uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Halldin, Maria
Alternative names
Publications (10 of 12) Show all publications
Katsu-Jimenez, Y., Vazquez-Calvo, C., Maffezzini, C., Halldin, M., Peng, X., Freyer, C., . . . Arner, E. S. J. (2019). Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate. Diabetes, 68(4), 709-723
Open this publication in new window or tab >>Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate
Show others...
2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 4, p. 709-723Article in journal (Refereed) Published
Abstract [en]

Thioredoxin-interacting protein (TXNIP) is an -arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes -cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-381116 (URN)10.2337/db18-0557 (DOI)000462053100004 ()30755400 (PubMedID)
Funder
Swedish Research Council, 2016-01082Swedish Research Council, VR521-201-2571Swedish Research Council, 2016-02179Swedish Research Council, 2013-765Swedish Research Council, 2014-2603Knut and Alice Wallenberg Foundation, KAW 2013.0026Knut and Alice Wallenberg Foundation, KAW 2014.0293Knut and Alice Wallenberg Foundation, KAW 2015.0063Swedish Cancer Society, 2015/238Stockholm County Council, 20170022Swedish Diabetes AssociationThe Karolinska Institutet's Research Foundation
Available from: 2019-04-05 Created: 2019-04-05 Last updated: 2019-04-05Bibliographically approved
Stenlid, R., Manell, H., Halldin, M., Kullberg, J., Ahlström, H., Manukyan, L., . . . Forslund, A. (2018). High DPP-4 concentrations in adolescents are associated with low intact GLP-1. Journal of Clinical Endocrinology and Metabolism, 103(8), 2958-2966
Open this publication in new window or tab >>High DPP-4 concentrations in adolescents are associated with low intact GLP-1
Show others...
2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 8, p. 2958-2966Article in journal (Refereed) Published
Abstract [en]

Context: Dipeptidyl Peptidase-4 (DPP-4) metabolizes glucagon-like peptide-1 (GLP-1) and increased DPP4 levels are associated with obesity and visceral adiposity in adults.

Objective: Investigating DPP-4 levels in adolescents and association with, firstly, circulating intact GLP-1 levels and glucose tolerance, secondly, BMI, and, thirdly visceral, subcutaneous and liver fat compartments.

Design: Cross-sectional study, July 2012 to April 2015.

Setting: Pediatric obesity clinic, Uppsala University Hospital.

Patients and participants: Children and adolescents with obesity (n=59) and lean controls (n=21), age 8-18.

Main outcome measures: BMI SDS, fasting plasma concentrations of DPP-4, total and intact GLP-1, fasting and OGTT concentrations of glucose and visceral (VAT) and subcutaneous (SAT) adipose tissue volumes and liver fat fraction.

Results: Plasma DPP-4 decreased with age both in obese (41 ng/ml per year) and lean subjects (48 ng/ml per year). Plasma DPP-4 was higher in males both in the obesity and lean group. When adjusting for age and sex, plasma DPP-4 was negatively associated with intact GLP-1 at fasting, B=-12.3, 95% CI [-22.9, -1.8] and during OGTT, B=-12.1, 95% CI [-22.5, -1.7]. No associations were found between DPP-4 and plasma glucose measured at fasting or after a 2-hour OGTT. Plasma DPP-4 was 19% higher in the obese subjects. Among adipose tissue compartments the strongest association was with VAT, B=0.05, 95% CI [-0.02, 0.12].

Conclusions: In adolescents, high plasma DPP-4 concentrations are associated with low proportion of intact GLP-1, high BMI, young age and male sex. The observed associations are compatible with an increased metabolism of GLP-1 in childhood obesity.

Place, publisher, year, edition, pages
Endocrine Society, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354234 (URN)10.1210/jc.2018-00194 (DOI)000442236900022 ()29850829 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 279153Swedish Diabetes Association, DIA 2016-146Ernfors Foundation, 160504Swedish Research Council, 2016-01040EXODIAB - Excellence of Diabetes Research in SwedenErik, Karin och Gösta Selanders Foundation
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2019-03-28Bibliographically approved
Dalin, F., Nordling Eriksson, G., Dahlqvist, P., Hallgren, Å., Wahlberg, J., Ekwall, O., . . . Bensing, S. (2017). Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study. Journal of Clinical Endocrinology and Metabolism, 102(2), 379-389
Open this publication in new window or tab >>Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study
Show others...
2017 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 379-389Article in journal (Refereed) Published
Abstract [en]

CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

Place, publisher, year, edition, pages
Oxford University Press, 2017
National Category
Medical and Health Sciences Endocrinology and Diabetes
Research subject
Endocrinology and Diabetology
Identifiers
urn:nbn:se:uu:diva-318344 (URN)10.1210/jc.2016-2522 (DOI)000397240900009 ()27870550 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201167Novo Nordisk, NNF13OC0005975 NNF15OC0015922 NNF14OC0011003Åke Wiberg FoundationTore Nilsons Stiftelse för medicinsk forskningMarianne and Marcus Wallenberg FoundationSwedish Society of MedicineTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseSwedish Research CouncilThe Karolinska Institutet's Research FoundationSwedish Society for Medical Research (SSMF)Stockholm County Council
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2019-02-26Bibliographically approved
Fahnehjelm, K. T., Liu, Y., Olsson, D., Amren, U., Haglind, C. B., Holmström, G., . . . Nordenstrom, A. (2016). Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function. Acta Paediatrica, 105(12), 1451-1460
Open this publication in new window or tab >>Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function
Show others...
2016 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, no 12, p. 1451-1460Article in journal (Refereed) Published
Abstract [en]

Aim: There have been few studies on long-term electroretinographic findings in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). This study correlated long-term electroretinographic findings with age, metabolic control and clinical symptoms. Methods: We examined 12 Swedish patients with LCHADD. Visual acuity testing, fundus examinations, optical coherence tomography and electroretinography were performed. The results were correlated to age, the levels of 3-hydroxyacylcarnitine and acylcarnitine and clinical metabolic control. Results: Blindness or moderate visual impairment was found in two patients. Retinal pigmentation, atrophy and fibrosis were present in 11, seven and one of the patients, respectively, and optical coherence tomography showed retinal thinning in three of the six patients examined. Electroretinography was performed on 11 of the 12 patients. It was pathological, with reduced rod and cone responses, in five patients, subnormal in four and was related to poor clinical metabolic control and severe neonatal symptoms. Repeated electroretinographies revealed reduced function with increasing age. Conclusion: More than 80% of the LCHADD patients developed pathological or subnormal retinal function. This was more pronounced in patients with neonatal symptoms, but ameliorated by strict dietary treatment. Annual ophthalmological follow-ups, with electroretinography every second or third year, are recommended.

Keywords
Chorioretinal atrophy, Electroretinography, Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-312045 (URN)10.1111/apa.13536 (DOI)000387793000030 ()27461099 (PubMedID)
Available from: 2017-01-05 Created: 2017-01-04 Last updated: 2017-11-29Bibliographically approved
Haglind, C. B., Ask, S., von Dobeln, U., Engvall, M., Ekblom, O., Stenlid, M. H. & Nordenström, A. (2015). Energy expenditure and lipid metabolism in very long-chain Acyl-CoA dehydrogenase (VLCAD) deficiency. Paper presented at 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD), MAR 28-31, 2015, Salt Lake City, UT. Molecular Genetics and Metabolism, 114(3), 333-333
Open this publication in new window or tab >>Energy expenditure and lipid metabolism in very long-chain Acyl-CoA dehydrogenase (VLCAD) deficiency
Show others...
2015 (English)In: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 114, no 3, p. 333-333Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-252399 (URN)000351191800047 ()
Conference
38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD), MAR 28-31, 2015, Salt Lake City, UT
Available from: 2015-05-07 Created: 2015-05-06 Last updated: 2018-01-11Bibliographically approved
Haglind, C. B., Nordenström, A., Ask, S., von Döbeln, U., Gustafsson, J. & Stenlid, M. H. (2015). Increased and early lipolysis in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency during fast. Journal of Inherited Metabolic Disease, 38(2), 315-322
Open this publication in new window or tab >>Increased and early lipolysis in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency during fast
Show others...
2015 (English)In: Journal of Inherited Metabolic Disease, ISSN 0141-8955, E-ISSN 1573-2665, Vol. 38, no 2, p. 315-322Article in journal (Refereed) Published
Abstract [en]

Children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) have a defect in the degradation of long-chain fatty acids and are at risk of hypoketotic hypoglycemia and insufficient energy production as well as accumulation of toxic fatty acid intermediates. Knowledge on substrate metabolism in children with LCHAD deficiency during fasting is limited. Treatment guidelines differ between centers, both as far as length of fasting periods and need for night feeds are concerned. To increase the understanding of fasting intolerance and improve treatment recommendations, children with LCHAD deficiency were investigated with stable isotope technique, microdialysis, and indirect calometry, in order to assess lipolysis and glucose production during 6 h of fasting. We found an early and increased lipolysis and accumulation of long chain acylcarnitines after 4 h of fasting, albeit no patients developed hypoglycemia. The rate of glycerol production, reflecting lipolysis, averaged 7.7 ± 1.6 µmol/kg/min, which is higher compared to that of peers. The rate of glucose production was normal for age; 19.6 ± 3.4 µmol/kg/min (3.5 ± 0.6 mg/kg/min). Resting energy expenditure was also normal, even though the respiratory quotient was increased indicating mainly glucose oxidation. The results show that lipolysis and accumulation of long chain acylcarnitines occurs before hypoglycemia in fasting children with LCHAD, which may indicate more limited fasting tolerance than previously suggested.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-238291 (URN)10.1007/s10545-014-9750-3 (DOI)000350360200013 ()25141826 (PubMedID)
Note

Correction in: Journal of Inherited Metabolic Disease, vol. 38, issue 2, pages 377-377.

DOI: 10.1007/s10545-014-9786-4

ISI: 000350360200026

Available from: 2014-12-11 Created: 2014-12-11 Last updated: 2017-12-05Bibliographically approved
Stenlid, M. H., Ahlsson, F., Forslund, A. H., von Döbeln, U. & Gustafsson, J. (2014). Energy substrate metabolism in pyruvate dehydrogenase complex deficiency. Journal of Pediatric Endocrinology & Metabolism (JPEM), 27(11-12), 1059-1064
Open this publication in new window or tab >>Energy substrate metabolism in pyruvate dehydrogenase complex deficiency
Show others...
2014 (English)In: Journal of Pediatric Endocrinology & Metabolism (JPEM), ISSN 0334-018X, E-ISSN 2191-0251, Vol. 27, no 11-12, p. 1059-1064Article in journal (Refereed) Published
Abstract [en]

Pyruvate dehydrogenase (PDH) deficiency is an inherited disorder of carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. In order to provide energy for the brain, a ketogenic diet has been tried. Both the disorder and the ketogenic therapy may influence energy production. The aim of the study was to assess hepatic glucose production, lipolysis and resting energy expenditure (REE) in an infant, given a ketogenic diet due to neonatal onset of the disease. Lipolysis and glucose production were determined for two consecutive time periods by constant-rate infusions of [1,1,2,3,3-2H5]-glycerol and [6,6-2H2]-glucose. The boy had been fasting for 2.5 h at the start of the sampling periods. REE was estimated by indirect calorimetry. Rates of glucose production and lipolysis were increased compared with those of term neonates. REE corresponded to 60% of normal values. Respiratory quotient (RQ) was increased, indicating a predominance of glucose oxidation. Blood lactate was within the normal range. Several mechanisms may underlie the increased rates of glucose production and lipolysis. A ketogenic diet will result in a low insulin secretion and reduced peripheral and hepatic insulin sensitivity, leading to increased production of glucose and decreased peripheral glucose uptake. Surprisingly, RQ was high, indicating active glucose oxidation, which may reflect a residual enzyme activity, sufficient during rest. Considering this, a strict ketogenic diet might not be the optimal choice for patients with PDH deficiency. We propose an individualised diet for this group of patients aiming at the highest glucose intake that each patient will tolerate without elevated lactate levels.

National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-238381 (URN)10.1515/jpem-2013-0423 (DOI)000345022900006 ()24914713 (PubMedID)
Available from: 2014-12-12 Created: 2014-12-12 Last updated: 2017-12-05Bibliographically approved
Stenlid, M. H., Ahlsson, F., Forslund, A. H., Döblen, U. v., Nordström, A., Brown, R., . . . Gustafsson, J. (2014). Glucose Production, Lipolysis and Energy Expenditure in an Infantwith Deficiency of the Pyruvate Dehydrogenase Complex. Journal of Pediatric Endocrinology & Metabolism (JPEM)
Open this publication in new window or tab >>Glucose Production, Lipolysis and Energy Expenditure in an Infantwith Deficiency of the Pyruvate Dehydrogenase Complex
Show others...
2014 (English)In: Journal of Pediatric Endocrinology & Metabolism (JPEM), ISSN 0334-018X, E-ISSN 2191-0251Article in journal (Refereed) Epub ahead of print
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-239053 (URN)
Available from: 2014-12-18 Created: 2014-12-18 Last updated: 2017-12-05
Decker, R., Albertsson-Wikland, K., Kristrom, B., Halldin, M. & Dahlgren, J. (2012). Decreased GH dose after the catch-up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency. Clinical Endocrinology, 77(3), 407-415
Open this publication in new window or tab >>Decreased GH dose after the catch-up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency
Show others...
2012 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 3, p. 407-415Article in journal (Refereed) Published
Abstract [en]

Objective Few studies have evaluated metabolic outcomes following growth hormone (GH) treatment in short prepubertal children during different periods of growth. Previously, we found that individualized GH dosing in the catch-up period reduced the variation in fasting insulin levels by 34% compared with those receiving a standard GH dose. We hypothesized that the GH dose required to maintain beneficial metabolic effects is lower during the prepubertal growth phase after an earlier catch-up growth period.

Design Short prepubertal children with isolated GH deficiency or idiopathic short stature were randomized to individualized GH treatment (range, 17100 mu g/kg/day) or a standard dose in a preceding 2-year study. After achieving near mid-parental heightSDS, children receiving an individualized dose were randomized to either a 50% reduced individualized dose (RID, n=28) or an unchanged individualized dose (UID, n=37) for 2years. The dose remained unchanged in 33 children initially randomized to receive a standard dose (FIX, 43 mu g/kg/day).We evaluated whether the variations in metabolic parameters measured during maintenance growth diminished in RID compared with UID or FIX.

Results We observed less variation in fasting insulin levels (-50%), insulin sensitivity as assessed by homoeostasis model assessment (-55.1%), lean soft tissue (-27.8%) and bone mineral content (-31.3%) in RID compared with UID (all P<0.05), but no differences compared with FIX.

Conclusions Continued reduced individualized GH treatment after the catch-up growth period is safe and reduces hyperinsulinism. Individualized GH dose can be reduced once the desired heightSDS is achieved to avoid overtreatment in terms of metabolic outcome.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-181836 (URN)10.1111/j.1365-2265.2012.04386.x (DOI)000307583300011 ()
Available from: 2012-10-02 Created: 2012-10-01 Last updated: 2017-12-07Bibliographically approved
Chaplin, J. E., Kriström, B., Jonsson, B., Halldin Stenlid, M., Aronson, A. S., Dahlgren, J. & Albertsson-Wikland, K. (2012). When Do Short Children Realize They Are Short?: Prepubertal Short Children's Perception of Height during 24 Months of Catch-Up Growth Hormone Treatment. Hormone Research in Paediatrics, 77(4), 241-249
Open this publication in new window or tab >>When Do Short Children Realize They Are Short?: Prepubertal Short Children's Perception of Height during 24 Months of Catch-Up Growth Hormone Treatment
Show others...
2012 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, Vol. 77, no 4, p. 241-249Article in journal (Refereed) Published
Abstract [en]

Aim: To examine perceived height during the first 24 months of growth hormone (GH) treatment in short prepubertal children. Methods: Ninety-nine 3- to 11-year-old short prepubertal children with either isolated GH deficiency (n = 32) or idiopathic short stature (n = 67) participated in a 24-month randomized trial of individualized or fixed-dose GH treatment. Children's and parents' responses to three perceived height measures: relative height (Silhouette Apperception Test), sense of height (VAS short/tall), and judgment of appropriate height (yes/no) were compared to measured height. Results: Children and parents overestimated height at start (72%, 54%) and at 24 months (52%, 30%). Short children described themselves as tall until 8.2 years (girls) and 9 years (boys). Prior to treatment, 38% of children described their height as appropriate and at 3 months, 63%. Mother's height, parental sense of the child's tallness and age explained more variance in children's sense of tallness (34%) than measured height (0%). Conclusion: Short children and parents overestimate height; a pivotal age exists for comparative height judgments. Even a small gain in height may be enough for the child to feel an appropriate age-related height has been reached and to no longer feel short. 

Keywords
Children, Growth hormone treatment, Height determination, Height prediction, Puberty, Quality of life, Short stature, Height perception
National Category
Pediatrics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-177643 (URN)10.1159/000337975 (DOI)000305678400006 ()
Available from: 2012-07-17 Created: 2012-07-17 Last updated: 2012-07-17Bibliographically approved
Organisations

Search in DiVA

Show all publications