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Lau, Joey
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Publications (10 of 36) Show all publications
Ullsten, S., Lau, J. & Carlsson, P.-O. (2019). Decreased beta-Cell Proliferation and Vascular Density in a Subpopulation of Low-Oxygenated Male Rat Islets. Journal of the Endocrine Society, 3(8), 1608-1616
Open this publication in new window or tab >>Decreased beta-Cell Proliferation and Vascular Density in a Subpopulation of Low-Oxygenated Male Rat Islets
2019 (English)In: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 3, no 8, p. 1608-1616Article in journal (Refereed) Published
Abstract [en]

Low-oxygenated and dormant islets with a capacity to become activated when neededmay play a crucial role in the complex machinery behind glucose homeostasis. We hypothesized that low-oxygenated islets, when not functionally challenged, do not rapidly cycle between activation and inactivation but are a stable population that remain low-oxygenated. As this was confirmed, we aimed to characterize these islets with regard to cell composition, vascular density, and endocrine cell proliferation. The 2-nitroimidazole low-oxygenation marker pimonidazole was administered as a single or repeated dose to Wistar Furth rats. The stability of oxygen status of islets was evaluated by immunohistochemistry as the number of islets with incorporated pimonidazole adducts after one or repeated pimonidazole injections. Adjacent sections were evaluated for islet cell composition, vascular density, and endocrine cell proliferation. Single and repeated pimonidazole injections over an 8-hour period yielded accumulation of pimonidazole adducts in the same islets. An average of 30% of all islets was in all cases positively stained for pimonidazole adducts. These islets showed a similar endocrine cell composition as other islets but had lower vascular density and beta-cell proliferation. In conclusion, low-oxygenated islets were found to be a stable subpopulation of islets for at least 8 hours. Although they have previously been observed to be less functionally active, their islet cell composition was similar to that of other islets. Consistent with their lower oxygenation, they had fewer blood vessels than other islets. Notably, beta-cell regeneration preferentially occurred in better-oxygenated islets.

Place, publisher, year, edition, pages
Endocrine Society, 2019
Keywords
islet vasculature, pancreatic islets, heterogeneity, beta-cell proliferation
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-330804 (URN)10.1210/js.2019-00101 (DOI)000484384400015 ()31404404 (PubMedID)
Funder
Swedish Research Council, 55X-15043Swedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenNovo Nordisk
Note

Title in thesis list of papers: Decreased beta cell proliferation and vascular density in a subpopulation of low-oxygenated rat islets

Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2019-10-17Bibliographically approved
Pereira, M. J., Lundkvist, P., Kamble, P. G., Lau, J., Martins, J. G., Sjostrom, C. D., . . . Eriksson, J. W. (2018). A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss. Diabetes Therapy, 9(4), 1511-1532
Open this publication in new window or tab >>A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss
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2018 (English)In: Diabetes Therapy, ISSN 1869-6953, E-ISSN 1869-6961, Vol. 9, no 4, p. 1511-1532Article in journal (Refereed) Published
Abstract [en]

The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes. In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m(2)] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation. Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 mu mol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW. Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation. AstraZeneca.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2018
Keywords
Dapagliflozin, Exenatide, Lipid metabolism, Obesity, Single-nucleotide polymorphism, Weight loss
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-362039 (URN)10.1007/s13300-018-0449-6 (DOI)000440115700010 ()29949016 (PubMedID)
Funder
AstraZeneca
Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12Bibliographically approved
Boersma, G. J., Johansson, E., Pereira, M. J., Heurling, K., Skrtic, S., Lau, J., . . . Eriksson, J. (2018). 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 Study. Hormone and Metabolic Research, 50(8), 627-639
Open this publication in new window or tab >>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 Study
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2018 (English)In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 50, no 8, p. 627-639Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Georg Thieme Verlag KG, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-356788 (URN)10.1055/a-0643-4739 (DOI)000440872200007 ()30001566 (PubMedID)
Funder
AstraZenecaEXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes AssociationSwedish Research CouncilErnfors Foundation
Available from: 2018-08-07 Created: 2018-08-07 Last updated: 2018-11-08Bibliographically approved
Monazzam, A., Lau, J., Velikyan, I., Li, S.-C., Razmara, M., Rosenström, U., . . . Skogseid, B. (2018). Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET. Scientific Reports, 8, Article ID 748.
Open this publication in new window or tab >>Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 748Article in journal (Refereed) Published
Abstract [en]

Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-342327 (URN)10.1038/s41598-017-18855-0 (DOI)000422637200007 ()29335487 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-28Bibliographically approved
Boersma, G. J., Heurling, K., Pereira, M. J., Johansson, E., Lubberink, M., Lau Börjesson, J., . . . Eriksson, J. W. (2017). Glucose uptake in skeletal muscle, brain and visceral adipose tissue assessed with PET/MR strongly predicts whole body glucose uptake during hyperinsulinaemia. Paper presented at 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL. Diabetologia, 60, S80-S80
Open this publication in new window or tab >>Glucose uptake in skeletal muscle, brain and visceral adipose tissue assessed with PET/MR strongly predicts whole body glucose uptake during hyperinsulinaemia
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S80-S80Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-346985 (URN)000408315000170 ()
Conference
53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-03-23Bibliographically approved
Sidibeh, C. O., Pereira, M. J., Börjesson, J. L., Kamble, P. G., Skrtic, S., Katsogiannos, P., . . . Eriksson, J. W. (2017). Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance. Endocrine (Basingstoke), 55(3), 839-852
Open this publication in new window or tab >>Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance
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2017 (English)In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 55, no 3, p. 839-852Article in journal (Refereed) Published
Abstract [en]

We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone. CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity. Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue. Subcutaneous adipose tissue was obtained from well-controlled type 2 diabetes subjects and controls. Subcutaneous adipose tissue gene expression levels of CNR1 and endocannabinoid synthesizing and degrading enzymes were assessed. Furthermore, paired human subcutaneous adipose tissue and omental adipose tissue from non-diabetic volunteers undergoing kidney donation or bariatric surgery, was incubated with or without dexamethasone. Subcutaneous adipose tissue obtained from volunteers through needle biopsy was incubated with or without dexamethasone and in the presence or absence of the CNR1-specific antagonist AM281. CNR1 gene and protein expression, lipolysis and glucose uptake were evaluated. Subcutaneous adipose tissue CNR1 gene expression levels were 2-fold elevated in type 2 diabetes subjects compared with control subjects. Additionally, gene expression levels of CNR1 and endocannabinoid-regulating enzymes from both groups correlated with markers of insulin resistance. Dexamethasone increased CNR1 expression dose-dependently in subcutaneous adipose tissue and omental adipose tissue by up to 25-fold. Dexamethasone pre-treatment of subcutaneous adipose tissue increased lipolysis rate and reduced glucose uptake. Co-incubation with the CNR1 antagonist AM281 prevented the stimulatory effect on lipolysis, but had no effect on glucose uptake. CNR1 is upregulated in states of type 2 diabetes and insulin resistance. Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis. Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.

Place, publisher, year, edition, pages
SPRINGER, 2017
Keywords
Type 2 diabetes, Glucocorticoids, Insulin resistance, Adipose tissue, Endocannabinoid system
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-320351 (URN)10.1007/s12020-016-1172-6 (DOI)000394966900021 ()27858284 (PubMedID)
Funder
AstraZenecaSwedish Heart Lung Foundation, 20100648Swedish Diabetes Association
Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-12-06Bibliographically approved
Aresh, B., Freitag, F. B., Perry, S., Blümel, E., Lau, J., Franck, M. C. .. & Lagerström, M. C. (2017). Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling. Pain, 158(5), 945-961
Open this publication in new window or tab >>Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling
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2017 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 5, p. 945-961Article in journal (Refereed) Published
Abstract [en]

Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox; Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.

Keywords
Itch, Gastrin-releasing peptide receptor population, Natriuretic polypeptide B, Spinal cord, Vesicular glutamate transporter 2, Neuronal networks, Labeled line of itch, Electrophysiology, Conditional knockout analysis, Tracing, Calcium imaging, Grpr, VGLUT2
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-284058 (URN)10.1097/j.pain.0000000000000861 (DOI)000402430600021 ()28157737 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationThe Royal Swedish Academy of SciencesRagnar Söderbergs stiftelseMagnus Bergvall FoundationGunvor och Josef Anérs stiftelse
Note

Title in thesis list of papers: Spinal Cord Interneurons Expressing the Gastrin Releasing Peptide Receptor Convey Itch through VGLUT2-mediated Signaling

Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2017-07-10Bibliographically approved
Espes, D., Lau, J. & Carlsson, P.-O. (2017). Towards the clinical translation of stem cell therapy for type 1 diabetes. European Journal of Endocrinology, 177(4), R159-R168
Open this publication in new window or tab >>Towards the clinical translation of stem cell therapy for type 1 diabetes
2017 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 177, no 4, p. R159-R168Article, review/survey (Refereed) Published
Abstract [en]

Insulin-producing cells derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) have for long been a promising, but elusive treatment far from clinical translation into type 1 diabetes therapy. However, the field is now on the verge of moving such insulin-producing cells into clinical trials. Although stem cell therapies provide great opportunities, there are also potential risks such as teratoma formation associated with the treatment. Many considerations are needed on how to proceed with clinical translation, including whether to use hESCs or iPSCs, and whether encapsulation of tissue will be needed. This review aims to give an overview of the current knowledge of stem cell therapy outcomes in animal models of type 1 diabetes and a proposed road map towards the clinical setting with special focus on the potential risks and hurdles which needs to be considered. From a clinical point of view, transplantation of insulin-producing cells derived from stem cells must be performed without immune suppression in order to be an attractive treatment option. Although costly and highly labour intensive, patient-derived iPSCs would be the only solution, if not clinically successful encapsulation or tolerance induction protocols are introduced.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-346616 (URN)10.1530/EJE-17-0080 (DOI)000414730300001 ()28487297 (PubMedID)
Available from: 2018-03-21 Created: 2018-03-21 Last updated: 2018-03-21Bibliographically approved
Kamble, P. G., Pereira, M. J., Sidibeh, C. O., Amini, S., Sundbom, M., Börjesson, J. L. & Eriksson, J. W. (2016). Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue. Molecular and Cellular Endocrinology, 427, 124-132
Open this publication in new window or tab >>Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue
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2016 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 427, p. 124-132Article in journal (Refereed) Published
Abstract [en]

The adipokine lipocalin 2 is linked to obesity and metabolic disorders. However, its role in human adipose tissue glucose and lipid metabolism is not explored. Here we show that the synthetic glucocorticoid dexamethasone dose-dependently increased lipocalin 2 gene expression in subcutaneous and omental adipose tissue from pre-menopausal females, while it had no effect in post-menopausal females or in males. Subcutaneous adipose tissue from both genders treated with recombinant human lipocalin 2 showed a reduction in protein levels of GLUT1 and GLUT4 and in glucose uptake in isolated adipocytes. In subcutaneous adipose tissue, lipocalin 2 increased IL-6 gene expression whereas expression of PPAR gamma and adiponectin was reduced. Our findings suggest that lipocalin 2 can contribute to insulin resistance in human adipose tissue. In pre-menopausal females, it may partly mediate adverse metabolic effects exerted by glucocorticoid excess.

Keywords
Glucocorticoids, Lipocalin 2, Human adipose tissue, Type 2 diabetes, Insulin resistance, PPAR gamma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-297263 (URN)10.1016/j.mce.2016.03.011 (DOI)000375335500013 ()26973291 (PubMedID)
Funder
Swedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenAstraZenecaSwedish Society for Medical Research (SSMF)
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2018-08-12Bibliographically approved
Lundkvist, P., Amini, S., Lau Börjesson, J., Pereira, M. J., Kamble, P. G., Sjostrom, C., . . . Eriksson, J. (2016). Metabolic effects of dapagliflozin QD and exenatide QW in obese adults without diabetes: a 24-week randomised placebo-controlled phase 2 study. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S377-S378
Open this publication in new window or tab >>Metabolic effects of dapagliflozin QD and exenatide QW in obese adults without diabetes: a 24-week randomised placebo-controlled phase 2 study
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S377-S378Article in journal (Refereed) Published
Place, publisher, year, edition, pages
SPRINGER, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-322046 (URN)000398373702161 ()
Conference
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Funder
AstraZeneca
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-16Bibliographically approved
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