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- Abu Seman, N, et al.
(author)
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Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy
- 2014
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 40:5, s. 408-416
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Journal article (peer-reviewed)abstract
- <b><i>Background/Aims:</i></b> Solute carrier family 12 member 3 (<i>SLC12A3</i>) encodes a sodium/chloride transporter in kidneys. Previous reports suggest that Arg913Gln polymorphism in this gene is associated with diabetic nephropathy (DN), but the data appear to be inconsistent. Up to now, there is no biological evidence concerning the effects of <i>SLC12A3</i> in DN. In this study, we aim to evaluate the genetic effects of the <i>SLC12A3 </i>gene and its Arg913Gln polymorphism with genetic and functional analyses. <b><i>Methods:</i></b> We genotyped <i>SLC12A3</i> genetic polymorphisms including Arg913Gln in 784 non-diabetes controls and 633 type 2 diabetes (T2D) subjects with or without DN in a Malaysian population and performed a meta-analysis of the present and previous studies. We further analyzed the role of <i>slc12a3</i> in kidney development and progress of DN in zebrafish and db/db mice. <b><i>Results:</i></b> We found that <i>SLC12A3</i> Arg913Gln polymorphism was associated with T2D (p = 0.028, OR = 0.772, 95% CI = 0.612-0.973) and DN (p = 0.038, OR = 0.547, 95% CI = 0.308-0.973) in the Malaysian cohort. The meta-analysis confirmed the protective effects of <i>SLC12A3</i> 913Gln allele in DN (Z-value = -1.992, p = 0.046, OR = 0.792). Furthermore, with knockdown of zebrafish ortholog, <i>slc12a3 </i>led to structural abnormality of kidney pronephric distal duct at 1-cell stage. <i>Slc12a3</i> mRNA and protein expression levels were upregulated in kidneys of db/db mice from 6, 12, and 26 weeks at the age. <b><i>Conclusion:</i></b> The present study provided the first biological and further genetic evidence that <i>SLC12A3</i> has genetic susceptibility in the development of DN, while the minor 913Gln allele in this gene confers a protective effect in the disease. i 2014 S. Karger AG, Basel
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- Agardh, EE, et al.
(author)
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The magnitude of bias in a cross-sectional study on lifestyle factors in relation to Type 2 diabetes
- 2006
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In: Scandinavian journal of public health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 34:6, s. 665-668
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Journal article (peer-reviewed)abstract
- Aim: In cross-sectional studies it may be difficult to ascertain the temporal order of exposure and disease, which may have consequences for causal inference. The authors aimed to illustrate the possible magnitude of this potential bias using data from a cross-sectional study on coffee consumption and work stress in relation to type 2 diabetes. Methods: By a series of computer simulations the authors examined to what extent the observed negative association between type 2 diabetes and high coffee consumption and positive association between type 2 diabetes and high work stress could be due to reverse causality, by assuming that cases changed their exposures in response to development of the disease. Results: If the negative association between coffee and type 2 diabetes was a consequence of reversed causality, 30—40% of the cases would have to decrease their coffee consumption from≥5 cups of coffee per day to 3—4 cups per day and from 3—4 cups per day to≤2 cups of coffee per day. Moreover, approximately 60% of the cases would have to increase their work stress from low to medium work stress and from medium to high work stress, in order to produce the positive association with diabetes that was observed. Conclusion: Even if the type 2 diabetic patients to some extent may have changed their exposure in response to disease development, it seems unlikely that the associations observed between type 2 diabetes, coffee consumption, and work stress are due to this bias.
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- Ahmed, AS, et al.
(author)
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Type 2 diabetes impairs tendon repair after injury in a rat model
- 2012
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In: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 113:11, s. 1784-1791
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Journal article (peer-reviewed)abstract
- Type 2 diabetes adversely affects the properties of native connective tissue. The underlying mechanisms, however, by which diabetes alters connective tissue metabolism, especially tendon, are poorly defined. The aim of this study was to determine the effect of type 2 diabetes on the mechanical, histological, and molecular properties of the intact and healing Achilles tendon. The right Achilles tendon was transected in 11 male diabetic Goto-Kakizaki (GK) and 10 age- and sex-matched Wistar control rats, while the left Achilles tendon was left intact. At 2 wk postinjury the intact and injured tendons were assessed by biomechanical testing and histology. The gene expression of collagen I and III, biglycan, versican, MMP-13, and MMP-3 was measured by quantitative RT-PCR, and their protein distribution was studied by immunohistochemistry. Intact tendons exhibited only small differences between the groups. In injured tendons, however, a significantly smaller transverse area and lower stiffness was found in diabetic GK compared with Wistar control rats. This correlated with impaired structural organization of collagen fibers and a reduced expression of collagen I and III in the injured tendons of the diabetic GK compared with Wistar control. Moreover, MMP-3 gene expression was downregulated in the injured diabetic GK tendons compared with injured Wistar controls. Our results indicate that in a rat model of diabetes tendon healing is impaired mainly due to altered expression of collagen and MMPs reflecting decreased degradation of matrix proteins and impaired tissue remodeling. Further our data suggest that therapeutic modulation of collagens or MMPs might be targets for new regenerative approaches in operated, injured, or maybe also degenerative tendon diseases in diabetes.
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- Bavenholm, PN, et al.
(author)
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Insulin sensitivity of suppression of endogenous glucose production is the single most important determinant of glucose tolerance
- 2001
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 50:6, s. 1449-1454
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Journal article (peer-reviewed)abstract
- Hyperglycemia results from an imbalance between endocrine pancreatic function and hepatic and extrahepatic insulin sensitivity. We studied 57 well-matched Swedish men with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or mild diabetes. Oral glucose tolerance and insulin release were assessed during an oral glucose tolerance test (OGTT). Insulin sensitivity and glucose turnover were determined during a two-step euglycemic insulin clamp (infusion 0.25 and 1.0 mU · kg–1 · min–1). High-performance liquid chromatography–purified [6-3H]glucose was used as a tracer. During low-insulin infusion, the rate of endogenous glucose production (EGP) decreased more in subjects with NGT than in subjects with IGT or diabetes (δ rate of appearance [Ra] 1.25 ± 0.10 vs. 0.75 ± 0.14 vs. 0.58 ± 0.09 mg · kg–1 · min–1, P < 0.001). The corresponding rates of glucose infusion during the high-dose insulin infusion (M values) were 8.3 ± 0.6 vs. 5.4 ± 0.9 vs. 4.7 ± 0.4 mg · kg–1 · min–1 (P < 0.001). A total of 56% of the variation in glucose area under the curve (AUC) during OGTT (glucose AUC) was mainly explained by δ Ra (increase in multiple R2 0.42) but also by δ Rd (rate of disapperance) (increase in multiple R2 0.05), and the early insulin response during OGTT contributed significantly (increase in multiple R2 0.07). When M value was included in the model, reflecting extrahepatic insulin sensitivity, it contributed to 20% of the variation in glucose AUC, and together with the incremental insulin response (increase in multiple R2 0.21), it explained 45% of the variation. In conclusion, insulin sensitivity of suppression of EGP plays the most important role in the determination of blood glucose response during OGTT.
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- Brismar, K, et al.
(author)
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Adiponectin, IGFBP-1 and -2 are independent predictors in forecasting prediabetes and type 2 diabetes
- 2023
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In: Frontiers in endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13, s. 1092307-
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Journal article (peer-reviewed)abstract
- Adiponectin and insulin-like growth factor (IGF) binding proteins IGFBP-1 and IGFBP-2 are biomarkers of insulin sensitivity. IGFBP-1 reflects insulin sensitivity in the liver, adiponectin in adipose tissue and IGFBP-2 in both tissues. Here, we study the power of the biomarkers adiponectin, IGFBP-1, IGFBP-2, and also included IGF-I and IGF-II, in predicting prediabetes and type 2 diabetes (T2D) in men and women with normal oral glucose tolerance (NGT).DesignSubjects with NGT (35-56 years) recruited during 1992-1998 were re-investigated 8-10 years later. In a nested case control study, subjects progressing to prediabetes (133 women, 164 men) or to T2D (55 women, 98 men) were compared with age and sex matched NGT controls (200 women and 277 men).MethodsThe evaluation included questionnaires, health status, anthropometry, biochemistry and oral glucose tolerance test.ResultsAfter adjustment, the lowest quartile of adiponectin, IGFBP-1 and IGFBP-2 associated independently with future abnormal glucose tolerance (AGT) in both genders in multivariate analyses. High IGFs predicted weakly AGT in women. In women, low IGFBP-2 was the strongest predictor for prediabetes (OR:7.5), and low adiponectin for T2D (OR:29.4). In men, low IGFBP-1 was the strongest predictor for both prediabetes (OR:13.4) and T2D (OR:14.9). When adiponectin, IGFBP-1 and IGFBP-2 were combined, the ROC-AUC reached 0.87 for women and 0.79 for men, higher than for BMI alone.ConclusionDifferences were observed comparing adipocyte- and hepatocyte-derived biomarkers in forecasting AGT in NGT subjects. In women the strongest predictor for T2D was adiponectin and in men IGFBP-1, and for prediabetes IGFBP-2 in women and IGFBP-1 in men.
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- Bulhak, AA, et al.
(author)
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PPAR-alpha activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway
- 2009
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In: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 296:3, s. H719-H727
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Journal article (peer-reviewed)abstract
- Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferator-activated receptor-α (PPAR-α) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-α would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and age-matched Wistar rats (n ≥ 7) were given either 1) the PPAR-α agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor NG-nitro-l-arginine (l-NNA), 4) l-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/nitrate were determined. The IS was 75 ± 3% and 72 ± 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 ± 3% in Wistar ( P < 0.05) and to 46 ± 5% in GK rats ( P < 0.001). The addition of either l-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 ± 5% and 65 ± 5%, respectively) and GK (IS, 66 ± 4% and 64 ± 4%, P < 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats ( P < 0.05). The results suggest that PPAR-α activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.
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- Carlsson, S, et al.
(author)
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Low birth weight, family history of diabetes, and glucose intolerance in Swedish middle-aged men
- 1999
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In: Diabetes care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 22:7, s. 1043-1047
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the association between low birth weight and glucose intolerance in relation to family history of diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cross-sectional study of 2,237 men born in 1938-1957 in four municipalities in the outskirts of Stockholm, 50% of whom had a family history of diabetes (at least one first-degree or two second-degree relatives with diabetes). Oral glucose tolerance testing detected 35 cases of type 2 diabetes, 102 cases of impaired glucose tolerance, and 57 cases of impaired fasting glucose. RESULTS: In subjects without a family history of diabetes, low (< or = 3,000 g) birth weight was associated with an odds ratio of 2.3 (95% confidence intervals = 0.4-14.4) for diabetes, 1.8 (0.7-4.3) for impaired glucose tolerance, and 3.3 (1.0-10.4) for impaired fasting glucose. In subjects with a family history of diabetes, the corresponding figures were approximately similar, except for diabetes, for which the odds ratio was 5.4 (2.0-14.9). For men with low birth weight in combination with a family history of diabetes, the odds ratio was 10.9 (2.9-41.2) for diabetes, 2.4 (1.1-5.6) for impaired glucose tolerance, and 5.9 (2.1-16.3) for impaired fasting glucose. CONCLUSIONS: This study indicated that low birth weight is associated with type 2 diabetes, impaired glucose tolerance, and impaired fasting glucose in men. This finding was most pronounced in subjects with diabetes in the family, but it was also indicated in those without a family history of diabetes. Men with the combination of low birth weight and family history of diabetes seem to be at particularly high risk of developing type 2 diabetes.
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