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Article ; Online: The Impact of Dietary Factors during Pregnancy on the Development of Islet Autoimmunity and Type 1 Diabetes: A Systematic Literature Review.

Johansen, Valdemar Brimnes Ingemann / Josefsen, Knud / Antvorskov, Julie Christine

2023 Volume 15, Issue 20

Abstract: Aims and hypothesis: The incidence of type 1 diabetes mellitus in children is considerably increasing in western countries. Thus, identification of the environmental determinants involved could ultimately lead to disease prevention. Here, we aimed to ... ...

Abstract	Aims and hypothesis: The incidence of type 1 diabetes mellitus in children is considerably increasing in western countries. Thus, identification of the environmental determinants involved could ultimately lead to disease prevention. Here, we aimed to systematically review (PROSPERO ID: CRD42022362522) the current evidence of the association between maternal dietary factors during gestation and the risk of developing type 1 diabetes and/or islet autoimmunity (IA) in murine and human offspring. Methods: In accordance with PRISMA guidelines, the present systematic review searched PubMed and Scopus ( Results: We found that the most investigated dietary factors in the present literature were gluten, dietary advanced glycosylated end products (dAGEs), vitamin D, fatty acids, and iron. The results concerning prenatal exposure to a gluten-free environment showed a consistently protective effect on the development of IA. Prenatal exposures to vitamin D and certain fatty acids appeared to protect against the development of IA, whereas in utero iron and fat exposures correlated with increased risks of IA. Conclusion: We conclude that a definite association is not established for most factors investigated as the literature represents a heterogeneous pool of data, although fetal exposures to some maternal dietary components, such as gluten, show consistent associations with increased risks of IA. We suggest that human prospective dietary intervention studies in both cohort and clinical settings are crucial to better evaluate critical and protective prenatal exposures from the maternal diet during pregnancy.
MeSH term(s)	Child ; Pregnancy ; Female ; Humans ; Animals ; Mice ; Diabetes Mellitus, Type 1/etiology ; Diabetes Mellitus, Type 1/prevention & control ; Diabetes Mellitus, Type 1/epidemiology ; Autoimmunity ; Islets of Langerhans ; Vitamin D ; Vitamins ; Fatty Acids ; Glutens ; Iron ; Autoantibodies ; Risk Factors
Chemical Substances	Vitamin D (1406-16-2) ; Vitamins ; Fatty Acids ; Glutens (8002-80-0) ; Iron (E1UOL152H7) ; Autoantibodies
Language	English
Publishing date	2023-10-11
Publishing country	Switzerland
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15204333
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Influence of sphingolipid enzymes on blood glucose levels, development of diabetes, and involvement of pericytes.

Buschard, Karsten / Josefsen, Knud / Krogvold, Lars / Gerling, Ivan / Dahl-Jørgensen, Knut / Pociot, Flemming

Diabetes/metabolism research and reviews

2024 Volume 40, Issue 3, Page(s) e3792

Abstract: Aims: Sulfatide is a chaperone for insulin manufacturing in beta cells. Here we explore whether the blood glucose values normally could be associated with this sphingolipid and especially two of its building enzymes CERS2 and CERS6. Both T1D and T2D ... ...

Abstract	Aims: Sulfatide is a chaperone for insulin manufacturing in beta cells. Here we explore whether the blood glucose values normally could be associated with this sphingolipid and especially two of its building enzymes CERS2 and CERS6. Both T1D and T2D have low blood sulfatide levels, and insulin resistance on beta cells at clinical diagnosis. Furthermore, we examined islet pericytes for sulfatide, and beta-cell receptors for GLP-1, both of which are related to the insulin production. Materials and methods: We examined mRNA levels in islets from the DiViD and nPOD studies, performed genetic association analyses, and histologically investigated pericytes in the islets for sulfatide. Results: Polymorphisms of the gene encoding the CERS6 enzyme responsible for synthesising dihydroceramide, a precursor to sulfatide, are associated with random blood glucose values in non-diabetic persons. This fits well with our finding of sulfatide in pericytes in the islets, which regulates the capillary blood flow in the islets of Langerhans, which is important for oxygen supply to insulin production. In the islets of newly diagnosed T1D patients, we observed low levels of GLP-1 receptors; this may explain the insulin resistance in their beta cells and their low insulin production. In T2D patients, we identified associated polymorphisms in both CERS2 and CERS6. Conclusions: Here, we describe several polymorphisms in sulfatide enzymes related to blood glucose levels and HbA1c in non-diabetic individuals. Islet pericytes from such persons contain sulfatide. Furthermore, low insulin secretion in newly diagnosed T1D may be explained by beta-cell insulin resistance due to low levels of GLP-1 receptors.
MeSH term(s)	Humans ; Islets of Langerhans ; Blood Glucose ; Diabetes Mellitus, Type 1 ; Sphingolipids ; Insulin Resistance/genetics ; Pericytes ; Sulfoglycosphingolipids ; Insulin ; Insulin, Regular, Human ; Diabetes Mellitus, Type 2/genetics ; Glucagon-Like Peptide 1 ; Glucose
Chemical Substances	Blood Glucose ; Sphingolipids ; Sulfoglycosphingolipids ; Insulin ; Insulin, Regular, Human ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2024-03-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1470192-3
ISSN	1520-7560 ; 1520-7552
ISSN (online)	1520-7560
ISSN	1520-7552
DOI	10.1002/dmrr.3792
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Article ; Online: Standardization parameters and synergism of source plant materials for the antidiabetic efficacy of the Rauvolfia-Citrus tea.

Campbell-Tofte, Joan / Mu, Huiling / Winther, Kaj / Mølgaard, Per / Belin, Nicolas / Josefsen, Knud

Fitoterapia

2024 , Page(s) 106004

Abstract: The introduction of glucagon-like peptide 1 (GLP-1)-based therapies has greatly improved the management of type 2 diabetes (T2D), as they ensure good blood glucose control and promote weight loss. Ingestion of standardized herbal remedies that promote ... ...

Abstract	The introduction of glucagon-like peptide 1 (GLP-1)-based therapies has greatly improved the management of type 2 diabetes (T2D), as they ensure good blood glucose control and promote weight loss. Ingestion of standardized herbal remedies that promote the same endogenous metabolic processes affected by the GLP-1-based treatments could provide cheaper alternatives in low- and middle-income countries, where there is currently an increase in the incidence of T2D. The focus in this study was to determine quality control parameters and the prime factors for the Rauvolfia-Citrus tea (RC-tea), as used in Nigerian traditional medicine to treat T2D. We have previously shown that the RC-tea that is made by boiling leaves of Rauvolfia vomitoria Afzel. and fruits of Citrus aurantium L. causes normalization of blood glucose and reduction of ectopic lipid accumulation in genetic diabetic (BKS-db) mice and in humans with T2D. The standardized RC-tea was made by boiling 40 g dried R. vomitoria foliage and 200 g fresh C. aurantium fruits per litre. The resulting golden-brown extract is free of microbial contamination, has pH 5 and contains ca. 230 mg naringin (marker compound for C. aurantium) and 25 mg robinin (marker compound for R. vomitoria) per litre. In addition, the herbal extract has the characteristic HPLC-DAD fingerprint where the marker compounds, naringin and robinin have retention times of approximately 26.3 min and 26.9 min, respectively, when using the outlined column and gradient elution conditions. Comparative evaluations of the antidiabetic effects of the standardized RC-tea and boiling water-extracts made with C. aurantium fruits alone (CA), R. vomitoria foliage alone (RV) and a combination of CA and RV, (CA + RV) in BKS-db mice, indicate that components from R. vomitoria foliage drive the reductions in ectopic lipid accumulation, since CA-treated mice lacked this effect. However, the normalization of blood glucose arises from combination of components from the two source plant materials as administration of either CA or RV resulted in hypoglycaemia. Interestingly, treatment with the CA + RV mixture, generated by mixing individually produced CA and RV plant extracts, resulted in hyperglycaemia, possibly due to drug-drug interactions of the blood glucose-reducing components in either plant extract. Hence, our data show that the best antidiabetic outcome results from the traditional practice of boiling R. vomitoria foliage and C. aurantium fruits together.
Language	English
Publishing date	2024-05-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	412385-2
ISSN	1873-6971 ; 0367-326X
ISSN (online)	1873-6971
ISSN	0367-326X
DOI	10.1016/j.fitote.2024.106004
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Article ; Online: Sulfatide and Longevity.

Buschard, Karsten / Josefsen, Knud / Råstam, Lennart / Lindblad, Ulf / Daka, Bledar

The journals of gerontology. Series A, Biological sciences and medical sciences

2022 Volume 77, Issue 9, Page(s) 1715–1716

MeSH term(s)	Longevity ; Sulfoglycosphingolipids
Chemical Substances	Sulfoglycosphingolipids
Language	English
Publishing date	2022-06-06
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glac126
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Article: Development of Type 1 Diabetes may occur through a Type 2 Diabetes mechanism.

Josefsen, Knud / Krogvold, Lars / Gerling, Ivan C / Pociot, Flemming / Dahl-Jørgensen, Knut / Buschard, Karsten

Frontiers in endocrinology

2022 Volume 13, Page(s) 1032822

Abstract: Background: At diagnosis of Type 1 Diabetes (T1D), 30% of the beta cells are dormant, i.e. alive, but inactive. This could reduce beta cell destruction, as cellular stress contributes to beta cell damage. However, the beta cells, that are still active, ... ...

Abstract	Background: At diagnosis of Type 1 Diabetes (T1D), 30% of the beta cells are dormant, i.e. alive, but inactive. This could reduce beta cell destruction, as cellular stress contributes to beta cell damage. However, the beta cells, that are still active, must produce more insulin and are therefore more vulnerable. The inactive beta cells represent a potential for restoring the insulin secretion. Methods: We analyzed the expression of selected genes in islets from live, newly diagnosed T1D patients from the DiViD study and organ doners with longer duration of T1D, type 2 diabetes (T2D), or no diabetes from the nPOD study. Additionally, analysis of polymorphisms was performed on all the investigated genes. Findings: Various possibilities were considered for the inactivity of the beta cells: secretion defect, fetal state, hibernation, and insulin resistance. We analyzed genes related to the ceramide and sphingomyelin synthesis and degradation, secretion, circadian rhythm and insulin action, and found changes in T1D islets that resemble fetal dedifferentiation and asynchrony. Furthermore, we found low levels of insulin receptor mRNA in the islets. No polymorphisms were found. Interpretation: Our findings suggest a secretion defect, but also fetal dedifferentiation and desynchronization in the inactive beta cells. Together with previous evidence, that predisposing factors for T2D are also present for T1D development, we raise the idea to treat individuals with ongoing T1D development prophylactically with T2D medicine like GLP-1 receptor agonists, metformin, or others, combined with anti-inflammatory compounds, in order to reactivate the dormant beta cells, and to prevent autoimmune destruction. T2D mechanisms during T1D development should be investigated further.
MeSH term(s)	Humans ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Islets of Langerhans/metabolism ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism
Chemical Substances	Insulin
Language	English
Publishing date	2022-12-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2022.1032822
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Article ; Online: Current Evidence on the Efficacy of Gluten-Free Diets in Multiple Sclerosis, Psoriasis, Type 1 Diabetes and Autoimmune Thyroid Diseases.

Passali, Moschoula / Josefsen, Knud / Frederiksen, Jette Lautrup / Antvorskov, Julie Christine

Nutrients

2020 Volume 12, Issue 8

Abstract: In this review, we summarize the clinical data addressing a potential role for gluten in multiple sclerosis (MS), psoriasis, type 1 diabetes (T1D) and autoimmune thyroid diseases (ATDs). Furthermore, data on the prevalence of celiac disease (CD) and ... ...

Abstract	In this review, we summarize the clinical data addressing a potential role for gluten in multiple sclerosis (MS), psoriasis, type 1 diabetes (T1D) and autoimmune thyroid diseases (ATDs). Furthermore, data on the prevalence of celiac disease (CD) and gluten-related antibodies in the above patient groups are presented. Adequately powered and properly controlled intervention trials investigating the effects of a gluten-free diet (GFD) in non-celiac patients with MS, psoriasis, T1D or ATDs are lacking. Only one clinical trial has studied the effects of a GFD among patients with MS. The trial found significant results, but it is subject to major methodological limitations. A few publications have found beneficial effects of a GFD in a subgroup of patients with psoriasis that were seropositive for anti-gliadin or deamidated gliadin antibodies, but no effects were seen among seronegative patients. Studies on the role of gluten in T1D are contradictive, however, it seems likely that a GFD may contribute to normalizing metabolic control without affecting levels of islet autoantibodies. Lastly, the effects of a GFD in non-celiac patients with ATDs have not been studied yet, but some publications report that thyroid-related antibodies respond to a GFD in patients with concomitant CD and ATDs. Overall, there is currently not enough evidence to recommend a GFD to non-celiac patients with MS, psoriasis, ATDs or T1D.
MeSH term(s)	Autoantibodies ; Autoimmunity ; Celiac Disease/diet therapy ; Comorbidity ; Diabetes Mellitus, Type 1/diet therapy ; Diabetes Mellitus, Type 1/immunology ; Diet, Gluten-Free/methods ; Gliadin/immunology ; Glutens/immunology ; Hashimoto Disease/drug therapy ; Hashimoto Disease/immunology ; Humans ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/immunology ; Prevalence ; Psoriasis/drug therapy ; Psoriasis/immunology
Chemical Substances	Autoantibodies ; Glutens (8002-80-0) ; Gliadin (9007-90-3)
Language	English
Publishing date	2020-08-01
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu12082316
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Article: Current Evidence on the Efficacy of Gluten-Free Diets in Multiple Sclerosis, Psoriasis, Type 1 Diabetes and Autoimmune Thyroid Diseases

Passali, Moschoula / Josefsen, Knud / Frederiksen, Jette Lautrup / Antvorskov, Julie Christine

Nutrients. 2020 Aug. 01, v. 12, no. 8

2020

Abstract	In this review, we summarize the clinical data addressing a potential role for gluten in multiple sclerosis (MS), psoriasis, type 1 diabetes (T1D) and autoimmune thyroid diseases (ATDs). Furthermore, data on the prevalence of celiac disease (CD) and gluten-related antibodies in the above patient groups are presented. Adequately powered and properly controlled intervention trials investigating the effects of a gluten-free diet (GFD) in non-celiac patients with MS, psoriasis, T1D or ATDs are lacking. Only one clinical trial has studied the effects of a GFD among patients with MS. The trial found significant results, but it is subject to major methodological limitations. A few publications have found beneficial effects of a GFD in a subgroup of patients with psoriasis that were seropositive for anti-gliadin or deamidated gliadin antibodies, but no effects were seen among seronegative patients. Studies on the role of gluten in T1D are contradictive, however, it seems likely that a GFD may contribute to normalizing metabolic control without affecting levels of islet autoantibodies. Lastly, the effects of a GFD in non-celiac patients with ATDs have not been studied yet, but some publications report that thyroid-related antibodies respond to a GFD in patients with concomitant CD and ATDs. Overall, there is currently not enough evidence to recommend a GFD to non-celiac patients with MS, psoriasis, ATDs or T1D.
Keywords	autoantibodies ; celiac disease ; clinical trials ; gliadin ; gluten ; gluten-free diet ; insulin-dependent diabetes mellitus ; patients ; prevalence ; psoriasis ; sclerosis ; seroprevalence
Language	English
Dates of publication	2020-0801
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-light
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu12082316
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: PDE12 in type 1 diabetes.

Tekin, Hasim / Josefsen, Knud / Krogvold, Lars / Dahl-Jørgensen, Knut / Gerling, Ivan / Pociot, Flemming / Buschard, Karsten

Scientific reports

2022 Volume 12, Issue 1, Page(s) 18149

Abstract: Type 1 diabetes (T1D) incidence is increased after COVID-19 infection in children under 18 years of age. Interferon-α-activated oligoadenylate synthetase and downstream RNAseL activation degrade pathogen RNA, but can also damage host RNA when RNAseL ... ...

Abstract	Type 1 diabetes (T1D) incidence is increased after COVID-19 infection in children under 18 years of age. Interferon-α-activated oligoadenylate synthetase and downstream RNAseL activation degrade pathogen RNA, but can also damage host RNA when RNAseL activity is poorly regulated. One such regulator is PDE12 which degrades 2'-5' oligoadenylate units, thereby decreasing RNAseL activity. We analyzed PDE12 expression in islets from non-diabetic donors, individuals with newly (median disease duration 35 days) and recently (5 years) diagnosed T1D, and individuals with type 2 diabetes (T2D). We also analyzed PDE12 single-nucleotide polymorphisms (SNPs) relative to T1D incidence. PDE12 expression was decreased in individuals with recently diagnosed T1D, in three of five individuals with newly diagnosed T1D, but not in individuals with T2D. Two rare PDE12 SNPs were found to have odds ratios of 1.80 and 1.74 for T1D development. We discuss whether decreased PDE12 expression after COVID-19 infection might be part of the up to 2.5-fold increase in T1D incidence.
MeSH term(s)	Child ; Humans ; Adolescent ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 2/genetics ; COVID-19/genetics ; Interferon-alpha ; RNA
Chemical Substances	Interferon-alpha ; RNA (63231-63-0)
Language	English
Publishing date	2022-10-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-22890-x
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Article ; Online: Antibiotic treatment during early childhood and risk of type 1 diabetes in children: A national birth cohort study.

Antvorskov, Julie Christine / Morgen, Camilla Schmidt / Buschard, Karsten / Jess, Tine / Allin, Kristine Højgaard / Josefsen, Knud

Pediatric diabetes

2020 Volume 21, Issue 8, Page(s) 1457–1464

Abstract: Objective/background: Antibiotics are widely used during childhood infections and influence the composition of the microbiota, which is established during the first years of life. Evidence from animal models of type 1 diabetes shows that antibiotics ... ...

Abstract	Objective/background: Antibiotics are widely used during childhood infections and influence the composition of the microbiota, which is established during the first years of life. Evidence from animal models of type 1 diabetes shows that antibiotics might accelerate disease progression, and altered intestinal microbiota has been reported in association with type 1 diabetes in humans. We aimed to test the hypothesis that early exposure to antibiotics (0-24 months of age) was associated with an increased risk of childhood type 1 diabetes development. Methods: We studied 75 615 mother-child dyads from the Danish National Birth Cohort. Information on the use of antibiotics during early childhood and type 1 diabetes development in childhood was available for all children via linkage to the Danish National Prescription Registry and the Danish National Patient Register, respectively. The mean follow-up time was 14.3 years (range 11.5 to 18.4 years, SD 1.4). Results: After adjustment for confounders, we found no association between antibiotic exposure and risk of type 1 diabetes (HR 1.26, 95% CI 0.89-1.79). The number of antibiotic courses during early childhood was not associated with type 1 diabetes development when analyzing for one (HR 1.31, 95% CI 0.87-1.99), two (HR 0.99, 95% CI 0.61-1.63), or 3 or more (HR 1.42, 95% CI 0.95-2.11) courses. Furthermore, no specific types of antibiotics (penicillins/beta-lactam antibacterials, sulfonamide/trimethroprim, or macrolides/lincosamides/streptogramins) were associated with increased risk of type 1 diabetes. Conclusion: Our nationwide cohort study suggests that postnatal exposure to antibiotics does not influence the development of childhood type 1 diabetes.
MeSH term(s)	Adult ; Anti-Bacterial Agents/therapeutic use ; Child Development ; Child, Preschool ; Diabetes Mellitus, Type 1/drug therapy ; Female ; Gastrointestinal Microbiome ; Humans ; Infant ; Infant, Newborn ; Male ; Registries ; Risk Factors
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2020-10-01
Publishing country	Denmark
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	1502504-4
ISSN	1399-5448 ; 1745-1426 ; 1399-543X
ISSN (online)	1399-5448
ISSN	1745-1426 ; 1399-543X
DOI	10.1111/pedi.13111
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Article ; Online: A Gluten-Free Diet during Pregnancy and Early Life Increases Short Chain Fatty Acid-Producing Bacteria and Regulatory T Cells in Prediabetic NOD Mice.

Johansen, Valdemar Brimnes Ingemann / Færø, Daisy / Buschard, Karsten / Kristiansen, Karsten / Pociot, Flemming / Kiilerich, Pia / Josefsen, Knud / Haupt-Jorgensen, Martin / Antvorskov, Julie Christine

Cells

2023 Volume 12, Issue 12

Abstract: The incidence of the autoimmune disease type 1 diabetes is increasing, likely caused by environmental factors. A gluten-free diet has previously been shown to ameliorate autoimmune diabetes in non-obese diabetic (NOD) mice and humans. Although the exact ... ...

Abstract	The incidence of the autoimmune disease type 1 diabetes is increasing, likely caused by environmental factors. A gluten-free diet has previously been shown to ameliorate autoimmune diabetes in non-obese diabetic (NOD) mice and humans. Although the exact mechanisms are not understood, interventions influencing the intestinal microbiota early in life affect the risk of type 1 diabetes. Here, we characterize how NOD mice that are fed a gluten-free (GF) diet differ from NOD mice that are fed a gluten-containing standard (STD) diet in terms of their microbiota composition by 16S rRNA gene amplicon sequencing and pancreatic immune environment by real-time quantitative PCR at the prediabetic stage at 6 and 13 weeks of age. Gut microbiota analysis revealed highly distinct microbiota compositions in both the cecum and the colon of GF-fed mice compared with STD-fed mice. The microbiotas of the GF-fed mice were characterized by an increased
MeSH term(s)	Animals ; Female ; Mice ; Pregnancy ; Bacteria ; Diabetes Mellitus, Type 1/prevention & control ; Diet, Gluten-Free ; Mice, Inbred NOD ; Prediabetic State/prevention & control ; RNA, Ribosomal, 16S/genetics ; T-Lymphocytes, Regulatory ; Gastrointestinal Microbiome
Chemical Substances	RNA, Ribosomal, 16S
Language	English
Publishing date	2023-06-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12121567
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