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- Cropano, Catrina, et al.
(författare)
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The rs7903146 variant in the tcf7l2 gene increases the risk of prediabetes/type 2 diabetes in obese adolescents by impairing b-cell function and hepatic insulin sensitivity
- 2017
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 40:8, s. 1082-1089
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE In this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents. RESEARCH DESIGN AND METHODS The rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 6 2.36 years. RESULTS The TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trendwas seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased b-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose productionwas lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370-3.612; P = 0.0012). CONCLUSIONS The rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing b-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.
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| 2. |
- Krause, Kerstin, et al.
(författare)
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Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis.
- 2008
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 198:2, s. 291-9
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Tidskriftsartikel (refereegranskat)abstract
- We have recently found an increased expression of amyloid precursor protein (APP) in cold thyroid nodules that are difficult to classify as a truly benign thyroid neoplasm or a lesion with the potential for further dedifferentiation. Since differences in APP activity have been found in other human cancers, we asked whether thyroid carcinogenesis might be associated with an altered APP expression and function. APP regulation was studied in vitro in differentiated (FRTL-5) and dedifferentiated follicular thyroid carcinomas (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the protein kinase c (PKC) cascades. In vivo analysis of APP expression and downstream signalling was performed in benign and malignant thyroid tissues. We found that upregulation of APP expression and sAPP secretion is induced by TSH in differentiated thyroid cells and by insulin in thyroid cancer cells. PKC is a strong activator of APP cleavage and in FTC-133 confers prolonged release of the APP ectodomain. FTC-133 but not FRTL-5 cells show a prominent cell surface expression of the APP ectodomain, which has been suggested to function as an autocrine growth factor. Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.
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| 3. |
- Santoro, Nicola, et al.
(författare)
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Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents
- 2012
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 55:3, s. 781-789
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Tidskriftsartikel (refereegranskat)abstract
- Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3, but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians (P = 0.00161), 39.0% in African Americans (P = 0.00000496), and 15% in Hispanics (P = 0.00342). Conclusion: The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths. (Hepatology 2012)
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| 4. |
- Savoye, Mary, et al.
(författare)
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Reversal of Early Abnormalities in Glucose Metabolism in Obese Youth: Results of an Intensive Lifestyle Randomized Controlled Trial
- 2014
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 37, s. 317-324
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The childhood obesity epidemic has been accompanied by an increasing prevalence of type 2 diabetes (T2D), particularly in minority children. Twenty to thirty percent of obese youth have “prediabetes,” a precursor to diabetes marked by insulin resistance, b-cell dysfunction, and impaired glucose tolerance. The Diabetes Prevention Programdemonstrated that T2D could be prevented/delayed by intensive lifestyle modification in adults with prediabetes, but efficacy of similar interventions in youth has not been established. Therefore, we evaluated the effects of the Bright Bodies (BB) Healthy Lifestyle Program on 2-h oral glucose tolerance test (OGTT) glucose in comparison with adolescents receiving standard of care.RESEARCH DESIGN AND METHODS: A parallel-group randomized controlled trial comparing BB with standard clinical care (CC) in obese adolescents (10–16 years old, Tanner stage >2) with elevated OGTT 2-h blood glucose (130–199 mg/dL) from a racially/ethnically diverse population. OGTTs, including cardiovascular and anthropometric assessments, were conducted at baseline and 6 months. Children attended BB twice per week for exercise and nutrition/behavior modification, and the CC group received CC from their pediatrician. Primary outcome was change in 2-h OGTT glucose and percentage conversion from elevated 2-h blood glucose to nonelevated (,130 mg/dL) 2-h blood glucose. Changes in outcomes were compared between groups using an ANCOVA, with adjustment for baseline outcome and multiple imputation for missing data.RESULTS: Reductions in 2-h glucose weremore favorable in BB compared with CC (227.2 vs. 210.1 mg/dL; difference = 217.1, 95% CI; P = 0.005). Moreover, greater conversion to ,130 mg/dL 2-h glucose occurred in BB than CC (P = 0.003), and other insulin sensitivity indices were significantly improved.CONCLUSIONS: Compared with standard of care, the Yale BB Program is amore effective means of reducing the risk of T2D in obese adolescents with elevated 2-h glucose levels.
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