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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
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
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
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
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
Lundkvist, P., Pereira, M. J., Katsogiannos, P., Sjöström, C. D., Johnsson, E. & Eriksson, J. W. (2017). Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes, obesity and metabolism, 19(9), 1276-1288
Open this publication in new window or tab >>Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year
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2017 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, no 9, p. 1276-1288Article in journal (Refereed) Published
Abstract [en]

Aims: Dapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24weeks. Here, we examined these effects over 1year in obese adults without diabetes.

Materials and methods: Obese adults without diabetes (N=50; aged 18-70years; body mass index, 30-45kg/m(2)) were initially randomized to double-blind oral dapagliflozin 10mg once daily plus subcutaneous long-acting exenatide 2mg once weekly or to placebo. They entered an open-label extension from 24 to 52weeks during which all participants received active treatment.

Results: Of the original 25 dapagliflozin+exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52weeks of treatment. At baseline, mean body weight was 104.6kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin+exenatide at 24weeks were sustained at 52weeks, respectively, for body weight (-4.5 and -5.7kg), total adipose tissue volume (-3.8 and -5.3L), proportion with prediabetes (34.8% and 35.3%), and SBP (-9.8 and -12.0mm Hg). Effects on body weight, SBP and glycaemia at 52weeks with placebodapagliflozin+exenatide were similar to those observed with continuation of dapagliflozin+exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin+exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed.

Conclusions: Dapagliflozin+exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52weeks and was well tolerated in obese adults without diabetes.

Keywords
dapagliflozin, exenatide, obesity, prediabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-334932 (URN)10.1111/dom.12954 (DOI)000408241200010 ()28345814 (PubMedID)
Funder
AstraZeneca
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2017-12-01Bibliographically approved
Lundkvist, P., Sjöström, C. D., Amini, S., Pereira, M. J., Johnsson, E. & Eriksson, J. W. (2017). Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes, obesity and metabolism, 19(1), 49-60
Open this publication in new window or tab >>Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes
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2017 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, no 1, p. 49-60Article in journal (Refereed) Published
Abstract [en]

Aims: To explore the effects of dual therapy with dapagliflozin and exenatide on body weight, body composition, glycaemic variables and systolic blood pressure (SBP) in obese adults without diabetes.

Materials and methods: In this single-centre, double-blind trial, we randomized 50 obese adults without diabetes (aged 18-70 years; body mass index 30-45 kg/m(2)) to oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or placebo. MRI was used to assess change in body composition. Participants were instructed to follow a balanced diet and exercise moderately.

Results: Of 25 dapagliflozin/exenatide-and 25 placebo-treated participants, 23 (92.0%) and 20 (80.0%) completed 24 weeks of treatment, respectively. At baseline, the mean participant age was 52 years, 61% were female, the mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks, for dapagliflozin/exenatide versus placebo: the difference in body weight change was -4.13 kg (95% confidence interval -6.44, -1.81; P <.001), which was mostly attributable to adipose tissue reduction without lean tissue change; 36.0% versus 4.2% of participants achieved >= 5% body weight loss, respectively; and prediabetes was less frequent with active treatment (34.8% vs 85.0%, respectively; P <.01). The difference in SBP change for dapagliflozin/ exenatide versus placebo was -6.7 mm Hg. As expected, nausea and injection-site reactions were more frequent with dapagliflozin/exenatide than with placebo. Only two and three participants, respectively, discontinued because of adverse events.

Conclusions: Compared with placebo, dapagliflozin/exenatide dual therapy reduced body weight, frequency of prediabetes and SBP over 24 weeks and was well tolerated in obese adults without diabetes.

Keywords
dapagliflozin, exenatide, obesity, prediabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-314407 (URN)10.1111/dom.12779 (DOI)000390987800006 ()
Funder
AstraZeneca
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved
Kamble, P. G., Gustafsson, S., Pereira, M. J., Lundkvist, P., Cook, N., Lind, L., . . . Ingelsson, E. (2017). Genotype-based recall to study metabolic effects of genetic variation: a pilot study of PPARG Pro12Ala carriers. Upsala Journal of Medical Sciences, 122(4), 234-242
Open this publication in new window or tab >>Genotype-based recall to study metabolic effects of genetic variation: a pilot study of PPARG Pro12Ala carriers
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 234-242Article in journal (Refereed) Published
Abstract [en]

AIM: To assess practical implications of genotype-based recall (GBR) studies, an increasingly popular approach for in-depth characterization of genotype-phenotype relationships.

METHODS: We genotyped 2500 participants from the Swedish EpiHealth cohort and considered loss-of-function and missense variants in genes with relation to cardiometabolic traits as the basis for our GBR study. Therefore, we focused on carriers and non-carriers of the PPARG Pro12Ala (rs1801282) variant, as it is a relatively common variant with a minor allele frequency (MAF) of 0.14. It has also been shown to affect ligand binding and transcription, and carriage of the minor allele (Ala12) is associated with a reduced risk of type 2 diabetes. We re-invited 39 Pro12Pro, 34 Pro12Ala, and 30 Ala12Ala carriers and performed detailed anthropometric and serological assessments.

RESULTS: The participation rates in the GBR study were 31%, 44%, and 40%, and accordingly we included 12, 15, and 13 individuals with Pro12Pro, Pro12Ala, and Ala12Ala variants, respectively. There were no differences in anthropometric or metabolic variables among the different genotype groups.

CONCLUSIONS: Our report highlights that from a practical perspective, GBR can be used to study genotype-phenotype relationships. This approach can prove to be a valuable tool for follow-up findings from large-scale genetic discovery studies by undertaking detailed phenotyping procedures that might not be feasible in large studies. However, our study also illustrates the need for a larger pool of genotyped or sequenced individuals to allow for selection of rare variants with larger effects that can be examined in a GBR study of the present size.

Place, publisher, year, edition, pages
Taylor & Francis, 2017
Keywords
Genotype-based recall, PPARG Pro12Ala, metabolism
National Category
Endocrinology and Diabetes Medical Genetics
Identifiers
urn:nbn:se:uu:diva-342240 (URN)10.1080/03009734.2017.1405127 (DOI)000423294800005 ()29303622 (PubMedID)
Funder
Swedish Research Council, 2015-02907Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Heart Lung Foundation, 20140422Knut and Alice Wallenberg Foundation, 2013.0126Swedish Diabetes Association
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-08-12Bibliographically approved
Lundkvist, P., Pereira, M. J., Kamble, P. G., Katsogiannos, P., Esterline, R., Langkilde, A. M., . . . Eriksson, J. W. (2017). Glucagon levels during short-term SGLT2 inhibition are largely regulated by plasma glucose changes. Paper presented at 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL. Diabetologia, 60, S410-S410
Open this publication in new window or tab >>Glucagon levels during short-term SGLT2 inhibition are largely regulated by plasma glucose changes
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S410-S410Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-347289 (URN)000408315003002 ()
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
Katsogiannos, P., Boersma, G. J., Pereira, M. J., Lundkvist, P., Sundbom, M. & Eriksson, J. W. (2017). Glucose homeostasis and whole-body insulin resistance improved 4 weeks after gastric bypass surgery in type 2 diabetes, whereas adipose tissue metabolism was unchanged. 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), S253-S254, Article ID 557.
Open this publication in new window or tab >>Glucose homeostasis and whole-body insulin resistance improved 4 weeks after gastric bypass surgery in type 2 diabetes, whereas adipose tissue metabolism was unchanged
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no S1, p. S253-S254, article id 557Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-347288 (URN)000408315001334 ()
Conference
53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL
Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2018-04-03Bibliographically approved
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