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Kullenberg, H., Wibom, M., Kumlin, M., Nyström, T. & Svedberg, M. (2023). Associations between the use of metformin and behavioral and psychological symptoms in patients with Alzheimer's disease, and type 2 diabetes mellitus: A register-based study. Current Alzheimer Research, 20(2), 109-119
Open this publication in new window or tab >>Associations between the use of metformin and behavioral and psychological symptoms in patients with Alzheimer's disease, and type 2 diabetes mellitus: A register-based study
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2023 (English)In: Current Alzheimer Research, ISSN 1567-2050, E-ISSN 1875-5828, Vol. 20, no 2, p. 109-119Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Metformin, the first-line anti-diabetic drug treatment in patients with type 2 diabetes mellitus (T2DM), is suggested to be anti-inflammatory, antioxidative, and improve cognitive function, making it a promising contribution to treating Alzheimer´s disease (AD). However, the effect of metformin on behavioral and psychological symptoms of dementia (BPSD) in patients with AD has not been explored.

OBJECTIVE: To investigate the associations between metformin and BPSD in patients with AD and T2DM and explore possible interaction with other antidiabetic drugs.

METHODS: This cross-sectional study was based on data from the Swedish BPSD register. A total of 3745 patients with AD and antidiabetic drug treatment were included. Associations and interactions between antidiabetic drugs and BPSD were investigated by binary logistic regression.

RESULTS: The use of metformin was associated with lower odds for symptoms of depression (OR 0.77, CI (95%) 0.61-0.96, p = 0.022) and anxiety (OR 0.74, CI (95%) 0.58-0.94, p = 0.015) after adjustment for age, gender, specific diagnosis, and drugs. We could not demonstrate this association with another antidiabetic drug. Interaction effects were limited to an increasing association in eating and appetite disorders using metformin and other antidiabetic drugs (i.e., drugs other than insulin, sulfonylurea, or dipeptidyl peptidase-4 inhibitors).

CONCLUSION: The result of this study suggests that metformin could be beneficial for patients diagnosed with AD, other than for blood glucose control. Although, more knowledge is needed before assigning metformin a role in treating BPSD.

Keywords
Alzheimer' acute;s disease, BPSD, Depression, Metformin, Neuropsychiatric inventory, Register data, Type 2 diabetes mellitus
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:shh:diva-4925 (URN)10.2174/1567205020666230522102641 (DOI)37221687 (PubMedID)
Available from: 2023-05-26 Created: 2023-05-26 Last updated: 2023-11-06Bibliographically approved
Kullenberg, H., Nyström, T., Kumlin, M. & Svedberg, M. (2023). Correlation between insulin-degrading enzyme versus total tau and selected cytokines in patients with Alzheimer´s disease compared to non-demented controls.. Neuroendocrinology Letters, 44(4), 199-205
Open this publication in new window or tab >>Correlation between insulin-degrading enzyme versus total tau and selected cytokines in patients with Alzheimer´s disease compared to non-demented controls.
2023 (English)In: Neuroendocrinology Letters, ISSN 2354-4716, Vol. 44, no 4, p. 199-205Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: It has been increasingly recognized that the pathological progress of Alzheimer´s disease (AD) is connected to metabolic function and inflammation. Insulin-degrading enzyme (IDE) is essential for glucose metabolism and the degradation of amyloid-β. We aimed to explore the associations between IDE, total tau, and cytokines levels in plasma from subjects with AD and non-demented controls.

METHODS AND MATERIAL: Plasma samples (18 patients diagnosed with AD and 6 non-demented controls) from the Netherlands Brain Bank were used to analyze IDE levels and total tau with an enzyme-linked immunosorbent assay. Cytokines were analyzed with Luminex custom plex assays for interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α). Results were analyzed using the Mann-Whitney U and Spearman´s rank correlation tests.

RESULTS: Total tau in plasma was significantly increased in AD subjects compared to non-demented control subjects (p = 0.044). Total tau was positively correlated with IDE levels in plasma in all subjects (r = 0.494, p = 0.017). Significant correlations could be demonstrated between plasma levels of IDE and IL-6 (r = 0.546, p = 0.019), IL-8 (r = 0.664, p = 0.003), IL-10 (r = 0.833, p < 0.001), and TNF-α (r = 0.633, p = 0.005) in subjects with AD, but not in non-demented controls.

CONCLUSION: Results from this study suggest that plasma IDE levels may be associated with inflammation and neurodegeneration and could potentially be a target for future diagnostic and treatment strategies.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:shh:diva-5043 (URN)37466059 (PubMedID)
Available from: 2023-10-27 Created: 2023-10-27 Last updated: 2024-02-01Bibliographically approved
Kullenberg, H., Rossen, J., Johansson, U.-B., Hagströmer, M., Nyström, T., Kumlin, M. & Svedberg, M. (2023). Correlations between insulin-degrading enzyme and metabolic markers in patients diagnosed with type 2 diabetes, Alzheimer's disease, and healthy controls: A comparative study. Endocrine
Open this publication in new window or tab >>Correlations between insulin-degrading enzyme and metabolic markers in patients diagnosed with type 2 diabetes, Alzheimer's disease, and healthy controls: A comparative study
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2023 (English)In: Endocrine, ISSN 1355-008X, E-ISSN 1559-0100Article in journal (Refereed) Epub ahead of print
Abstract [en]

PURPOSE: This study aimed to explore correlations between insulin-degrading enzyme (IDE) and markers of metabolic function in a group of patients diagnosed with type 2 diabetes mellitus (T2DM) or Alzheimer's disease (AD) and metabolically healthy volunteers.

METHOD: We included 120 individuals (47 with T2DM, 9 with AD, and 64 healthy controls). Serum levels of IDE were measured with commercial kits for ELISA. Differences in IDE levels between groups were analyzed with non-parametric ANCOVA, and correlations were analyzed with Spearman's rank correlations. We also investigated the influence of age, sex, and the use of insulin on the correlation using a non-parametric version of partial correlation.

RESULTS: Patients diagnosed with T2DM had higher IDE levels than patients diagnosed with AD and healthy controls after adjustment for age and sex. IDE was increasingly associated with body mass index (BMI), fasting blood glucose, C-peptide, hemoglobin A1c (HbA1c), insulin resistance, and triglycerides. In stratified analyses, we found a decreasing partial correlation between IDE and HbA1c in patients diagnosed with AD and a decreasing partial correlation between IDE and C-peptide in healthy controls. In patients diagnosed with T2DM, we found no partial correlations.

CONCLUSION: These results indicate that IDE is essential in metabolic function and might reflect metabolic status, although it is not yet a biomarker that can be utilized in clinical practice. Further research on IDE in human blood may provide crucial insights into the full function of the enzyme.

Keywords
Alzheimer’s disease, Insulin resistance, Insulin-degrading enzyme, Metabolic disorder, Serum, Type 2 diabetes mellitus
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:shh:diva-5079 (URN)10.1007/s12020-023-03603-4 (DOI)37980298 (PubMedID)
Available from: 2023-11-23 Created: 2023-11-23 Last updated: 2023-11-23Bibliographically approved
Nordström, A., Jangard, M., Svedberg, M., Ryott, M. & Kumlin, M. (2023). Distinct eicosanoid patterns in severe recalcitrant nasal polyposis. International Forum of Allergy & Rhinology, 13(11), 2043-2054
Open this publication in new window or tab >>Distinct eicosanoid patterns in severe recalcitrant nasal polyposis
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2023 (English)In: International Forum of Allergy & Rhinology, ISSN 2042-6984, Vol. 13, no 11, p. 2043-2054Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Although altered eicosanoid levels are related to disease severity in chronic rhinosinusitis with nasal polyps (CRSwNP), identifying patients prone to recurrent NPs is still difficult. We investigated levels of nasally secreted eicosanoids before and after NP surgery in patients with or without NP recurrence and explored potential endotypes based on pre-surgical eicosanoid levels.

METHODS: Levels of leukotriene (LT) E4 , LTB4 , prostaglandin (PG) D2 , PGE2 and 15(S) hydroxyeicosatetraenoic acid (15(S)-HETE) were measured in nasal secretions with specific immunoassays at pre-surgery (n = 38) and six- and 12-months post-surgery (n = 35) where NP recurrence was identified endoscopically. Pre- and post-surgical levels were compared between patients with and without NP recurrence. Eicosanoid patterns among patients were explored with cluster analysis and evaluated with clinical parameters.

RESULTS: Patients with recurrent NPs had pronounced pre-surgical levels of nasal 15(S)-HETE, PGD2 and LTE4 . From pre-surgery to 12-months after, NP recurrence was associated with significant decrease of 15(S)-HETE and PGD2 relative to non-recurrence whereas levels of LTE4 decreased at six-months but increased again at 12-months. Clustering revealed three potential endotypes. Cluster 1 and 3 featured high and low eicosanoid levels, respectively. Cluster 2 had higher levels of LTE4 and PGD2 , lower levels of PGE2 and LTB4 , and more cases of recurrent NPs and previous NP surgeries.

CONCLUSION: Elevated nasal LTE4 , 12-month post-surgery, in NP recurrent subjects suggests that postoperative LTE4 measurements may indicate rapid NP regrowth. A distinct nasal eicosanoid profile may be used for the identification of the most severe recalcitrant patients in need of targeted immunomodulatory therapies. This article is protected by copyright. All rights reserved.

Keywords
Biomarker, Chronic Rhinosinusitis, Disease Severity, Eosinophilic rhinitis and nasal polyposis, Post-Operative
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-4917 (URN)10.1002/alr.23181 (DOI)37179460 (PubMedID)
Available from: 2023-05-25 Created: 2023-05-25 Last updated: 2023-12-21Bibliographically approved
Nordström, A., Jangard, M., Svedberg, M., Ryott, M. & Kumlin, M. (2022). Altered eicosanoid profile in association with nasal polyp severity in patients with chronic rhinosinusitis. In: : . Paper presented at 20th ERS Lung Science Conference, Estoril, Portugal, 10-13 mars 2022 (digital konferens).
Open this publication in new window or tab >>Altered eicosanoid profile in association with nasal polyp severity in patients with chronic rhinosinusitis
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2022 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-4717 (URN)
Conference
20th ERS Lung Science Conference, Estoril, Portugal, 10-13 mars 2022 (digital konferens)
Available from: 2023-01-18 Created: 2023-01-18 Last updated: 2023-01-18Bibliographically approved
Kullenberg, H., Wibom, M., Nyström, T., Kumlin, M. & Svedberg, M. (2022). Behavioral and psychological symptoms in patients with cognitive disease and diabetes: A register based study. In: : . Paper presented at The 32nd Alzheimer Europe Conference, Bukarest, Rumänien, 17-19 oktober 2022.
Open this publication in new window or tab >>Behavioral and psychological symptoms in patients with cognitive disease and diabetes: A register based study
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2022 (English)Conference paper, Oral presentation only (Other academic)
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:shh:diva-4707 (URN)
Conference
The 32nd Alzheimer Europe Conference, Bukarest, Rumänien, 17-19 oktober 2022
Available from: 2023-01-13 Created: 2023-01-13 Last updated: 2023-01-13Bibliographically approved
Nordström, A., Jangard, M., Svedberg, M., Ryott, M. & Kumlin, M. (2022). Exploring nasally secreted eicosanoids as prognostic markers for nasal polyp recurrence in chronic rhinosinusitis. In: : . Paper presented at 17th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases, New Orleans, USA, 30 oktober-2 november 2022.
Open this publication in new window or tab >>Exploring nasally secreted eicosanoids as prognostic markers for nasal polyp recurrence in chronic rhinosinusitis
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2022 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-4715 (URN)
Conference
17th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases, New Orleans, USA, 30 oktober-2 november 2022
Available from: 2023-01-18 Created: 2023-01-18 Last updated: 2023-01-18Bibliographically approved
Kullenberg, H., Rossen, J., Johansson, U.-B., Hagströmer, M., Nyström, T., Kumlin, M. & Svedberg, M. (2022). Increased levels of insulin-degrading enzyme in patients with type 2 diabetes mellitus. Endocrine, 77(3), 561-565
Open this publication in new window or tab >>Increased levels of insulin-degrading enzyme in patients with type 2 diabetes mellitus
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2022 (English)In: Endocrine, ISSN 1355-008X, E-ISSN 1559-0100, Vol. 77, no 3, p. 561-565Article in journal (Refereed) Epub ahead of print
Abstract [en]

PURPOSE: Decreasing levels of serum insulin-degrading enzyme (IDE) have been associated with an increased risk for Alzheimer´s disease (AD) in patients with type 2 diabetes mellitus (T2DM). Research on serum IDE levels in patients with T2DM is sparse and the aim of this study was to explore serum levels of IDE in patients with T2DM.

METHOD: Blood serum samples were obtained from a biobank. Samples from subjects with T2DM and without metabolic disease were divided into subgroups; lifestyle treatment (n = 10), oral antidiabetic treatment (n = 17), insulin treatment (n = 20) and metabolically healthy controls (n = 18). Serum levels of IDE were analysed using specific ELISA assays.

RESULTS: Serum levels of IDE were elevated in subjects with T2DM compared to metabolically healthy individuals (p = 0.033). No significant differences were detected between treatment subgroups.

CONCLUSION: The present study indicates that patients with T2DM have increased serum IDE levels, compared to metabolically healthy individuals. However, for IDE to be clinically useful as a biomarker, its full function and possible use needs to be further elucidated in larger studies showing reproducible outcomes.

Keywords
Insulin resistance, Insulin-degrading enzyme, Type 2 diabetes mellitus
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:shh:diva-4539 (URN)10.1007/s12020-022-03123-7 (DOI)35751775 (PubMedID)
Available from: 2022-12-14 Created: 2022-12-14 Last updated: 2023-11-06Bibliographically approved
Nordström, A., Jangard, M., Svedberg, M., Ryott, M. & Kumlin, M. (2022). Levels of eicosanoids in nasal secretions and urine associated with nasal polyp severity in chronic rhinosinusitis. In: : . Paper presented at 8th European Workshop on Lipid Mediators, Stockholm, 29 juni-1 juli 2022.
Open this publication in new window or tab >>Levels of eicosanoids in nasal secretions and urine associated with nasal polyp severity in chronic rhinosinusitis
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2022 (English)Conference paper, Oral presentation only (Other academic)
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-4716 (URN)
Conference
8th European Workshop on Lipid Mediators, Stockholm, 29 juni-1 juli 2022
Available from: 2023-01-18 Created: 2023-01-18 Last updated: 2023-01-18Bibliographically approved
Nordström, A., Jangard, M., Svedberg, M., Ryott, M. & Kumlin, M. (2022). Levels of eicosanoids in nasal secretions associated with nasal polyp severity in chronic rhinosinusitis. Prostaglandins, Leukotrienes and Essential Fatty Acids, 184, Article ID 102474.
Open this publication in new window or tab >>Levels of eicosanoids in nasal secretions associated with nasal polyp severity in chronic rhinosinusitis
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2022 (English)In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 184, article id 102474Article in journal (Refereed) Published
Abstract [en]

Severe nasal polyposis and mucosal inflammation, in patients with chronic rhinosinusitis (CRS) may include a dysregulated eicosanoid profile, but a clinical role for eicosanoids in CRS with nasal polyps (NP; CRSwNP) remains to be elucidated. This study focused on assessing levels and clinical implications of inflammatory mediators in nasal secretions and urine from patients with different NP severity or Aspirin Exacerbated Respiratory Disease (AERD). Levels of leukotrienes E4 and B4, prostaglandins D2 and E2 as well as 15(S)-hydroxyeicosatetraenoic acid were measured with enzyme immunoassays and cytokines with magnetic bead immunoassays. Patients with CRSwNP were subdivided based on NP score; CRSwNP-low (NP score ≤ 4, n = 11) or CRSwNP-high (NP score ≥ 5, n = 32) and compared to CRS without polyps (CRSsNP, n = 12), CRSwNP-AERD (n = 11) and individuals without CRS (n = 25). Smell test score, fractional exhaled nitric oxide (FeNO), blood eosinophils and Sinonasal outcome test-22 were assessed as clinical markers. Leukotriene E4, prostaglandin D2 and 15(S)-hydroxyeicosatetraenoic acid in nasal secretions correlated with NP score. Nasal leukotriene E4 also correlated with FeNO and smell test score, with highest levels found in CRSwNP-AERD. Levels of prostaglandin D2 in nasal secretion as well as urinary levels of the prostaglandin D2 metabolite 11β-prostaglandin F differed between CRSNP-high and CRSwNP-low. Urinary 11β-prostaglandin F was associated with asthma comorbidity whereas a similar association with prostaglandin D2 in nasal secretions was not observed. In conclusion, subdividing patients based on NP severity in combination with analysis of eicosanoids in non-invasively collected nasal secretions, may have clinical implications when assessing CRS disease severity.

Keywords
AERD, CRS, Leukotriene, Nasal polyp score, Nasal secretions, Prostaglandin
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:shh:diva-4584 (URN)10.1016/j.plefa.2022.102474 (DOI)35917595 (PubMedID)
Available from: 2022-09-27 Created: 2022-09-27 Last updated: 2022-09-27Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8101-9915

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