Study population
Men and women with IGT were recruited to the Optimal Fibre Trial for Diabetes Prevention (OptiFiT) between March 2010 and October 2012, and enrolled at two study sites (German Institute of Human Nutrition, Potsdam-Rehbrücke, and Department of Endocrinology and Metabolic Diseases, Charité University Medicine, Berlin). The participants were recruited via an existing database, public advertisement, word of mouth, radio advertisements and flyers. A total of 652 participants were screened using an OGTT, and 180 participants with IGT were enrolled into the study. IGT was defined as a 2 h plasma glucose concentration of 7.8–11.1 mmol/l.
According to the inclusion criteria, eligible study volunteers were aged ≥18 years and were willing to participate in one of the two intervention groups over a period of 2 years. Exclusion criteria were a history of type 1 or type 2 diabetes, pregnancy, breastfeeding or plans to become pregnant in the next 2 years, chronic or malignant diseases, other wasting illnesses (e.g. severe cardiopulmonary or autoimmune disorders), or a history or presence of a significant psychiatric disorder, eating disorders, medication with systemic corticosteroids, food allergies or food intolerances that precludes a supplementation with dietary fibre, and any other condition that would interfere with participation in the study.
The study protocol was approved by the ethics committee of the University of Potsdam as well as the ethics committee of the Charité, and all individuals gave written informed consent. The trial was registered at clinicaltrials.gov (NCT 01681173).
Study design
OptiFiT is a randomised, placebo-controlled, double-blind, parallel-group 24 month intervention study. Volunteers were randomly assigned using a computer algorithm to either placebo or fibre supplement by office staff who were not involved in other study procedures. Study enrolment was carried out by four study physicians, and dietary intervention was conducted by the nutritionist. Every 6 months, anthropometric data and serum markers were assessed, and all participants repeated the OGTT after 12 and 24 months.
In addition to having the dietary supplement, all participants started the 24 month study with a modified 1 year lifestyle programme, based on PREvention of DIAbetes Self-management (PREDIAS), a structured ‘Treatment and Education Program for Prevention of type 2 diabetes’ [1, 19]. Within this course, the volunteers had group-based consultations at regular intervals. During the second year of the study, the participants continued receiving their study supplement and were asked to continue regular intake twice daily.
Dietary intervention
The 12 month lifestyle PREDIAS consisted of 12 individual 2 h lessons divided into a core intervention (eight lessons in 8 weeks) and booster sessions (four lessons throughout the following 10 months) [20]. With this cost-effective self-management approach, participants should learn how to achieve a healthy balanced diet and adequate physical activity. For our modified lifestyle intervention, participants completed food records for 4 consecutive days, including 1 weekend day, before the study and after 6, 12 and 24 months. They were advised to record everything they ate and drank, and the completeness of the food records was checked with the study nutritionist. Nutrient intake was determined using nutrition software PRODI 5.8 (Wissenschaftliche Verlagsgesellschaft, Stuttgart) based on Bundeslebensmittelschlüssel 3.0 [21].
All participants were given detailed advice about how to achieve the goals of the lifestyle intervention: an increase in fibre intake to at least 15 g per 4200 kJ; a reduction in weight of 5% or more (if baseline BMI >25 kg/m2); a reduction in total intake of fat to less than 30% of energy consumed and of saturated fat to less than 10% of energy consumed; and moderate exercise for at least 30 min per day. Frequent ingestion of whole-grain products, legumes, vegetables, fruits, in particular berries, low-fat milk and meat products, soft margarines, and vegetable oils rich in unsaturated fatty acids was recommended. At regular intervals, all participants received a pedometer to assess their physical activity.
Dietary supplements
The supplements were provided as drinking powders every 6 months, when the individuals attended the metabolic unit, and participants were instructed to take the supplements twice daily. To enrich the high-fibre supplement with insoluble cereal fibre, a purified fibre extract derived from oat hulls was used, which contained 70 wt% cellulose, 25 wt% hemicellulose and 3–5 wt% lignin (Vitacel OF 560-30; Rettenmaier & Söhne, Holzmuehle, Germany). Further details on the supplement composition can be found elsewhere [8]. In addition to this main component, the supplement contained guar gum (1.92 wt%), isomaltulose, sucralose, flavouring and dyes in small amounts. This supplement added 15 g of mainly insoluble fibre per day (7.5 g per serving) to the normal nutrition. The appearance of the placebo supplement was comparable, but instead of the high-fibre extract, a waxy maize starch with negligible content of insoluble fibre and guar gum (0.8 g and 0.4 g per serving, respectively) and isomaltulose was used.
The fibre and placebo supplements contained 251 and 276 kJ per serving, respectively, had a comparable fruity taste and did not differ in appearance or texture. Blinding applied to both participants and study personnel. The volunteers were provided with instructions on how to use the drinking powder: the recommended intake was twice daily dissolved in 300 ml water, preferably before breakfast and dinner. The participants received accurately weighed quantities of the supplement in individual tins and were asked to return the amount they did not consume during their 6-monthly visits to the study unit.
Measurements and laboratory variables
The primary outcome was the change in 2 h post-challenge plasma glucose in the annual 75 g OGTT after a 12 h fast. IGT and diabetes were defined according to the recommendations of the ADA, IDF and WHO: participants with IGT had plasma glucose levels between 7.8 and 11.1 mmol/l, and a glucose value above that range was an indicator of diabetes. If diabetes was diagnosed during the study, the participants were referred to their general physician for treatment, and follow-up in OptiFiT was discontinued.
Blood samples for the OGTT were taken before and at 60, 120 and 180 min to measure glucose, insulin and C-peptide. Capillary blood glucose concentrations were measured immediately using the glucose oxidase method (Super-GL glucose analyser; Dr Müller Gerätebau, Freital, Germany); venous serum blood samples were analysed batch-wise after storage (Horiba ABX Pentra 400, Montpellier, France). Serum insulin and C-peptide were measured using an ELISA technique (Mercodia, Uppsala, Sweden).
In addition to the annual OGTT, routine laboratory markers were measured every 6 months by standard methods in the research laboratories of the German Institute of Human Nutrition. After sampling in EDTA or serum tubes, blood was immediately chilled on ice and centrifuged, and aliquots were immediately frozen at −80°C until assayed. Blood samples were analysed for total cholesterol, LDL- and HDL-cholesterol, triacylglycerols, NEFA, C-reactive protein, liver enzymes and HbA1c levels (ABX Pentra 400; Horiba ABX).
The baseline and 6-monthly clinical examinations included measurements of weight to the nearest 0.1 kg (in light indoor clothes without shoes), height to the nearest 0.5 cm and waist and hip circumference. Fat mass was assessed by bioelectrical impedance analysis (BIA; Body Impedance Analyser Quantum/S, Akern Bioresearch, Florence, Italy).
Calculations
The AUC in response to the 75 g OGTT was calculated for plasma glucose, insulin and C-peptide to combine multiple readings into a single index by the trapezoidal method. Insulin resistance was estimated by calculating the following fasting indices: HOMA-IR [22], QUICKI [23] and insulin sensitivity index of blood NEFA [24]. Additionally, dynamic insulin sensitivity indices—glucose effectiveness Sg [25] and the Cederholm index [26]—integrating plasma glucose and insulin concentrations during the OGTT, were used.
There is increasing evidence that hyperinsulinaemia in the insulin-resistant state reflects two pathophysiological processes: an increase in insulin secretion and a decrease in hepatic insulin clearance (HIC) [27]. Based on the OGTT data, HICC-peptide was calculated using the ratio of incremental areas under the insulin and C-peptide curve:
$$ {\mathrm{HIC}}_{\mathrm{C}\hbox{-} \mathrm{peptide}}={\mathrm{AUC}}_{\mathrm{C}\hbox{-} \mathrm{peptide}}\left[\mathrm{nmol}/\mathrm{l}\right]/{\mathrm{AUC}}_{\mathrm{Insulin}}\left[\mathrm{pmol}/\mathrm{l}\right] $$
Statistical analyses
The power calculation was based on an estimated effect size of 0.39 mmol/l difference in 2 h OGTT blood glucose levels (primary outcome) between the two groups, an SD of 1.1 mmol/l and 80% power to detect the effect. Such effects have recently been reported in other lifestyle intervention studies [2, 19]. The estimated number of participants to show these effects was 252, excluding a 25% allowance for dropouts (n = 63).
Changes in fasting glucose, HbA1c, body weight, measures of insulin sensitivity and insulin secretion, inflammation and adipokines were defined as secondary outcomes.
To ensure uniform representation, calculations within groups were performed assuming a non-normal distribution, and thus differences in the variables studied before and after the intervention within the groups were calculated by Wilcoxon test. Using parametric tests whenever appropriate did not lead to different overall results. For the comparison of changes between groups, the unpaired Student’s t test with an adjustment for change in body weight was used as far as data normality was given. The characteristics of the participants are presented as means ± SD. The results were considered significantly different if p ≤ 0.05. Every analysis was conducted both as an intention-to-treat (last observation carried forward) and as a per-protocol (completers only) analysis. If not explicitly stated, intention-to-treat and per-protocol analysis did not lead to different results, and intention-to-treat data are presented.
All statistical analyses were performed using SPSS for Windows version 22.0 (SPSS, Chicago, IL, USA). The graphs were created using GraphPad Prism version 6.0 (GraphPad Software, San Diego, CA, USA).