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Ahlgren, Ulf
Publications (10 of 38) Show all publications
Medina, A., Parween, S., Ullsten, S., Vishnu, N., Siu, Y. T., Quach, M., . . . Fex, M. (2018). Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats. Diabetologia, 61(4), 896-905
Open this publication in new window or tab >>Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 4, p. 896-905Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available.

Methods: We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells.

Results: DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 +/- 121.3 vs 633.3 +/- 148.7; p < 0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5-7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9 +/- 1593.7 vs 4416.8 +/- 1230.5 pg islet-1 h-1; p < 0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1 x 109 +/- 9.5 x 107 vs 3.8 x 109 +/- 5.8 x 107 μm3; p = 0.044) and small sized islets (1.6 x 109 +/- 5.1 x 107 vs 1.4 x 109 +/- 4.5 x 107 μm3; p = 0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1 +/- 16.8 vs 76.9 +/- 11.8 μl min-1 [g pancreas]-1; p = 0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats.

Conclusions/interpretation: The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Beta cell dysfunction, Beta cell mass, Insulin secretion, Islet blood flow, Type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-146201 (URN)10.1007/s00125-017-4512-z (DOI)000427049100017 ()29209740 (PubMedID)
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2018-06-09Bibliographically approved
Grong, E., Nord, C., Arbo, I. B., Eriksson, M., Kulseng, B. E., Ahlgren, U. & Mårvik, R. (2018). The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats. Journal of Endocrinological Investigation, 41(6), 691-701
Open this publication in new window or tab >>The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats
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2018 (English)In: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 41, no 6, p. 691-701Article in journal (Refereed) Published
Abstract [en]

Purpose: Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals.

Methods: Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography.

Results: After surgery, body weight development was equal among groups (Pg = 0.75). Fasting and stimulated gastrin increased for GK-PPI and GK-SG vs. GK-V (p < 0.05 for all). Fasting blood glucose was decreased for GK-PPI and GK-SG vs. GK-V (p < 0.05 and p = 0.052). HbA1c was lower for GK-SG vs. GK-V at 6 weeks and for GK-PPI vs. GK-V at twelve- and eighteen weeks postoperative (p < 0.05 for all); a borderline difference was observed for GK-SG vs. GK-V at 18 weeks (p = 0.054). Total- and LDL cholesterol was elevated for GK-PPI compared to the other two groups (p < 0.05 for all). Beta-cell mass did not differ among groups (p = 0.35).

Conclusions: Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
sleeve gastrectomy, pantoprazole, gastrin, optical projection tomography, beta-cell mass, glycosylated hemoglobin
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-148827 (URN)10.1007/s40618-017-0793-9 (DOI)000432236400008 ()29168078 (PubMedID)2-s2.0-85034636636 (Scopus ID)
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-06-13Bibliographically approved
Nord, C., Eriksson, M., Dicker, A., Eriksson, A., Grong, E., Ilegems, E., . . . Ahlgren, U. (2017). Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas. Scientific Reports, 7, Article ID 6646.
Open this publication in new window or tab >>Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6646Article in journal (Refereed) Published
Abstract [en]

Despite the dramatic increase in the prevalence of diabetes, techniques for in situ studies of the underlying pancreatic biochemistry are lacking. Such methods would facilitate obtaining mechanistic understanding of diabetes pathophysiology and aid in prognostic and/or diagnostic assessments. In this report we demonstrate how a multivariate imaging approach (orthogonal projections to latent structures - discriminant analysis) can be applied to generate full vibrational microspectroscopic profiles of pancreatic tissues. These profiles enable extraction of known and previously unrecorded biochemical alterations in models of diabetes, and allow for classification of the investigated tissue with regards to tissue type, strain and stage of disease progression. Most significantly, the approach provided evidence for dramatic alterations of the pancreatic biochemistry at the initial onset of immune-infiltration in the Non Obese Diabetic model for type 1 diabetes. Further, it enabled detection of a previously undocumented accumulation of collagen fibrils in the leptin deficient ob/ob mouse islets. By generating high quality spectral profiles through the tissue capsule of hydrated human pancreata and by in vivo Raman imaging of pancreatic islets transplanted to the anterior chamber of the eye, we provide critical feasibility studies for the translation of this technique to diagnostic assessments of pancreatic biochemistry in vivo.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-138420 (URN)10.1038/s41598-017-07015-z (DOI)000406366000004 ()
Available from: 2017-08-23 Created: 2017-08-23 Last updated: 2018-06-09Bibliographically approved
van Krieken, P. P., Dicker, A., Eriksson, M., Herrera, P. L., Ahlgren, U., Berggren, P.-O. & Ilegems, E. (2017). Kinetics of functional beta cell mass decay in a diphtheria toxin receptor mouse model of diabetes. Scientific Reports, 7, Article ID 12440.
Open this publication in new window or tab >>Kinetics of functional beta cell mass decay in a diphtheria toxin receptor mouse model of diabetes
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12440Article in journal (Refereed) Published
Abstract [en]

Functional beta cell mass is an essential biomarker for the diagnosis and staging of diabetes. It has however proven technically challenging to study this parameter during diabetes progression. Here we have detailed the kinetics of the rapid decline in functional beta cell mass in the RIP-DTR mouse, a model of hyperglycemia resulting from diphtheria toxin induced beta cell ablation. A novel combination of imaging modalities was employed to study the pattern of beta cell destruction. Optical projection tomography of the pancreas and longitudinal in vivo confocal microscopy of islets transplanted into the anterior chamber of the eye allowed to investigate kinetics and tomographic location of beta cell mass decay in individual islets as well as at the entire islet population level. The correlation between beta cell mass and function was determined by complementary in vivo and ex vivo characterizations, demonstrating that beta cell function and glucose tolerance were impaired within the first two days following treatment when more than 50% of beta cell mass was remaining. Our results illustrate the importance of acquiring quantitative functional and morphological parameters to assess the functional status of the endocrine pancreas.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-140901 (URN)10.1038/s41598-017-12124-w (DOI)000412032600006 ()28963457 (PubMedID)
Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2018-06-09Bibliographically approved
Parween, S., Eriksson, M., Nord, C., Kostromina, E. & Ahlgren, U. (2017). Spatial and quantitative datasets of the pancreatic beta-cell mass distribution in lean and obese mice. Scientific Data, 4, Article ID 170031.
Open this publication in new window or tab >>Spatial and quantitative datasets of the pancreatic beta-cell mass distribution in lean and obese mice
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2017 (English)In: Scientific Data, E-ISSN 2052-4463, Vol. 4, article id 170031Article in journal (Refereed) Published
Abstract [en]

A detailed understanding of pancreatic β-cell mass distribution is a key element to fully appreciate the pathophysiology of models of diabetes and metabolic stress. Commonly, such assessments have been performed by stereological approaches that rely on the extrapolation of two-dimensional data and provide very limited topological information. We present ex vivo optical tomographic data sets of the full β-cell mass distribution in cohorts of obese ob/ob mice and their lean controls, together with information about individual islet β-cell volumes, their three-dimensional coordinates and shape throughout the volume of the pancreas between 4 and 52 weeks of age. These data sets offer the currently most comprehensive public record of the β-cell mass distribution in the mouse. As such, they may serve as a quantitative and topological reference for the planning of a variety of in vivo or ex vivo experiments including computational modelling and statistical analyses. By shedding light on intra- and inter-lobular variations in β-cell mass distribution, they further provide a powerful tool for the planning of stereological sampling assessments.

National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:umu:diva-133764 (URN)10.1038/sdata.2017.31 (DOI)000396109500001 ()
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2018-06-09Bibliographically approved
Parween, S., Kostromina, E., Nord, C., Eriksson, M., Lindström, P. & Ahlgren, U. (2016). Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas. Scientific Reports, 6, Article ID 34885.
Open this publication in new window or tab >>Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 34885Article in journal (Refereed) Published
Abstract [en]

The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of the characteristics of β-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-127539 (URN)10.1038/srep34885 (DOI)000392007800001 ()27713548 (PubMedID)2-s2.0-84990210699 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 289932Swedish Research Council
Available from: 2016-11-15 Created: 2016-11-15 Last updated: 2018-06-09Bibliographically approved
Grong, E., Kulseng, B., Arbo, I. B., Nord, C., Eriksson, M., Ahlgren, U. & Mårvik, R. (2016). Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography. Surgical Endoscopy, 30(2), 532-542
Open this publication in new window or tab >>Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography
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2016 (English)In: Surgical Endoscopy, ISSN 0930-2794, E-ISSN 1432-2218, Vol. 30, no 2, p. 532-542Article in journal (Refereed) Published
Abstract [en]

Background In type 2 diabetes mellitus, there is a progressive loss of beta-cell mass. Bariatric surgery has in recent investigations showed promising results in terms of diabetes remission, but little is established regarding the effect of surgery on the survival or regeneration of pancreatic beta-cells. In this study, we aim to explore how bariatric surgery with its subsequent hormonal alterations affects the islets of Langerhans.

Methods Twenty-four Goto-Kakizaki rats were operated with duodenojejunostomy (DJ), sleeve gastrectomy (SG) or sham operation. From the 38th week after surgery, body weight, fasting blood glucose, glycosylated hemoglobin, mixed meal tolerance with repeated measures of insulin, glucagon-like peptide 1, gastrin and total ghrelin were evaluated. Forty-six weeks after surgery, the animals were euthanized and the total beta-cell mass in all animals was examined by three-dimensional volume quantification by optical projection tomography based on the signal from insulin-specific antibody staining.

Results Body weight did not differ between groups (Pg = 0.37). SG showed lower fasting blood glucose compared to DJ and sham (Pg = 0.037); HbA1c levels in SG were lower compared to DJ only (p\0.05). GLP-1 levels were elevated for DJ compared to SG and sham (Pg = 0.001), whereas gastrin levels were higher in SG compared to the two other groups (Pg = 0.002). Beta-cell mass was significantly greater in animals operated with SG compared to both DJ and sham (p = 0.036).

Conclusion Sleeve gastrectomy is superior to duodenojejunostomy and sham operation when comparing the preservation of beta-cell mass 46 weeks after surgery in Goto-Kakizaki rats. This could be related to both the increased gastrin levels and the long-term improvement in glycemic parameters observed after this procedure.

Keywords
Duodenojejunostomy, Sleeve gastrectomy, Gastrin, Glucagon-like peptide 1, Beta-cell mass, Optical projection tomography, Goto-Kakizaki rats, Type 2 diabetes mellitus
National Category
Cell and Molecular Biology Endocrinology and Diabetes Surgery
Identifiers
urn:nbn:se:umu:diva-117395 (URN)10.1007/s00464-015-4236-4 (DOI)000369335900018 ()26065537 (PubMedID)
Available from: 2016-03-30 Created: 2016-02-29 Last updated: 2018-06-07Bibliographically approved
Eter, W. A., Parween, S., Joosten, L., Frielink, C., Eriksson, M., Brom, M., . . . Gotthardt, M. (2016). SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments. Scientific Reports, 6, Article ID 24576.
Open this publication in new window or tab >>SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 24576Article in journal (Refereed) Published
Abstract [en]

Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in beta-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total beta-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Alternative methods are therefore warranted to cross-validate beta-cell imaging using radiotracers. In this study, we introduce multimodal SPECT - optical projection tomography (OPT) imaging as an accurate approach to cross-validate radionuclide-based imaging of beta-cells. Uptake of a promising radiotracer for beta-cell imaging by SPECT, In-111-exendin-3, was measured by ex vivo-SPECT and cross evaluated by 3D quantitative OPT imaging as well as with histology within healthy and alloxan-treated Brown Norway rat pancreata. SPECT signal was in excellent linear correlation with OPT data as compared to histology. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of In-111-exendin-3 and insulin positive beta-cell volumes between different pancreatic lobes, both visually and quantitatively. We propose ex vivo SPECT-OPT multimodal imaging as a highly accurate strategy for validating the performance of beta-cell radiotracers.

Keywords
Diabetes Mellitus, Pancreas, Radioisotopes, SPECT
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-120360 (URN)10.1038/srep24576 (DOI)000374221700001 ()27080529 (PubMedID)
Available from: 2016-05-23 Created: 2016-05-16 Last updated: 2018-06-07Bibliographically approved
Jones, I., Hägglund, A.-C., Törnqvist, G., Nord, C., Ahlgren, U. & Carlsson, L. (2015). A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development. Disease Models and Mechanisms, 8(12), 1517-1529
Open this publication in new window or tab >>A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development
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2015 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 8, no 12, p. 1517-1529Article in journal (Refereed) Published
Abstract [en]

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-120197 (URN)10.1242/dmm.021972 (DOI)000368905300004 ()26449264 (PubMedID)
Available from: 2016-05-11 Created: 2016-05-11 Last updated: 2018-06-07Bibliographically approved
Ilegems, E., van Krieken, P. P., Edlund, P. K., Dicker, A., Alanentalo, T., Eriksson, M., . . . Berggren, P.-O. -. (2015). Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion. Scientific Reports, 5, Article ID 10740.
Open this publication in new window or tab >>Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10740Article in journal (Refereed) Published
Abstract [en]

The pancreatic islet of Langerhans is composed of endocrine cells producing and releasing hormones from secretory granules in response to various stimuli for maintenance of blood glucose homeostasis. In order to adapt to a variation in functional demands, these islets are capable of modulating their hormone secretion by increasing the number of endocrine cells as well as the functional response of individual cells. A failure in adaptive mechanisms will lead to inadequate blood glucose regulation and thereby to the development of diabetes. It is therefore necessary to develop tools for the assessment of both pancreatic islet mass and function, with the aim of understanding cellular regulatory mechanisms and factors guiding islet plasticity. Although most of the existing techniques rely on the use of artificial indicators, we present an imaging methodology based on intrinsic optical properties originating from mature insulin secretory granules within endocrine cells that reveals both pancreatic islet mass and function. We demonstrate the advantage of using this imaging strategy by monitoring in vivo scattering signal from pancreatic islets engrafted into the anterior chamber of the mouse eye, and how this versatile and noninvasive methodology permits the characterization of islet morphology and plasticity as well as hormone secretory status.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-106501 (URN)10.1038/srep10740 (DOI)000355603100002 ()26030284 (PubMedID)
Available from: 2015-07-16 Created: 2015-07-14 Last updated: 2018-06-07Bibliographically approved
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