Geneettisen analytiikan mahdollisuudet sikiödiagnostiikassa

Teema : sikiölääketiede. English summaryPeer reviewe

Genetic Prediction of Future Type 2 Diabetes

BACKGROUND: Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated with T2D but our knowledge of their ability to predict T2D prospectively is limited. METHODS AND FINDINGS: By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44), KCNJ11 (E23K), UCP2 (−866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland. After a median follow-up of 6 y, 132 (6%) persons developed T2D. The hazard ratio for risk of developing T2D was 1.7 (95% confidence interval [CI] 1.1–2.7) for the PPARG PP genotype, 1.5 (95% CI 1.0–2.2) for the CAPN10 SNP44 TT genotype, and 2.6 (95% CI 1.5–4.5) for the combination of PPARG and CAPN10 risk genotypes. In individuals with fasting plasma glucose ≥ 5.6 mmol/l and body mass index ≥ 30 kg/m(2), the hazard ratio increased to 21.2 (95% CI 8.7–51.4) for the combination of the PPARG PP and CAPN10 SNP43/44 GG/TT genotypes as compared to those with the low-risk genotypes with normal fasting plasma glucose and body mass index < 30 kg/m(2). CONCLUSION: We demonstrate in a large prospective study that variants in the PPARG and CAPN10 genes predict future T2D. Genetic testing might become a future approach to identify individuals at risk of developing T2D

Nateglinide Improves Early Insulin Secretion and Controls Postprandial Glucose Excursions in a Prediabetic Population.

OBJECTIVE—The purpose of this study was to evaluate the metabolic effectiveness, safety, and tolerability of nateglinide in subjects with impaired glucose tolerance (IGT) and to identify a dose appropriate for use in a diabetes prevention study. RESEARCH DESIGN AND METHODS—This multicenter, double-blind, randomized, parallel-group, fixed-dose study of 8 weeks’ duration was performed in a total of 288 subjects with IGT using a 2:2:2:1 randomization. Subjects received nateglinide (30, 60, and 120 mg) or placebo before each main meal. Metabolic effectiveness was assessed during a standardized meal challenge performed before and after the 8-week treatment. All adverse events (AEs) were recorded, and confirmed hypoglycemia was defined as symptoms accompanied by a self-monitoring of blood glucose measurement ≤3.3 mmol/l (plasma glucose ≤3.7 mmol/l). RESULTS—Nateglinide elicited a dose-related increase of insulin and a decrease of glucose during standardized meal challenges, with the predominant effect on early insulin release, leading to a substantial reduction in peak plasma glucose levels. Nateglinide was well tolerated, and symptoms of hypoglycemia were the only treatment-emergent AEs. Confirmed hypoglycemia occurred in 28 subjects receiving nateglinide (30 mg, 0 [0%]; 60 mg, 5 [6.6%]; 120 mg, 23 [26.7%]) and in 1 (2.3%) subject receiving placebo. CONCLUSIONS—Nateglinide was safe and effective in reducing postprandial hyperglycemia in subjects with IGT. Preprandial doses of 30 or 60 mg nateglinide would be appropriate to use for longer-term studies to determine whether a rapid-onset, rapidly reversible, insulinotropic agent can delay or prevent the development of type 2 diabetes

Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes.

Identification of individuals at high risk of developing type 2 diabetes is a prerequisite for prevention of the disease. We therefore studied risk factors predicting type 2 diabetes in the Botnia Study in western Finland. A total of 2,115 nondiabetic individuals were prospectively followed with repeated oral glucose tolerance tests. After a median follow-up of 6 years, 127 (6%) subjects developed diabetes. A family history of diabetes (hazard ratio [HR] 2.2, P = 0.008), BMI (HR for comparison of values below or above the median 2.1, P < 0.001), waist-to-height index (2.3, P < 0.001), insulin resistance (2.1, P = 0.0004), and β-cell function adjusted for insulin resistance (2.7, P < 0.0001) predicted diabetes. Marked deterioration in β-cell function with modest changes in insulin sensitivity was observed during the transition to diabetes. The combination of FPG ≥5.6 mmol/l, BMI ≥30 kg/m2, and family history of diabetes was a strong predictor of diabetes (3.7, P < 0.0001). Of note, using FPG ≥6.1 mmol/l or 2-h glucose ≥7.8 mmol/l did not significantly improve prediction of type 2 diabetes. In conclusion, a marked deterioration in β-cell function precedes the onset of type 2 diabetes. These individuals can be identified early by knowledge of FPG, BMI, and family history of diabetes

The Effect of Insulin Resistance Together with the Risk Genotype of the <i>PPARG</i> P12A Polymorphism on Risk of Developing T2D

<p><i>y</i>-Axis denotes HR and its 95% CI. <i>x</i>-Axis denotes increase in insulin resistance estimated as HOMA_IR.</p

Unadjusted Kaplan–Meier Diabetes-Free Survival Probability Curves

<p>Curves for different carriers of <i>PPARG</i> P12A (PP versus PA/AA), <i>CAPN10</i> SNP44 (TT versus TC/CC), <i>UCP2</i> −866 G/A (GG versus GA/AA), and the combination of <i>PPARG</i> and <i>CAPN10</i> SNP43/44 (PP/GG/TT versus other). <i>y-</i>Axis shows probability of diabetes-free survival time. <i>x</i>-Axis shows follow-up time in years. The HR of developing T2D in different genotype carriers obtained from Cox proportional hazards regression stratified on sex and adjusted for age, BMI, and family history of diabetes with robust variance estimate is shown (see also <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020345#pmed-0020345-t003" target="_blank">Table 3</a>).</p

The Effects of Risk Genotypes of the <i>PPARG</i> P12A Polymorphism (PP), the Combination of <i>CAPN10</i> SNP43/44 (GG/TT), and the Combination of <i>PPARG</i> and <i>CAPN10</i> SNP43/44 (PP/GG/TT) Together with FPG and BMI for the Risk of Developing T2D

<p><i>y</i>-Axis denotes incident diabetes estimated as the proportion (percent) of participants who developed diabetes during the follow-up period in the groups with each risk factor defined as risk genotype, elevated FPG (≥5.6 mmol/l), and high BMI (≥30 kg/m²). The absolute number of individuals who developed diabetes in the groups with each risk factor is given within the bars (in parentheses) and in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020345#st002" target="_blank">Table S2</a>. The incidence of T2D was significantly increased in carriers of the risk PP genotype, GG/TT genotypes, and PP/GG/TT genotypes with elevated FPG and high BMI as compared with individuals carrying low risk genotypes without risk factors (χ² test, <i>p <</i> 0.001).</p