| 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. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
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| 8. |
- 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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| 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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