Meal-derived glucagon responses are related to lower hepatic phosphate concentrations in obesity and type 2 diabetes.

AIM: Type 2 diabetes (T2D) alters glucagon, glucagon-like peptide (GLP)-1, glucose-dependent insulinotropic polypeptide (GIP) and hepatic energy metabolism, yet the possible relationships remain unclear. METHODS: In this observational study, lean insulin-sensitive control subjects (BMI: 23.2±1.5kg/m2), age-matched insulin-resistant obese subjects (BMI: 34.3±1.7kg/m2) and similarly obese elderly T2D patients (BMI: 32.0±2.4kg/m2) underwent mixed-meal tolerance tests (MMTTs), and assessment of hepatic γATP, inorganic phosphate (Pi) and lipids using 31P/1H magnetic resonance spectroscopy. Meal-induced secretion of glucagon and incretins was calculated from incremental areas under the concentration-time curves (iAUCs). Peripheral and adipose tissue insulin sensitivity were assessed from time courses of circulating glucose, insulin and free fatty acids. RESULTS: MMTT-derived peripheral insulin sensitivity was lowest in T2D patients (P<0.001), while glucagon concentrations were comparable across all three groups. At 260min, GLP-1 was lower in T2D patients than in controls, whereas GIP was lowest in obese individuals. Fasting glucagon concentrations correlated positively with fasting (r=0.60) and postprandial hepatocellular lipid levels (160min: r=0.51, 240min: r=0.59), and negatively with adipose tissue insulin sensitivity (r=-0.73). Higher meal-induced glucagon release (iAUC0-260min) correlated with lower fasting (r=-0.62) and postprandial Pi levels (160min: r=-0.43, 240min: r=-0.42; all P<0.05). Higher meal-induced release of GIP (iAUC0-260min) correlated positively with fasting (r=0.54) and postprandial serum triglyceride concentrations (iAUC0-260min, r=0.54; all P<0.01). CONCLUSION: Correlations between fasting glucagon and hepatic lipids and between meal-induced glucagon and hepatic Pi suggest a role for glucagon in hepatic energy metabolism.

Inverse association of insulin antibody levels with insulin sensitivity in adults with Type 1 diabetes.

AIMS: Insulin resistance may contribute to the pathogenesis of autoimmune-mediated diabetes. Antibodies against ß-cell-associated molecules, comprising islet cell antigen (ICA), glutamic acid decarboxylase (GAD) and insulin, characterize the autoimmune process. Because the link between insulin resistance and autoimmunity might be relevant for disease progression and treatment, we hypothesized that insulin resistance associates positively with ß-cell-directed antibodies in newly diagnosed Type 1 diabetes. METHODS: Within the German Diabetes Study, an observational study including adults with newly diagnosed diabetes, 142 adults [84 men, 58 women; age 33.1 (26.4, 41.9) years; diabetes duration 6.3 (4.2, 9.1) months] positive for at least one antibody against ICA, GAD or insulin underwent hyperinsulinaemic-euglycaemic clamp tests to assess insulin sensitivity (M-value) in a cross-sectional setting. RESULTS: Insulin-directed antibodies were inversely correlated with M-values (ß = -0.039). Albeit not strong, the association persisted after adjustment for age, sex and BMI, and even after further adjustment for confounders reflecting exposure to exogenous insulin and residual ß-cell secretory capacity. Correlation network-based analyses revealed a complex interaction between levels of fasting insulin and of insulin antibodies with respect to their relationship with the M-value. GAD- or ICA-directed antibodies did not correlate with insulin sensitivity. CONCLUSIONS: In adults with recent-onset Type 1 diabetes expressing at least one ß-cell-directed antibody, insulin sensitivity is inversely related to insulin antibody titres, but not to other autoantibodies. Our finding may allow for the identification of insulin resistance in adults with high levels of insulin antibodies.

Circulating adiponectin concentration is inversely associated with glucose tolerance and insulin secretion in people with newly diagnosed diabetes.

AIMS: To examine the hypothesis that changes in serum adiponectin concentration inversely relate to changes in glucose tolerance and ß-cell function already during the early stage of disease progression in recently diagnosed Type 1 and Type 2 diabetes mellitus. METHODS: Participants in the prospective observational German Diabetes Study (Type 2 diabetes, n = 94; Type 1 diabetes, n = 42) underwent i.v. glucose tolerance and glucagon stimulation testing to assess pre-hepatic ß-cell function, glucose tolerance index and C-peptide secretion within the first year of diabetes diagnosis and 2 years later. Associations of changes in serum concentrations of total adiponectin, high-molecular-weight adiponectin and their ratio with changes in the aforementioned metabolic variables were calculated using linear regression. RESULTS: Among people with Type 2 diabetes, 2-year increases in high-molecular-weight adiponectin and in high-molecular-weight/total adiponectin ratio were associated with decreases in glucose tolerance index of 0.1%/min (P = 0.020) and 0.8%/min (P = 0.013), respectively. Increases in high-molecular-weight/total adiponectin ratio were related to decreases in acute C-peptide secretion of 54.6% (P = 0.020). Among people with Type 1 diabetes, 2-year increases in total adiponectin were associated with 2-year decreases in acute C-peptide secretion of 56.2% (P = 0.035). CONCLUSIONS: Increases in adiponectin concentrations in the first 2 years after diagnosis were related to a worsening of acute insulin secretion and glucose tolerance index in Type 1 and Type 2 diabetes. (Clinical Trials Registry no.: NCT01055093).

The Impact of Dietary Factors on Glycemic Control, Insulin Sensitivity and Secretion in the First Years after Diagnosis of Diabetes.

BACKGROUND: Dietary factors play an important role in the prevention of diabetes mellitus. We tested the hypothesis that dietary factors related to diabetes onset also associate with its progression, i. e., early time courses of insulin sensitivity and secretion in both type 1 and type 2 diabetes. METHODS: In a prospective observational study, well-controlled recent-onset diabetes patients (n=127) underwent detailed metabolic characterization within the first year after diagnosis. A follow-up was conducted 2 years after the first examination. Insulin secretion and sensitivity were assessed by intravenous glucose tolerance testing. Baseline food consumption was analyzed by a food propensity questionnaire. Multivariate linear regression analysis was used to assess associations between consumption frequencies at baseline with metabolic changes during the first 2 years. RESULTS: Within the first 2 years, metabolic control did not change in patients with type 1 and type 2 diabetes on average. In type 1 diabetes, an increased consumption frequency of refined grains by one time/day at baseline associated with higher HbA1c by 0.60% (95% CI: 0.04; 1.16), P=0.04 after 2 years compared to baseline. In type 2 diabetes, an increased consumption frequency of meat/meat products by one time/day at baseline associated with lower beta-cell adaptation index (-7.25% (95% CI: -13.16; -0.93), P=0.03) after adjustment for age, sex, BMI, and changes of BMI and glucose-lowering medication. CONCLUSION: Dietary factors associate with the initial course of diabetes. Reduced consumption of refined grains in type 1 diabetes and of meat products in type 2 diabetes may contribute to preservation of insulin secretion and sensitivity.

Medication costs by glucose tolerance stage in younger and older women and men: results from the population-based KORA survey in Germany.

To estimate medication costs in individuals with diagnosed diabetes, undetected diabetes, impaired glucose regulation and normal blood glucose values in a population-based sample by age and sex.Using the KORA F4 follow-up survey, conducted in 2006-2008 (n=2611, age 40-82 years), we identified individuals' glucose tolerance status by means of an oral glucose tolerance test. We assessed all medications taken regularly, calculated age-sex specific medication costs and estimated cost ratios for total, total without antihyperglycemic drugs, and cardiovascular medication, using multiple 2-part regression models.Compared to individuals with normal glucose values, costs were increased in known diabetes, undetected diabetes and impaired glucose regulation, which was more pronounced in participants aged 40-59 years than in those aged 60-82 years (cost ratios for all medications: 40-59 years: 2.85; 95%-confidence interval: 1.78-4.54, 2.00; 1.22-3.29 and 1.53; 1.12-2.09; 60-82 years: 2.04; 1.71-2.43, 1.17; 0.90-1.51 and 1.09; 0.94-1.28). Compared to individuals with diagnosed diabetes, costs were significantly lower among individuals with impaired glucose regulation across all age and sex strata, also when antihyperglycemic medication was excluded (40-59 years: 0.60; 0.36-0.98, 60-82 years: 0.74; 0.60-0.90; men: 0.72; 0.56-0.93; women: 0.72; 0.54-0.96).We could quantify age- and sex-specific medication costs and cost ratios in individuals with diagnosed diabetes, undetected diabetes and impaired glucose regulation compared to those with normal glucose values, using data of a population-based sample, with oral glucose tolerance test-based identification of diabetes states. These results may help to validly estimate cost-effectiveness of screening and early treatment or prevention of diabetes.

Patient time costs attributable to healthcare use in diabetes: results from the population-based KORA survey in Germany.

AIMS: Patient time costs have been described to be substantial; however, data are highly limited. We estimated patient time costs attributable to outpatient and inpatient care in study participants with diagnosed diabetes, previously undetected diabetes, impaired glucose regulation and normal glucose tolerance. METHODS: Using data of the population-based KORA S4 study (55-74 years, random sample of n = 350), we identified participants' stage of glucose tolerance by oral glucose tolerance test. To estimate mean patient time costs per year (crude and standardized with respect to age and sex), we used data regarding time spent with ambulatory visits including travel and waiting time and with hospital stays (time valued at a 2011 net wage rate of €20.63/h). The observation period was 24 weeks and data were extrapolated to 1 year. RESULTS: Eighty-nine to 97% of participants in the four groups (diagnosed diabetes, undetected diabetes, impaired glucose regulation and normal glucose tolerance.) had at least one physician contact and 4-14% at least one hospital admission during the observation period. Patient time [h/year (95% CI)] was 102.0 (33.7-254.8), 53.8 (15.0-236.7), 59.3 (25.1-146.8) and 28.6 (21.1-43.7), respectively. Age-sex standardized patient time costs per year (95% CI) were €2447.1 (804.5-6143.6), €880.4 (259.1-3606.7), €1151.6 (454.6-2957.6) and €589.2 (435.8-904.8). CONCLUSIONS: Patient time costs were substantial--even higher than medication costs in the same study population. They are higher in participants with diagnosed diabetes, but also in those with undetected diabetes and impaired glucose regulation compared with those with normal glucose tolerance. Research is needed in larger populations to receive more precise and certain estimates that can be used in health economic evaluation.

Frequency and cost of diabetic ketoacidosis in Germany--study in 12,001 paediatric patients.

AIMS: Recently, medical expenditures were found to be 2-fold increased in paediatric patients with diabetic ketoacidotic events (DKA) in the U.S., in particular due to hospitalization. Aim of our study was to analyse DKAs and associated costs in Germany, where structured diabetes care including education is available for all patients. METHODS: For all 12,001 diabetic patients 0-19 years of age (52.6% male, mean age (SD) 12.6 (3.9) years) documented in a German-wide database, all DKAs were assessed, as well as costs for diabetes-related treatment. Associations between costs and DKA were estimated using log-linear models. RESULTS: 457 (3.8%) patients had at least 1 DKA during 2007. Total annual costs for patients without, with 1, or ≥ 2 DKAs were € 3,330 (95%-CI 3,292-3,368), € 6,935 (CI 6,627-7,244), and € 10,728 (CI 9,813-11,644), respectively, with largest differences for hospitalization costs (€ 693, € 4,145, € 8,092). Age-sex-diabetes duration-adjusted cost ratios for patients with 1, or ≥ 2 DKAs compared to patients without DKA were 2.2 (CI 2.1-2.3) and 3.6 (CI 3.1-4.1), respectively. CONCLUSIONS: In Germany, paediatric diabetic patients with DKA had up to 3.6-fold higher diabetes-related costs compared to those without DKA. This cost excess was higher compared to a U.S. study, however, the proportion of patients with DKA was much lower (3.8% versus 14.9%). The lower frequency of DKA in Germany may be due to a higher access to and utilization of diabetes education. Interventions should reduce DKA and resulting hospital admission in pediatric patients in order to reduce costs and improve quality of life.

Costs of paediatric diabetes care in Germany: current situation and comparison with the year 2000.

AIMS: To estimate direct costs of paediatric Type 1 diabetes care and associated factors in Germany for the year 2007 and to compare results with the costs for the year 2000. METHODS: Our study includes clinical data and charges for any diabetes-related health care service of 14,185 continually treated subjects with paediatric diabetes aged < 20 years [52.5% male, mean age (SD) 12.1 (4.2) years], derived from a nationwide prospective patient documentation system (DPV). Health-care utilization was valued in monetary terms by using inpatient and outpatient medical fees and retail prices (perspective of the statutory health insurance). Associations between average total diabetes-related costs or various single cost categories per patient and age, sex, migration background, diabetes duration, and metabolic control were analysed by multiple regression procedures and by a two-part model for hospitalization costs. Total direct costs in the whole paediatric diabetes population in Germany were estimated. Mean costs per patient as well as total costs in the German paediatric diabetes population in 2007 were compared to 2000 costs (inflated to the year 2007). RESULTS: Mean direct diabetes-associated costs per subject were €3524 (inter-quartile range: 1831-4743). Main cost categories were hospitalization (32%), glucose self-monitoring (29%), insulin pump therapy (18%), and insulin (15%). Based on the present estimation, the total costs of paediatric diabetes care in Germany exceeded €110 million in 2007. Compared with estimates of the year 2000, average costs per patient had increased by 20% and total costs for German paediatric diabetes care by 47%. CONCLUSIONS: Direct costs for paediatric Type 1 diabetes care increased between 2000 and 2007, probably partly because of new therapeutic strategies and an increase in diabetes prevalence.

Impact of weight and weight change on normalization of prediabetes and on persistence of normal glucose tolerance in an older population: the KORA S4/F4 study.

BACKGROUND AND AIMS: In a population-based cohort study with older subjects and without specific interventions, we investigated the impact of body mass index (BMI) and BMI change (as well as waist circumference and change of waist circumference) on reversion from prediabetes to normal glucose tolerance (NGT) and on long-term persistence of NGT. MATERIALS AND METHODS: Oral glucose tolerance tests were conducted at baseline and at follow-up in a cohort study in Southern Germany (KORA S4/F4; 1223 subjects without diabetes aged 55-74 years at baseline in 1999-2001; 887 subjects (73%), of whom 436 had prediabetes at baseline, participated in the follow-up 7 years later). RESULTS: BMI reduction, but not initial BMI, predicted reversion from prediabetes to NGT. The odds ratio (OR) for returning to NGT was 1.43 (95% CI: 1.18-1.73) for a BMI decrease of 1 kg m(-2), after adjustment for age, sex, baseline glucose values and lifestyle factors. Initial BMI had no effect on reversion to NGT (OR=0.98, 95% CI: 0.91-1.06, per kg m(-2)). Persistence of NGT was associated with baseline BMI (OR=0.94, 95% CI: 0.88-0.998) and BMI reduction (OR=1.16, 95% CI: 1.02-1.33, per decrease by 1 kg m(-2)). For waist circumference and change of waist circumference similar results were obtained. CONCLUSION: In older adults, weight loss strongly increased the chances of returning from prediabetes to NGT irrespective of initial BMI. Long-term persistence of NGT depended both on initial BMI and on BMI change.

Precision and accuracy of blood glucose measurements using three different instruments.

AIMS: Assessment of insulin sensitivity by dynamic metabolic tests such as the hyperinsulinemic euglycemic clamp critically relies on the reproducible and fast measurement of blood glucose concentrations. Although various instruments have been developed over the last decades, little is known as to the accuracy and comparability. We therefore compared the best new instrument with the former gold standard instruments to measure glucose concentrations in metabolic tests. METHODS: Fasting blood samples of 15 diabetic and 10 healthy subjects were collected into sodium-fluoride tubes, spiked with glucose (0, 2.8, 6.9 and 11.1 mmol/l) and measured either as whole blood (range 3.3-26.3 mmol/l) or following centrifugation as plasma (range 3.9-32.0 mmol/l). Plasma samples were analyzed in the YSI-2300 STAT plus (YSI), EKF Biosen C-Line (EKF) and the reference method, Beckman Glucose analyzer-II (BMG), whole blood samples in EKF instruments with YSI as reference method. RESULTS: The average deviation of the EKF from the reference, BMG, was 3.0 ± 3.5% without any concentration-dependent variability. Glucose measurements by YSI were in good agreement with that by BMG (plasma) and EKF (plasma and whole blood) up to concentrations of 13.13 mmol/l (0.5 ± 3.7%), but deviation increased to -6.2 ± 3.8% at higher concentrations. Precision (n = 6) was ±2.2% (YSI), ±3.9% (EKF) and ±5.2% (BMG). CONCLUSIONS: The EKF instrument is comparable regarding accuracy and precision to the reference method BMG and can be used in metabolic tests, while the YSI showed a systematic shift at higher glucose concentrations. Based on these results we decided to replace BMG with EKF instrument in metabolic tests.

Prediction models for incident type 2 diabetes mellitusin the older population: KORA S4/F4 cohort study.

BACKGROUND: The aim was to derive Type 2 diabetes prediction models for the older population and to check to what degree addition of 2-h glucose measurements (oral glucose tolerance test) and biomarkers improves the predictive power of risk scores which are based on non-biochemical as well as conventional clinical parameters. METHODS: Oral glucose tolerance tests were carried out in a population-based sample of 1353 subjects, aged 55-74 years (62% response) in Augsburg (Southern Germany) from 1999 to 2001. The cohort was reinvestigated in 2006-2008. Of those individuals without diabetes at baseline, 887 (74%) participated in the follow-up. Ninety-three (10.5%) validated diabetes cases occurred during the follow-up. In logistic regression analyses for model 1, variables were selected from personal characteristics and additional variables were selected from routinely measurable blood parameters (model 2) and from 2-h glucose, adiponectin, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (model 3). RESULTS: Age, sex, BMI, parental diabetes, smoking and hypertension were selected for model 1. Model 2 additionally included fasting glucose, HbA(1c) and uric acid. The same variables plus 2-h glucose were selected for model 3. The area under the receiver operating characteristic curve significantly increased from 0.763 (model 1) to 0.844 (model 2) and 0.886 (model 3) (P<0.01). Biomarkers such as adiponectin and insulin did not improve the predictive abilities of models 2 and 3. Cross-validation and bootstrap-corrected model performance indicated high internal validity. CONCLUSIONS: This longitudinal study in an older population provides models to predict the future risk of Type 2 diabetes. The OGTT, but not biomarkers, improved discrimination of incident diabetes.

Prevalence of undiagnosed diabetes and impaired glucose regulation in 35-59-year-old individuals in Southern Germany: the KORA F4 Study.

AIMS: Limited data are available for European populations regarding the prevalence of diabetes and disturbed glucose metabolism in younger individuals. Our aim was to estimate the prevalence of diagnosed and undiagnosed diabetes, isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT) and combined IFG/IGT in a population-based sample (n = 1653) from Southern Germany aged 35-59 years. METHODS: Oral glucose tolerance tests were carried out in all non-diabetic participants of the KORA F4 Study (2006-2008). Diabetes, IGT and IFG were defined according to the 1999 World Health Organization diagnostic criteria. The original IFG criteria (6.1-6.9 mmol/l) were used as recommended by the European Diabetes Epidemiology Group. RESULTS: The age-standardized prevalence was 2.2% for known diabetes, 2.0% for newly detected diabetes, 2.9% for i-IFG, 6.3% for i-IGT and 1.1% for combined IFG/IGT. About half of the cases with overt diabetes were undiagnosed in all age groups. The prevalence of i-IGT was approximately twice as high as that of i-IFG. The proportion of i-IGT varied between 3.2% (age group 35-44 years) and 11.8% (age group 55-59 years); the corresponding numbers for i-IFG were 1.1% and 5.9%. IFG/IGT was present in 1.2% of the total sample, and was most frequently found in the age group 55-59 years (2.4%). Overall, 16% of the study population had either diabetes or abnormalities of glucose metabolism. CONCLUSIONS: The study reveals for the first time a high prevalence of impaired glucose regulation in the younger and middle-aged German population. The detection of disturbed glucose metabolism or diabetes needs to be improved.

Vaspin (SERPINA12) genotypes and risk of type 2 diabetes: Results from the MONICA/KORA studies.

Vaspin has recently been identified as novel adipokine with high expression in adipose tissue of obese and type 2 diabetic subjects and with potentially insulin-sensitising properties. However, the impact of vaspin gene variants on the risk of type 2 diabetes mellitus (T2DM) has not been determined yet. Therefore, the aim of our study was to investigate the association of vaspin single nucleotide polymorphisms (SNPs) with T2DM and obesity. We analysed the association between 25 vaspin SNPs and T2DM in initially healthy 35-84 year-old individuals of the population-based, cross-sectional German KORA F3 study and assessed the association with measures of obesity. Genotyping was carried out with matrix-assisted laser desorption/ionisation-time of flight mass spectrometry of allele-dependent primer extension products and associations with T2DM and obesity were analysed by logistic regression analysis. Our results demonstrate a significant association of vaspin SNP rs2236242 with T2DM in the KORA F3 study with the AA genotype bearing an increased risk (adjusted OR 2.35 [1.59; 3.46] versus AT/TT). This association appears to be independent of obesity. Our finding corroborates previous studies that suggested a link between the novel adipokine vaspin and glucose metabolism.

Incidence of Type 2 diabetes in the elderly German population and the effect of clinical and lifestyle risk factors: KORA S4/F4 cohort study.

AIMS: To determine the incidence of Type 2 diabetes in an elderly population in Germany and its association with clinical and lifestyle factors. METHODS: Oral glucose tolerance tests (OGTT, World Health Organization criteria) were carried out in a random sample of 1353 subjects (age group 55-74 years; 62% response) in Augsburg (Southern Germany) (1999-2001). The cohort was re-investigated in 2006-2008. Of those individuals without diabetes (baseline), 887 (74%) participated in the follow-up. RESULTS: Ninety-three (10.5%) developed diabetes during the 7-year follow-up period {standardized incidence rates [95% confidence interval (CI)] per 1000 person-years: total 15.5; 12.6, 19.1; men 20.2; 15.6, 26.1; women 11.3; 7.9, 16.1}. In both sexes, those who developed diabetes were slightly older, were more obese, had a more adverse metabolic profile (higher glucose values, HbA(1c), fasting insulin, uric acid, and triglycerides) and were more likely to have hypertension at baseline than were participants remaining free of diabetes (P < 0.05). On stepwise logistic regression, age, parental diabetes, body mass index, uric acid, current smoking, HbA(1c) and fasting and 2-h glucose (OGTT) were strong predictors of diabetes incidence. The risk of diabetes was higher in subjects with isolated impaired glucose tolerance (odds ratio 8.8; 95% CI 5.0, 15.6) than in isolated impaired fasting glucose (4.7; 2.2, 10.0), although the difference did not reach statistical significance. CONCLUSIONS: For the first time, we have estimated the incidence of Type 2 diabetes in an elderly German cohort and demonstrated that it is among the highest in Europe. The OGTT appears to be useful in identifying individuals with high Type 2 diabetes risk. Our results support a role of smoking in the progression to diabetes.

Longitudinal change in HbA1c in patients with type 2 diabetes: comparison of short-acting, biphasic and basal insulin.

OBJECTIVE: To evaluate the annual change in HbA1c values among patients with type 2 diabetes in primary care practices comparing different insulin regimens. RESEARCH DESIGN AND METHODS: Longitudinal data from 666 nationwide general and internal medicine practices in Germany (Disease Analyser, IMS HEALTH) from 7/2004 to 6/2006 were analysed, including 348 patients (mean age+/-SD: 61+/-11 years) with continuous short-acting (regular insulin or analogues), 1 906 with biphasic (72+/-9 years), 439 with basal-bolus (68+/-10 years), and 1 719 with basal insulin therapy (65+/-10 years). The mean of the individual relative changes in HbA1c (level in 2006 divided by level in 2005) were compared between insulin groups, adjusting for age, sex, BMI, diabetes duration, oral antidiabetics, comorbidity, health insurance, visits, hospitalisations, and practice type using general linear models. RESULTS: There was only a small difference in baseline HbA1c values (range 7.3-7.5%) between the four insulin groups (p=0.008). Substantial group differences were observed for age, diabetes duration, and additional prescriptions of oral antidiabetics (p<0.0001). After adjusting for potential confounders, the relative annual increase in HbA1c was highest for biphasic insulin (1.021; 95%CI 1.016-1.025), followed by basal-bolus therapy (1.017; 1.012-1.022), and basal insulin (monotherapy) (1.012; 1.002-1.021). No significant change in HbA1c was found for short-acting insulin (1.006; 0.996-1.016). CONCLUSIONS: Although many options for insulin therapy are now available, a progression of glycemia still occurs in the majority of insulin-treated type 2 diabetic patients in primary care.

Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies.

Genome-wide association (GWA) studies identified novel gene variants that are associated with type 2 diabetes. However, results were not always consistent across different populations. Thus, the aims of this study were (i) to replicate findings from previous GWA studies in mainly Northern European populations using data from the German KORA 500 K diabetes project and (ii) to assess the impact of BMI on associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. The KORA 500 K diabetes project includes 433 cases with validated type 2 diabetes and 1 438 nondiabetic controls from two population-based KORA surveys. Genotyping was performed using the Affymetrix GeneChip Human Mapping 500 K Array Set. We investigated associations between SNPs and type 2 diabetes in 10 genes that have been reported to increase the risk of type 2 diabetes or were in complete or near-complete linkage disequilibrium with these variants. SNPs in the CDKAL1 gene showed the strongest association with type 2 diabetes [range of age and sex-adjusted odds ratios (OR): 1.30-1.39, p-values 0.0008-0.0004]. In addition, we found evidence for association of SNPs in the genes PPARG, IGF2BP2, HHEX, TCF7L2, and FTO with type 2 diabetes in the same directions as previously described (p<0.05), but not for WFS1, CDKN2A/B, KCNJ11, or EXT2. Adjustment for BMI slightly strengthened the link between CDKAL1 and type 2 diabetes, but had almost no impact on the other associations. We conclude that gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500 K study population. These associations appear to be independent of BMI.

Genetic variants in the leukemia-associated Rho guanine nucleotide exchange factor (ARHGEF12) gene are not associated with T2DM and related parameters in Caucasians (KORA study).

OBJECTIVE: The aim of our study was to determine the variant pattern of the leukemia-associated Rho guanine nucleotide exchange factor (LARG, or ARHGEF12) gene and investigate whether LARG variants are associated with diabetes mellitus type 2 (T2DM), the metabolic syndrome (MetS), or related parameters such as insulin sensitivity in German Caucasians. DESIGN: We analyzed single nucleotide polymorphisms (SNPs) in the LARG gene in the 55-74-year-old individuals of the population-based German Caucasian Cooperative Health Research in the region of Augsberg (KORA) survey 4 (S4). METHODS: Sequencing of Tyr1306Cys, which was of functional relevance in Pima Indians, in 48 randomly selected individuals and genotyping of 11 additional LARG SNPs in 1653 subjects were performed. Four linkage disequilibrium (LD) blocks (r(2)> or =0.8) were established and each block was statistically analyzed for association with metabolic traits. The association with T2DM and the MetS was analyzed by logistic regression in 1462 subjects, and HOMA-IR (homeostasis model assessment of insulin resistance) as a measure of insulin sensitivity was analyzed by the Kruskal-Wallis test in 1346 fasting subjects. RESULTS: The polymorphism Tyr1306Cys, which was significantly associated with insulin sensitivity in Pima Indians, was not found in the KORA S4 population. Statistical analysis yielded no significant associations (P>0.05) between the analyzed LARG variants and T2DM, the MetS, or related parameters such as insulin sensitivity. CONCLUSIONS: Caucasian individuals and Pima Indians differ in their genetic variance pattern in the LARG gene region. There is no evidence in the Caucasian KORA study that variants of the LARG gene confer susceptibility for T2DM, insulin sensitivity, or the MetS.

Ordered multiple comparisons with the best and their applications to dose-response studies.

This article considers the problem of comparing several treatments (dose levels, interventions, etc.) with the best, where the best treatment is unknown and the treatments are ordered in some sense. Order relations among treatments often occur quite naturally in practice. They may be ordered according to increasing risks, such as tolerability or safety problems with increasing dose levels in a dose-response study, for example. We tackle the problem of constructing a lower confidence bound for the smallest index of all treatments being at most marginally less effective than the (best) treatment having the largest effect. Such a bound ensures at confidence level 1 -alpha that all treatments with lower indices are relevantly less effective than the best competitor. We derive a multiple testing strategy that results in sharp confidence bounds. The proposed lower confidence bound is compared with those derived from other testing strategies. We further derive closed-form expressions for power and sample size calculations. Finally, we investigate several real data sets to illustrate various applications of our methods.