Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Alternative names
Publications (10 of 40) Show all publications
Landfors, F., Chorell, E. & Kersten, S. (2023). Genetic mimicry analysis reveals the specific lipases targeted by the ANGPTL3-ANGPTL8 complex and ANGPTL4. Journal of Lipid Research, 64(1), Article ID 100313.
Open this publication in new window or tab >>Genetic mimicry analysis reveals the specific lipases targeted by the ANGPTL3-ANGPTL8 complex and ANGPTL4
2023 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 64, no 1, article id 100313Article in journal (Refereed) Published
Abstract [en]

Angiopoietin-like proteins, ANGPTL3, ANGPTL4, and ANGPTL8, are involved in regulating plasma lipids. In vitro and animal-based studies point to LPL and endothelial lipase (EL, LIPG) as key targets of ANGPTLs. To examine the ANGPTL mechanisms for plasma lipid modulation in humans, we pursued a genetic mimicry analysis of enhancing or suppressing variants in the LPL, LIPG, lipase C hepatic type (LIPC), ANGPTL3, ANGPTL4, and ANGPTL8 genes using data on 248 metabolic parameters derived from over 110,000 nonfasted individuals in the UK Biobank and validated in over 13,000 overnight fasted individuals from 11 other European populations. ANGPTL4 suppression was highly concordant with LPL enhancement but not HL or EL, suggesting ANGPTL4 impacts plasma metabolic parameters exclusively via LPL. The LPL-independent effects of ANGPTL3 suppression on plasma metabolic parameters showed a striking inverse resemblance with EL suppression, suggesting ANGPTL3 not only targets LPL but also targets EL. Investigation of the impact of the ANGPTL3-ANGPTL8 complex on plasma metabolite traits via the ANGPTL8 R59W substitution as an instrumental variable showed a much higher concordance between R59W and EL activity than between R59W and LPL activity, suggesting the R59W substitution more strongly affects EL inhibition than LPL inhibition. Meanwhile, when using a rare and deleterious protein-truncating ANGPTL8 variant as an instrumental variable, the ANGPTL3-ANGPTL8 complex was very LPL specific. In conclusion, our analysis provides strong human genetic evidence that the ANGPTL3-ANGPTL8 complex regulates plasma metabolic parameters, which is achieved by impacting LPL and EL. By contrast, ANGPTL4 influences plasma metabolic parameters exclusively via LPL.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
angiopoietin-like proteins, cardiovascular disease, dyslipidemias, lipase/endothelial, lipase/hepatic, lipidomics, lipids, lipolysis and fatty acid metabolism, lipoprotein/metabolism, triglycerides
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-204492 (URN)10.1016/j.jlr.2022.100313 (DOI)000993186300001 ()36372100 (PubMedID)2-s2.0-85147047013 (Scopus ID)
Funder
Region Västerbotten, RV-970117
Available from: 2023-02-08 Created: 2023-02-08 Last updated: 2023-09-05Bibliographically approved
Landfors, F., Vikström, S., Wennberg, P., Jansson, J.-H., Andersson, J. & Chorell, E. (2022). Leukotriene A4 Hydrolase and Hepatocyte Growth Factor Are Risk Factors of Sudden Cardiac Death Due to First-Ever Myocardial Infarction. International Journal of Molecular Sciences, 23(18), Article ID 10251.
Open this publication in new window or tab >>Leukotriene A4 Hydrolase and Hepatocyte Growth Factor Are Risk Factors of Sudden Cardiac Death Due to First-Ever Myocardial Infarction
Show others...
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 18, article id 10251Article in journal (Refereed) Published
Abstract [en]

Patients at a high risk for sudden cardiac death (SCD) without previous history of cardiovascular disease remain a challenge to identify. Atherosclerosis and prothrombotic states involve inflammation and non-cardiac tissue damage that may play active roles in SCD development. Therefore, we hypothesized that circulating proteins implicated in inflammation and tissue damage are linked to the future risk of SCD. We conducted a prospective nested case–control study of SCD cases with verified myocardial infarction (N = 224) and matched controls without myocardial infarction (N = 224), aged 60 ± 10 years time and median time to event was 8 years. Protein concentrations (N = 122) were measured using a proximity extension immunoassay. The analyses revealed 14 proteins significantly associated with an increased risk of SCD, from which two remained significant after adjusting for smoking status, systolic blood pressure, BMI, cholesterol, and glucose levels. We identified leukotriene A4 hydrolase (LTA4H, odds ratio 1.80, corrected confidence interval (CIcorr) 1.02–3.17) and hepatocyte growth factor (HGF; odds ratio 1.81, CIcorr 1.06–3.11) as independent risk markers of SCD. Elevated LTA4H may reflect increased systemic and pulmonary neutrophilic inflammatory processes that can contribute to atherosclerotic plaque instability. Increased HGF levels are linked to obesity-related metabolic disturbances that are more prevalent in SCD cases than the controls.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
circulating risk marker, myocardial infarction, plaque instability, plasma protein, sudden cardiac death
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-200233 (URN)10.3390/ijms231810251 (DOI)000857533300001 ()36142157 (PubMedID)2-s2.0-85138980596 (Scopus ID)
Funder
Region VästerbottenSwedish Heart Lung Foundation, 20180539Swedish Research Council, 2017-00650
Available from: 2022-10-13 Created: 2022-10-13 Last updated: 2024-04-08Bibliographically approved
Sjögren, R. J. O., Rizo-Roca, D., Chibalin, A. V., Chorell, E., Furrer, R., Katayama, S., . . . Zierath, J. R. (2021). Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes. Diabetologia, 64(9), 2077-2091
Open this publication in new window or tab >>Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes
Show others...
2021 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 64, no 9, p. 2077-2091Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified.

Methods: Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation.

Results: Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37–56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretation: Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent. Graphical abstract: [Figure not available: see fulltext.]

Place, publisher, year, edition, pages
Springer, 2021
Keywords
Branched-chain amino acid, Oestrogen-related receptor α, Oral glucose tolerance test, Peroxisome proliferator-activated receptor γ coactivator 1-α, Skeletal muscle, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-186285 (URN)10.1007/s00125-021-05481-9 (DOI)000661758500002 ()34131782 (PubMedID)2-s2.0-85108018123 (Scopus ID)
Funder
Novo Nordisk, NNF17OC0030088Diabetesfonden, DIA2018-357Swedish Research Council, 2015-00165, 2018-02389Knut and Alice Wallenberg Foundation, 2018-0094
Available from: 2021-07-20 Created: 2021-07-20 Last updated: 2023-03-24Bibliographically approved
Mendham, A. E., Goedecke, J. H., Zeng, Y., Larsen, S., George, C., Hauksson, J., . . . Chorell, E. (2021). Exercise training improves mitochondrial respiration and is associated with an altered intramuscular phospholipid signature in women with obesity. Diabetologia, 64(7), 1642-1659
Open this publication in new window or tab >>Exercise training improves mitochondrial respiration and is associated with an altered intramuscular phospholipid signature in women with obesity
Show others...
2021 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 64, no 7, p. 1642-1659Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: We sought to determine putative relationships among improved mitochondrial respiration, insulin sensitivity and altered skeletal muscle lipids and metabolite signature in response to combined aerobic and resistance training in women with obesity.

Methods: This study reports a secondary analysis of a randomised controlled trial including additional measures of mitochondrial respiration, skeletal muscle lipidomics, metabolomics and protein content. Women with obesity were randomised into 12 weeks of combined aerobic and resistance exercise training (n = 20) or control (n = 15) groups. Pre- and post-intervention testing included peak oxygen consumption, whole-body insulin sensitivity (intravenous glucose tolerance test), skeletal muscle mitochondrial respiration (high-resolution respirometry), lipidomics and metabolomics (mass spectrometry) and lipid content (magnetic resonance imaging and spectroscopy). Proteins involved in glucose transport (i.e. GLUT4) and lipid turnover (i.e. sphingomyelin synthase 1 and 2) were assessed by western blotting.

Results: The original randomised controlled trial showed that exercise training increased insulin sensitivity (median [IQR]; 3.4 [2.0–4.6] to 3.6 [2.4–6.2] x10−5 pmol l−1 min−1), peak oxygen consumption (mean ± SD; 24.9 ± 2.4 to 27.6 ± 3.4 ml kg−1 min−1), and decreased body weight (84.1 ± 8.7 to 83.3 ± 9.7 kg), with an increase in weight (pre intervention, 87.8± 10.9 to post intervention 88.8 ± 11.0 kg) in the control group (interaction p < 0.05). The current study shows an increase in mitochondrial respiration and content in response to exercise training (interaction p < 0.05). The metabolite and lipid signature at baseline were significantly associated with mitochondrial respiratory capacity (p < 0.05) but were not associated with whole-body insulin sensitivity or GLUT4 protein content. Exercise training significantly altered the skeletal muscle lipid profile, increasing specific diacylglycerol(32:2) and ceramide(d18:1/24:0) levels, without changes in other intermediates or total content of diacylglycerol and ceramide. The total content of cardiolipin, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased with exercise training with a decrease in the PC:PE ratios containing 22:5 and 20:4 fatty acids. These changes were associated with content-driven increases in mitochondrial respiration (p < 0.05), but not with the increase in whole-body insulin sensitivity or GLUT4 protein content. Exercise training increased sphingomyelin synthase 1 (p < 0.05), with no change in plasma-membrane-located sphingomyelin synthase 2.

Conclusions/interpretation: The major findings of our study were that exercise training altered specific intramuscular lipid intermediates, associated with content-driven increases in mitochondrial respiration but not whole-body insulin sensitivity. This highlights the benefits of exercise training and presents putative target pathways for preventing lipotoxicity in skeletal muscle, which is typically associated with the development of type 2 diabetes.

Place, publisher, year, edition, pages
Springer, 2021
Keywords
Acylcarnitines, Aerobic and resistance training, Cardiolipins, Cardiorespiratory fitness, Ectopic fat, Mitochondrial biogenesis, Obesity, Phospholipid hydrolysis, Sphingomyelin, Triacylglycerol
National Category
Sport and Fitness Sciences Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-182159 (URN)10.1007/s00125-021-05430-6 (DOI)000633274200001 ()33770195 (PubMedID)2-s2.0-85103352083 (Scopus ID)
Available from: 2021-04-21 Created: 2021-04-21 Last updated: 2023-03-24Bibliographically approved
Goedecke, J. H., Chorell, E., van Jaarsveld, P. J., Risérus, U. & Olsson, T. (2021). Fatty Acid Metabolism and Associations with Insulin Sensitivity Differs Between Black and White South African Women. Journal of Clinical Endocrinology and Metabolism, 106(1), E140-E151
Open this publication in new window or tab >>Fatty Acid Metabolism and Associations with Insulin Sensitivity Differs Between Black and White South African Women
Show others...
2021 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, no 1, p. E140-E151Article in journal (Refereed) Published
Abstract [en]

Purpose: Genetic differences in desaturase genes and consequently fatty acid metabolism have been reported. The aims were to examine ethnic differences in serum fatty acid composition and desaturase indices, and assess the ethnic-specific associations with insulin sensitivity (IS) and liver fat in black and white South African (SA) women.

Methods: In this cross-sectional study including 92 premenopausal black (n = 46) and white (n = 46) SA women, serum fatty acid composition was measured in cholesteryl ester (CE) and nonesterified fatty acid (NEFA) fractions. Desaturase activities were estimated as product-to-precursor ratios: stearoyl-CoA desaturase-1 (SCD1-16, 16:1n-7/16:0); d-5 desaturase (D5D, 20:4n-6/20:3n-6), and d-6 desaturase (D6D, 18:3n-6/18:2n-6). Whole-body IS was estimated from an oral glucose tolerance test using the Matsuda index. In a subsample (n = 30), liver fat and hepatic IS were measured by 1H-magnetic resonance spectroscopy and hyperinsulinemic euglycemic clamp, respectively.

Results: Despite lower whole-body IS (P = .006), black women had higher CE D5D and lower D6D and SCD1-16 indices than white women (P < .01). CE D6D index was associated with lower IS in white women only (r = -0.31, P = .045), whereas D5D index was associated with higher IS in black women only (r = 0.31, P = .041). In the subsample, D6D and SCD1-16 indices were positively and D5D was negatively associated with liver fat (P < .05). Conversely, CE SCD1-16 was negatively associated with hepatic IS (P < .05), but not independently of liver fat. Conclusions: Ethnic differences in fatty acid-derived desaturation indices were observed, with insulin-resistant black SA women paradoxically showing a fatty acid pattern typical for higher insulin sensitivity in European populations.

Place, publisher, year, edition, pages
Endocrine Society, 2021
Keywords
desaturase enzymes, stearoyl-CoA desaturase-1, liver fat, ethnicity, cholesteryl ester, non-esterified fatty acid
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-180212 (URN)10.1210/clinem/dgaa696 (DOI)000608480200014 ()32995848 (PubMedID)2-s2.0-85099072596 (Scopus ID)
Available from: 2021-02-23 Created: 2021-02-23 Last updated: 2022-04-27Bibliographically approved
Chorell, E., Otten, J., Stomby, A., Ryberg, M., Waling, M., Hauksson, J., . . . Olsson, T. (2021). Improved peripheral and hepatic insulin sensitivity after lifestyle interventions in type 2 diabetes is associated with specific metabolomic and lipidomic signatures in skeletal muscle and plasma. Metabolites, 11(12), Article ID 834.
Open this publication in new window or tab >>Improved peripheral and hepatic insulin sensitivity after lifestyle interventions in type 2 diabetes is associated with specific metabolomic and lipidomic signatures in skeletal muscle and plasma
Show others...
2021 (English)In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 11, no 12, article id 834Article in journal (Refereed) Published
Abstract [en]

Lifestyle interventions with weight loss can improve insulin sensitivity in type 2 diabetes (T2D), but mechanisms are unclear. We explored circulating and skeletal muscle metabolite signatures of altered peripheral (pIS) and hepatic insulin sensitivity (hIS) in overweight and obese T2D individuals that were randomly assigned a 12-week Paleolithic-type diet with (diet-ex, n = 13) or without (diet, n = 13) supervised exercise. Baseline and post-intervention measures included: mass spectrometry-based metabolomics and lipidomics of skeletal muscle and plasma; pIS and hIS; ectopic lipid deposits in the liver and skeletal muscle; and skeletal muscle fat oxidation rate. Both groups lowered BMI and total % fat mass and increased their pIS. Only the diet-group improved hIS and reduced ectopic lipids in the liver and muscle. The combined improvement in pIS and hIS in the diet-group were associated with decreases in muscle and circulating branched-chain amino acid (BCAA) metabolites, specifically valine. Improved pIS with diet-ex was instead linked to increased diacylglycerol (34:2) and triacylglycerol (56:0) and decreased phosphatidylcholine (34:3) in muscle coupled with improved muscle fat oxidation rate. This suggests a tissue crosstalk involving BCAA-metabolites after diet intervention with improved pIS and hIS, reflecting reduced lipid influx. Increased skeletal muscle lipid utilization with exercise may prevent specific lipid accumulation at sites that perturb insulin signaling.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Branched-chain amino acids (BCAA), Diacylglycerol (DAG), Diet, Ectopic fat, Exercise training, Hepatic insulin sensitivity (hIS), Peripheral insulin sensitivity (pIS), Skeletal muscle, Type 2 diabetes
National Category
Physiology Nutrition and Dietetics Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-190949 (URN)10.3390/metabo11120834 (DOI)000735530300001 ()34940592 (PubMedID)2-s2.0-85121572914 (Scopus ID)
Funder
The Kempe Foundations, JCK-1725Swedish Heart Lung Foundation, 20150553
Available from: 2022-01-05 Created: 2022-01-05 Last updated: 2023-09-05Bibliographically approved
Chorell, E., Olsson, T., Jansson, J.-H. & Wennberg, P. (2021). Lysophospholipids as Predictive Markers of ST-Elevation Myocardial Infarction (STEMI) and Non-ST-Elevation Myocardial Infarction (NSTEMI). Metabolites, 11(1), Article ID 25.
Open this publication in new window or tab >>Lysophospholipids as Predictive Markers of ST-Elevation Myocardial Infarction (STEMI) and Non-ST-Elevation Myocardial Infarction (NSTEMI)
2021 (English)In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 11, no 1, article id 25Article in journal (Refereed) Published
Abstract [en]

The present study explored patterns of circulating metabolites and proteins that can predict future risk for ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). We conducted a prospective nested case-control study in northern Sweden in individuals who developed STEMI (N = 50) and NSTEMI (N = 50) within 5 years and individually matched controls (N = 100). Fasted plasma samples were subjected to multiplatform mass spectrometry-based metabolomics and multiplex protein analyses. Multivariate analyses were used to elucidate infarction-specific metabolite and protein risk profiles associated with future incident STEMI and NSTEMI. We found that altered lysophosphatidylcholine (LPC) to lysophosphatidylethanolamine (LPE) ratio predicted STEMI and NSTEMI events in different ways. In STEMI, lysophospholipids (mainly LPEs) were lower, whereas in NSTEMI, lysophospholipids (mainly LPEs) were higher. We found a similar response for all detected lysophospholipids but significant alterations only for those containing linoleic acid (C18:2, p < 0.05). Patients with STEMI had higher secretoglobin family 3A member 2 and tartrate-resistant acid phosphate type 5 and lower platelet-derived growth factor subunit A, which are proteins associated with atherosclerosis severity and plaque development mediated via altered phospholipid metabolism. In contrast, patients with NSTEMI had higher levels of proteins associated with inflammation and macrophage activation, including interleukin 6, C-reactive protein, chemerin, and cathepsin X and D. The STEMI risk marker profile includes factors closely related to the development of unstable plaque, including a higher LPC:LPE ratio, whereas NSTEMI is characterized by a lower LPC:LPE ratio and increased inflammation.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
myocardial infarction, ST-elevation, non-ST-elevation, metabolomics, plasma protein, lysophospholipids, prediction, risk factors
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-180158 (URN)10.3390/metabo11010025 (DOI)000610405500001 ()33396480 (PubMedID)2-s2.0-85099103882 (Scopus ID)
Available from: 2021-02-22 Created: 2021-02-22 Last updated: 2023-03-23Bibliographically approved
Stenlund, H., Nilholm, C., Chorell, E., Roth, B., D'Amato, M. & Ohlsson, B. (2021). Metabolic Profiling of Plasma in Patients with Irritable Bowel Syndrome after a 4-Week Starch- and Sucrose-Reduced Diet. Metabolites, 11(7), Article ID 440.
Open this publication in new window or tab >>Metabolic Profiling of Plasma in Patients with Irritable Bowel Syndrome after a 4-Week Starch- and Sucrose-Reduced Diet
Show others...
2021 (English)In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 11, no 7, article id 440Article in journal (Refereed) Published
Abstract [en]

A 4-week dietary intervention with a starch- and sucrose-restricted diet (SSRD) was conducted in patients with irritable bowel syndrome (IBS) to examine the metabolic profile in relation to nutrient intake and gastrointestinal symptoms. IBS patients were randomized to SSRD intervention (n = 69) or control continuing with their ordinary food habits (n = 22). Food intake was registered and the questionnaires IBS-symptoms severity scale (IBS-SSS) and visual analog scale for IBS (VAS-IBS) were completed. Metabolomics untargeted analysis was performed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS) in positive and negative ionization modes. SSRD led to marked changes in circulating metabolite concentrations at the group level, most prominent for reduced starch intake and increased polyunsaturated fat, with small changes in the control group. On an individual level, the correlations were weak. The marked reduction in gastrointestinal symptoms did not correlate with the metabolic changes. SSRD was observed by clear metabolic effects mainly related to linoleic acid metabolism, fatty acid biosynthesis, and beta-oxidation.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
metabolomics, metabolic profiling, dietary advice, IBS, starch, sucrose
National Category
Gastroenterology and Hepatology Analytical Chemistry
Identifiers
urn:nbn:se:umu:diva-187467 (URN)10.3390/metabo11070440 (DOI)000676470200001 ()34357334 (PubMedID)2-s2.0-85109844778 (Scopus ID)
Available from: 2021-09-13 Created: 2021-09-13 Last updated: 2022-04-27Bibliographically approved
Otten, J., Stomby, A., Waling, M., Chorell, E., Ryberg, M., Svensson, M. B., . . . Olsson, T. (2021). The liver-alpha-cell axis after a mixed meal and during weight loss in type 2 diabetes. Endocrine Connections, 10(9), 1101-1110
Open this publication in new window or tab >>The liver-alpha-cell axis after a mixed meal and during weight loss in type 2 diabetes
Show others...
2021 (English)In: Endocrine Connections, E-ISSN 2049-3614, Vol. 10, no 9, p. 1101-1110Article in journal (Refereed) Published
Abstract [en]

Objective: Glucagon and amino acids may be regulated in a feedback loop called the liver-alpha-cell axis with alanine or glutamine as suggested signal molecules. We assessed this concept in individuals with type 2 diabetes in the fasting state, after ingestion of a protein-rich meal, and during weight loss. Moreover, we investigated if postprandial glucagon secretion and hepatic insulin sensitivity were related.

Methods: This is a secondary analysis of a 12-week weight-loss trial (Paleolithic diet ± exercise) in 29 individuals with type 2 diabetes. Before and after the intervention, plasma glucagon and amino acids were measured in the fasting state and during 180 min after a protein-rich mixed meal. Hepatic insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose as a tracer.

Results: The postprandial increase of plasma glucagon was associated with the postprandial increase of alanine and several other amino acids but not glutamine. In the fasted state and after the meal, glucagon levels were negatively correlated with hepatic insulin sensitivity (rS = −0.51/r = −0.58, respectively; both P < 0.05). Improved hepatic insulin sensitivity with weight loss was correlated with decreased postprandial glucagon response (r = −0.78; P < 0.001).

Conclusions: Several amino acids, notably alanine, but not glutamine could be key signals to the alpha cell to increase glucagon secretion. Amino acids may be part of a feedback mechanism as glucagon increases endogenous glucose production and ureagenesis in the liver. Moreover, postprandial glucagon secretion seems to be tightly related to hepatic insulin sensitivity.

Place, publisher, year, edition, pages
Bioscientifica, 2021
Keywords
Amino acids, Glucagon, Hepatic insulin sensitivity, Mixed meal, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-188157 (URN)10.1530/EC-21-0171 (DOI)000704561100017 ()2-s2.0-85115733491 (Scopus ID)
Available from: 2021-10-07 Created: 2021-10-07 Last updated: 2023-09-05Bibliographically approved
Nankam, P. A. N., van Jaarsveld, P. J., Chorell, E., Fortuin-de Smidt, M. C., Adams, K., Blueher, M., . . . Goedecke, J. H. (2020). Circulating and Adipose Tissue Fatty Acid Composition in Black South African Women with Obesity: A Cross-Sectional Study. Nutrients, 12(6), Article ID 1619.
Open this publication in new window or tab >>Circulating and Adipose Tissue Fatty Acid Composition in Black South African Women with Obesity: A Cross-Sectional Study
Show others...
2020 (English)In: Nutrients, E-ISSN 2072-6643, Vol. 12, no 6, article id 1619Article in journal (Refereed) Published
Abstract [en]

Background and Aims: During positive energy balance, excess lipid storage in subcutaneous adipose tissue (SAT) is associated with increased lipolysis. Elevated circulating fatty acid (FA) concentrations from both SAT lipolysis and dietary fat intake may result in visceral adipose tissue (VAT) accumulation, impairment of glucose metabolism, altogether increasing obesity-associated metabolic risks. We aimed to test the hypothesis that FA composition of red blood cell total phospholipids (RBC-TPL) and SAT is associated with body fat centralisation (VAT/SAT ratio) and insulin sensitivity (SI) in black South African women with obesity. Methods: Participants’ (n = 41) body fat composition and distribution, SI, and RBC-TPL, abdominal and gluteal SAT (gSAT) FA composition (gas-liquid chromatography) were measured. Results: RBC-TPL contained higher proportions of saturated fatty acids (SFAs) than SAT (p < 0.001), which were associated with lower SI (p < 0.05). Mono-unsaturated fatty acids (MUFAs) and stearoyl-CoA desaturase-1 (SCD1)-16 were lower, while poly-unsaturated fatty acids (PUFAs), and delta-5 and delta-6 desaturase indices were higher in RBC-TPL than SAT (p < 0.001). Interestingly, FA profiles differed between SAT depots with higher SFAs and lower MUFAs, SCD1-16 and SCD1-18 indices in abdominal compared to gluteal SAT (p < 0.01). In both SAT depots, higher SFAs and lower PUFAs (n-3 and n-6) correlated with lower VAT/SAT ratio; and lower PUFAs (n-3 and n-6) and higher total MUFA correlated with higher SI. Conclusion: Our findings confirm the relationships between the FA composition of RBC-TPL and SAT and metabolic risk in black women with obesity, which are dependent on both the FA class, and the tissue type/blood compartment in which they are distributed.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
fatty acids metabolism, desaturase enzyme indices, erythrocytes, subcutaneous adipose tissue, body composition, insulin sensitivity
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-173792 (URN)10.3390/nu12061619 (DOI)000549355800001 ()32486525 (PubMedID)2-s2.0-85085908752 (Scopus ID)
Available from: 2020-08-04 Created: 2020-08-04 Last updated: 2023-08-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8057-1684

Search in DiVA

Show all publications