IGF-1 and IGFBP-1 as Possible Predictors of Response to Lifestyle Intervention-Results from Randomized Controlled Trials.

Lifestyle interventions can prevent type 2 diabetes (T2DM). However, some individuals do not experience anticipated improvements despite weight loss. Biomarkers to identify such individuals at early stages are lacking. Insulin-like growth factor 1 (IGF- 1) and Insulin-like growth factor binding protein 1(IGFBP-1) were shown to predict T2DM onset in prediabetes. We assessed whether these markers also predict the success of lifestyle interventions, thereby possibly guiding personalized strategies. We analyzed the fasting serum levels of IGF-1, IGFBP-1, and Insulin-like growth factor binding protein 2 (IGFBP-2) in relation to changes in metabolic and anthropometric parameters, including intrahepatic lipids (IHLs) and visceral adipose tissue (VAT) volume, measured by magnetic resonance imaging (MRI), in 345 participants with a high risk for prediabetes (54% female; aged 36-80 years). Participants were enrolled in three randomized dietary intervention trials and assessed both at baseline and one year post-intervention. Statistical analyses were performed using IBM SPSS Statistics (version 28), and significance was set at p < 0.05. Within the 1-year intervention, overall significant improvements were observed. Stratifying individuals by baseline IGF-1 and IGFBP-1 percentiles revealed significant differences: higher IGF-1 levels were associated with more favorable changes compared to lower levels, especially in VAT and IHL. Lower baseline IGFBP-1 levels were associated with greater improvements, especially in IHL and 2 h glucose. Higher bioactive IGF-1 levels might predict better metabolic outcomes following lifestyle interventions in prediabetes, potentially serving as biomarkers for personalized interventions.

Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: the randomised controlled Optimal Fibre Trial (OptiFiT).

AIMS/HYPOTHESIS: Insoluble cereal fibres have been shown in large prospective cohort studies to be highly effective in preventing type 2 diabetes, but there is a lack of interventional data. Our 2 year randomised double-blind prospective intervention study compared the effect of an insoluble oat fibre extract with that of placebo on glucose metabolism and incidence of diabetes. METHODS: A total of 180 participants with impaired glucose tolerance underwent a modified version of the 1 year lifestyle training programme PREvention of DIAbetes Self-management (PREDIAS) and were randomised to receive a fibre supplement (n = 89; 7.5 g of insoluble fibre per serving) or placebo (n = 91; 0.8 g of insoluble fibre per serving) twice daily for 2 years. Eligible participants were men and women, were at least 18 years old and did not report corticosteroid or other intensive anti-inflammatory treatment, fibre intolerance or any of the following disorders: overt diabetes, chronic or malignant disease, or severe cardiopulmonary, endocrine, psychiatric, gastrointestinal, autoimmune or eating disorder. Participants were recruited at two clinical wards in Berlin and Nuthetal. The allocation was blinded to participants and study caregivers (physicians, dietitians, study nurses). Randomisation was conducted by non-clinical staff, providing neutrally numbered supplement tins. Both supplements were similar in their visual, olfactory and gustatory appearance. Intention-to-treat analysis was applied to all individuals. RESULTS: After 1 year, 2 h OGTT levels decreased significantly in both groups but without a significant difference between the groups (fibre -0.78 ± 1.88 mmol/l [p ≤ 0.001] vs placebo -0.46 ± 1.80 mmol/l [p = 0.020]; total difference 0.32 ± 0.29 mmol/l; not significant). The 2 year incidence of diabetes was 9/89 (fibre group) compared with 16/91 (placebo group; difference not significant). As secondary outcomes, the change in HbA1c level was significantly different between the two groups (-0.2 ± 4.6 mmol/mol [-0.0 ± 0.0%; not significant] vs +1.2 ± 5.2 mmol/mol [+0.1 ± 0.0%; not significant]; total difference 1.4 ± 0.7 mmol/mol [0.1 + 0.0%]); p = 0.018); insulin sensitivity and hepatic insulin clearance increased in both groups. After 2 years, improved insulin sensitivity was still present in both groups, although the effect size had diminished. Separate analysis of the sexes revealed a significantly greater reduction in 2 h glucose levels for women in the fibre group (-0.88 ± 1.59 mmol/l [p ≤ 0.001] vs -0.22 ± 1.52 mmol/l [p = 0.311]; total difference 0.67 ± 0.31 mmol/l; p = 0.015). Levels of fasting glucose, adipokines and inflammatory markers remained unchanged in the two groups. Significantly increased fibre intake was restricted to the fibre group, despite dietary counselling for both groups. No severe side effects occurred. CONCLUSIONS/INTERPRETATION: We cannot currently provide strong evidence for a beneficial effect of insoluble cereal fibre on glycaemic metabolism, although further studies may support minor effects of fibre supplementation in reducing glucose levels, insulin resistance and the incidence of type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov NCT01681173 Funding: German Diabetes Foundation (grant no. 232/11/08).

Predicting Factors for Metabolic Non-Response to a Complex Lifestyle Intervention-A Replication Analysis to a Randomized-Controlled Trial.

BACKGROUND: T2DM heterogeneity affects responsiveness to lifestyle treatment. Beta-cell failure and nonalcoholic fatty liver disease (NAFLD) independently predict T2DM, but NAFLD inconsistently predicts metabolic response to lifestyle intervention. AIM: We attempt to replicate a prediction model deducted from the Tübinger Lifestyle Intervention Program by assessing similar metabolic factors to predict conversion to normal glucose regulation (NGR) in a comparable lifestyle intervention trial. METHODS: In the Optimal Fiber Trial (OptiFiT), 131 Caucasian participants with prediabetes completed a one-year lifestyle intervention program and received a fiber or placebo supplement. We compared baseline parameters for responders and non-responders, assessed correlations of major metabolic changes and conducted a logistic regression analysis for predictors of remission to NGR. RESULTS: NGR was achieved by 33 participants, respectively. At baseline, for the placebo group only, 1 h and 2 h glucose levels, glucose AUC and Cederholm index predicted conversion to NGR. HOMA-beta, HOMA-IR or liver fat indices did not differ between responders and non-responders of the placebo or the fiber group. Changes in waist circumference or fatty liver index correlated with changes in glycemia and insulin resistance, but not with changes in insulin secretion. Insulin-resistant NAFLD did not predict non-response. Differences in compliance did not explain the results. CONCLUSIONS: Higher post-challenge glucose levels strongly predicted the metabolic non-response to complex lifestyle intervention in our cohort. Depending on the specific intervention and the investigated cohort, fasting glucose levels and insulin sensitivity might contribute to the risk pattern. Beta-cell function did not improve in accordance with other metabolic improvements, qualifying as a potential risk factor for non-response. We could not replicate previous data suggesting that an insulin-resistant fatty liver is a specific risk factor for treatment failure. Replication studies are required.

Low IGF1 and high IGFBP1 predict diabetes onset in prediabetic patients.

Objectives: Some individuals develop type 2 diabetes mellitus (T2DM) despite significant metabolic improvements through lifestyle intervention. We tested the hypotheses that insulin growth factor 1 (IGF1) and its binding proteins 1 and 2 predict the onset of T2DM in prediabetes patients and determine the capacity for metabolic regeneration. Design: We measured fasting serum IGF1, insulin growth factor-binding protein 1 (IGFBP1) and IGFBP2 in three randomized controlled lifestyle intervention trials, covering at least 1 year of intervention period and 1 year of additional follow-up. Methods: Within a sample of 414 high-risk prediabetes patients (58% women; 28-80 years), we analyzed fasting serum concentrations of IGF1, IGFBP1 and IGFBP2 in relation to diabetes incidence and metabolic parameters over 2 years. Three hundred and forty-five subjects finished the first year of intervention. Results: The interventions significantly improved body weight (BMI: -3.24%, P < 0.001), liver fat (-36.8%, P < 0.001), insulin sensitivity (IS) (homeostatic model assessment-insulin resistance: -6.3%, P < 0.001) and insulin secretion (disposition index: +35%, P < 0.001) in the cohort. Fourteen percent developed T2DM within 2 years. Mean IGFBP1 levels at baseline were lower in prediabetes compared to a healthy population. Also, prediabetes patients with obesity and nonalcoholic fatty liver disease had lower IGFBP1. Those with impaired glucose tolerance had higher IGFBP1 compared to those with only impaired fasting glucose. Baseline IGF1 was lower (122.5 vs 146.6 µg/L) and IGFBP1 was higher (3.32 vs 2.09 µg/L) in subjects who developed T2DM (n = 57), resulting in a significant prediction of diabetes incidence (hazard ratio (HR) IGF1: 0.991 µg/L, P = 0.003; HR IGFBP1: 1.061 µg/L, P = 0.002). This translates into a 20% and 9% difference in T2DM incidence for IGF1 and IGFBP1, respectively. Despite reduced weight, visceral fat and hepatic fat in response to 1 year of lifestyle intervention, those who developed T2DM had not improved insulin sensitivity, glucose tolerance or IGFBP1. Conclusions: Lower IGF1 and higher IGFBP1 in prediabetes predicted the incidence of T2DM, indicating an impairment of beta-cell function, which explains the unresponsiveness to lifestyle intervention.

Dose-dependent effects of insoluble fibre on glucose metabolism: a stratified post hoc analysis of the Optimal Fibre Trial (OptiFiT).

AIMS: As the first long-term RCT on insoluble cereal fibre, the optimal fibre trial demonstrated glycometabolic benefits, confirming cohort studies. The combined study intervention of lifestyle recommendations and supplementation with insoluble oat hulls fibre allows to clarify, which amount of fibre is required for a beneficial effect. METHODS: One hundred and eighty participants with impaired glucose tolerance underwent the one-year PREDIAS lifestyle programme and received a blinded, randomized fibre or placebo supplement for two years. We conducted a regression analyses and cut-off-based tertile comparisons in subjects with full data on dietary compliance (food records and accounted supplement; n = 120) after one year, investigating effects on fasting blood parameters, oral glucose tolerance test and anthropometry. RESULTS: We found a nonlinear inverse relation between fibre intake and change in postprandial 2-h glucose levels, showing a metabolic benefit beyond 14 g and a plateau beyond 25 g of total insoluble fibre per day. 2-h glucose levels improved significantly stronger in both upper tertiles (-0.9 [-1.6;-0.2] mmol/l, p = 0.047, and -0.6 [-1.6;0.3] mmol/l, p = 0.010) compared to the lowest tertile (0.1 [-1.2;1.1] mmol/l), also when adjusted for changes in bodyweight. Subjects with the highest fibre intake showed superior effects on fasting and postprandial insulin resistance, hepatic insulin clearance, leucocyte count and fatty liver index. CONCLUSIONS: Extending the knowledge on the benefits of insoluble oat hulls fibre, our post hoc analysis demonstrates a dose effect for glycaemia and associated metabolic markers. Further research is needed in order to replicate our findings in larger trials.

Effects of Insoluble Cereal Fibre on Body Fat Distribution in the Optimal Fibre Trial.

SCOPE: The Optimal Fibre Trial (OptiFiT) investigates metabolic effects of insoluble cereal fibre in subjects with impaired glucose tolerance (IGT), showing moderate glycemic and anti-inflammatory benefits, especially in subjects with an obesity-related phenotype. An OptiFiT sub-group is analysed for effects on body fat distribution. METHODS AND RESULTS: 180 participants with IGT receive a blinded, randomized supplementation with insoluble cereal fibre or placebo for 2 years. Once a year, all subjects undergo fasting blood sampling, oral glucose tolerance test, and anthropometric measurements. A subgroup (n=47) also received magnetic resonance imaging and spectroscopy for quantification of adipose tissue distribution and liver fat content. We compared MR, metabolic and inflammatory outcomes between fibre and placebo group metabolism and inflammation. Visceral and non-visceral fat, fasting glucose, HbA1c, fasting insulin, insulin resistance, and uric acid decrease only in the fibre group, mirroring effects of the entire cohort. However, after adjustment for weight loss, there are no significant between-group differences. There is a statistical trend for fibre-driven liver fat reduction in subjects with confirmed non-alcoholic fatty liver disease (NAFLD; n = 19). CONCLUSIONS: Data and evidence on beneficial effects of insoluble cereal fibre on visceral and hepatic fatstorage is limited, but warrants further research. Targeted trials are required.

Different Effects of Lifestyle Intervention in High- and Low-Risk Prediabetes: Results of the Randomized Controlled Prediabetes Lifestyle Intervention Study (PLIS).

Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested whether individuals with prediabetes with low risk (LR) benefit from conventional LI and individuals with high risk (HR) benefit from an intensification of LI in a multicenter randomized controlled intervention over 12 months with 2 years' follow-up. A total of 1,105 individuals with prediabetes based on American Diabetes Association glucose criteria were stratified into an HR or LR phenotype based on previously described thresholds of insulin secretion, insulin sensitivity, and liver fat content. LR individuals were randomly assigned to conventional LI according to the Diabetes Prevention Program (DPP) protocol or control (1:1) and HR individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In HR individuals, the difference between conventional and intensified LI in postchallenge glucose change was -0.29 mmol/L [95% CI -0.54; -0.04], P = 0.025. Liver fat (-1.34 percentage points [95% CI -2.17; -0.50], P = 0.002) and cardiovascular risk (-1.82 percentage points [95% CI -3.13; -0.50], P = 0.007) underwent larger reductions with intensified than with conventional LI. During a follow-up of 3 years, intensified compared with conventional LI had a higher probability of normalizing glucose tolerance (P = 0.008). In conclusion, it is possible in HR individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk phenotype-based LI may be beneficial for the prevention of diabetes.

Predictive effect of GIPR SNP rs10423928 on glucose metabolism liver fat and adiposity in prediabetic and diabetic subjects.

The gastric inhibitory polypeptide receptor (GIPR) regulates postprandial metabolism. In this context GIPR SNP rs10423928 seems toplay an important role in modulating glucose metabolism and insulinsensitivity. However, evidence regarding thisparticular SNP is still vague. In this study, we collected baseline data from four different dietaryintervention studies. We genotyped 424 subjects with prediabetes and 73with diabetes for GIPR SNP rs10423928 and examined its impact on glucosemetabolism, insulin sensitivity and body fat accumulation. We extended previous data by showing that carriers of the A allele withprediabetes displayed increased fasting glucose (p = 0.015). Unexpectedly,A allele carriers showed lower glucose levels 2 h (p = 0.021) after anoral glucose challenge compared to T/T homozygous individuals. A allelecarriers also showed significantly higher insulin sensitivity (p < 0.001)(assessed by Cederholm Index), indicating an enhanced ß-cell response. This study points to a potential protective role for rs10423928 inglucose metabolism and insulin sensitivity in subjects with prediabetes.Further studies are necessary to confirm these results.

Obesity Does Not Modulate the Glycometabolic Benefit of Insoluble Cereal Fibre in Subjects with Prediabetes-A Stratified Post Hoc Analysis of the Optimal Fibre Trial (OptiFiT).

Obesity does not modulate the glycometabolic benefit of insoluble cereal fibre in subjects with prediabetes-a stratified post hoc analysis of the Optimal Fibre Trial (OptiFiT). BACKGROUND: OptiFiT demonstrated the beneficial effect of insoluble oat fibres on dysglycemia in prediabetes. Recent analyses of OptiFiT and other randomised controlled trials (RCTs) indicated that this effect might be specific for the subgroup of patients with impaired fasting glucose (IFG). As subjects with IFG are more often obese, there is a need to clarify if the effect modulation is actually driven by glycemic state or body mass index (BMI). AIM: We conducted a stratified post hoc analysis of OptiFiT based on the presence or absence of obesity. METHODS: 180 Caucasian participants with impaired glucose tolerance (IGT) were randomised in a double-blinded fashion to either twice-a-day fibre or placebo supplementation for 2 years (n = 89 and 91, respectively). Once a year, they underwent fasting blood sampling, an oral glucose tolerance test (oGTT) and full anthropometry. At baseline, out of 136 subjects who completed the first year of intervention, 87 (62%) were classified as OBESE (BMI >30) and 49 subjects were NONOBESE. We performed a stratified per-protocol analysis of the primary glycemic and secondary metabolic effects attributable to dietary fibre supplementation after 1 year of intervention. RESULTS: Neither the NONOBESE nor the OBESE subgroup showed significant differences between the respective fibre and placebo groups in metabolic, anthropometric or inflammatory outcomes. None of the four subgroups showed a significant improvement in either fasting glucose or glycated haemoglobin (HbA1c) after 1 year of intervention and only OBESE fibre subjects improved 2 h glucose. Within the NONOBESE stratum, there were no significant differences in the change of primary or secondary metabolic parameters between the fibre and placebo arms. We found a significant interaction effect for leukocyte count (time × supplement × obesity status). Within the OBESE stratum, leukocyte count and gamma-glutamyl transferase (GGT) levels decreased more in the fibre group compared with placebo (adjusted for change in body weight). Comparison of both fibre groups revealed that OBESE subjects had a significantly stronger benefit with respect to leukocyte count and fasting C-peptide levels than NONOBESE participants. Only the effect on leukocyte count survived correction for multiple comparisons. In contrast, under placebo conditions, NONOBESE subjects managed to decrease their body fat content significantly more than OBESE ones. Intention-to-treat (ITT) analysis resulted in similar outcomes. CONCLUSIONS: The state of obesity does not relevantly modulate the beneficial effect of cereal fibre on major glycometabolic parameters by fibre supplementation, but leukocyte levels may be affected. Hence, BMI is not a suitable parameter to stratify this cohort with respect to diabetes risk or responsiveness to cereal fibre, but obesity needs to be accounted for when assessing anti-inflammatory effects of fibre treatments. Targeted diabetes prevention should focus on the actual metabolic state rather than on mere obesity.

Fasting Glucose State Determines Metabolic Response to Supplementation with Insoluble Cereal Fibre: A Secondary Analysis of the Optimal Fibre Trial (OptiFiT).

BACKGROUND: High intake of cereal fibre is associated with reduced risk for type 2 diabetes and long-term complications. Within the first long-term randomized controlled trial specifically targeting cereal fibre, the Optimal Fibre Trial (OptiFiT), intake of insoluble oat fibre was shown to significantly reduce glycaemia. Previous studies suggested that this effect might be limited to subjects with impaired fasting glucose (IFG). AIM: We stratified the OptiFiT cohort for normal and impaired fasting glucose (NFG, IFG) and conducted a secondary analysis comparing the effects of fibre supplementation between these subgroups. METHODS: 180 Caucasian participants with impaired glucose tolerance (IGT) were randomized to twice-a-day fibre or placebo supplementation for 2 years (n = 89 and 91, respectively), while assuring double-blinded intervention. Fasting blood sampling, oral glucose tolerance test and full anthropometry were assessed annually. At baseline, out of 136 subjects completing the first year of intervention, 72 (54 %) showed IFG and IGT, while 64 subjects had IGT only (labelled "NFG"). Based on these two groups, we performed a stratified per-protocol analysis of glycometabolic and secondary effects during the first year of intervention. RESULTS: The NFG group did not show significant differences between fibre and placebo group concerning anthropometric, glycometabolic, or other biochemical parameters. Within the IFG stratum, 2-h glucose, HbA1c, and gamma-glutamyl transferase levels decreased more in the fibre group, with a significant supplement x IFG interaction effect for HbA1c. Compared to NFG subjects, IFG subjects had larger benefits from fibre supplementation with respect to fasting glucose levels. Results were robust against adjustment for weight change and sex. An ITT analysis did not reveal any differences from the per-protocol analysis. CONCLUSIONS: Although stratification resulted in relatively small subgroups, we were able to pinpoint our previous findings from the entire cohort to the IFG subgroup. Cereal fibre can beneficially affect glycemic metabolism, with most pronounced or even isolated effectiveness in subjects with impaired fasting glucose.

Acute Endothelial Benefits of Fat Restriction over Carbohydrate Restriction in Type 2 Diabetes Mellitus: Beyond Carbs and Fats.

BACKGROUND: Cardiovascular diseases (CVD) are the major cause of mortality in type 2 diabetes patients (T2DM). The causes are embedded in a complex interplay between excess body fat, insulin resistance and serum lipid anomalies. Endothelial homeostasis is strongly affected by this pathogenic network. Even though metabolic changes and weight loss improve vascular endothelial function, the effect of different dietary approaches is still uncertain for type 2 diabetes patients. OBJECTIVE: We aimed to compare the acute effects of a hypocaloric very low carbohydrate (VLC) diet versus a hypocaloric low fat (LF) diet on flow mediated dilation (FMD), intrahepatic lipid (IHL) accumulation and visceral adipose tissue as independent risk factors of CVD in T2DM patients. DESIGN: 36 T2DM patients (age 63 ± 8 years, 60% females) were randomly assigned to the VLC diet (4⁻10% of total energy intake (E)) or to the LF diet (<30% E) for 3 weeks. Endothelial function was assessed by the flow mediated dilation (FMD) method. Adipose tissue depots and IHL were determined by magnetic resonance. RESULTS: Both dietary strategies reduced body weight, body fat content and IHL. Unexpectedly, the LF group experienced significantly greater enhancement of FMD, compared to the VLC group. The FMD showed a positive correlation with protein intake and fat intake in the LF group, while it revealed a negative correlation with protein intake in the VLC diet group. CONCLUSIONS: Reduction of total and hepatic adiposity was shown to be successful using either the VLC or LF hypocaloric diets, however, improvements in FMD may be related to the interplay of fat and protein intake.

Liver Fat Scores Moderately Reflect Interventional Changes in Liver Fat Content by a Low-Fat Diet but Not by a Low-Carb Diet.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder all over the world, mainly being associated with a sedentary lifestyle, adiposity, and nutrient imbalance. The increasing prevalence of NAFLD accommodates similar developments for type 2 diabetes and diabetes-related comorbidities and complications. Therefore, early detection of NAFLD is an utmost necessity. Potentially helpful tools for the prediction of NAFLD are liver fat indices. The fatty liver index (FLI) and the NAFLD-liver fat score (NAFLD-LFS) have been recently introduced for this aim. However, both indices have been shown to correlate with liver fat status, but there is neither sufficient data on the longitudinal representation of liver fat change, nor proof of a diet-independent correlation between actual liver fat change and change of index values. While few data sets on low-fat diets have been published recently, low-carb diets have not been yet assessed in this context. AIM: We aim to provide such data from a highly effective short-term intervention to reduce liver fat, comparing a low-fat and a low-carb diet in subjects with prediabetes. METHODS: Anthropometric measurements, magnetic resonance (MR)-based intrahepatic lipid (IHL) content, and several serum markers for liver damage have been collected in 140 subjects, completing the diet phase in this trial. Area-under-the-responder-operator-curves (AUROC) calculations as well as cross-sectional and longitudinal Spearman correlations were used. RESULTS: Both FLI and NAFLD-LFS predict liver fat with moderate accuracy at baseline (AUROC 0.775-0.786). These results are supported by correlation analyses. Changes in liver fat, achieved by the dietary intervention, correlate moderately with changes in FLI and NAFLD-LFS in the low-fat diet, but not in the low-carb diet. A correlation analysis between change of actual IHL content and change of single elements of the liver fat indices revealed diet-specific moderate to strong correlations between ΔIHL and changes of measures of obesity, ΔTG, and ΔALT (all low-fat, only) and between ΔIHL and ΔGGT (low-carb, only). With exception for a stronger decrease of triglycerides (TG) levels in the low-carb diet, there is no statistically significant difference in the effect of the diets on anthropometric or serum-based score parameters. CONCLUSION: While liver fat indices have proved useful in the early detection of NAFLD and may serve as a cost-saving substitute for expensive MR measurements in the cross-sectional evaluation of liver status, their capability to represent interventional changes of liver fat content appears to be diet-specific and lacks accuracy. Liver fat reduction by low-fat diets can be monitored with moderate precision, while low-carb diets require different measuring techniques to demonstrate the same dietary effect.