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Benedet, P. O., Safikhan, N. S., Pereira, M. J., Lum, B. M., Botezelli, J. D., Kuo, C.-H., . . . Conway, E. M. (2024). CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation. EBioMedicine, 99, Article ID 104906.
Open this publication in new window or tab >>CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation
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2024 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 99, article id 104906Article in journal (Refereed) Published
Abstract [en]

Background

In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance.

Methods

Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens.

Findings

Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis.

Interpretation

Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Adipocyte, Insulin resistance, Glucose, Metabolism, Obesity, CD248, Lipid, Insulin receptor
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-523256 (URN)10.1016/j.ebiom.2023.104906 (DOI)001135042400001 ()38061240 (PubMedID)
Funder
DiabetesfondenErnfors FoundationNovo Nordisk
Available from: 2024-02-16 Created: 2024-02-16 Last updated: 2024-02-16Bibliographically approved
Eriksson, J., Emad, R. A., Lundqvist, M. H., Abrahamsson, N. & Kjellsson, M. C. (2023). Altered glucose-dependent secretion of glucagon and ACTH is associated with insulin resistance, assessed by population analysis. Endocrine Connections, 12(4), Article ID e220506.
Open this publication in new window or tab >>Altered glucose-dependent secretion of glucagon and ACTH is associated with insulin resistance, assessed by population analysis
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2023 (English)In: Endocrine Connections, E-ISSN 2049-3614, Vol. 12, no 4, article id e220506Article in journal (Refereed) Published
Abstract [en]

This study aimed to characterize how the dysregulation of counter-regulatory hormones can contribute to insulin resistance and potentially to diabetes. Therefore, we investigated the association between insulin sensitivity and the glucose- and insulin-dependent secretion of glucagon, adrenocorticotropic hormone (ACTH), and cortisol in non-diabetic individuals using a population model analysis. Data, from hyperinsulinemic-hypoglycemic clamps, were pooled for analysis, including 52 individuals with a wide range of insulin resistance (reflected by glucose infusion rate 20-60 min; GIR(20-60min)). Glucagon secretion was suppressed by glucose and, to a lesser extent, insulin. The GIR(20-60min) and BMI were identified as predictors of the insulin effect on glucagon. At normoglycemia (5 mmol/L), a 90% suppression of glucagon was achieved at insulin concentrations of 16.3 and 43.4 mu U/mL in individuals belonging to the highest and lowest quantiles of insulin sensitivity, respectively. Insulin resistance of glucagon secretion explained the elevated fasting glucagon for individuals with a low GIR(20-60min). ACTH secretion was suppressed by glucose and not affected by insulin. The GIR(20-60min) was superior to other measures as a predictor of glucose-dependent ACTH secretion, with 90% suppression of ACTH secretion by glucose at 3.1 and 3.5 mmol/L for insulin-sensitive and insulin-resistant individuals, respectively. This difference may appear small but shifts the suppression range into normoglycemia for individuals with insulin resistance, thus, leading to earlier and greater ACTH/cortisol response when the glucose falls. Based on modeling of pooled glucose-clamp data, insulin resistance was associated with generally elevated glucagon and a potentiated cortisol-axis response to hypoglycemia, and over time both hormonal pathways may therefore contribute to dysglycemia and possibly type 2 diabetes.

Place, publisher, year, edition, pages
Bioscientifica, 2023
Keywords
metabolism, obesity
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-502502 (URN)10.1530/EC-22-0506 (DOI)000981623700006 ()36752854 (PubMedID)
Available from: 2023-05-29 Created: 2023-05-29 Last updated: 2023-08-28Bibliographically approved
Hetty, S., Vranic, M., Kamble, P. G., Lundqvist, M. H., Pereira, M. J. & Eriksson, J. (2023). CABLES1 expression is reduced in human subcutaneous adipose tissue in obesity and type 2 diabetes but may not directly impact adipocyte glucose and lipid metabolism. Adipocyte, 12(1), Article ID 2242997.
Open this publication in new window or tab >>CABLES1 expression is reduced in human subcutaneous adipose tissue in obesity and type 2 diabetes but may not directly impact adipocyte glucose and lipid metabolism
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2023 (English)In: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 12, no 1, article id 2242997Article in journal (Refereed) Published
Abstract [en]

Cdk5 and Abl enzyme substrate 1 (CABLES1) is a cell cycle regulator that has previously been identified as a candidate gene for obesity-related phenotypes, but little is known about its role in adipose tissue metabolism. In this study, we explore the role of CABLES1 in obesity and type 2 diabetes (T2D) in human subcutaneous adipose tissue (SAT). We performed gene expression analysis of SAT obtained from subjects with and without T2D, and from a second validation cohort consisting of subjects without T2D. We used CRISPR/Cas9 genome editing to perform CABLES1 loss-of-function studies in human primary preadipocytes and assessed them functionally after differentiation. CABLES1 gene expression in SAT was decreased in T2D by almost 25%, and inversely associated with insulin resistance markers and hyperglycaemia. mRNA levels were reduced with increasing BMI and negatively correlated with obesity markers. We found that adipocytes are likely the main CABLES1-expressing cell type in SAT, but CABLES1 depletion in adipocytes caused no phenotypical changes in regards to differentiation, glucose uptake, or expression of key genes of adipocyte function. These findings suggest that CABLES1 gene expression in SAT might be altered in obesity and T2D as a consequence of metabolic dysregulation rather than being a causal factor.

Place, publisher, year, edition, pages
Informa UK Limited, 2023
Keywords
CABLES1, type 2 diabetes, obesity, adipose tissue, adipocytes, >
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-510001 (URN)10.1080/21623945.2023.2242997 (DOI)001044742500001 ()37555665 (PubMedID)
Funder
Swedish Diabetes Association, DIA2021-661EXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationP.O. Zetterling FoundationNovo Nordisk Foundation, NNF20OC0063864Agnes and Mac Rudberg FoundationEuropean Commission, H2020-MSCA-ITN-721236AstraZeneca
Available from: 2023-08-28 Created: 2023-08-28 Last updated: 2023-08-28Bibliographically approved
Randell, E., Katsogiannos, P., Leksell, J., Eriksson, J. W., Sundbom, M. & Svedbo Engström, M. (2023). Complementary elements of support after gastric-bypass surgery perceived by adults with previous type 2 diabetes: A qualitative study 2 years after bariatric surgery. Clinical Obesity, Article ID e12610.
Open this publication in new window or tab >>Complementary elements of support after gastric-bypass surgery perceived by adults with previous type 2 diabetes: A qualitative study 2 years after bariatric surgery
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2023 (English)In: Clinical Obesity, ISSN 1758-8103, E-ISSN 1758-8111, article id e12610Article in journal (Refereed) Epub ahead of print
Abstract [en]

Bariatric surgery is the most medically and cost-effective treatment for adults with obesity and type 2 diabetes mellitus (T2DM). Our findings suggest initial improvements in health-related quality of life that may decline as support from follow-up care ends. How patients experience long-term support is not well described. This study therefore aimed to investigate how adults with previous T2DM perceived different sources of support 2 years after bariatric surgery. In this qualitative study individual interviews were conducted with 13 adults (10 women) 2 years after surgery. Using thematic analysis, one overarching theme (compiling complementary elements of support after gastric-bypass surgery), four themes and nine subthemes emerged. The results show that support was given and received from various sources, support needs varied over time depending on where the patient was in the process and that the sources of support were complementary. To conclude, our results show that support needs change in adults who have undergone bariatric surgery. Long-term professional and day-to-day support from family and other networks are essential and complementary elements of support. Health care staff should consider these findings, especially during the early follow-up period. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
gastric by-pass, psychosocial needs, qualitative, support
National Category
Endocrinology and Diabetes Gastroenterology and Hepatology Surgery
Research subject
Health Care Research
Identifiers
urn:nbn:se:uu:diva-507760 (URN)10.1111/cob.12610 (DOI)001026499000001 ()37431181 (PubMedID)
Funder
DiabetesfondenNovo Nordisk FoundationEXODIAB - Excellence of Diabetes Research in SwedenErnfors Foundation
Available from: 2023-07-11 Created: 2023-07-11 Last updated: 2023-08-01
Fanni, G., Kagios, C., Roman, E., Sundbom, M., Wikström, J., Haller, S. & Eriksson, J. (2023). Effects of gastric bypass surgery on brain connectivity responses to hypoglycemia. Endocrine, 79(2), 304-312
Open this publication in new window or tab >>Effects of gastric bypass surgery on brain connectivity responses to hypoglycemia
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2023 (English)In: Endocrine, ISSN 1355-008X, E-ISSN 1559-0100, Vol. 79, no 2, p. 304-312Article in journal (Refereed) Published
Abstract [en]

Introduction

Roux-en-Y gastric bypass (RYGB) leads to beneficial effects on glucose homeostasis, and attenuated hormonal counterregulatory responses to hypoglycemia are likely to contribute. RYGB also induces alterations in neural activity of cortical and subcortical brain regions. We aimed to characterize RYGB-induced changes in resting-state connectivity of specific brain regions of interest for energy homeostasis and behavioral control during hypoglycemia.

Method

Ten patients with BMI > 35 kg/m2 were investigated with brain PET/MR imaging during a hyperinsulinemic normo- and hypoglycemic clamp, before and 4 months after RYGB. Hormonal levels were assessed throughout the clamp. Resting-state (RS) fMRI scans were acquired in the glucose-lowering phase of the clamp, and they were analyzed with a seed-to-voxel approach.

Results

RS connectivity during initiation of hypoglycemia was significantly altered after RYGB between nucleus accumbens, thalamus, caudate, hypothalamus and their crosstalk with cortical and subcortical regions. Connectivity between the nucleus accumbens and the frontal pole was increased after RYGB, and this was associated with a reduction of ACTH (r = −0.639, p = 0.047) and cortisol (r = −0.635, p = 0.048) responses. Instead, connectivity between the caudate and the frontal pole after RYGB was reduced and this was associated with less attenuation of glucagon response during the hypoglycemic clamp (r = −0.728, p = 0.017), smaller reduction in fasting glucose (r = −0.798, p = 0.007) and less excess weight loss (r = 0.753, p = 0.012). No other significant associations were found between post-RYGB changes in ROI-to-voxel regional connectivity hormonal responses and metabolic or anthropometric outcomes.

Conclusion

RYGB alters brain connectivity during hypoglycemia of several neural pathways involved in reward, inhibitory control, and energy homeostasis. These changes are associated with altered hormonal responses to hypoglycemia and may be involved in the glucometabolic outcome of RYGB.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Radiology
Identifiers
urn:nbn:se:uu:diva-489736 (URN)10.1007/s12020-022-03253-y (DOI)000914873500001 ()36459336 (PubMedID)
Funder
Diabetesfonden, 2019-490EXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationSwedish Society for Medical Research (SSMF)P.O. Zetterling FoundationNovo Nordisk Foundation, NNF20OC0063864EU, Horizon 2020, MSCA-ITN-721236Uppsala University
Available from: 2022-12-03 Created: 2022-12-03 Last updated: 2023-08-28Bibliographically approved
Vranic, M., Ahmed, F., Hetty, S., Sarsenbayeva, A., Ferreira, V., Fanni, G., . . . Pereira, M. J. (2023). Effects of the second-generation antipsychotic drugs aripiprazole and olanzapine on human adipocyte differentiation. Molecular and Cellular Endocrinology, 561, Article ID 111828.
Open this publication in new window or tab >>Effects of the second-generation antipsychotic drugs aripiprazole and olanzapine on human adipocyte differentiation
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2023 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 561, article id 111828Article in journal (Refereed) Published
Abstract [en]

Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose uptake while the expression of gene markers of fatty acid oxidation were increased. Additionally, the use of a supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, olanzapine (OLA), a highly obesogenic SGA, directly increased leptin gene expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and potentially by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may effect crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Aripiprazole, Olanzapine, Adipocyte, Adipogenesis
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-493866 (URN)10.1016/j.mce.2022.111828 (DOI)000911784900001 ()
Funder
EU, Horizon 2020, H2020-MSCA-ITN-721236DiabetesfondenEXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationP.O. Zetterling FoundationSwedish Society for Medical Research (SSMF)Novo NordiskAgnes and Mac Rudberg Foundation
Available from: 2023-01-13 Created: 2023-01-13 Last updated: 2023-02-28Bibliographically approved
Lundqvist, M. H., Pereira, M. J. & Eriksson, J. (2023). Glucose-dependent inflammatory responses in obese compared to lean individuals. Endocrine, 81(3), 464-476
Open this publication in new window or tab >>Glucose-dependent inflammatory responses in obese compared to lean individuals
2023 (English)In: Endocrine, ISSN 1355-008X, E-ISSN 1559-0100, Vol. 81, no 3, p. 464-476Article in journal (Refereed) Published
Abstract [en]

Purpose Obesity is characterized by chronic inflammation that may contribute to insulin resistance and promote type 2 diabetes. We have investigated whether inflammatory responses to glycemic and insulinemic variations are altered in obese individuals.

Methods Eight obese and eight lean individuals without diabetes had undergone hyperinsulinemic-euglycemic-hypoglycemic and hyperglycemic clamps in a previous study. Using Proximity Extension Assay, 92 inflammatory markers were analyzed from plasma samples at fasting, hyperinsulinemia-euglycemia, hypoglycemia and hyperglycemia.

Results In all participants, hyperinsulinemia, hypoglycemia and hyperglycemia led to reductions of 11, 19 and 62 out of the 70 fully evaluable biomarkers, respectively. FGF-21 increased during both hypoglycemia and hyperglycemia while IL-6 and IL-10 increased during hypoglycemia. In obese vs lean participants, Oncostatin-M, Caspase-8 and 4E-BP1 were more markedly suppressed during hypoglycemia, whereas VEGF-A was more markedly suppressed during hyperglycemia. BMI correlated inversely with changes of PD-L1 and CD40 during hyperinsulinemia, Oncostatin-M, TNFSF14, FGF-21 and 4EBP-1 during hypoglycemia and CCL23, VEGF-A and CDCP1 during hyperglycemia (Rho & LE; -0.50). HbA1c correlated positively with changes of MCP-2 and IL-15-RA during hyperinsulinemia (Rho & GE; 0.51) and inversely with changes of CXCL1, MMP-1 and Axin-1 during hypoglycemia (Rho & LE; -0.55). M-value correlated positively with changes of IL-12B and VEGF-A during hyperglycemia (Rho & GE; 0.51). Results above were significant (p < 0.05).

Conclusion Overall, hyperinsulinemia, hypo- and hyperglycemia led to suppression of several inflammatory markers and this tended to be more marked in individuals with obesity, insulin resistance and dysglycemia. Thus, acute glycemic or insulinemic variations do not seem to potentiate possible inflammatory pathways in the development of insulin resistance and disturbed glucose metabolism.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Inflammation, Obesity, Insulin resistance, Hypoglycemia, Hyperglycemia
National Category
Endocrinology and Diabetes Pediatrics
Identifiers
urn:nbn:se:uu:diva-510964 (URN)10.1007/s12020-023-03433-4 (DOI)001018746600001 ()37400734 (PubMedID)
Funder
Diabetesfonden, DIA2021-661EXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationNovo Nordisk Foundation, NNF20OC0063864Agnes and Mac Rudberg Foundation
Available from: 2023-09-06 Created: 2023-09-06 Last updated: 2023-09-06Bibliographically approved
Lundqvist, M. H., Patsoukaki, V., Jansson, S. P. .., Norman, H., Granstam, E., Svensson, M. K., . . . Eriksson, J. (2023). Health care registers can be instrumental for endpoint capture in clinical diabetes trials: example of microvascular complications in Swedish patients with type 2 diabetes. Diabetes & Vascular Disease Research, 20(3), Article ID 14791641231179878.
Open this publication in new window or tab >>Health care registers can be instrumental for endpoint capture in clinical diabetes trials: example of microvascular complications in Swedish patients with type 2 diabetes
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2023 (English)In: Diabetes & Vascular Disease Research, ISSN 1479-1641, E-ISSN 1752-8984, Vol. 20, no 3, article id 14791641231179878Article in journal (Refereed) Published
Abstract [en]

Aims SMARTEST is a register-based randomized clinical trial (RRCT) that compares dapagliflozin to metformin in early-stage type 2 diabetes. The primary outcome includes progression of microvascular complications based on data from the Swedish National Diabetes Register (NDR). In this sub-study, the aim was to validate microvascular complication variables in the NDR against electronic health records (EHRs).

Methods Data were extracted from EHRs of 276 SMARTEST participants with a median observation period of 3 years in the Uppsala, orebro and Sormland counties and compared with NDR data. Agreement was determined for all corresponding data entries as well as for progression of microvascular complications after randomization.

Results The agreement for all corresponding data entries was 98.9% (Intraclass Correlation Coefficient 0.999) for creatinine and eGFR, 95.1% for albuminuria, 91.6% for foot-at-risk and 98.2% for retinopathy status (Kappa 0.67-0.91). The agreement for progression of microvascular complications was 98.0% for CKD stage, 98.9% for albuminuria grade, 96.3% for foot-at-risk grade and 99.6% for retinopathy grade progression (Gwet's AC(1) 0.96-1.00).

Conclusion Microvascular complication variables in the NDR show good agreement with EHR data. The use of a well-established national health care registry, exemplified by the NDR, for endpoint collection in RRCTs such as SMARTEST is supported by this study.

Place, publisher, year, edition, pages
Sage Publications, 2023
Keywords
Type 2 diabetes, microvascular complications, diabetes register, validation, register-based randomized clinical trial, endpoint
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-508130 (URN)10.1177/14791641231179878 (DOI)001019606800001 ()37318227 (PubMedID)
Funder
Swedish Research Council, 2018-00904Swedish Research Council, 2019-00978VinnovaSwedish Heart Lung Foundation, 20190403
Available from: 2023-09-01 Created: 2023-09-01 Last updated: 2023-09-01Bibliographically approved
Ritsinger, V., Bodegard, J., Kristófi, R., Thuresson, M., Nathanson, D., Nystrom, T., . . . Norhammar, A. (2023). History of heart failure and chronic kidney disease and risk of all-cause death after COVID-19 during the first three waves of the pandemic in comparison with influenza outbreaks in Sweden: a registry-based, retrospective, case-control study. BMJ Open, 13(4), Article ID e069037.
Open this publication in new window or tab >>History of heart failure and chronic kidney disease and risk of all-cause death after COVID-19 during the first three waves of the pandemic in comparison with influenza outbreaks in Sweden: a registry-based, retrospective, case-control study
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2023 (English)In: BMJ Open, E-ISSN 2044-6055, Vol. 13, no 4, article id e069037Article in journal (Refereed) Published
Abstract [en]

Objectives To explore how cardiorenal disease (CRD; heart failure and/or chronic kidney disease) impacted mortality in men and women hospitalised for COVID-19 during the first three waves of the pandemic in Sweden in comparison to previous influenza outbreaks.

Design A registry-based, retrospective, case-control study.SettingHospital care in Sweden.

Participants All patients in Sweden with a main hospital diagnosis of COVID-19 (January 2020-September 2021) or influenza (January 2015-December 2019) with previous CRD were identified in registries and compared with a reference group free from CRD but with COVID-19 or influenza.

Primary outcome measure Associated risk of all-cause death during the first year was analysed using adjusted Cox proportional hazards models.

Results In COVID-19 patients with and without prior history of CRD (n=44 866), mean age was 79.8 years (SD 11.8) and 43% were women. In influenza patients (n=8897), mean age was 80.6 years (SD 11.5) and 45% were women. COVID-19 versus influenza was associated with higher mortality risk during the first two COVID-19 waves (HR 1.53; 95% CI 1.45 to 1.62, p<0.001 and HR 1.52; 95% CI 1.44 to 1.61, p<0.001), but not in the third wave (HR 1.07; 95% CI 0.99 to 1.14, p=0.072). CRD was an independent risk factor for all-cause death after COVID-19 in men and women (men: 1.37; 95% CI 1.31 to 1.44, p<0.001; women: 1.46; 95% CI 1.38 to 1.54, p<0.001). At ages <70 years, women with CRD had a similar mortality rate to men with CRD, while at ages >= 70 years, the mortality rate was higher in men.

Conclusions Outcome after COVID-19 is worse if CRD is present. In women at ages <70 years, the presence of CRD attenuates the protective effect of female sex. COVID-19 was associated with higher mortality risk than influenza during the first two pandemic waves.

Place, publisher, year, edition, pages
BMJ, 2023
Keywords
COVID-19, heart failure, epidemiology, chronic renal failure
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-512195 (URN)10.1136/bmjopen-2022-069037 (DOI)001057956000094 ()37117003 (PubMedID)
Funder
AstraZeneca
Available from: 2023-09-28 Created: 2023-09-28 Last updated: 2023-09-28Bibliographically approved
Ahmed, F., Vranic, M., Hetty, S., Mathioudaki, A., Patsoukaki, V., Fanni, G., . . . Eriksson, J. (2023). Increased OCT3 Expression in Adipose Tissue With Aging: Implications for Catecholamine and Lipid Turnover and Insulin Resistance in Women. Endocrinology, 165(1), Article ID bqad172.
Open this publication in new window or tab >>Increased OCT3 Expression in Adipose Tissue With Aging: Implications for Catecholamine and Lipid Turnover and Insulin Resistance in Women
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2023 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 165, no 1, article id bqad172Article in journal (Refereed) Published
Abstract [en]

Background Catecholamine-stimulated lipolysis is reduced with aging, which may promote adiposity and insulin resistance. Organic cation transporter 3 (OCT3), which is inhibited by estradiol (E2), mediates catecholamine transport into adipocytes for degradation, thus decreasing lipolysis. In this study, we investigated the association of OCT3 mRNA levels in subcutaneous adipose tissue (SAT) with aging and markers of insulin resistance in women.Methods SAT biopsies were obtained from 66 women with (19) or without (47) type 2 diabetes (age 22-76 years, 20.0-40.1 kg/m2). OCT3 mRNA and protein levels were measured for group comparisons and correlation analysis. SAT was incubated with E2 and OCT3 mRNA levels were measured. Associations between OCT3 single nucleotide polymorphisms (SNPs) and diabetes-associated traits were assessed.Results OCT3 mRNA and protein levels in SAT increased with aging. SAT from postmenopausal women had higher levels of OCT3 than premenopausal women, and there was a dose-dependent reduction in OCT3 mRNA levels in SAT treated with E2. OCT3 mRNA levels were negatively associated with markers of insulin resistance, and ex vivo lipolysis. OCT3 SNPs were associated with BMI, waist to hip ratio, and circulating lipids (eg, triglycerides).Conclusion OCT3 mRNA and protein levels in SAT increased with aging, and mRNA levels were negatively associated with markers of insulin resistance. E2 incubation downregulated OCT3 mRNA levels, which may explain lower OCT3 mRNA in premenopausal vs postmenopausal women. High OCT3 protein levels in adipose tissue may result in increased catecholamine degradation, and this can contribute to the reduction in lipolysis observed in women with aging.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
OCT3, adipose tissue, estradiol, aging, T2D
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-518092 (URN)10.1210/endocr/bqad172 (DOI)001111781700001 ()37972266 (PubMedID)
Funder
AstraZeneca
Available from: 2024-01-03 Created: 2024-01-03 Last updated: 2024-01-03Bibliographically approved
Projects
SGLT2 inhibitor or metformin as standard treatment in early type 2 diabetes (SMART) [2018-00904_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2639-9481

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