| 1. |
- Drake, Isabel, et al.
(författare)
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The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease: evidence from cross-sectional, longitudinal and Mendelian randomisation analyses
- 2022
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65, s. 128-139
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects. Methods Participants (n = 4022; 58.6% women) in the Malmo Diet and Cancer Study-Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 +/- 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 +/- 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 x 10(-11)). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort. Results Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 x 10(-89)) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 x 10(-3)). Conclusions/interpretation Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.
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| 2. |
- Fryk, Emanuel, et al.
(författare)
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Feasibility of high-dose tadalafil and effects on insulin resistance in well-controlled patients with type 2 diabetes (MAKROTAD): a single-centre, double-blind, randomised, placebo-controlled, cross-over phase 2 trial
- 2023
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Ingår i: Eclinicalmedicine. ; 59
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Tidskriftsartikel (refereegranskat)abstract
- Background Phosphodiesterase-5 inhibitors exert positive vascular and metabolic effects in type 2 diabetes (T2D), but the effect on insulin resistance in T2D is unclear. Methods This randomised, double blind, placebo-controlled, two-period crossover trial was conducted at Sahlgrenska University Hospital (Gothenburg, Sweden). Men without apparent erectile dysfunction (age 40-70 years) and women (age 55-70 years, post-menopause) diagnosed with T2D between 3 months and 10 years, haemoglobin A1c (HbA1c) < 60 mmol/mol and a body mass index (BMI) 27-40 kg/m2 were enrolled. Participants were randomly assigned to one period of oral tadalafil 20 mg once a day and one period of placebo for 6 weeks, separated by an 8-week wash-out period. Placebo and tadalafil tablets were made visually indistinguishable and delivered randomized in two separate boxes for each participant. Both treatment periods ended with a glucose clamp, and measurements of body composition and metabolic markers in blood, subcutaneous and muscular interstitial fluid. The primary aim was to assess difference in whole-body insulin resistance after 6-weeks of treatment, determined after completion of the two study arms, and secondary aims were to study effects of tadalafil on pathophysiology of T2D as well as tolerability of high-dose tadalafil in T2D. Primary analysis was performed in participants with full analysis set (FAS) and safety analysis in all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT02601989), and EudraCT (2015-000573). Findings Between January 22nd, 2016, and January 31st, 2019, 23 participants with T2D were enrolled, of whom 18 were included in the full analysis set. The effect of tadalafil on insulin resistance was neutral compared with placebo. However, tadalafil decreased glycaemia measured as HbA1c (mean difference -2.50 mmol/mol, 95% confidence interval (CI), -4.20; -0.78, p = 0.005), and, further, we observed amelioration of endothelial function and markers of liver steatosis and glycolysis, whereas no statistically significant differences of other clinical phenotyping were shown. Muscle pain, dyspepsia, and headache were more frequent in participants on high-dose tadalafil compared with placebo (p < 0.05) but no difference between treatments appeared for serious adverse events. Interpretation High-dose tadalafil does not decrease whole-body insulin resistance, but increases microcirculation, induces positive effects in the liver and in intermediate metabolites, in parallel with an improved metabolic control measured as HbA1c. High-dose tadalafil is moderately well tolerated, warranting larger trials to define the optimal treatment regimen in T2D.
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| 3. |
- Fryk, Emanuel, et al.
(författare)
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Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study
- 2021
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Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is commonly accepted that in obesity free fatty acids (FFA) cause insulin resistance and hyperglycemia, which drives hyperinsulinemia. However, hyperinsulinemia is observed in subjects with normoglycaemia and thus the paradigm above should be reevaluated. Methods: We describe two studies: MD-Lipolysis, a case control study investigating the mechanisms of obesity-driven insulin resistance by a systemic metabolic analysis, measurements of adipose tissue lipolysis by microdialysis, and adipose tissue genomics; and POEM, a cohort study used for validating differences in circulating metabolites in relation to adiposity and insulin resistance observed in the MD-Lipolysis study. Findings: In insulin-resistant obese with normal glycaemia from the MD-Lipolysis study, hyperinsulinemia was associated with elevated FFA. Lipolysis, assessed by glycerol release per adipose tissue mass or adipocyte surface, was similar between obese and lean individuals. Adipose tissue from obese subjects showed reduced expression of genes mediating catecholamine-driven lipolysis, lipid storage, and increased expression of genes driving hyperplastic growth. In the POEM study, FFA levels were specifically elevated in obese-overweight subjects with normal fasting glucose and high fasting levels of insulin and C-peptide. Interpretation: In obese subjects with normal glycaemia elevated circulating levels of FFA at fasting are the major metabolic derangement candidate driving fasting hyperinsulinemia. Elevated FFA in obese with normal glycaemia were better explained by increased fat mass rather than by adipose tissue insulin resistance. These results support the idea that hyperinsulinemia and insulin resistance may develop as part of a homeostatic adaptive response to increased adiposity and FFA. (C) 2021 The Author(s). Published by Elsevier B.V.
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| 4. |
- Fryk, Emanuel, et al.
(författare)
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Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients
- 2016
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:7, s. 998-1006
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. Methods. Proteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16 weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4 weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. Results. Galectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p < 0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p < 0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p < 0.05) and increased by overfeeding (p < 0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p < 0.05) but this was independent of the insulin signal. Conclusion. Proteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes. (C) 2016 Elsevier Inc. All rights reserved.
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| 5. |
- Jansson, Per-Anders, 1961, et al.
(författare)
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Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes
- 2010
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Ingår i: DIABETOLOGIA. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 53:10, s. 2205-2208
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Recent evidence suggests that reduced synthesis of nitric oxide in endothelial cells, i.e. endothelial dysfunction, contributes to the impaired action of insulin in the vasculature of patients with type 2 diabetes. We investigated whether selective inhibition of phosphodiesterase-5 by tadalafil has beneficial effects on peripheral microcirculation and glucose uptake in these patients. Methods We enrolled seven postmenopausal women with type 2 diabetes and ten age-matched healthy women as controls in a placebo-controlled study to evaluate the acute metabolic effects of tadalafil. We performed microdialysis and blood flow measurements in muscle, and sampled arterial and deep venous blood before and after a single dose of tadalafil 20 mg or placebo. Circulating glucose and insulin levels, muscle capillary recruitment as reflected by permeability surface area for glucose (PSglu) and forearm glucose uptake were measured. Results In women with type 2 diabetes, but not in the control group, tadalafil induced increases in the incremental AUC for PSglu (tadalafil vs placebo 41±11 vs 4±2 ml [100 g]−1 min−1, p<0.05) and forearm glucose uptake (46±9 vs 8±4 µmol [100 g]−1 min−1, p<0.05). The variable that best predicted forearm glucose uptake was PSglu, which explained 70% of its variance. However, fasting glucose and insulin concentrations were similar following treatment with placebo or tadalafil in the two groups. Conclusions/interpretation This study suggests that tadalafil evokes positive metabolic effects in insulin-resistant women with type 2 diabetes.
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| 6. |
- Murdolo, G., et al.
(författare)
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The Selective Phosphodiesterase-5 Inhibitor Tadalafil Induces Microvascular and Metabolic Effects in Type 2 Diabetic Postmenopausal Females
- 2013
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:1, s. 245-254
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The objective of the study was to explore the acute in vivo effects of the selective phosphodiesterase-5 inhibitor tadalafil on local microcirculation and regional metabolism in skeletal muscle and adipose tissue (AT). Design, Setting, and Participants: We studied eight postmenopausal female patients with type 2 diabetes (T2D) and eight nondiabetic controls (Ctrl) in the postabsorptive state and 180 min after the administration of tadalafil 10 mg. Intramuscular and sc microdialysis were combined with measurements of forearm (FBF) and AT blood flow as well as with arterial and deep venous blood sampling. Muscle capillary recruitment, as ascertained by the permeability surface area product for glucose (PSglu), forearm glucose uptake (FGU), interstitial lactate, and glycerol concentrations, was measured. Results: When compared with Ctrl, T2D patients exhibited lower (P = 0.01) PSglu but similar FGU and FBF. After tadalafil, PSglu (P = 0.01) and muscle interstitial-arterial (I-A) lactate concentration gradient (P < 0.01) increased significantly in both groups, whereas FBF, FGU, and I-A glycerol remained unchanged. In AT, tadalafil did not significantly affect local blood flow, whereas the sc interstitial (I) lactate and I-A lactate concentrations increased (P < 0.01), and the I-A glycerol decreased in both groups. Finally, in multivariate analysis the PSglu was a strong and independent predictor of muscle glucose disposal (β: 0.737 and 0.963, P < 0.05, in Ctrl and T2D, respectively). Conclusions: Tadalafil emerges as an acutely acting modulator of microvascular recruitment and glucose metabolism in skeletal muscle and adipose tissue. We suggest that selective phosphodiesterase-5 blockade may provide a path forward to new therapeutics in the setting of insulin resistance.
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| 7. |
- Sandqvist, Madelene, 1974, et al.
(författare)
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Decreased Permeability Surface Area for Glucose in Obese Women with Postprandial Hyperglycemia: No Effect of Phosphodiesterase-5 (PDE-5) Inhibition
- 2013
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 45:8, s. 556-560
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-mediated microvascular recruitment is recognized as a potential mechanism contributing to insulin resistance. In this study, we compared a marker of microvascular function, the permeability surface area for glucose (PSglu), and forearm glucose uptake after an OGTT in obese women with impaired glucose metabolism and healthy lean nondiabetic women, with the aim to characterize whether decreased permeability surface area for glucose or decreased glucose uptake may contribute to postprandial hyperglycemia in the obese group. In addition, we evaluated whether the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, in a randomized double blind placebo controlled design, might attenuate postprandial glucose levels in obese women. For these purposes, intramuscular microdialysis, blood sampling from arterial and venous blood of the forearm, and measurements of forearm blood flow were performed. The results showed an impaired permeability surface area for glucose (IAUC PSglu 31 +/- 13 vs. 124 +/- 31; p < 0.05) in obese when compared with lean participants, but no differences in forearm glucose uptake appeared between the groups. Furthermore, a single dose of tadalafil 10 mg showed no improvement of the permeability surface area for glucose, glucose uptake, or circulating glucose levels in obese participants. In conclusion, the postprandial PSglu response was impaired in obese women showing postprandial hyperglycemia, indicating a compromised microcirculation. However, we were unable to demonstrate any acute effect on either vascular function or glucose uptake of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil.
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| 8. |
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| 9. |
- Sjögren, Lovisa, et al.
(författare)
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Postprandial effects of the phosphodiesterase-5 inhibitor tadalafil in people with well-controlled Type 2 diabetes mellitus: a randomized controlled trial.
- 2016
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Ingår i: Diabetic medicine : a journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 33:9, s. 1299-1301
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes mellitus is a serious global health problem that is hard to treat in the long term, prompting great efforts to find new drug targets. Little attention has been paid, however, to the metabolic significance of the microcirculation in insulin-sensitive tissues, despite the fact that microvascular insulin resistance and endothelial dysfunction are closely associated and have been shown to precede Type 2 diabetes [1]. Endothelial nitric oxide plays a major role in mediating the beneficial effects of insulin on capillary recruitment and muscle glucose uptake [2] and in suppression of inflammatory pathways, including those activated by a high-fat diet [3]. This article is protected by copyright. All rights reserved.
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