce peripheral insulin resistance. This further implies that even though normoglycemia is achieved other circulating factors can still negatively affect insulin sensitivity in type 2 diabetic patients.

  • 12. Ross, I. L.
    et al.
    Levitt, N. S.
    Van der Walt, Jan-Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schatz, D. A.
    Johannsson, G.
    Haarburger, D. H.
    Pillay, T. S.
    Salivary Cortisol Day Curves in Addison's Disease in Patients on Hydrocortisone Replacement2013In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 45, no 1, p. 62-68Article in journal (Refereed)
    Abstract [en]

    Using salivary cortisol (SC) measurements, cortisol exposure in Addison's disease patients on hydrocortisone replacement was determined and compared with healthy controls. Cortisol pharmacokinetics was assessed in 31 patients with Addison's disease on replacement hydrocortisone doses ( median daily dose 20mg; range 5-50mg) and 30 healthy control subjects. Saliva samples (n=16) were collected between 08:00 and 00:00h in 1 day, using a passive drool technique. Cortisol exposure was evaluated by noncompartmental approach. In the patients, cortisol exposure was significantly higher than in controls: median inter-quartile range (IQR) peak cortisol (C-max ) 174.5 (59.3-837.0) vs. 6.50 (4.7-19.3) nmol/l, p=0.0001; area under the curve (AUC) 390.1 (177.1-928.9) vs. 21.4 (14.6-28.4) minutes*nmol/l, p=0.0001, trough cortisol level (C-min) 0.49 (0.49-0.96) vs. 0.49 (0.49-0.49) nmol/l, p=0.02, occurring at 480.0 (0.1- 660.0) vs. 405.0 (180.0-570.0) min, p=0.56. First peak cortisol was 174.5 (53.0-754.7) vs. 6.27 (3.90-8.47 ) nmol/l, p=0.0001 and second peak cortisol 18.90 (5.22-76.9) vs. 3.12 (1.76-4.79) nmol/l, p=0.0001. The time to first peak cortisol differed between the 2 groups, 30 (30-75) vs. 0.1 (0.1-30) minutes; p=0.0001. At doses studied, hydrocortisone replacement therapy results in cortisol pharmacokinetics being markedly different from endogenous cortisol profiles in healthy control subjects. Addison's disease patients had significantly higher SC levels compared to healthy control subjects.

  • 13.
    Sandberg, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pettersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Henriksnas, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The alpha(2)-Adrenoceptor Antagonist Yohimbine Normalizes Increased Islet Blood Flow in GK Rats: A Model of Type 2 Diabetes2013In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 45, no 3, p. 252-254Article in journal (Refereed)
    Abstract [en]

    Overexpression of alpha(2A)-adrenoceptors contributes to type 2 diabetes in GK rats. We aimed to investigate if alpha(2)-adrenoceptor inhibition affected islet blood flow in these rats. Anesthetized GK and Wistar-F rats were given the alpha(2)-adrenoceptor inhibitor yohimbine (2.5 mg/kg BW) intravenously. The GK rats had higher blood glucose and serum insulin concentrations than WF rats. Yohimbine affected neither of these values in WF rats, but decreased blood glucose and increased serum insulin concentrations in GK rats. Total pancreatic and islet blood flows, measured with microspheres, were increased in GK when compared to WF rats. Yohimbine affected none of the blood flow values in WF rats, whereas islet blood flow in GK rats was reduced to values similar to those seen in WF rats. Overexpression of alpha(2)-adrenoceptors may contribute to the increased islet blood flow seen in GK rats, and may be eligible for pharmacologic intervention.

  • 14. Schott, M
    et al.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Neuroendocrine neoplasms2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 12, p. 823-824Article in journal (Refereed)
  • 15. Sjöstrand, M
    et al.
    Jansson, P-A
    Palming, J
    de Schoolmeester, J
    Gill, D
    Rees, A
    Sjögren, L
    Persson, T
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Dept of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Repeated measurements of 11β-HSD-1 activity in subcutaneous adipose tissue from lean, abdominally obese, and type 2 diabetes subjects: no change following a mixed meal2010In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 42, no 11, p. 798-802Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to measure 11β-HSD-1 activity in subcutaneous adipose tissue by an ex vivo method in three subgroups; lean, obese, and type 2 diabetes subjects, both in the fasting state and after a mixed meal and to determine the variability and reproducibility of this method. Eighteen subjects were investigated; 6 lean, 6 abdominally obese, and 6 type 2 diabetes subjects (BMI 22±1, 30±3 and 31±3 kg/m2, respectively). Needle biopsies were taken repeatedly and an index of 11β-HSD-1 activity was measured as percent conversion of 3H-cortisone to 3H-cortisol/100 mg tissue. For two separate biopsies taken in the fasting state on the same day, the within subjects CV was 16% and the between CV was 36% for 11β-HSD-1 activity for all subjects. For two biopsies taken in the fasting state at two different days, the total within subjects CV was 38% and the between subjects CV was 46%. Lean subjects had lower 11β-HSD-1 activity (4.8±1.5% conversion of 3H-cortisone to 3H-cortisol/100 mg tissue) than both obese (14.4±1.6% conversion, p<0.01) and type 2 diabetes subjects (11.7±1.9% conversion, p<0.05) in the fasting state. There was no effect of a meal on 11β-HSD-1 activity in any of the three groups. The conclusions from this study are: 1) the variation coefficient for the ex vivo adipose tissue 11β-HSD-1 activity method was ∼25% for repeat measures within subjects; 2) food intake had no major impact on enzyme activity; and 3) 11β-HSD-1 activity in subcutaneous adipose tissue was significantly increased in obese subjects with or without T2DM compared to lean subjects without diabetes.

  • 16. Svensson, M K
    et al.
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Change in the amount of body fat and IL-6 levels is related to altered insulin sensitivity in type 1 diabetes patients with or without diabetic nephropathy2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 3, p. 209-215Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) is found early-on in renal disease. The aim of this study was to prospectively evaluate if a change in glomerular filtration rate (GFR) or in endocrine and inflammatory factors over time alters insulin sensitivity in patients with type 1 diabetes (T1D) or without diabetic nephropathy (DN) at baseline. 20 T1D with (DN+, n=12) or without DN (DN–, n=8) were re-examined after 5.0±0.4 years. GFR was determined by 51Cr-EDTA clearance. Insulin sensitivity was assessed by hyperinsulinemic (56 mU/m2/min), euglycemic clamp (M-value at steady state during clamp) and calculated per lean body mass. Body composition was determined by bioimpedance. No association was found between change in GFR and change in M-value over time. Instead, change in M-value was associated to change in fat mass (%) and change in IL-6 levels in all subjects taken together (r=−0.55, p=0.012 and r=−0.62, p=0.006). These association were verified in the multivariate regression analyses. Findings were similar in DN − and DN +, respectively, but the change in IL-6 was only significantly associated with altered M-value in DN+ subjects. This prospective study indicates that change in amount body fat and levels of inflammatory cytokines, such as IL-6, contribute to change in insulin resistance over time in type 1 diabetes patients with and without diabetic nephropathy.

  • 17. Svensson, Maria
    et al.
    Eriksson, Jan W
    Department of Medicine, Umeå University Hospital, Sweden.
    No direct link between albumin excretion rate and insulin resistance: A study in type 1 diabetes patients with mild nephropathy2002In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 34, no 5, p. 254-259Article in journal (Refereed)
    Abstract [en]

    Aims:

    Albuminuria is thought to be associated with insulin resistance in patients with type 1 and type 2 diabetes as well as in non-diabetic subjects. The aim of this study was to find out about any direct correlation between the albumin excretion rate (AER) and insulin resistance; this was investigated in patients with type 1 diabetes.

    Methods:

    Euglycemic hyperinsulinemic clamps were performed in 18 patients with type 1 diabetes and incipient nephropathy - elevated albumin excretion rate (AER > 20 µg/min) but normal glomerular filtration rate (GFR) (81 - 135 ml/min/1.73 m2).

    Results:

    AER, determined as mean of two overnight urine collections, was 137 ± 157 (mean ± S.D.) µg/min (range 24 - 447). Insulin sensitivity, expressed as the M-value, was 6.8 ± 2.9 mg/kg/min, insulin sensitivity index (ISI = 100 × M/plasma insulin) 7.9 ± 3.4 and insulin clearance (MCRins) 17.0 ± 4.0 ml/kg/min. Simple regression analyses showed no direct association between AER and M, ISI or MCRins. GFR was not associated with M, ISI or MCRins in this group, either. AER was, however, positively associated with poor glucose control (high HbAlc) and tobacco use.

    Conclusions:

    These results suggest that the degree of albuminuria is not directly linked to insulin resistance. This was shown in type 1 diabetics, but could possibly be applicable in other subjects as well.

  • 18.
    Wilander, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Boquist, L.
    Streptozotocin-diabetes in the Chinese hamster. Blood glucose and structural changes during the first 24 hours1972In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 4, no 6, p. 426-433Article in journal (Refereed)
    Abstract [en]

    Intraperitoneal administration of 200 mg/kg body weight of streptozotocin to non-diabetic adult Chinese hamsters, evoked a triphasic blood glucose response. There was a hyperglycemic peak after 3 hours and a hypoglycemic phase with a minimum at 6 hours, after which time there was a rather rapid return to hyperglycemia. Light and electron microscopic examinations during the first 24 hours after the injection of streptozotocin showed pyknosis, vacuolization, marked degeneration and necrosis of the β-cells. Degenerative and necrotic changes were also seen in a few α2-cells. The results denote that in the Chinese hamster streptozotocin has an early and direct cytotoxic action on the β-cells and probably also on a few α2-cells.

  • 19. Yu, Z W
    et al.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    The upregulating effect of insulin and vanadate on cell surface insulin receptors in rat adipocytes is modulated by glucose and energy availability.2000In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 32, no 8, p. 310-5Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to further characterize the rapid effects of insulin and the tyrosine phosphatase inhibitor vanadate to amplify cell surface insulin binding capacity in isolated rat adipocytes. The effect of 20 min insulin treatment (1000 microU/ml) was 2- to 3-fold (p < 0.01) when cells were treated in medium containing 5.6 mM D-glucose, but it was totally absent in glucose-free medium. Other carbon energy sources, such as fructose and pyruvate, could only partly substitute for D-glucose, with an approximately 1.5-fold insulin effect. Moreover, inhibiting transmembrane glucose transport with cytochalasin B completely blocked the effect of insulin to enhance cell surface binding. The effect of vanadate was only partly glucose-dependent, since a submaximal effect (1.5- to 2-fold, p<0.05) was seen also in the absence of glucose. The tyrosine kinase inhibitor genistein markedly blunted the effect of vanadate (from 3- to 4-fold to approximately 2-fold, p < 0.05) also indicating the importance of tyrosine phosphorylation-related mechanisms in the upregulation of cell surface insulin binding. Glycosylation of insulin receptors as a mechanism for this effect appears unlikely since neither the effect of insulin nor that of vanadate was altered by the glycosylation inhibitor tunicamycin. The time course for the insulin effect displayed a long duration (at least 6 h), suggesting a maintenance role of insulin keeping its receptors accessible for ligand binding at the cell surface. In conclusion, the effect of insulin and vanadate to upregulate cell-surface insulin receptors is energy-dependent and to some extent specifically glucose-dependent.

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