| 1. |
- Ahlin, Sofie, 1985, et al.
(författare)
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Macrophage Gene Expression in Adipose Tissue is Associated with Insulin Sensitivity and Serum Lipid Levels Independent of Obesity.
- 2013
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Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-739X .- 1930-7381. ; 21:12
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.
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| 2. |
- Boström, Pontus, 1982, et al.
(författare)
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The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes.
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:8, s. 1870-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23. RESEARCH DESIGN AND METHODS: We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6. RESULTS: We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23. CONCLUSIONS: We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.
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| 3. |
- Daka, Bledar, 1976, et al.
(författare)
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Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden
- 2013
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Ingår i: Endocrine Connections. - 2049-3614. ; 2:1, s. 18-22
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Obesity is associated with low levels of sex hormone-binding globulin (SHBG). While the reason is not fully understood, we aimed to study the association between serum insulin and levels of SHBG in a random population. DESIGN AND METHODS: Between 2001 and 2005, a random sample of 2816 participants aged 30-74 years were enrolled in a cross-sectional survey in the South-west of Sweden. Fasting blood samples were collected and an oral glucose tolerance test (OGTT) was conducted in all subjects without known diabetes. Diabetes mellitus was defined according to criteria from WHO, and clinical characteristics were used to discriminate between type 1 (T1D) and type 2 diabetes (T2D). Analyses of SHBG were successful in 2782 participants (98%), who thus constituted the current study population. RESULTS: WE FOUND SIGNIFICANT INVERSE ASSOCIATION BETWEEN LEVELS OF SHBG AND FASTING SERUM INSULIN IN BOTH GENDERS (MEN: β=-0.090, P=0.001; women: β=-0.197, P<0.001), which was independent of differences in age and BMI. The associations remained when also differences in fasting plasma glucose were accounted for (men: β=-0.062, P=0.022; women: β=-0.176, P≤0.001). Subjects with T1D exhibited higher levels of SHBG than both T2D (men: δ=15.9nmol/l, P<0.001; women: δ=71.1nmol/l, P<0.001) and non-diabetic subjects (men: δ=15.1nmol/l, P<0.001; women: δ=72.9nmol/l, P<0.001) independent of age, BMI and fasting glucose levels. CONCLUSION: These findings are consistent with high levels of SHBG in T1D, and correspondingly low levels in T2D subjects, suggesting an inhibitory effect of insulin on the SHBG production in the liver.
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| 4. |
- Daka, Bledar, et al.
(författare)
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Low sex hormone-binding globulin is associated with hypertension: a cross-sectional study in a Swedish population
- 2013
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate the association of sex hormone-binding globulin (SHBG) and hypertension in a Swedish population. Methods: The study is based on a random sample of a Swedish population of men and women aged 30-74 years (n=2,816). Total testosterone, oestradiol and SHBG were measured in 2,782 participants. Free androgen index was then calculated according to the formula FAI=100 x (Total testosterone)/SHBG. Hypertension was diagnosed according to JNC7. Results: In men, but not in women, significant association between SHBG and both diastolic (diastolic blood pressure: beta=-0.143 p<0.001) and systolic blood pressure (systolic blood pressure beta=-0.114 p<0.001) was found. The association was still significant after adjusting for age, body mass index (BMI), homeostatic model assessment insulin resistance (HOMA-IR), triglycerides, high density lipoproteins (HDL) and C-reactive protein (CRP) (diastolic blood pressure: beta=-0.113 p<0.001; systolic blood pressure beta=-0.093 p=0.001). An inverse association was observed between SHBG and hypertension in both men (B=-0.024 p<0.001) and women (B=-0.022 p<0.001). The association was still significant in women older than 50 years after adjustments for age, BMI, physical activity, CRP and alcohol consumption (B=-0.014, p=0.008). Conclusion: In conclusion, these results show a strong association between SHBG and blood pressure independent of major determinants of high blood pressure. This association might be addressed to direct effects of SHBG in endothelial cells through the receptor for SHBG. If this is confirmed by other observational and experimental studies, it might become a new field for the development of therapies for lowering blood pressure.
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| 5. |
- Hellgren, Margareta, 1955, et al.
(författare)
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Feasibility of a randomized controlled intervention with physical activity in participants with impaired glucose tolerance recruited by FINDRISC: A pilot study
- 2014
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 42:5, s. 463-470
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study aimed to explore the feasibility and effect of an intervention in clinical practice with isolated physical activity in individuals with IGT, recruited by the FINDRISC questionnaire. Methods: The questionnaire was sent to a population of 9734 individuals, 35-75 years old, in Sweden. Those with a risk score >= 15 were encouraged to perform an oral glucose tolerance test. Individuals with IGT were invited to participate in a randomized controlled trial with a focus on physical activity. The participants were allocated to one of three arms; basic intervention, intensive intervention or to care as usual. A total of 52 individuals were carefully examined and questionnaires about diet and lifestyle were completed at baseline and after one year. All analyses were adjusted for differences in age and sex, and calorie intake when relevant. Results: The prevalence of chronic diseases in the study population was high, creating considerable difficulties in conducting a standardized test for fitness. Waist circumference (p=0.020), sagittal diameter (p=0.035), body weight (p=0.038) and BMI (p=0.043) decreased significantly more in the intensive care group than in care as usual and the basic care group. However, the significance was abolished when differences in energy intake were accounted for. Conclusions: In an intention to treat, prospective lifestyle interventions with physical activity are feasible, but a high prevalence of comorbidities needs to be considered. Also, an intervention focused on isolated physical activity inevitably led to changes in diet with weight loss and significant improvement of essential risk factors in spite of the participants' burden of chronic diseases.
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| 6. |
- Hellgren, Margareta, 1955, et al.
(författare)
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Feasibility of the FINDRISC questionnaire to identify individuals with impaired glucose tolerance in Swedish primary care. A cross-sectional population-based study.
- 2012
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 29:12, s. 1501-1505
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To evaluate the performance of the FINDRISC questionnaire as a tool to recruit individuals with impaired glucose tolerance for lifestyle intervention programmes. Methods: A cross-sectional population-based study in primary Health Care Centres in a middle-sized Swedish town. All 9734 individuals, aged 35–75 years, living within a defined area, were invited by mail to fill in and return the FINDRISC questionnaire. Participants with a risk score ≥ 15 (n = 525) were invited to perform an oral glucose tolerance test while those with known diabetes were excluded. Results: In total, 5452 questionnaires (58%) were returned and revealed a mean risk-score of 8.5 ± 4.5 (mean ± SD). We found that 525 participants had a risk-score ≥ 15 and 302 (58%) were further examined with an oral glucose tolerance testing (OGTT). Among them we detected 11% with previously undiagnosed Type 2 diabetes, 16% with impaired glucose tolerance and 29% with impaired fasting glucose. A FINDRISC score ≥ 15 was associated with a positive predictive value of 55% for impaired glucose metabolism (impaired fasting glucose + impaired glucose tolerance + Type 2 diabetes) and of 16% for impaired glucose tolerance, respectively. The positive predictive value for impaired glucose tolerance did not increase to more than 17% when choosing the cut-point 17, while there was a significant increase in the positive predictive value for impaired glucose metabolism (70%). Conclusions: The FINDRISC questionnaire is a useful instrument for identification of individuals with impaired glucose metabolism but seems less effective for detection of individuals with impaired glucose tolerance. Strategies to find individuals with impaired glucose tolerance for implementation of lifestyle changes in primary care should therefore be developed further.
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| 7. |
- Hribal, M. L., et al.
(författare)
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Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B
- 2011
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 54:4, s. 795-802
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry. METHODS: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. RESULTS: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples). CONCLUSIONS/INTERPRETATION: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Nilsson, Emma A, et al.
(författare)
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Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:9, s. 2962-2976
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Tidskriftsartikel (refereegranskat)abstract
- Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
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