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Jansson, Leif
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Publications (10 of 63) Show all publications
Gao, X., Lindqvist, A., Sandberg, M., Groop, L., Wierup, N. & Jansson, L. (2018). Effects of GIP on regional blood flow during normoglycemia and hyperglycemia in anesthetized rats. Physiological Reports, 6(8), Article ID e13685.
Open this publication in new window or tab >>Effects of GIP on regional blood flow during normoglycemia and hyperglycemia in anesthetized rats
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2018 (English)In: Physiological Reports, E-ISSN 2051-817X, Vol. 6, no 8, article id e13685Article in journal (Refereed) Published
Abstract [en]

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion, and affects -cell turnover. This study aimed at evaluating if some of the beneficial effects of GIP on glucose homeostasis can be explained by modulation of islet blood flow. Anesthetized Sprague-Dawley rats were infused intravenously with different doses of GIP (10, 20, or 60ng/kg*min) for 30min. Subsequent organ blood flow measurements were performed with microspheres. In separate animals, islets were perfused exvivo with GIP (10(-6)-10(-12)mol/L) during normo- and hyperglycemia and arteriolar responsiveness was recorded. The highest dose of GIP potentiated insulin secretion during hyperglycemia, but had no effect in normoglycemic rats. The highest GIP concentration decreased blood perfusion of whole pancreas, pancreatic islets, duodenum, colon, liver and kidneys. The decrease in blood flow was unaffected by ganglion blockade or adenosine receptor inhibition. In contrast to this, in single perfused islets GIP induced a dose-dependent arteriolar dilation. Thus, high doses of GIP exert a direct dilatory effect on islet arterioles in isolated islets, but induce a generalized vasoconstriction in splanchnic organs, including the whole pancreas and islets, invivo. The latter effect is unlikely to be mediated by adenosine, the autonomic nervous system, or endothelial mediators.

Keyword
Glucose-dependent insulinotropic peptide, incretin hormones, Islet blood flow, pancreatic islets, splanchnic blood flow
National Category
Physiology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354242 (URN)10.14814/phy2.13685 (DOI)000430922300017 ()29673130 (PubMedID)
Funder
Swedish Research Council, 521-2011-3777Swedish Research Council, 2008-4216Swedish Research Council, 521-2012-2119
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Gao, X., Liu, Z. Z., Mohammed, H., Braun, D., Zhuge, Z., Liu, M., . . . Persson, A. E. (2018). Extravasal albumin concentration modulates contractile responses of renal afferent arterioles. Acta Physiologica, 222(2), Article ID e12925.
Open this publication in new window or tab >>Extravasal albumin concentration modulates contractile responses of renal afferent arterioles
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2018 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 222, no 2, article id e12925Article in journal (Refereed) Published
Abstract [en]

Aim: Afferent arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback, the afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates afferent arteriolar tone, a mechanism which may contribute to body fluid volume control.

Method: The effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, in rat renal AA and in pancreatic islet arterioles.

Results: Albumin (2 and 4% in the bath solution) significantly potentiated the contractile response of renal afferent arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet arterioles. Mimicking the increase in the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in afferent arterioles exposed to 4% albumin.

Conclusion: The protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.

Place, publisher, year, edition, pages
WILEY, 2018
Keyword
adenosine, angiotensin II, glomerular filtration, nitric oxide, protein, renal autoregulation
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-343780 (URN)10.1111/apha.12925 (DOI)000423367700009 ()
Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-03-07Bibliographically approved
Sandberg, M., Johansson, S., Sagulin, L., Jansson, L. & Johansson, S. (2017). Scavenging Endothelium of Pancreatic Islets Differential Expression of Stabilin-1 and Stabilin-2 in Mice and Humans [Letter to the editor]. Pancreas, 46(1), E4-E5
Open this publication in new window or tab >>Scavenging Endothelium of Pancreatic Islets Differential Expression of Stabilin-1 and Stabilin-2 in Mice and Humans
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2017 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 1, p. E4-E5Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321001 (URN)10.1097/MPA.0000000000000709 (DOI)000397644300005 ()27977633 (PubMedID)
Funder
Swedish Research Council, 521-2011-3777, 7147EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes Association
Available from: 2017-04-28 Created: 2017-04-28 Last updated: 2017-04-28Bibliographically approved
Jansson, L., Barbu, A., Bodin, B., Drott, C. J., Espes, D., Gao, X., . . . Carlsson, P.-O. (2016). Pancreatic islet blood flow and its measurement. Upsala Journal of Medical Sciences, 121(2), 81-95
Open this publication in new window or tab >>Pancreatic islet blood flow and its measurement
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2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 81-95Article, review/survey (Refereed) Published
Abstract [en]

Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.

Keyword
Blood flow measurements, islet blood flow, microspheres, pancreatic islets
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-299775 (URN)10.3109/03009734.2016.1164769 (DOI)000376695600004 ()27124642 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Childhood Cancer FoundationNovo Nordisk
Available from: 2016-07-27 Created: 2016-07-27 Last updated: 2018-01-10Bibliographically approved
Carlbom, L., Espes, D., Lubberink, M., Eriksson, O., Johansson, L., Jansson, L., . . . Carlsson, P.-O. (2016). Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes. Diabetologia, 59(9), 1968-1972
Open this publication in new window or tab >>Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 9, p. 1968-1972Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: The aim of this study was to investigate pancreatic perfusion and its response to a glucose load in patients with type 1 diabetes mellitus compared with non-diabetic ('healthy') individuals.

METHODS: Eight individuals with longstanding type 1 diabetes and ten sex-, age- and BMI-matched healthy controls underwent dynamic positron emission tomography scanning with (15)O-labelled water before and after intravenous administration of glucose. Perfusion in the pancreas was measured. Portal and arterial hepatic perfusion were recorded as references.

RESULTS: Under fasting conditions, total pancreatic perfusion was on average 23% lower in the individuals with diabetes compared with healthy individuals. Glucose increased total pancreatic and portal hepatic blood perfusion in healthy individuals by 48% and 38%, respectively. In individuals with diabetes there was no significant increase in either total pancreatic or portal hepatic perfusion.

CONCLUSIONS/INTERPRETATION: Individuals with type 1 diabetes have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation.

Keyword
Blood flow; Glucose; Pancreas; Pancreatic islets; Perfusion; Type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-297684 (URN)10.1007/s00125-016-4016-2 (DOI)000380668800021 ()27306617 (PubMedID)
External cooperation:
Funder
Swedish Research Council, K2013-55-X-15043-10-5 K2015-54X-12219-19-4 K2013-64X-08268-26-3Swedish Diabetes AssociationSwedish Child Diabetes FoundationNovo Nordisk
Note

De 2 sista författarna delar sistaförfattarskapet

Available from: 2016-06-27 Created: 2016-06-27 Last updated: 2018-01-25Bibliographically approved
Li, X., Padhan, N., Sjöström, E. O., Roche, F. P., Testini, C., Honkura, N., . . . Claesson-Welsh, L. (2016). VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications, 7, Article ID 11017.
Open this publication in new window or tab >>VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11017Article in journal (Refereed) Published
Abstract [en]

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-288617 (URN)10.1038/ncomms11017 (DOI)000372721400001 ()27005951 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research Council, 294556 BBBARRIERWenner-Gren Foundations
Available from: 2016-05-11 Created: 2016-04-28 Last updated: 2017-11-30Bibliographically approved
Yang, T., Gao, X., Sandberg, M., Zollbrecht, C., Zhang, X.-M., Hezel, M., . . . Carlstrom, M. (2015). Abrogation of adenosine A(1) receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses. Diabetologia, 58(7), 1610-1620
Open this publication in new window or tab >>Abrogation of adenosine A(1) receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses
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2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 7, p. 1610-1620Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis Adenosine is an important regulator of metabolism; however, the role of the A(1) receptor during ageing and obesity is unclear. The aim of this study was to investigate the effects of A(1) signalling in modulating metabolic function during ageing. Methods Age-matched young and aged A (1) (also known as Adora1)-knockout (A (1) (-/-)) and wild-type (A (1) (+/+)) mice were used. Metabolic regulation was evaluated by body composition, and glucose and insulin tolerance tests. Isolated islets and islet arterioles were used to detect islet endocrine and vascular function. Oxidative stress and inflammation status were measured in metabolic organs and systemically. Results Advanced age was associated with both reduced glucose clearance and insulin sensitivity, as well as increased visceral adipose tissue (VAT) in A (1) (+/+) compared with A (1) (-/-) mice. Islet morphology and insulin content were similar between genotypes, but relative changes in in vitro insulin release following glucose stimulation were reduced in aged A (1) (+/+) compared with A (1) (-/-) mice. Islet arteriolar responses to angiotensin II were stronger in aged A (1) (+/+) mice, this being associated with increased NADPH oxidase activity. Ageing resulted in multiple changes in A (1) (+/+) compared with A (1) (-/-) mice, including enhanced NADPH oxidase-derived O-2 (-) formation and NADPH oxidase isoform 2 (Nox2) protein expression in pancreas and VAT; elevated levels of circulating insulin, leptin and proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6 and IL-12); and accumulation of CD4(+) T cells in VAT. This was associated with impaired insulin signalling in VAT from aged A (1) (+/+) mice. Conclusions/interpretation These studies emphasise that A(1) receptors regulate metabolism and islet endocrine and vascular functions during ageing, including via the modulation of oxidative stress and inflammatory responses, among other things.

Keyword
Insulin sensitivity and resistance, Islets, Metabolic physiology in vivo, Metabolic syndrome, Oxidative stress, Type 2 diabetes, Visceral adipose tissue
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-258321 (URN)10.1007/s00125-015-3570-3 (DOI)000356528900026 ()25835725 (PubMedID)
Funder
Swedish Research Council, 521-2011-2639, 521-2011-3777Swedish Heart Lung Foundation, 20140448, 20110589
Available from: 2015-07-15 Created: 2015-07-13 Last updated: 2017-12-04Bibliographically approved
Zang, G., Sandberg, M., Carlsson, P.-O., Welsh, N., Jansson, L. & Barbu, A. (2015). Activated pancreatic stellate cells can impair pancreatic islet function in mice. Upsala Journal of Medical Sciences, 120(3), 169-180
Open this publication in new window or tab >>Activated pancreatic stellate cells can impair pancreatic islet function in mice
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2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 169-180Article in journal (Refereed) Published
Abstract [en]

Background. Pancreatic or islet fibrosis is often associated with activated pancreatic stellate cells (PSCs). PSCs are considered not only to promote fibrosis, but also to be associated with glucose intolerance in some diseases. We therefore evaluated morphological and functional relationships between islets and PSCs in the normal mouse pancreas and transplanted islets. Methods. Immunohistochemistry was used to map the presence of PSCs in the normal mouse pancreas and islets implanted under the renal capsule. We isolated and cultured mouse PSCs and characterized them morphologically by immunofluorescence staining. Furthermore, we measured their cytokine production and determined their effects on insulin release from simultaneously cultured islets. Results. PSCs were scattered throughout the pancreas, with occasional cells within the islets, particularly in the islet capsule. In islet transplants they were found mainly in the graft periphery. Cultured PSCs became functionally activated and produced several cytokines. Throughout the culture period they linearly increased their production of interleukin-6 and mammalian keratinocyte-derived chemokine. PSC cytokine production was not affected by acute hyperglycemia. Syngeneic islets cocultured with PSCs for 24-48 h increased their insulin release and lowered their insulin content. However, short-term insulin release in batch-type incubations was unaffected after 48 h of co-culture. Increased islet cell caspase-3 activation and a decreased islet cell replication were consistently observed after co-culture for 2 or 7 days. Conclusion. Activated PSCs may contribute to impaired islet endocrine function seen in exocrine pancreatitis and in islet fibrosis associated with some cases of type 2 diabetes.

Keyword
Beta-cell replication, insulin release, pancreatic islets, stellate cells
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-261989 (URN)10.3109/03009734.2015.1032453 (DOI)000359819800004 ()25854824 (PubMedID)
Funder
Swedish Research Council, 521-2011-3777
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2017-12-04Bibliographically approved
Grapensparr, L., Vasylovska, S., Li, Z., Olerud, J., Jansson, L., Kozlova, E. & Carlsson, P.-O. (2015). Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth. Journal of Clinical Endocrinology and Metabolism, 100(4), E583-E590
Open this publication in new window or tab >>Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth
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2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. E583-E590Article in journal (Refereed) Published
Abstract [en]

Context: Neural crest stem cells (NCSCs) are capable of substantially improving murine islet function by promoting beta-cell proliferation. Objective: The present study aimed to investigate the potential of NCSCs to stimulate human beta-cell proliferation, and improve neural and vascular engraftment of human islets. Design, Setting, and Subjects: Human pancreatic islets from 18 brain-dead cadaveric donors (age range, 19-78 y) were obtained through the Nordic Network for Clinical Islet Transplantation. beta-cell proliferation and graft function was investigated at our experimental laboratory. Intervention and Main Outcome Measures: Human islets were transplanted, either alone or together with spheres of NCSCs. beta-cell proliferation, as well as islet neuralandvascular densities, were assessed by immunohistochemistry. Graft blood perfusion and oxygen tension were measured using laser-Doppler flowmetry and Clark microelectrodes, respectively. Results: Two days posttransplantation, the number of Ki67-positive beta-cells was doubled in human islets that had been exposed to NCSCs. Similar findings were obtained in vitro, as well as with EdU as proliferation marker. Four weeks posttransplantation, NCSC-exposed human islet grafts had much higher neural and vascular densities. The newly formed blood vessels were also functional, given that these human islets had a substantially higher blood perfusion and oxygen tension when compared with control transplants. Conclusion: We conclude that exposure to NCSCs stimulates human beta-cell proliferation, andthat these cells improve both the neural and vascular engraftment of transplanted human islets. NCSCs are a promising cellular therapy for translation into clinical use.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-253267 (URN)10.1210/jc.2014-4070 (DOI)000353361500009 ()25668197 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-25 Last updated: 2017-12-04Bibliographically approved
Carlsson, P.-O. & Jansson, L. (2015). Disruption of Insulin Receptor Signaling in Endothelial Cells Shows the Central Role of an Intact Islet Blood Flow for In Vivo beta-Cell Function. Diabetes, 64(3), 700-702
Open this publication in new window or tab >>Disruption of Insulin Receptor Signaling in Endothelial Cells Shows the Central Role of an Intact Islet Blood Flow for In Vivo beta-Cell Function
2015 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 3, p. 700-702Article in journal, Editorial material (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-251678 (URN)10.2337/db14-1523 (DOI)000350235900008 ()25713194 (PubMedID)
Available from: 2015-04-24 Created: 2015-04-23 Last updated: 2017-12-04Bibliographically approved
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