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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
Edén, D., Mokhtari, D., Eriksson, J. W., Åberg, M. & Siegbahn, A. (2018). Adipocytes are coagulant active in a TF/FVIIa dependent manner but lipolysis is unaffected by TF/FVIIa. Paper presented at 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, APR 20-22, 2018, Vienna, AUSTRIA. Cardiovascular Research, 114, S131-S131
Open this publication in new window or tab >>Adipocytes are coagulant active in a TF/FVIIa dependent manner but lipolysis is unaffected by TF/FVIIa
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2018 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S131-S131Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-357491 (URN)000430678500386 ()
Conference
5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, APR 20-22, 2018, Vienna, AUSTRIA
Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-23Bibliographically approved
Fonseca, A. C. G., Carvalho, E., Eriksson, J. & Pereira, M. J. (2018). Calcineurin is an important factor involved in glucose uptake in human adipocytes. Molecular and Cellular Biochemistry, 445(1-2), 157-168
Open this publication in new window or tab >>Calcineurin is an important factor involved in glucose uptake in human adipocytes
2018 (English)In: Molecular and Cellular Biochemistry, ISSN 0300-8177, E-ISSN 1573-4919, Vol. 445, no 1-2, p. 157-168Article in journal (Refereed) Published
Abstract [en]

Calcineurin inhibitors are used in immunosuppressive therapy applied after transplantation, but they are associated with major metabolic side effects including the development of new onset diabetes. Previously, we have shown that the calcineurin inhibiting drugs tacrolimus and cyclosporin A reduce adipocyte and myocyte glucose uptakes by reducing the amount of glucose transporter type 4 (GLUT4) at the cell surface, due to an increased internalization rate. However, this happens without alteration in total protein and phosphorylation levels of key proteins involved in insulin signalling or in the total amount of GLUT4. The present study evaluates possible pathways involved in the altered internalization of GLUT4 and consequent reduction of glucose uptake provoked by calcineurin inhibitors in human subcutaneous adipose tissue. Short- and long-term treatments with tacrolimus, cyclosporin A or another CNI deltamethrin (herbicide) decreased basal and insulin-dependent glucose uptake in adipocytes, without any additive effects observed when added together. However, no tacrolimus effects were observed on glucose uptake when gene transcription and protein translation were inhibited. Investigation of genes potentially involved in GLUT4 trafficking showed only a small effect on ARHGEF11 gene expression (p < 0.05). In conlusion, the specific inhibition of calcineurin, but not that of protein phosphatases, decreases glucose uptake in human subcutaneous adipocytes, suggesting that calcineurin is an important regulator of glucose transport. This inhibitory effect is mediated via gene transcription or protein translation; however, expression of genes potentially involved in GLUT4 trafficking and endocytosis appears not to be involved in these effects.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
Diabetes, Calcineurin inhibitors, Adipose tissue, Adipocytes, Glucose uptake, Gene expression
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-360178 (URN)10.1007/s11010-017-3261-0 (DOI)000437464800016 ()29380240 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenErnfors Foundation
Available from: 2018-09-12 Created: 2018-09-12 Last updated: 2018-09-12Bibliographically approved
Nyström, T., Bodegård, J., Nathanson, D., Thuresson, M., Norhammar, A. & Eriksson, J. W. (2018). Comment on Suissa. Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias? Diabetes Care 2018;41:6–10 [Letter to the editor]. Diabetes Care, 41(6), E104-E105
Open this publication in new window or tab >>Comment on Suissa. Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias? Diabetes Care 2018;41:6–10
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2018 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 41, no 6, p. E104-E105Article in journal, Letter (Refereed) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-359371 (URN)10.2337/dc18-0339 (DOI)000432673000011 ()29784707 (PubMedID)
Funder
AstraZenecaNovo NordiskEli Lilly and Company
Available from: 2018-09-04 Created: 2018-09-04 Last updated: 2018-09-04Bibliographically approved
Persson, F., Nystrom, T., Jorgensen, M. E., Carstensen, B., Gulseth, H. L., Thuresson, M., . . . Birkeland, K. I. (2018). Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study. Diabetes, obesity and metabolism, 20(2), 344-351
Open this publication in new window or tab >>Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study
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2018 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, no 2, p. 344-351Article in journal (Refereed) Published
Abstract [en]

Aims

To compare the sodium-glucose-cotransporter-2 (SGLT-2) inhibitor dapagliflozin with dipeptidyl peptidase-4 (DPP-4) inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non-fatal myocardial infarction, non-fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world setting.

Methods

All patients with T2D prescribed glucose-lowering drugs (GLDs) during 2012 to 2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided into two groups: new users of dapagliflozin and new users of DPP-4 inhibitors, matched 1:3 by propensity score, calculated by patient characteristics, comorbidities and drug treatment. Cox survival models were used to estimate hazard ratio (HR) per country separately, and a weighted average was calculated.

Results

After matching, a total of 40908 patients with T2D were identified as new users of dapagliflozin (n=10227) or a DPP-4 inhibitor (n=30681). The groups were well balanced at baseline; their mean age was 61years and 23% had CV disease. The mean follow-up time was 0.95years, with a total of 38760 patient-years. Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors: HRs 0.79 (95% confidence interval [CI] 0.67-0.94), 0.62 (95% CI 0.50-0.77), and 0.59 (95% CI 0.49-0.72), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [95% CI 0.72-1.16]), stroke (0.79 [95% CI 0.61-1.03]) and CV mortality (0.76 [95% CI 0.53-1.08]) Neutral associations with atrial fibrillation and severe hypoglycaemia were observed.

Conclusions

Dapagliflozin was associated with lower risks of CV events and all-cause mortality compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D population.

Keywords
cardiovascular disease, dapagliflozin, diabetes complications, DPP-4 inhibitor, hypoglycaemia, type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-343661 (URN)10.1111/dom.13077 (DOI)000422678600013 ()28771923 (PubMedID)
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-05-09Bibliographically approved
Hansson, S. F., Zhou, A.-X., Vachet, P., Eriksson, J. W., Pereira, M. J., Skrtic, S., . . . Davidsson, P. (2018). Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction. PLoS ONE, 13(4), Article ID e0196601.
Open this publication in new window or tab >>Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0196601Article in journal (Refereed) Published
Abstract [en]

Beta cell dysfunction accompanies and drives the progression of type 2 diabetes mellitus (T2D), but there are few clinical biomarkers available to assess islet cell stress in humans. Secretagogin, a protein enriched in pancreatic islets, demonstrates protective effects on beta cell function in animals. However, its potential as a circulating biomarker released from human beta cells and islets has not been studied. In this study primary human islets, beta cells and plasma samples were used to explore secretion and expression of secretagogin in relation to the T2D pathology. Secretagogin was abundantly and specifically expressed and secreted from human islets. Furthermore, T2D patients had an elevated plasma level of secretagogin compared with matched healthy controls, which was confirmed in plasma of diabetic mice transplanted with human islets. Additionally, the plasma secretagogin level of the human cohort had an inverse correlation to clinical assessments of beta cell function. To explore the mechanism of secretagogin release in vitro, human beta cells (EndoC-[beta H1) were exposed to elevated glucose or cellular stress-inducing agents. Secretagogin was not released in parallel with glucose stimulated insulin release, but was markedly elevated in response to endoplasmic reticulum stressors and cytokines. These findings indicate that secretagogin is a potential novel biomarker, reflecting stress and islet cell dysfunction in T2D patients.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-356093 (URN)10.1371/journal.pone.0196601 (DOI)000431013300043 ()29702679 (PubMedID)
Funder
AstraZenecaSwedish Diabetes Association
Available from: 2018-07-19 Created: 2018-07-19 Last updated: 2018-07-19Bibliographically approved
Johansson, E., Lubberink, M., Heurling, K., Eriksson, J. W., Skrtic, S., Ahlström, H. & Kullberg, J. (2018). Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study.. Radiology, 286(1), 271-278
Open this publication in new window or tab >>Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study.
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2018 (English)In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 286, no 1, p. 271-278Article in journal (Refereed) Published
Abstract [en]

Purpose

To develop, evaluate, and demonstrate the feasibility of a whole-body protocol for simultaneous assessment of tissue-specific insulin-mediated fluorine 18 (18F) fluorodeoxyglucose (FDG) influx rates, tissue depots, and whole-body insulin sensitivity (referred to as the M value).

Materials and Methods

An integrated positron emission tomography (PET)/magnetic resonance (MR) imaging system combined with hyperinsulinemic euglycemic clamp (HEC) was used. Dynamic whole-body PET imaging was used to determine the insulin-mediated 18F-FDG tissue influx rate (Ki) in the whole-body region by using the Patlak method. M value was determined with the HEC method at PET imaging. Tissue depots were quantified by using water-fat separated MR imaging and manual segmentations. Feasibility of the imaging protocol was demonstrated by using five healthy control participants and five patients with type 2 diabetes. Associations between M value and Ki were studied in multiple tissues by using the Pearson correlation.

Results

Positive correlations were found between M value and Ki in multiple tissues: the gluteus muscle (r = 0.875; P = .001), thigh muscle (r = 0.903; P , .001), calf muscle (r = 0.825; P = .003), and abdominal visceral adipose tissue (r = 0.820; P = .004). A negative correlation was found in the brain (r = 20.798; P = .006). The MR imaging–based method for quantification of tissue depots was feasible for determining adipose tissue volumes and fat fractions.

Conclusion

This PET/MR imaging protocol may be feasible for simultaneous assessment of tissue-specific insulin-mediated 18F-FDG influx rates, tissue depots, and M value.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-329272 (URN)10.1148/radiol.2017162949 (DOI)000422905200034 ()28846496 (PubMedID)
Funder
AstraZeneca
Available from: 2017-09-11 Created: 2017-09-11 Last updated: 2018-03-16Bibliographically approved
Fonseca, A. R. G., Carvalho, E., Eriksson, J. W. & Pereira, M. J. (2017). Calcineurin is involved in the regulation of human adipocyte glucose uptake. Paper presented at 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL. Diabetologia, 60, S227-S227
Open this publication in new window or tab >>Calcineurin is involved in the regulation of human adipocyte glucose uptake
2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S227-S227Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-347284 (URN)000408315001275 ()
Conference
53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL
Available from: 2018-03-29 Created: 2018-03-29 Last updated: 2018-03-29Bibliographically approved
Birkeland, K. I., Jorgensen, M. E., Carstensen, B., Persson, F., Gulseth, H. L., Thuresson, M., . . . Norhammar, A. (2017). Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A Multinational Observational Analysis. The Lancet Diabetes and Endocrinology, 5(9), 709-717
Open this publication in new window or tab >>Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A Multinational Observational Analysis
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2017 (English)In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, no 9, p. 709-717Article in journal (Refereed) Published
Abstract [en]

Background In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile. Methods CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0.9 (SD 4.1) years (80 669 patient-years) and mean age of 61 (12.0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0.53 [95% CI 0.40-0.71]), major adverse cardiovascular events (0.78 [0.69-0.87]), and hospital events for heart failure (0.70 [0.61-0.81]; p<0.0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0.76 [0.65-0.90]; p=0.001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0.60 [0.42-0.85] vs 0.55 [0.34-0.90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0.70 (0.59-0.83) versus 0.90 (0.76-1.07) in the group without. Interpretation In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk.

Place, publisher, year, edition, pages
New York: Elsevier, 2017
Keywords
All-Cause Mortality; Heart-Failure; Severe Hypoglycemia; Dpp-4 Inhibitors; Increased Risk; Events; Prevalence; Outcomes; Diagnosis; Accuracy
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-330539 (URN)10.1016/S2213-8587(17)30258-9 (DOI)000408369600017 ()
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-03
Pereira, M. J., Skrtic, S., Katsogiannos, P., Abrahamsson, N., Kullberg, J., Nowak, C. & Eriksson, J. W. (2017). CDKN2C expression is low in type 2 diabetes and associated with reduced lipid storage capacity in subcutaneous adipose tissue and elevated free fatty acid levels. Paper presented at 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL. Diabetologia, 60(S1), S272-S272, Article ID 598.
Open this publication in new window or tab >>CDKN2C expression is low in type 2 diabetes and associated with reduced lipid storage capacity in subcutaneous adipose tissue and elevated free fatty acid levels
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no S1, p. S272-S272, article id 598Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-347293 (URN)000408315001375 ()
Conference
53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2639-9481

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