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Lindström, P
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Publications (10 of 12) Show all publications
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
Nyrén, R., Chang, C. L., Lindström, P., Barmina, A., Vorrsjö, E., Ali, Y., . . . Olivecrona, G. (2012). Localization of lipoprotein lipase and GPIHBP1 in mouse pancreas: effects of diet and leptin deficiency. BMC Physiology, 12, 14
Open this publication in new window or tab >>Localization of lipoprotein lipase and GPIHBP1 in mouse pancreas: effects of diet and leptin deficiency
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2012 (English)In: BMC Physiology, ISSN 1472-6793, E-ISSN 1472-6793, Vol. 12, p. 14-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins and enables uptake of lipolysis products for energy production or storage in tissues. Our aim was to study the localization of LPL and its endothelial anchoring protein glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in mouse pancreas, and effects of diet and leptin deficiency on their expression patterns. For this, immunofluorescence microscopy was used on pancreatic tissue from C57BL/6 mouse embryos (E18), adult mice on normal or high-fat diet, and adult ob/ob-mice treated or not with leptin. The distribution of LPL and GPIHBP1 was compared to insulin, glucagon and CD31. Heparin injections were used to discriminate between intracellular and extracellular LPL.

RESULTS: In the exocrine pancreas LPL was found in capillaries, and was mostly co-localized with GPIHBP1. LPL was releasable by heparin, indicating localization on cell surfaces. Within the islets, most of the LPL was associated with beta cells and could not be released by heparin, indicating that the enzyme remained mostly within cells. Staining for LPL was found also in the glucagon-producing alpha cells, both in embryos (E18) and in adult mice. Only small amounts of LPL were found together with GPIHBP1 within the capillaries of islets. Neither a high fat diet nor fasting/re-feeding markedly altered the distribution pattern of LPL or GPIHBP1 in mouse pancreas. Islets from ob/ob mice appeared completely deficient of LPL in the beta cells, while LPL-staining was normal in alpha cells and in the exocrine pancreas. Leptin treatment of ob/ob mice for 12 days reversed this pattern, so that most of the islets expressed LPL in beta cells.

CONCLUSIONS: We conclude that both LPL and GPIHBP1 are present in mouse pancreas, and that LPL expression in beta cells is dependent on leptin.

Place, publisher, year, edition, pages
BioMed Central, 2012
Keywords
Lipoprotein lipase, Diabetes mellitus, Islet cells, Exocrine pancreas, Endothelium, Ob/ob mice, High fat diet, Heparin, qPCR, Immunofluorescence
National Category
Nutrition and Dietetics Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-68286 (URN)10.1186/1472-6793-12-14 (DOI)23186339 (PubMedID)
Available from: 2013-04-15 Created: 2013-04-15 Last updated: 2018-06-08Bibliographically approved
Lindström, P. (2010). β-cell function in obese-hyperglycemic mice [ob/ob Mice]. Advances in Experimental Medicine and Biology, 654, 463-477
Open this publication in new window or tab >>β-cell function in obese-hyperglycemic mice [ob/ob Mice]
2010 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 654, p. 463-477Article in journal (Refereed) Published
Abstract [en]

This review summarizes key aspects of what has been learned about the physiology of pancreatic islets and leptin deficiency from studies in obese ob/ob mice. ob/ob Mice lack functional leptin. They are grossly overweight and hyperphagic particularly at young ages and develop severe insulin resistance with hyperglycemia and hyperinsulinemia. ob/ob Mice have large pancreatic islets. The beta-cells respond adequately to most stimuli, and ob/ob mice have been used as a rich source of pancreatic islets with high insulin release capacity. ob/ob Mice can perhaps be described as a model for the prediabetic state. The large capacity for islet growth and insulin release makes ob/ob mice a good model for studies on how beta-cells can cope with prolonged functional stress.

Place, publisher, year, edition, pages
Springer Netherlands, 2010
Keywords
ob/ob, Mice, Leptin, Growth
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-42396 (URN)10.1007/978-90-481-3271-3_20 (DOI)000278074700020 ()20217510 (PubMedID)
Note

ISBN: 978-90-481-3270-6 (Print), 978-90-481-3271-3 (Online)

Available from: 2011-04-07 Created: 2011-04-07 Last updated: 2018-06-08Bibliographically approved
Lindström, P. (2007). The physiology of obese-hyperglycemic mice [ob/ob mice].. ScientificWorldJournal, 7, 666-85
Open this publication in new window or tab >>The physiology of obese-hyperglycemic mice [ob/ob mice].
2007 (English)In: ScientificWorldJournal, ISSN 1537-744X, Vol. 7, p. 666-85Article in journal (Other academic) Published
Abstract [en]

This review summarizes key aspects of what has been learned about the physiology of leptin deficiency as it can be observed in obese-hyperglycemic ob/ob mice. These mice lack functional leptin. They are grossly overweight and hyperphagic, particularly at young ages, and develop severe insulin resistance. They have been used as a model for obesity and as a rich source of pancreatic islets with high insulin release capacity. The leptin deficiency manifests also with regard to immune function, the cardiovascular system including angiogenesis, supportive tissue function, malignancies, and reproductive function. ob/ob Mice are well suited for studies on the interaction between leptin and insulin, and for studies on initial aspects of metabolic disturbances leading to type-2 diabetes.

Keywords
Animals, Disease Models; Animal, Humans, Hyperglycemia/*pathology/*physiopathology, Insulin/*metabolism, Islets of Langerhans/*metabolism, Leptin/*deficiency, Mice, Mice; Obese, Obesity/pathology/*physiopathology
Identifiers
urn:nbn:se:umu:diva-8153 (URN)doi:10.1100/tsw.2007.117 (DOI)17619751 (PubMedID)
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2018-06-09Bibliographically approved
Gustavsson, N., Larsson-Nyrén, G. & Lindström, P. (2006). Cell specificity of Ca2+ response to tolbutamide is impaired in ß-cells from hyperglycemic mice. Journal of Endocrinology, 190(2), 461-470
Open this publication in new window or tab >>Cell specificity of Ca2+ response to tolbutamide is impaired in ß-cells from hyperglycemic mice
2006 (English)In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 190, no 2, p. 461-470Article in journal (Refereed) Published
Keywords
diabetes mellitus, pancreatic islets, insulin secretagogues, intact islets, amino-acids, delta-cells, b-cells, glucose, secretion, single
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-4886 (URN)10.1677/joe.1.06794 (DOI)
Available from: 2005-12-21 Created: 2005-12-21 Last updated: 2018-06-09Bibliographically approved
Persson-Sjögren, S., Forsgren, S. & Lindström, P. (2006). Vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide: effects on insulin release in isolated mouse islets in relation to metabolic status and age.. Neuropeptides, 40(4), 283-90
Open this publication in new window or tab >>Vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide: effects on insulin release in isolated mouse islets in relation to metabolic status and age.
2006 (English)In: Neuropeptides, ISSN 0143-4179, Vol. 40, no 4, p. 283-90Article in journal (Refereed) Published
Abstract [en]

Obesity and development of the metabolic syndrome is related to an increased parasympathetic tone and hyperinsulinemia. We have now studied the effects of age and metabolic status on glucose-induced insulin release stimulated by the neuropeptides vasoactive intestinal polypeptide (VIP; 10 nM) and pituitary adenylate cyclase activating polypeptide (PACAP; 10 nM), that are constituents of the parasympathetic nerves in the islets, and the cholinergic agonists acetylcholine (ACh; 10 microM) and carbachol (10 microM), in isolated islets from female obese ob/ob mice and lean mice. Both VIP and PACAP enhanced insulin secretion in islets from 4-week-old hyperglycemic ob/ob mice. VIP did not increase 11.1 mM glucose-induced insulin release in islets from 4-week-old lean normoglycemic mice and neither did PACAP in the absence of bicarbonate. The neuropeptides increased insulin release in islets from 9 to 10-month-old mice but VIP and PACAP had no effect in islets from very old mice. ACh had no effect in islets from 9 to 10-months and older ob/ob mice in the absence of bicarbonate. The combination of VIP and cholinergic agonists had an additive effect in islets from ob/ob mice, and PACAP combined with carbachol potentiated insulin release in islets from 4-week-old lean mice. VIP increased early phase insulin release in perifused islets from young mice. A higher concentration of theophylline was needed to potentiate glucose-induced insulin release in islets from young lean mice than in islets from old lean mice and ob/ob mice. The present results demonstrate age-related dynamics in the effects of neuropeptides affecting cAMP in pancreatic islets. We suggest that VIP and PACAP contribute to the developing metabolic syndrome in ob/ob mice by aggravating hyperinsulinemia.

Keywords
Aging/*physiology, Animals, Carbachol/pharmacology, Energy Metabolism, Female, Insulin/*metabolism, Islets of Langerhans/*drug effects/metabolism, Mice, Mice; Obese, Muscarinic Agonists/pharmacology, Pituitary Adenylate Cyclase-Activating Polypeptide/*pharmacology, Tissue Culture Techniques, Vasoactive Intestinal Peptide/*pharmacology
Identifiers
urn:nbn:se:umu:diva-12695 (URN)doi:10.1016/j.npep.2006.04.001 (DOI)16797701 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2018-06-09Bibliographically approved
Gustavsson, N., Larsson-Nyrén, G. & Lindström, P. (2005). Pancreatic beta cells from db/db mice show cell-specific [Ca2+]i and NADH responses to glucose but not to alpha-ketoisocaproic acid.. Pancreas, 31(3), 242-250
Open this publication in new window or tab >>Pancreatic beta cells from db/db mice show cell-specific [Ca2+]i and NADH responses to glucose but not to alpha-ketoisocaproic acid.
2005 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 31, no 3, p. 242-250Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: We recently showed that timing and magnitude of the glucose-induced cytoplasmic calcium [Ca2+]i response are reproducible and specific for the individual beta cell. We now wanted to identify which step(s) of stimulus-secretion coupling determine the cell specificity of the [Ca2+]i response and whether cell specificity is lost in beta-cells from diabetic animals. Besides glucose, we studied the effects of glyceraldehyde, a glycolytic intermediate, and alpha-ketoisocaproic acid (KIC), a mitochondrial substrate. METHODS: Early [Ca2+]i changes were studied stimulations in fura-2-labeled dispersed beta cells from lean, ob/ob, and db/db mice. Lag time and peak height were compared during 2 consecutive stimulations with the same stimulator. Nicotinamide adenine dinucleotide (NADH) responses to glucose and KIC were studied as a measure of metabolic flux. RESULTS: Both glyceraldehyde and KIC induced cell-specific temporal responses in lean mouse beta cells with a correlation between lag times for [Ca2+]i rise during the first and second stimulation. Beta cells from ob/ob and db/db mice showed cell-specific temporal [Ca2+]i responses to glucose and glyceraldehyde but not to KIC. Glucose induced cell-specific NADH responses in all 3 models, but KIC did so only in lean mouse [beta] cells. CONCLUSIONS: A cell-specific response may be induced at several steps of beta-cell stimulus-secretion coupling. Mitochondrial metabolism generates a cell-specific response in normal beta cells but not in db/db and ob/ob mouse beta cells.

Keywords
Animals, Body Weight, Calcium/*metabolism, Diabetes Mellitus; Type 2/*metabolism, Glucose/*pharmacology, Glycolysis/physiology, Insulin-Secreting Cells/cytology/drug effects/*metabolism, Keto Acids/*pharmacology, Mice, Mice; Obese, Mitochondria/metabolism, NAD/*metabolism, Signal Transduction/drug effects/physiology
Identifiers
urn:nbn:se:umu:diva-12233 (URN)16163056 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2018-06-09Bibliographically approved
Persson-Sjögren, S. & Lindström, P. (2004). Effects of cholinergic m-receptor agonists on insulin release in islets from obese and lean mice of different ages: the importance of bicarbonate.. Pancreas, 29(4), e90-9
Open this publication in new window or tab >>Effects of cholinergic m-receptor agonists on insulin release in islets from obese and lean mice of different ages: the importance of bicarbonate.
2004 (English)In: Pancreas, ISSN 1536-4828, Vol. 29, no 4, p. e90-9Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Decreased beta-cell function is often observed in older individuals and may predispose to the development of type 2 diabetes. We have studied the age-related effects of M-receptor agonism on insulin release in islets isolated from female ob/ ob and lean mice. METHODS: Islets were challenged with 11.1 or 16.7 mmol/L glucose in media with HCO3/CO2 (KRBH) or without (KRH). RESULTS: Acetylcholine (ACh) (10 micromol/L) increased glucose-induced insulin release in islets from 4- to 5-week-old ob/ob mice both in KRBH and KRH. In islets from 9- to 13-month-old ob/ob mice, 10 micromol/L ACh and 10 micromol/L carbachol enhanced insulin release in KRBH but not in KRH. ACh increased insulin release in islets from 4- to 5-week-old and 16-month-old lean mice incubated in KRH but not in islets from 24-month-old lean mice. The Na/H exchange inhibitor dimethylamiloride (100 micromol/L) did not affect insulin release stimulated by M-receptor agonists. Carbachol did not enhance glucose-induced insulin secretion in islets from 9- to 10-month-old ob/ob mice in the presence of low extracellular Na concentration. ACh stimulated cytoplasmic Ca mobilization in islets from 9- to 10-month-old mice also when bicarbonate was omitted. The results suggest that cholinergic signal transduction involving extracellular bicarbonate and Na is reduced with age in mouse pancreatic islets. CONCLUSION: Chronic hyperglycemia may add to the age-related decrease in M-receptor-mediated insulin release by affecting the buffering capacity of the islets through mechanisms other than amiloride-sensitive proton exchange.

Keywords
4;4'-Diisothiocyanostilbene-2;2'-Disulfonic Acid/pharmacology, Acetylcholine/pharmacology, Age Factors, Amiloride/pharmacology, Ammonium Chloride/pharmacology, Animals, Bicarbonates/*metabolism, Calcium/metabolism, Carbachol/pharmacology, Chlorides/metabolism, Cytoplasm/chemistry/metabolism, Female, Glucose/metabolism, Insulin/*metabolism, Islets of Langerhans/chemistry/cytology/*drug effects, Mice, Mice; Inbred BALB C, Mice; Obese, Muscarinic Agonists/*pharmacology, Obesity/*metabolism, Oxidation-Reduction, Sodium/metabolism, Thinness/*metabolism
Identifiers
urn:nbn:se:umu:diva-12236 (URN)15502638 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2018-06-09Bibliographically approved
Persson-Sjögren, S., Elmi, A. & Lindström, P. (2004). Effects of leptin, acetylcholine and vasoactive intestinal polypeptide on insulin secretion in isolated ob/ob mouse pancreatic islets. Acta Diabetologica, 41(3), 104-112
Open this publication in new window or tab >>Effects of leptin, acetylcholine and vasoactive intestinal polypeptide on insulin secretion in isolated ob/ob mouse pancreatic islets
2004 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 41, no 3, p. 104-112Article in journal (Refereed) Published
Abstract [en]

Obesity is often accompanied by hyperleptinemia, hyperinsulinemia, and an increased parasympathetic tone. Obese-hyperglycemic mice (Umeå ob/ob) have functional leptin receptors and a raised parasympathetic tone. We studied insulin release in islets isolated from 9-month-old severely obese ob/ob mice. Leptin (0.5-18 nM) did not affect insulin release together with 2.8-20 mM glucose. Leptin (18 microM) had no effect in the presence of low glucose (2.8-5.5 mM), but increased insulin secretion in islets challenged with 11.1 or 16.7 mM glucose. Leptin at 18 microM increased insulin secretion stimulated by the parasympathetic neurotransmitters acetylcholine (ACh; 10 microM) or vasoactive intestinal peptide (VIP; 10 nM), and by 5 mM theophylline or 2.5 microM forskolin. Overnight culture increased the effect of 18 microM leptin, but no effects were observed with 18 nM leptin. Pretreatment of islets with phorbol 12-myristate 13-acetate (PMA) did not suggest any involvement of protein kinase C. In summary, a high concentration of leptin stimulates insulin release in the presence of stimulatory concentrations of glucose alone and with parasympathetic neurotransmitters. Hyperleptinemia and increased parasympathetic stimulation may in part cause the hyperinsulinemia observed in obesity. This may aggravate insulin resistance and the abnormal metabolism in diabetes mellitus.

Place, publisher, year, edition, pages
Berlin: Springer, 2004
Keywords
leptin, insulin, acetylcholine, vasoactive intestinal polypeptide, ob/ob mouse
Identifiers
urn:nbn:se:umu:diva-22633 (URN)10.1007/s00592-004-0152-0 (DOI)15666577 (PubMedID)
Available from: 2009-05-14 Created: 2009-05-14 Last updated: 2018-06-08Bibliographically approved
Pakhtusova, N., Zaostrovskaya, L., Lindström, P. & Larsson-Nyrén, G. (2003). Cell-specific Ca2+ responses in glucose-stimulated single and aggregated ß-cells. Cell Calcium, 34(2), 121-129
Open this publication in new window or tab >>Cell-specific Ca2+ responses in glucose-stimulated single and aggregated ß-cells
2003 (English)In: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, Vol. 34, no 2, p. 121-129Article in journal (Refereed) Published
Abstract [en]

A rise in the cytoplasmic calcium concentration ([Ca(2+)](i)) is a key event for insulin exocytosis. We have recently found that the 'early [Ca(2+)](i) response' in single ob/ob mouse beta-cells is reproduced during consecutive glucose stimulations. It, therefore, appears that the response pattern is a characteristic of the individual beta-cell. We have now investigated if a cell-specific [Ca(2+)](i) response is a general phenomenon in rodent beta-cells, and if it can be observed when cells are functionally coupled. With the use of the fura-2 technique, we have studied the 'early [Ca(2+)](i) response' in single dispersed beta-cells, in beta-cell clusters of different size and in intact islets from the ob/ob mouse during repeated glucose stimulation (20mM). beta-Cells from lean mouse and rat, and intact islets from lean mouse were also investigated. Significant correlations between the first and second stimulation were found for the parameters lag-time for Ca(2+) rise (calculated as the time from start of stimulation of the cell until the first value above an extrapolated baseline), nadir of initial lowering (difference between the baseline and lowest [Ca(2+)](i) value), and peak height (difference between baseline and the highest [Ca(2+)](i) value of the first calcium peak) in single dispersed beta-cells, in 'single beta-cell within a small cluster', in clusters of medium and large size, and in single dispersed beta-cells from lean mouse and rat. The lag-times for Ca(2+) rise and peak heights were correlated within the pairs of stimulation also in intact ob/ob islets. In summary, despite a large heterogeneity of the 'early [Ca(2+)](i) response' among individual cells, the lag-time for [Ca(2+)](i) rise, the nadir of initial lowering and the height of the first peak response can be identified as cell-specific markers in beta-cells.

Place, publisher, year, edition, pages
Elsevier ScienceDirect, 2003
Keywords
Islets of Langerhans, Lag-time, Heterogeneity, Calcium, Cell specific
Identifiers
urn:nbn:se:umu:diva-4884 (URN)10.1016/S0143-4160(03)00027-7 (DOI)12810054 (PubMedID)
Available from: 2005-12-21 Created: 2005-12-21 Last updated: 2018-06-09Bibliographically approved
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