| 1. |
- Ahmed, Fozia, et al.
(författare)
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Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 107:5, s. E1879-E1889
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Tidskriftsartikel (refereegranskat)abstract
- Context: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood.Objective: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes.Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits.Results: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage.Conclusion: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.
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| 2. |
- Almby, Kristina E., et al.
(författare)
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Anastomotic Strictures After Roux-en-Y Gastric Bypass : a Cohort Study from the Scandinavian Obesity Surgery Registry
- 2019
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Ingår i: Obesity Surgery. - New York City : Springer. - 0960-8923 .- 1708-0428. ; 29:1, s. 172-177
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRoux-en-Y gastric bypass (RYGB) is the most common bariatric procedure worldwide. Anastomotic stricture is a known complication of RYGB. The aim was to explore the incidence and outcomes of strictures within the Scandinavian Obesity Surgery Registry (SOReg).MethodSOReg included prospective data from 36,362 patients undergoing bariatric surgery in the years 2007–2013. Outcomes were recorded at 30-day and at 1-year follow-up according to the standard SOReg routine. The medical charts of patients suffering from stricture after RYGB were requested and assessed.SettingNational bariatric surgery registryResultsAnastomotic stricture within 1 year of surgery was confirmed in 101 patients representing an incidence of 0.3%. Risk factors for stricture were patient age above 60 years (odds ratio (OR), 6.2 95% confidence interval (CI) 2.7–14.3), circular stapled gastrojejunostomy (OR 2.7, 95% CI 1.4–5.5), postoperative anastomotic leak (OR 8.9 95%, CI 4.7–17.0), and marginal ulcer (OR 30.0, 95% CI 19.2–47.0). Seventy-five percent of the strictures were diagnosed within 70 days of surgery. Two dilatations or less was sufficient to successfully treat 50% of patients. Ten pecent of patients developed perforation during dilatation, and the risk of perforating at each dilatation was 3.8%. Perforation required surgery in six cases but there was no mortality. Strictures in SOReg may be underreported, which could explain the low incidence in the study.ConclusionMost strictures present within 2 months and are successfully treated with two dilatations or less. Dilating a strictured gastrojejunostomy entails a risk of perforation (3.8%).
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| 3. |
- Almby, Kristina E., et al.
(författare)
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Effects of Gastric Bypass Surgery on the Brain : Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:6, s. 1265-1277
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Tidskriftsartikel (refereegranskat)abstract
- While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by F-18-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.
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| 4. |
- Almby, Kristina E., et al.
(författare)
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Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery
- 2019
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Ingår i: European Journal of Endocrinology. - : Bioscientifica. - 0804-4643 .- 1479-683X. ; 181:2, s. 161-171
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).Design: Experimental hyperinsulinemic–hypoglycemic clamp study.Methods: Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.Results: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.Conclusions/interpretation: Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.
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| 5. |
- Almby, Kristina E., et al.
(författare)
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Time course of metabolic, neuroendocrine, and adipose effects during 2 years of follow-up after gastric bypass in patients with type 2 diabetes
- 2021
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 106:10, s. E4049-E4061
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Tidskriftsartikel (refereegranskat)abstract
- Context: Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.Objective: Integrated assessment of neuroendocrine and metabolic changes over time inT2D patients undergoing RYGB.Design and Setting: Follow-up of single-center randomized study.Patients: Thirteen patients with obesity andT2D compared to 22 healthy subjects.Interventions: Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.Results: After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P < 0.001). At 4 weeks, morning cortisol (P < 0.05) and adrenocorticotropin (P = 0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P < 0.05) and peaked at 24 weeks (P < 0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P < 0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P < 0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P < 0.01).Conclusions: We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls).Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.
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| 6. |
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| 7. |
- Kamble, Prasad G., et al.
(författare)
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Estrogen interacts with glucocorticoids in the regulation of lipocalin 2 expression in human adipose tissue. Reciprocal roles of estrogen receptor alpha and beta in insulin resistance?
- 2019
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Ingår i: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 490, s. 28-36
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Tidskriftsartikel (refereegranskat)abstract
- The adipokine lipocalin 2 (LCN2) is linked to insulin resistance. Its expression in human adipose tissue (AT) can be regulated in a sex-specific manner by a synthetic glucocorticoid, dexamethasone, suggesting an underlying role of sex steroids. We show that 17-beta-estradiol (E2) dose-dependently increased LCN2 gene expression in subcutaneous AT from postmenopausal women. This was also seen in the presence of estrogen receptor (ER) alpha antagonist alone but not with ER beta antagonist, suggesting that E2 effects on LCN2 are mediated via ER beta pathway. Dexamethasone alone or E2 + dexamethasone had no significant effect on LCN2. However, E2+ dexamethasone increased LCN2 expression with ER alpha-blockade. Dexamethasone reduced ER alpha but increased ER beta expression. Dexamethasone can regulate LCN2 expression via inhibition of ER alpha and stimulation of ER beta and may contribute to the development of glucocorticoid-induced insulin resistance in human AT. In conclusion, ER beta and ER alpha pathways have opposite effects on LCN2 expression and they interact with glucocorticoid action.
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| 8. |
- Khamisi, Selwan, et al.
(författare)
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Serum thyroglobulin is associated with orbitopathy in Graves' disease
- 2021
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Ingår i: Journal of Endocrinological Investigation. - : Springer Nature. - 0391-4097 .- 1720-8386. ; 44:9, s. 1905-1911
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Serum thyroglobulin levels are often elevated in Graves' disease (GD) and in most cases decrease during treatment. Its relation to Graves' orbitopathy (GO) has not been clarified. Previously, a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb). Methods We examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO n = 12, non-GO n = 10) completed the drug regimen. Results At diagnosis, Tg levels in GO patients (n = 11) were higher (84, 30-555 mu g/L, median, range) than in non-GO patients (n = 19) (38, 3.5-287 mu g/L), p = 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (n = 17), yielded p = 0.001 vs. non-GO (n = 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (n = 12) vs. non-GO (n = 10), p = 0.004, whereas TRAb levels did not differ. Conclusion The data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.
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| 9. |
- Lundqvist, Martin H., et al.
(författare)
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Altered hormonal and autonomic nerve responses to hypo- and hyperglycaemia are found in overweight and insulin-resistant individuals and may contribute to the development of type 2 diabetes
- 2021
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 64:3, s. 641-655
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Results from animal models and some clinical work suggest a role for the central nervous system (CNS) in glucose regulation and type 2 diabetes pathogenesis by modulation of glucoregulatory hormones and the autonomic nervous system (ANS). The aim of this study was to characterise the neuroendocrine response to various glucose concentrations in overweight and insulin-resistant individuals compared with lean individuals.Methods: Overweight/obese (HI, n = 15, BMI ≥27.0 kg/m2) and lean (LO, n = 15, BMI <27.0 kg/m2) individuals without diabetes underwent hyperinsulinaemic euglycaemic–hypoglycaemic clamps and hyperglycaemic clamps on two separate occasions with measurements of hormones, Edinburgh Hypoglycaemic Symptom Scale (ESS) score and heart rate variability (HRV). Statistical methods included groupwise comparisons with Mann–Whitney U tests, multilinear regressions and linear mixed models between neuroendocrine responses and continuous metabolic variables.Results: During hypoglycaemic clamps, there was an elevated cortisol response in HI vs LO (median ΔAUC 12,383 vs 4793 nmol/l × min; p = 0.050) and a significantly elevated adrenocorticotropic hormone (ACTH) response in HI vs LO (median ΔAUC 437.3 vs 162.0 nmol/l × min; p = 0.021). When adjusting for clamp glucose levels, obesity (p = 0.033) and insulin resistance (p = 0.009) were associated with elevated glucagon levels. By contrast, parasympathetic activity was less suppressed in overweight individuals at the last stage of hypoglycaemia compared with euglycaemia (high-frequency power of HRV, p = 0.024). M value was the strongest predictor for the ACTH and PHF responses, independent of BMI and other variables. There was a BMI-independent association between the cortisol response and ESS score response (p = 0.024). During hyperglycaemic clamps, overweight individuals displayed less suppression of glucagon levels (median ΔAUC −63.4% vs −73.0%; p = 0.010) and more suppression of sympathetic relative to parasympathetic activity (low-frequency/high-frequency power, p = 0.011).Conclusions/interpretation: This study supports the hypothesis that altered responses of insulin-antagonistic hormones and the ANS to glucose fluctuations occur in overweight and insulin-resistant individuals, and that these responses are probably partly mediated by the CNS. Their potential role in development of type 2 diabetes needs to be addressed in future research.
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| 10. |
- Lundqvist, Martin H., et al.
(författare)
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Is the Brain a Key Player in Glucose Regulation and Development of Type 2 Diabetes?
- 2019
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Ingår i: Frontiers in Physiology. - : FRONTIERS MEDIA SA. - 1664-042X. ; 10
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Forskningsöversikt (refereegranskat)abstract
- Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic. We conclude that there is much evidence in favor of active CNS involvement in glucose homeostasis but the relative importance of central vs. peripheral mechanisms remains to be elucidated. An increased understanding of this field may lead to new CNS-focusing pharmacologic strategies in the treatment of type 2 diabetes.
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| 11. |
- Lundqvist, Martin H., et al.
(författare)
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Regulation of the Cortisol Axis, Glucagon, and Growth Hormone by Glucose Is Altered in Prediabetes and Type 2 Diabetes
- 2024
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 109:2, s. e675-e688
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Tidskriftsartikel (refereegranskat)abstract
- Context Insulin-antagonistic, counter-regulatory hormones have been implicated in the development of type 2 diabetes (T2D).Objective In this cross-sectional study, we investigated whether glucose-dependent regulation of such hormones differ in individuals with T2D, prediabetes (PD), and normoglycemia (NG).Methods Fifty-four individuals with or without T2D underwent one hyperinsulinemic-normoglycemic-hypoglycemic and one hyperglycemic clamp with repeated hormonal measurements. Participants with T2D (n = 19) were compared with a group-matched (age, sex, BMI) subset of participants without diabetes (ND, n = 17), and also with participants with PD (n = 18) and NG (n = 17).Results In T2D vs ND, glucagon levels were higher and less suppressed during the hyperglycemic clamp whereas growth hormone (GH) levels were lower during hypoglycemia (P < .05). Augmented ACTH response to hypoglycemia was present in PD vs NG (P < .05), with no further elevation in T2D. In contrast, glucagon and GH alterations were more marked in T2D vs PD (P < .05). In the full cohort (n = 54), augmented responses of glucagon, cortisol, and ACTH and attenuated responses of GH correlated with adiposity, dysglycemia, and insulin resistance. In multilinear regressions, insulin resistance was the strongest predictor of elevated hypoglycemic responses of glucagon, cortisol, and ACTH. Conversely, fasting glucose and HbA1c were the strongest predictors of low GH levels during hypoglycemia and elevated, i.e. less suppressed glucagon levels during hyperglycemia, respectively. Notably, adiposity measures were also strongly associated with the responses above.Conclusions Altered counter-regulatory hormonal responses to glucose variations are observed at different stages of T2D development and may contribute to its progression by promoting insulin resistance and dysglycemia.
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| 12. |
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| 13. |
- Sarsenbayeva, Assel, et al.
(författare)
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Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism
- 2019
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Ingår i: Psychoneuroendocrinology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0306-4530 .- 1873-3360. ; 110
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism.Methods: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m(2)). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 mu M - 20 mu M) and aripiprazole (0.002 mu M - 100 mu M). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis.Results: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term preincubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondria] functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG.Conclusion: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.
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| 14. |
- Sarsenbayeva, Assel, et al.
(författare)
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Excess glucocorticoid exposure contributes to adipose tissue fibrosis which involves macrophage interaction with adipose precursor cells
- 2022
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Ingår i: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839. ; 198
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Tidskriftsartikel (refereegranskat)abstract
- Chronic exposure to elevated glucocorticoid levels, as seen in patients with Cushing’s syndrome, can induce adipose tissue fibrosis. Macrophages play a pivotal role in adipose tissue remodelling. We used the synthetic glucocorticoid analogue dexamethasone to address glucocorticoid effects on adipose tissue fibrosis, in particular involving macrophage to preadipocyte communication. We analysed the direct effects of dexamethasone at a supra-physiological level, 0.3 µM, on gene expression of pro-fibrotic markers in human subcutaneous adipose tissue. The effects of dexamethasone on the differentiation of human SGBS preadipocytes were assessed in the presence or absence of THP1-macrophages or macrophage-conditioned medium. We measured the expression of different pro-fibrotic factors, including α-smooth muscle actin gene (ACTA2) and protein (α-SMA). Dexamethasone increased the expression of pro-fibrotic genes, e.g. CTGF, COL6A3, FN1, in adipose tissue. Macrophages abolished preadipocyte differentiation and increased the expression of the ACTA2 gene and α-SMA protein in preadipocytes after differentiation. Exposure to dexamethasone during differentiation reduced adipogenesis in preadipocytes, and elevated the expression of pro-fibrotic genes. Moreover, dexamethasone added together with macrophages further increased ACTA2 and α-SMA expression in preadipocytes, making them more myofibroblast-like. Cells differentiated in the presence of conditioned media from macrophages pretreated with or without dexamethasone had a higher expression of profibrotic genes compared to control cells. Our data suggest that macrophages promote adipose tissue fibrosis by directly interfering with preadipocyte differentiation and stimulating gene expression of pro-fibrotic factors. Excess glucocorticoid exposure also has pro-fibrotic effect on adipose tissue, but this requires the presence of macrophages.
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| 15. |
- Sarsenbayeva, Assel, et al.
(författare)
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Human macrophages stimulate expression of inflammatory mediators in adipocytes; effects of second-generation antipsychotics and glucocorticoids on cellular cross-talk
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 125
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Adipose tissue inflammation and distorted macrophage-adipocyte communication are positively associated with metabolic disturbances. Some pharmacological agents, such as second-generation antipsychotics (SGAs) and synthetic glucocorticoid (GC) dexamethasone, tend to induce adverse metabolic side effects and the underlying mechanisms are not fully understood. Our work aimed to study whether SGAs and dexamethasone affect macrophage phenotype and macrophage-adipocyte communication on gene expression level. We selected the model involving THP-1-derived macrophages, polarized into M0, M1, and M2 phenotypes, and primary human mature subcutaneous adipocytes.Methods: Abdominal subcutaneous adipose tissue needle biopsies were obtained from 6 healthy subjects (4F/2M; age: 22-64 yr; BMI: 21.7-27.6 kg/m2) followed by isolation of mature adipocytes. THP-1-human monocytic cell line was used for the study. THP-1 monocytes were differentiated and polarized into M0 (naive), M1 (classically activated), and M2 (alternatively activated) macrophages. During and after polarization the macrophages were treated for 24 h without (control) or with therapeutic and supra-therapeutic concentrations of olanzapine (0.2 mu M and 2.0 mu M), aripiprazole (1.0 mu M and 10 mu M) and its active metabolite dehydroaripiprazole (0.4 mu M and 4.0 mu M). Isolated mature human adipocytes were co-incubated with THP-1-derived polarized macrophages pretreated with SGAs after their polarization. Adipocytes and macrophages were collected before and after co culture for mRNA expression analysis of genes involved in inflammation.Results: Co-incubation of mature human adipocytes with human macrophages, regardless of polarization, resulted in a marked induction of pro-inflammatory cytokines in adipocytes, including IL1B,IL6, TNFA, and IL10. Remarkably, it did not affect the expression of adipokines and genes involved in the regulation of energy, lipid, and glucose metabolism in adipocytes. Dexamethasone markedly reduced gene expression of pro-inflammatory cytokines in macrophages and prevented macrophage-induced inflammatory response in adipocytes. In contrast, SGAs did not affect macrophage-adipocyte communication and had a minute anti-inflammatory effect in macrophages at supra-therapeutic concentrations. Interestingly, the adipocytes co-incubated with M1 macrophages pre-treated with dexamethasone and SGAs particularly the supra-therapeutic concentration of olanzapine, reduced expression of LPL, LIPE, AKT1, and SLC2A4, suggesting that the expression of metabolic genes in adipocytes was dependent on the presence of pro-inflammatory M1 macrophages.Conclusion: Together, these data suggest that macrophages induce expression of pro-inflammatory genes in human subcutaneous adipocytes without affecting the expression of adipokines or genes involved in energy regulation. Furthermore, our findings demonstrated that SGAs and dexamethasone had a mild effect on macrophage-adipocyte communication in M1 macrophage phenotype.
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| 16. |
- Sarsenbayeva, Assel, et al.
(författare)
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Role of glucocorticoids in adipose tissue fibrosis and interplay between macrophages and adipose cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and aimsExcessive endogenous production and administration of glucocorticoids leads to adipose tissue fibrosis as well as metabolic complications. Alternatively activated M2 macrophages are known to interfere with adipocyte differentiation and to promote phenotypic switch of preadipocytes into pro-fibrotic myofibroblasts. Glucocorticoids are known to promote M2 phenotype in macrophages. Therefore, the aim of this study was to investigate whether the effects of synthetic glucocorticoid dexamethasone on adipose tissue fibrosis are mediated through on macrophages to adipocyte communication. MethodsTranscriptomics analysis was performed on human adipose tissue treated without and with dexamethasone. We tested the effects of dexamethasone on differentiation of human SGBS adipocyte cells in the absence or presence of macrophages derived from THP-1 monocytic cell line plated on inserts. The differentiation rate was assessed by measuring cell lipid accumulation, expression of markers of adipogenesis PPARG and CEBPA. Acquisition of myofibroblast phenotype by preadipocytes was assessed by measuring the expression of myofibroblast marker α-smooth muscle actin. The pro-fibrotic activity of these cells was measured by the expression of collagen VI.ResultsOur transcriptomics data demonstrated that dexamethasone is able to directly double the expression of pro-fibrotic genes, such as CTGF, COL6A3, FN1, in adipose tissue, compared to control (p<0.05). Expression of CD163, a marker of M2 macrophages, positively correlated with the components of extracellular matrix COL6A3 and FN1 (p<0.01), and with the pro-fibrotic genes CTGF and AXL (p<0.01) in human adipose tissue. In addition, dexamethasone induced the expression of CD163 and MRC1 in THP-1 macrophages (p<0.05), suggesting that dexamethasone drives M2 phenotype in macrophages. We observed that dexamethasone inhibited adipogenesis by ~30% (p<0.01). Macrophages almost completely abolished differentiation of adipocytes by ~90% (p<0.01). Additionally, macrophages induced 2-3 fold increase in the expression of ACTA2 gene and protein in adipocytes (p<0.01). Dexamethasone alone did not affect ACTA2 in adipocytes,but in the presence of macrophages, increased ACTA2, when compared to macrophages alone (p<0.05). A similar nominal increase was observed in COL6A3. ConclusionOur data show that dexamethasone has a direct pro-fibrotic effect on adipose tissue and promotes M2 phenotype in macrophages. Furthermore, dexamethasone potentiated macrophage-induced phenotype switch of adipocytes to myofibroblasts, which suggests that its effect on adipose tissue fibrosis is mediated though macrophage-adipocyte communication.
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| 17. |
- Sundström, Johan, Professor, 1971-, et al.
(författare)
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A registry-based randomised trial comparing an SGLT2 inhibitor and metformin as standard treatment of early stage type 2 diabetes (SMARTEST): Rationale, design and protocol
- 2021
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Ingår i: Journal of Diabetes and Its Complications. - : Elsevier BV. - 1056-8727 .- 1873-460X. ; 35:10
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Tidskriftsartikel (refereegranskat)abstract
- Aim: SGLT2 inhibitors have been shown to reduce cardiovascular and renal complications in type 2 diabetes (T2D) patients at high cardiovascular risk. Metformin is currently widely used as initial monotherapy in T2D but lacks convincing data to show that it reduces risk of complications. We aim to compare the SGLT2 inhibitor dapagliflozin and metformin as first-line T2D medication with regard to development of complications in a registry-based randomised controlled trial. Methods: The SGLT2 inhibitor or metformin as standard treatment of early stage type 2 diabetes (SMARTEST) trial will enrol 4300 subjects at 30-40 study sites in Sweden who will be randomised 1:1 to either metformin or dapagliflozin. Participants must have T2D duration <4 years, no prior cardiovascular disease, and be either drug-naive or on monotherapy for T2D. Results: The primary endpoint is a composite of all-cause death, major adverse cardiovascular events and occurrence or progression of microvascular complications (retinopathy, nephropathy, diabetic foot lesions). Secondary endpoints include individual components of the primary endpoint, start of insulin therapy, risk factor biomarkers, patient-reported outcome measures, and cost-effectiveness analysis. Outcomes will primarily be assessed using nationwide healthcare registries. Conclusions: The SMARTEST trial will investigate whether dapagliflozin is superior to metformin in preventing complications in early stage T2D. (Clinicaltrials.gov identifier NCT03982381, EudraCT 2019-001046-17).
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