Self-initiated lifestyle changes during a fasting-mimicking diet programme in patients with type 2 diabetes: a mixed-methods study.

BACKGROUND: Lifestyle changes, especially regarding diet quality and physical activity, are important in the management of type 2 diabetes (T2D). This mixed-methods study explores self-initiated lifestyle changes in patients with T2D who followed a periodic fasting-mimicking diet (FMD). METHODS: Quantitative data were obtained from the Fasting In diabetes Treatment trial (November 2018 to August 2021) in which 100 participants with T2D, using metformin only or no medication, were randomised to receive a monthly 5-day FMD for twelve months next to usual care, or usual care only. Diet quality and physical activity questionnaires were completed at baseline, six and twelve months. Changes over time were analysed using linear mixed models. Focus groups were organized with FMD participants to explore experiences regarding self-initiated lifestyle changes. The qualitative data was analysed using the Theoretical Domains Framework. RESULTS: Questionnaires were available from 49 FMD participants and 43 controls. No differences in diet quality were found. Total physical activity in the FMD participants changed from 34.6 to 38.5 h per week (h/wk) from baseline to twelve months, while in controls it changed from 34.9 to 29.0 h/wk (between group difference, p = 0.03). In six focus groups with FMD participants (n = 20), individual participants perceived the FMD as an encouragement for (minor) lifestyle changes. There were no barriers to behaviour change related to the FMD. Important facilitators of healthy behaviour were an increase in awareness of the impact of lifestyle on health (knowledge), better physical fitness (physical) and health improvement (reinforcement). Facilitators unrelated to the FMD included family support (social influences) and opportunities in the neighbourhood (environmental context and resources), while barriers unrelated to the FMD were experiencing health problems (physical) and social events (social influences). CONCLUSIONS: Using an FMD for five consecutive days per month did not affect diet quality in between FMD periods in quantitative analysis, but increased the number of hours per week spent on physical activity. Qualitative analysis revealed self-initiated improvements in both diet quality and physical activity in individual participants using an FMD. Healthcare professionals could use an FMD programme as a 'teachable moment' to stimulate additional lifestyle changes. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03811587. Registered 22 January 2019.

Participatory Development of an Integrated, eHealth-Supported, Educational Care Pathway (Diabetes Box) for People With Type 2 Diabetes: Development and Usability Study.

BACKGROUND: Type 2 diabetes (T2D) tremendously affects patient health and health care globally. Changing lifestyle behaviors can help curb the burden of T2D. However, health behavior change is a complex interplay of medical, behavioral, and psychological factors. Personalized lifestyle advice and promotion of self-management can help patients change their health behavior and improve glucose regulation. Digital tools are effective in areas of self-management and have great potential to support patient self-management due to low costs, 24/7 availability, and the option of dynamic automated feedback. To develop successful eHealth solutions, it is important to include stakeholders throughout the development and use a structured approach to guide the development team in planning, coordinating, and executing the development process. OBJECTIVE: The aim of this study is to develop an integrated, eHealth-supported, educational care pathway for patients with T2D. METHODS: The educational care pathway was developed using the first 3 phases of the Center for eHealth and Wellbeing Research roadmap: the contextual inquiry, the value specification, and the design phase. Following this roadmap, we used a scoping review about diabetes self-management education and eHealth, past experiences of eHealth practices in our hospital, focus groups with health care professionals (HCPs), and a patient panel to develop a prototype of an educational care pathway. This care pathway is called the Diabetes Box (Leiden University Medical Center) and consists of personalized education, digital educational material, self-measurements of glucose, blood pressure, activity, and sleep, and a smartphone app to bring it all together. RESULTS: The scoping review highlights the importance of self-management education and the potential of telemonitoring and mobile apps for blood glucose regulation in patients with T2D. Focus groups with HCPs revealed the importance of including all relevant lifestyle factors, using a tailored approach, and using digital consultations. The contextual inquiry led to a set of values that stakeholders found important to include in the educational care pathway. All values were specified in biweekly meetings with key stakeholders, and a prototype was designed. This prototype was evaluated in a patient panel that revealed an overall positive impression of the care pathway but stressed that the number of apps should be restricted to one, that there should be no delay in glucose value visualization, and that insulin use should be incorporated into the app. Both patients and HCPs stressed the importance of direct automated feedback in the Diabetes Box. CONCLUSIONS: After developing the Diabetes Box prototype using the Center for eHealth and Wellbeing Research roadmap, all stakeholders believe that the concept of the Diabetes Box is useful and feasible and that direct automated feedback and education on stress and sleep are essential. A pilot study is planned to assess feasibility, acceptability, and usefulness in more detail.

Impact of dietary carbohydrate, fat or protein restriction on the human gut microbiome: a systematic review.

Restriction of dietary carbohydrates, fat and/or protein is often used to reduce body weight and/or treat (metabolic) diseases. Since diet is a key modulator of the human gut microbiome, which plays an important role in health and disease, this review aims to provide an overview of current knowledge of the effects of macronutrient-restricted diets on gut microbial composition and metabolites. A structured search strategy was performed in several databases. After screening for inclusion and exclusion criteria, thirty-six articles could be included. Data are included in the results only when supported by at least three independent studies to enhance the reliability of our conclusions. Low-carbohydrate (<30 energy%) diets tended to induce a decrease in the relative abundance of several health-promoting bacteria, including Bifidobacterium, as well as a reduction in short-chain fatty acid (SCFA) levels in faeces. In contrast, low-fat diets (<30 energy%) increased alpha diversity, faecal SCFA levels and abundance of some beneficial bacteria, including Faecalibacterium prausnitzii. There were insufficient data to draw conclusions concerning the effects of low-protein (<10 energy%) diets on gut microbiota. Although the data of included studies unveil possible benefits of low-fat and potential drawbacks of low-carbohydrate diets for human gut microbiota, the diversity in study designs made it difficult to draw firm conclusions. Using a more uniform methodology in design, sample processing and sharing raw sequence data could foster our understanding of the effects of macronutrient restriction on gut microbiota composition and metabolic dynamics relevant to health. This systematic review was registered at https://www.crd.york.ac.uk/prospero as CRD42020156929.

Role of dietary interventions on microvascular health in South-Asian Surinamese people with type 2 diabetes in the Netherlands: A randomized controlled trial.

BACKGROUND/OBJECTIVES: We investigated whether dietary interventions, i.e. a fasting mimicking diet (FMD, Prolon®) or glycocalyx mimetic supplementation (EndocalyxTM) could stabilize microvascular function in Surinamese South-Asian patients with type 2 diabetes (SA-T2DM) in the Netherlands, a patient population more prone to develop vascular complications. SUBJECTS/METHODS: A randomized, placebo controlled, 3-arm intervention study was conducted in 56 SA-T2DM patients between 18 and 75 years old, for 3 consecutive months, with one additional follow up measurement 3 months after the last intervention. Sublingual microcirculation was assessed with SDF-imaging coupled to the GlycoCheckTM software, detecting red blood cell velocity, capillary density, static and dynamic perfused boundary region (PBR), and the overall microvascular health score (MVHS). Linear mixed models and interaction analysis were used to investigate the effects the interventions had on microvascular function. RESULTS: Despite a temporal improvement in BMI and HbA1c after FMD the major treatment effect on microvascular health was worsening for RBC-velocity independent PBRdynamic, especially at follow-up. Glycocalyx supplementation, however, reduced urinary MCP-1 presence and improved both PBRdynamic and MVHSdynamic, which persisted at follow-up. CONCLUSIONS: We showed that despite temporal beneficial changes in BMI and HbA1c after FMD, this intervention is not able to preserve microvascular endothelial health in Dutch South-Asian patients with T2DM. In contrast, glycocalyx mimetics preserves the microvascular endothelial health and reduces the inflammatory cytokine MCP-1. CLINICAL STUDY REGISTRATION: NCT03889236.

Integration of a fasting-mimicking diet programme in primary care for type 2 diabetes reduces the need for medication and improves glycaemic control: a 12-month randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the impact on metabolic control of periodic use of a 5-day fasting-mimicking diet (FMD) programme as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance. METHODS: In this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin as the only glucose-lowering drug and/or diet for glycaemic control were randomised to receive 5-day cycles of an FMD monthly as an adjunct to regular care by their general practitioner or to receive regular care only. The primary outcomes were changes in glucose-lowering medication (as reflected by the medication effect score) and HbA1c levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA1c levels in individual participants were combined to yield a clinically relevant outcome measure ('glycaemic management'), which was categorised as improved, stable or deteriorated after 1 year of follow-up. Several secondary outcome measures were also examined, including changes in body weight. RESULTS: One hundred individuals with type 2 diabetes, age 18-75 years, BMI ≥27 kg/m2, were randomised to the FMD group (n=51) or the control group (n=49). Eight FMD participants and ten control participants were lost to follow-up. Intention-to-treat analyses, using linear mixed models, revealed adjusted estimated treatment effects for the medication effect score (-0.3; 95% CI -0.4, -0.2; p<0.001), HbA1c (-3.2 mmol/mol; 95% CI -6.2, -0.2 and -0.3%; 95% CI -0.6, -0.0; p=0.04) and body weight (-3.6 kg; 95% CI -5.2, -2.1; p<0.001) at 12 months. Glycaemic management improved in 53% of participants using FMD vs 8% of control participants, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.001). CONCLUSIONS/INTERPRETATION: Integration of a monthly FMD programme in regular primary care for people with type 2 diabetes who use metformin as the only glucose-lowering drug and/or diet for glycaemic control reduces the need for glucose-lowering medication, improves HbA1c despite the reduction in medication use, and appears to be safe in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03811587 FUNDING: The project was co-funded by Health~Holland, Top Sector Life Sciences & Health, the Dutch Diabetes Foundation and L-Nutra.

A Digitally Enabled Combined Lifestyle Intervention for Weight Loss: Pilot Study in a Dutch General Population Cohort.

BACKGROUND: Overweight and obesity rates among the general population of the Netherlands keep increasing. Combined lifestyle interventions (CLIs) focused on physical activity, nutrition, sleep, and stress management can be effective in reducing weight and improving health behaviors. Currently available CLIs for weight loss (CLI-WLs) in the Netherlands consist of face-to-face and community-based sessions, which face scalability challenges. A digitally enabled CLI-WL with digital and human components may provide a solution for this challenge; however, the feasibility of such an intervention has not yet been assessed in the Netherlands. OBJECTIVE: The aim of this study was two-fold: (1) to determine how weight and other secondary cardiometabolic outcomes (lipids and blood pressure) change over time in a Dutch population with overweight or obesity and cardiometabolic risk participating in a pilot digitally enabled CLI-WL and (2) to collect feedback from participants to guide the further development of future iterations of the intervention. METHODS: Participants followed a 16-week digitally enabled lifestyle coaching program rooted in the Fogg Behavior Model, focused on nutrition, physical activity, and other health behaviors, from January 2020 to December 2021. Participants could access the digital app to register and track health behaviors, weight, and anthropometrics data at any time. We retrospectively analyzed changes in weight, blood pressure, and lipids for remeasured users. Surveys and semistructured interviews were conducted to assess critical positive and improvement points reported by participants and health care professionals. RESULTS: Of the 420 participants evaluated at baseline, 53 participated in the pilot. Of these, 37 (70%) were classified as overweight and 16 (30%) had obesity. Mean weight loss of 4.2% occurred at a median of 10 months postintervention. The subpopulation with obesity (n=16) showed a 5.6% weight loss on average. Total cholesterol decreased by 10.2% and low-density lipoprotein cholesterol decreased by 12.9% on average. Systolic and diastolic blood pressure decreased by 3.5% and 7.5%, respectively. Participants identified the possibility of setting clear action plans to work toward and the multiple weekly touch points with coaches as two of the most positive and distinctive components of the digitally enabled intervention. Surveys and interviews demonstrated that the digital implementation of a CLI-WL is feasible and well-received by both participants and health care professionals. CONCLUSIONS: Albeit preliminary, these findings suggest that a behavioral lifestyle program with a digital component can achieve greater weight loss than reported for currently available offline CLI-WLs. Thus, a digitally enabled CLI-WL is feasible and may be a scalable alternative to offline CLI-WL programs. Evidence from future studies in a Dutch population may help elucidate the mechanisms behind the effectiveness of a digitally enabled CLI-WL.

IGF1 and Insulin Receptor Single Nucleotide Variants Associated with Response in HER2-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without a Fasting Mimicking Diet (BOOG 2013-04 DIRECT Trial).

AIM: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. METHODS: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. RESULTS: IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). CONCLUSIONS: The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD.

Influencing the Insulin System by Placebo Effects in Patients With Diabetes Type 2 and Healthy Controls: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to investigate whether placebo effect induced by pharmacological conditioning with intranasal insulin can affect glucose, insulin, C-peptide, hunger, and memory in patients with diabetes type 2 and healthy controls. METHODS: Placebo effect was induced by pharmacological conditioning. Thirty-two older patients (mean age = 68.3 years) with diabetes type 2 and age- and sex-matched thirty-two healthy older adults (mean age = 67.8 years) were randomly assigned to a conditioned or a control group. On day 1, conditioned group received six administrations of intranasal insulin with a conditioned stimulus (CS; smell of rosewood oil), whereas the control group received a placebo with the CS. On day 2, both groups received a placebo spray with the CS. Glucose, insulin, and C-peptide were repeatedly measured in blood. Hunger and memory were assessed with validated measures. RESULTS: Intranasal insulin stabilized dropping glucose levels in patients ( B = 0.03, SE = 0.02, p = .027) and healthy men ( B = 0.046, SE = 0.02, p = .021), and decreased C-peptide levels in healthy controls ( B = 0.01, SE = 0.001, p = .008). Conditioning also prevented the drop of glucose levels but only in men (both healthy and patients; B = 0.001, SE = 0.0003, p = .024). Conditioning significantly decreased hunger in healthy participants ( B = 0.31, SE = 0.09, p < .001). No effects were found on other measures. CONCLUSIONS: Placebo effect induced by conditioning with intranasal insulin modifies blood glucose levels and decreases hunger in older adults, but its effects depend on health status and sex. Insulin conditioning might be beneficial for groups suffering from intensive hunger but seems not be particularly suitable for blood glucose reduction. TRIAL REGISTRATION: Netherlands Trial Register, NL7783 ( https://www.trialregister.nl/trial/7783 ).

Metabolic impact of intermittent energy restriction and periodic fasting in patients with type 2 diabetes: a systematic review.

CONTEXT: The effectiveness of intermittent energy restriction (IER) and periodic fasting (PF) in the management of type 2 diabetes (T2D) remains a subject of discussion. OBJECTIVE: The aim of this systematic review is to summarize current knowledge of the effects of IER and PF in patients with T2D on markers of metabolic control and the need for glucose-lowering medication. DATA SOURCES: PubMed, Embase, Emcare, Web of Science, Cochrane Library, CENTRAL, Academic Search Premier, Science Direct, Google Scholar, Wiley Online Library, and LWW Health Library were searched for eligible articles on March 20, 2018 (last update performed November 11, 2022). Studies that evaluated the effects of IER or PF diets in adult patients with T2D were included. DATA EXTRACTION: This systematic review is reported according to PRISMA guidelines. Risk of bias was assessed through the Cochrane risk of bias tool. The search identified 692 unique records. Thirteen original studies were included. DATA ANALYSIS: A qualitative synthesis of the results was constructed because the studies differed widely in terms of dietary interventions, study design, and study duration. Glycated hemoglobin (HbA1c) declined in response to IER or PF in 5 of 10 studies, and fasting glucose declined in 5 of 7 studies. In 4 studies, the dosage of glucose-lowering medication could be reduced during IER or PF. Two studies evaluated long-term effects (≥1 year after ending the intervention). The benefits to HbA1c or fasting glucose were generally not sustained over the long term. There are a limited number of studies on IER and PF interventions in patients with T2D. Most were judged to have at least some risk of bias. CONCLUSION: The results of this systematic review suggest that IER and PF can improve glucose regulation in patients with T2D, at least in the short term. Moreover, these diets may allow for dosage reduction of glucose-lowering medication. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42018104627.

Phase 1 Study to Evaluate the Safety of Reducing the Prophylactic Dose of Dexamethasone around Docetaxel Infusion in Patients with Prostate and Breast Cancer.

BACKGROUND: There is little evidence that supports the registered high dose of dexamethasone used around docetaxel. However, this high dose is associated with considerable side effects. This study evaluates the feasibility of reducing the prophylactic oral dosage of dexamethasone around docetaxel infusion. PATIENTS AND METHODS: Eligible patients had a histologically confirmed diagnosis of prostate or breast cancer and had received at least three cycles of docetaxel as monotherapy or combination therapy. Prophylactic dexamethasone around docetaxel infusion was administered in a de-escalating order per cohort of patients. Primary endpoint was the occurrence of grade III/IV fluid retention and hypersensitivity reactions (HSRs). RESULTS: Of the 46 enrolled patients, 39 were evaluable (prostate cancer (n = 25), breast cancer (n = 14). In patients with prostate cancer, the dosage of dexamethasone was reduced to a single dose of 4 mg; in patients with breast cancer, the dosage was reduced to a 3-day schedule of 4 mg-8 mg-4 mg once daily, after which no further reduction has been tested. None of the 39 patients developed grade III/IV fluid retention or HSR. One patient (2.6%) had a grade 1 HSR, and there were six patients (15.4%) with grade I or II edema. There were no differences in quality of life (QoL) between cohorts. CONCLUSIONS: It seems that the prophylactic dose of dexamethasone around docetaxel infusion can be safely reduced with respect to the occurrence of grade III/IV HSRs or the fluid retention syndrome.

Short-Term Fasting Synergizes with Solid Cancer Therapy by Boosting Antitumor Immunity.

Short-term fasting (STF), using a low caloric, low protein fasting mimicking diet (FMD), appears to be a promising strategy to enhance chemotherapy-based cancer efficacy, while potentially alleviating toxicity. Preclinical results suggest that enhanced tumor immunity and decreased growth signaling, via lowering of circulating insulin and insulin growth factor 1 (IGF-1) levels form the potential underlying mechanisms. STF may boost anti-tumor responses by promoting tumor immunogenicity and decreasing local immunosuppression. These findings warrant further studies focused on the combination of STF, not only with chemotherapy, but also with immunotherapy to evaluate the full range of benefits of STF in cancer treatment. Here, we delineate the underlying anticancer mechanisms of fasting. We summarize preclinical evidence of STF boosting antitumor immunity and alleviating immunosuppression, as well as the clinical findings reporting the immunomodulatory effects of STF during various cancer treatments, including immunotherapy.

Observational study on dietary changes of participants following a multicomponent lifestyle program (Reverse Diabetes2 Now).

BACKGROUND: Lifestyle intervention studies to treat type 2 diabetes (T2D) are on the rise. However, in-depth research is lacking into the dietary changes that participants make. METHODS: The present study aimed to observe the dietary intake of participants following the group program 'Reverse Diabetes2 Now' (RD2N) over 12 months. The web-based 24-h dietary recall-tool Compl-eat was used to collect dietary intake data. RESULTS: In total, 147 T2D patients were included in a cross-sectional study (n = 37 at baseline, n = 58 at 6 months, n = 52 at 12 months). A lower intake of total energy, carbohydrates and iodine was found for the groups at 6 and 12 months compared to the baseline group. The absolute consumption of total fat and saturated fat did not differ between the groups; only the percentage as total calorie consumption decreased. Consumption of vegetables and full-fat yoghurt was higher in groups at 6 and 12 months compared to the group at baseline. Consumption of bread, cakes and sweet biscuits, pasta/rice/tortillas, artificially sweetened soft drinks, and crisps were lower in the groups at 6 and 12 months compared to the group at baseline. Similar results were observed in a separate prospective study in 22 participants over 12 months following the same lifestyle-intervention. CONCLUSIONS: Overall, participants shifted their dietary intake somewhat towards a healthier dietary pattern with overall lower energy and carbohydrates and more vegetables. Moreover, participants largely maintained this healthier pattern over 12 months. There were some concerns regarding iodine intake. These promising results need to be confirmed in a fully-scaled study, as well in a comparison with controls.

Retrospective analysis on the effect of Reverse Diabetes2 Now on kidney function in patients with type 2 diabetes with impaired kidney function.

Objective: Type 2 diabetes is one of the main causes of kidney damage. Recent intervention studies suggest that the progression of type 2 diabetes can be halted, or even brought into remission by lifestyle interventions. In a pragmatic trial, the Reverse Diabetes2 Now programme (RD2N, NL: Keer Diabetes2 Om), a multicomponent lifestyle intervention, reduced the need for bloodglucose lowering medications up to 24 months. Research design and methods: Here, we retrospectively investigate the effect of RD2N on markers of kidney function in patients selected for impaired kidney function at baseline (eGFR <70 mL/min/1.73 m2 (n=45). Baseline data were retrieved from the intervention database and follow-up data on renal markers were collected from routine medical records. Wilcoxon non-parametric tests were used to assess changes over 6 and 12 months. Results: After 6 months median eGFR increased significantly from 62.0 (IQR 55.5-65.0) to 69.0 (IQR 55.0-76.5) mL/min/1.73 m2 (p=0.002). Median albumin/creatinine ratio (n=26) remained within the normal range (<3 mg/mmol). The effect on eGFR was similar after exclusion of patients in whom medication was changed (median eGFR 62.0 ((IQR 59.5-66.0) to 69.0 (IQR 60.0-77.0) mL/min/1.73 m2, p=0.006, n=29), suggesting that the effect on eGFR is not related to medication changes. At 12 months, eGFR was not significantly changed (n=22, median eGFR 63.5 mL/min/1.73 m2 (IQR 58.5-71.0), p=0.067). Conclusions: The retrospective nature of this study and the despite guidelines limited availability of renal markers in routine type 2 diabetes care are limiting. Nevertheless, these data support a favourable effect of RD2N on renal function. Further research, with proper documentation of renal function, urinary protein excretion and dietary intake, is needed to substantiate these results, ideally in a large-scale prospective cohort study.

Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH.

CONTEXT: Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear. OBJECTIVE: Based on the hypothesis that TSH may inhibit bone resorption, we explored whether offspring of long-lived families have lower bone turnover than controls at baseline as well as following a challenge with recombinant human TSH (rhTSH). METHODS: Bone turnover markers CTX and P1NP were measured in fasted morning samples from 14 offspring and 12 controls at baseline and at 24 hour intervals following 0.1 mg rhTSH i.m. administration for four consecutive days. RESULTS: At baseline, mean (SEM) CTX was 0.32 (0.03) ng/ml in offspring and 0.50 (0.04) ng/ml in controls, p < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, p < 0.01. Following rhTSH administration, both CTX and P1NP levels transiently increased over time and normalized towards baseline after 72 h (general linear modelling: CTX time p = 0.01, P1NP time p < 0.01); the response was similar between offspring and controls. CONCLUSIONS: Bone turnover markers were lower at baseline in offspring from long-lived families than in controls but increased similarly following an rhTSH challenge.

The Effect of a Lifestyle Intervention on Type 2 Diabetes Pathophysiology and Remission: The Stevenshof Pilot Study.

Although lifestyle interventions can lead to diabetes remission, it is unclear to what extent type 2 diabetes (T2D) remission alters or improves the underlying pathophysiology of the disease. Here, we assess the effects of a lifestyle intervention on T2D reversal or remission and the effects on the underlying pathology. In a Dutch primary care setting, 15 adults with an average T2D duration of 13.4 years who were (pharmacologically) treated for T2D received a diabetes subtyping ("diabetyping") lifestyle intervention (DLI) for six months, aiming for T2D remission. T2D subtype was determined based on an OGTT. Insulin and sulphonylurea (SU) derivative treatment could be terminated for all participants. Body weight, waist/hip ratio, triglyceride levels, HbA1c, fasting, and 2h glucose were significantly improved after three and six months of intervention. Remission and reversal were achieved in two and three participants, respectively. Indices of insulin resistance and beta cell capacity improved, but never reached healthy values, resulting in unchanged T2D subtypes. Our study implies that achieving diabetes remission in individuals with a longer T2D duration is possible, but underlying pathology is only minimally affected, possibly due to an impaired beta cell function. Thus, even when T2D remission is achieved, patients need to continue adhering to lifestyle therapy.

Soluble mannose receptor induces proinflammatory macrophage activation and metaflammation.

Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB-mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.

Tumor-stroma ratio is associated with Miller-Payne score and pathological response to neoadjuvant chemotherapy in HER2-negative early breast cancer.

The tumor-stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma-low tumors. Since the role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown, this association was evaluated for HER2-negative breast cancer in the prospective DIRECT and NEOZOTAC trials. The TSR was assessed on 375 hematoxylin and eosin-stained sections of pre-treatment biopsies. Associations between the TSR and chemotherapy response according to the Miller-Payne (MP) grading system, and between the TSR and pathological response were examined using Pearson's chi-square, Cochran-Armitage test for trend and regression analyses. A stroma-low tumor prior to neoadjuvant chemotherapy was significantly associated with a higher MP score (P = .005). This relationship remained significant in the estrogen receptor (ER)-negative subgroup (P = .047). The univariable odds ratio (OR) of a stroma-low tumor on pathological complete response (pCR) was 2.46 (95% CI 1.34-4.51, P = .004), which attenuated to 1.90 (95% CI 0.85-4.25, P = .119) after adjustment for relevant prognostic factors. Subgroup analyses revealed an OR of 5.91 in univariable analyses for ER-negativity (95% CI 1.19-29.48, P = .030) and 1.48 for ER-positivity (95% CI 0.73-3.01, P = .281). In conclusion, a low amount of stroma on pre-treatment biopsies is associated with a higher MP score and pCR rate. Therefore, the TSR is a promising biomarker in predicting neoadjuvant treatment outcome. Incorporating this parameter in routine pathological diagnostics could be worthwhile to prevent overtreatment and undertreatment.

Increased stress, weight gain and less exercise in relation to glycemic control in people with type 1 and type 2 diabetes during the COVID-19 pandemic.

INTRODUCTION: Lockdown measures have a profound effect on many aspects of daily life relevant for diabetes self-management. We assessed whether lockdown measures, in the context of the COVID-19 pandemic, differentially affect perceived stress, body weight, exercise and related this to glycemic control in people with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a short-term observational cohort study at the Leiden University Medical Center. People with type 1 and type 2 diabetes ≥18 years were eligible to participate. Participants filled out online questionnaires, sent in blood for hemoglobin A1c (HbA1c) analysis and shared data of their flash or continuous glucose sensors. HbA1c during the lockdown was compared with the last known HbA1c before the lockdown. RESULTS: In total, 435 people were included (type 1 diabetes n=280, type 2 diabetes n=155). An increase in perceived stress and anxiety, weight gain and less exercise was observed in both groups. There was improvement in glycemic control in the group with the highest HbA1c tertile (type 1 diabetes: -0.39% (-4.3 mmol/mol) (p<0.0001 and type 2 diabetes: -0.62% (-6.8 mmol/mol) (p=0.0036). Perceived stress was associated with difficulty with glycemic control (p<0.0001). CONCLUSIONS: An increase in perceived stress and anxiety, weight gain and less exercise but no deterioration of glycemic control occurs in both people with relatively well-controlled type 1 and type 2 diabetes during short-term lockdown measures. As perceived stress showed to be associated with glycemic control, this provides opportunities for healthcare professionals to put more emphasis on psychological aspects during diabetes care consultations.

Brain activity and connectivity changes in response to nutritive natural sugars, non-nutritive natural sugar replacements and artificial sweeteners.

INTRODUCTION: The brain plays an important regulatory role in directing energy homeostasis and eating behavior. The increased ingestion of sugars and sweeteners over the last decades makes investigating the effects of these substances on the regulatory function of the brain of particular interest. We investigated whole brain functional response to the ingestion of nutrient shakes sweetened with either the nutritive natural sugars glucose and fructose, the low- nutritive natural sugar replacement allulose or the non-nutritive artificial sweetener sucralose. METHODS: Twenty healthy, normal weight, adult males underwent functional MRI on four separate visits. In a double-blind randomized study setup, participants received shakes sweetened with glucose, fructose, allulose or sucralose. Resting state functional MRI was performed before and after ingestion. Changes in Blood Oxygen Level Dependent (BOLD) signal, functional network connectivity and voxel based connectivity by Eigenvector Centrality Mapping (ECM) were measured. RESULTS: Glucose and fructose led to significant decreased BOLD signal in the cingulate cortex, insula and the basal ganglia. Glucose led to a significant increase in eigen vector centrality throughout the brain and a significant decrease in eigen vector centrality in the midbrain. Sucralose and allulose had no effect on BOLD signal or network connectivity but sucralose did lead to a significant increase in eigen vector centrality values in the cingulate cortex, central gyri and temporal lobe. DISCUSSION: Taken together our findings show that even in a shake containing fat and protein, the type of sweetener can affect brain responses and might thus affect reward and satiety responses and feeding behavior. The sweet taste without the corresponding energy content of the non-nutritive sweeteners appeared to have only small effects on the brain. Indicating that the while ingestion of nutritive sugars could have a strong effect on feeding behavior, both in a satiety aspect as well as rewarding aspects, non-nutritive sweeteners appear to not have these effects. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov under number NCT02745730.

Quality of life and illness perceptions in patients with breast cancer using a fasting mimicking diet as an adjunct to neoadjuvant chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial.

PURPOSE: In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness perceptions regarding the possible side effects of chemotherapy and the FMD were secondary outcomes of the trial. METHODS: 131 patients with HER2-negative stage II/III breast cancer were recruited, of whom 129 were randomly assigned (1:1) to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and the day of neoadjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires EORTC-QLQ-C30 and EORTC-QLQ-BR23; the Brief Illness Perception Questionnaire (BIPQ) and the Distress Thermometer were used to assess these outcomes at baseline, halfway chemotherapy, before the last cycle of chemotherapy and 6 months after surgery. RESULTS: Overall QoL and distress scores declined during treatment in both arms and returned to baseline values 6 months after surgery. However, patients' perceptions differed slightly over time. In particular, patients receiving the FMD were less concerned and had better understanding of the possible adverse effects of their treatment in comparison with patients on a regular diet. Per-protocol analyses yielded better emotional, physical, role, cognitive and social functioning scores as well as lower fatigue, nausea and insomnia symptom scores for patients adherent to the FMD in comparison with non-adherent patients and patients on their regular diet. CONCLUSIONS: FMD as an adjunct to neoadjuvant chemotherapy appears to improve certain QoL and illness perception domains in patients with HER2-negative breast cancer. Trialregister ClinicalTrials.gov Identifier: NCT02126449.