Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial.

BACKGROUND: One-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant depression (TRD). Some case reports suggest that ketogenic diets (KDs) may improve some mental illnesses, and preclinical data indicate that KDs can influence brain reward signalling, anhedonia, cortisol, and gut microbiome which are associated with depression. To date, no trials have examined the clinical effect of a KD on TRD. METHODS: This is a proof-of-concept randomised controlled trial to investigate the efficacy of a six-week programme of weekly dietitian counselling plus provision of KD meals, compared with an intervention involving similar dietetic contact time and promoting a healthy diet with increased vegetable consumption and reduction in saturated fat, plus food vouchers to purchase healthier items. At 12 weeks we will assess whether participants have continued to follow the assigned diet. The primary outcome is the difference between groups in the change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 6 weeks. PHQ-9 will be measured at weeks 2, 4, 6 and 12. The secondary outcomes are the differences between groups in the change in remission of depression, change in anxiety score, functioning ability, quality of life, cognitive performance, reward sensitivity, and anhedonia from baseline to 6 and 12 weeks. We will also assess whether changes in reward sensitivity, anhedonia, cortisol awakening response and gut microbiome may explain any changes in depression severity. DISCUSSION: This study will test whether a ketogenic diet is an effective intervention to reduce the severity of depression, anxiety and improve quality of life and functioning ability for people with treatment-resistant depression.

Developing an intervention to support dietary change for shift workers living with type 2 diabetes: A stakeholder consultation.

BACKGROUND: Shift workers, compared to day workers, are more likely to be diagnosed with type 2 diabetes (T2D). Currently, there is no tailored programme of dietary support available to either shift workers living with T2D or employers. METHODS: An intervention development consultation workshop was convened in June 2023 with the aim of evaluating potential interventions to identify those with a potential to take forward for further development. Findings from prior formative research into factors influencing dietary behaviour in shift workers with T2D were mapped to potential interventions addressing the barriers and enablers to healthy eating reported by shift workers with T2D. The findings of the Shift-Diabetes Study were presented in the context of the COM-B (Capability, Opportunity, Motivation, Behaviour) theoretical framework of behaviour change. Three interventions in turn were presented to attendees: (1) Educational resources and structured education, (2) Increasing availability and accessibility of food on a night shift and (3) Biofeedback and tailored advice. Seven workshop attendees were invited to express their thoughts, using the APEASE criteria (Affordability, Practicability, Effectiveness, Acceptability, Side-effects/Safety, Equity) to guide the discussion. The workshop was conducted online and recorded, and transcripts were thematically coded to the APEASE framework. RESULTS/CONCLUSIONS: The workshop highlighted the importance of multilevel interventions to support dietary behaviour change in this occupational group. Priority actions identified include (i) understanding barriers to 24/7 food availability, (ii) including shift workers in clinical diabetes studies and (iii) research to understand the effectiveness of continuous glucose monitoring in shift workers with T2D.

Identifying Preferred Features of Weight Loss Programs for Adults With or at Risk of Type 2 Diabetes: A Discrete Choice Experiment With 3,960 Adults in the U.K.

OBJECTIVE: To understand preferences for features of weight loss programs among adults with or at risk of type 2 diabetes in the U.K. RESEARCH DESIGN AND METHODS: We conducted a discrete choice experiment with 3,960 U.K. adults living with overweight (n = 675 with type 2 diabetes). Preferences for seven characteristics of weight loss programs were analyzed. Simulations from choice models using the experimental data predicted uptake of available weight loss programs. Patient groups comprising those who have experience with weight loss programs, including from minority communities, informed the experimental design. RESULTS: Preferences did not differ between individuals with and without type 2 diabetes. Preferences were strongest for type of diet. Healthy eating was most preferred relative to total diet replacement (odds ratio [OR] 2.24; 95% CI 2.04-2.44). Individual interventions were more popular than group interventions (OR 1.40; 95% CI 1.34-1.47). Participants preferred programs offering weight loss of 10-15 kg (OR 1.37; 95% CI 1.28-1.47) to those offering loss of 2-4 kg. Online content was preferred over in-person contact (OR 1.24; 95% CI 1.18-1.30). There were few differences in preferences by gender or ethnicity, although weight loss was more important to women than to men, and individuals from ethnic minority populations identified more with programs where others shared their characteristics. Modeling suggested that tailoring programs to individual preferences could increase participation by ∼17 percentage points (68% in relative terms). CONCLUSIONS: Offering a range of weight loss programs targeting the preferred attributes of different patient groups could potentially encourage more people to participate in weight loss programs and support those living with overweight to reduce their weight.

Exploration of the individual, social and environmental factors influencing dietary behaviour in shift workers with type 2 diabetes working in UK healthcare-The Shift-Diabetes Study: A qualitative study using the theoretical domains framework.

AIM: To identify factors influencing dietary behaviour in shift workers with type 2 diabetes (T2D) working in UK healthcare settings. METHODS: Semi-structured qualitative interviews based on the theoretical domains framework (TDF) were conducted with a convenience sample (n = 15) of shift workers (32-59 years) diagnosed with T2D who worked night shifts as part of a mixed shift schedule. The TDF was applied to analyse transcripts using a combined deductive framework and inductive thematic analysis approach. Identified influences were mapped to the behaviour change technique taxonomy to identify potential strategies to change dietary behaviour in this context. RESULTS: Key barriers to healthy dietary behaviours were access and cost of food available during night work (TDF domain: Environment Context and Resources). Factors identified as both enablers and barriers included: availability of staff facilities and time to take a break, (Environment Context and Resources), the physical impact of night work (Beliefs About Consequences), eating in response to stress or tiredness (Emotion), advance planning of meals/food and taking own food to work (Behavioural Regulation). Potential techniques to address these influences and improve dietary behaviour in this context include: meal planning templates, self-monitoring and biofeedback, and increasing accessibility and availability of healthier food choices during night shifts. CONCLUSIONS: The dietary behaviour of shift workers with T2D is influenced by interacting individual, socio-cultural and environmental factors. Intervention should focus on environmental restructuring and strategies that enable monitoring and meal planning.

Amino acid-stimulated insulin secretion: a path forward in type 2 diabetes.

Qualitative and quantitatively appropriate insulin secretion is essential for optimal control of blood glucose. Beta-cells of the pancreas produce and secrete insulin in response to glucose and non-glucose stimuli including amino acids. In this manuscript, we review the literature on amino acid-stimulated insulin secretion in oral and intravenous in vivo studies, in addition to the in vitro literature, and describe areas of consensus and gaps in understanding. We find promising evidence that the synergism of amino acid-stimulated insulin secretion could be exploited to develop novel therapeutics, but that a systematic approach to investigating these lines of evidence is lacking. We highlight evidence that supports the relative preservation of amino acid-stimulated insulin secretion compared to glucose-stimulated insulin secretion in type 2 diabetes, and make the case for the therapeutic potential of amino acids. Finally, we make recommendations for research and describe the potential clinical utility of nutrient-based treatments for type 2 diabetes including remission services.

Individual, social and environmental factors influencing dietary behaviour in shift workers with type 2 diabetes working in UK healthcare: A cross-sectional survey.

BACKGROUND: The present study aimed to understand the individual, social and environmental factors influencing dietary behaviour in shift workers with type 2 diabetes (T2D) working in UK healthcare settings. METHODS: A cross-sectional study was conducted using data collected from an anonymous online survey. Participant agreement was measured using five-point Likert scale (strongly disagree to strongly agree) against 38 belief statements informed by the Theoretical Domains Framework (TDF) of behaviour change. RESULTS: From the complete responses (n = 119), 65% worked shifts without nights, 27% worked mixed shift rota including nights and 8% worked only night shifts. The statements ranked with the highest agreements were in the TDF domains: Environment Context/Resources (ECR) - mainly identified as a barrier to healthy eating, Behaviour Regulation (BR) and intention (IN) - identified as enablers to healthy eating. For the belief statement 'the available options for purchasing food are too expensive' (ECR), 80% of night workers and 75% non-night workers agreed/strongly agreed. Taking their own food to work to prevent making unhealthy food choices (BR) had agreement/strong agreement in 73% of non-night and 70% night workers; 74% non-night workers and 80% of night workers agreed/strongly agreed with the statement 'I would like to eat healthily at work' (IN). Mixed shift workers agreed that following dietary advice was easier when working a non-night compared to a night shift (p = 0.002). CONCLUSIONS: Access and affordability of food were identified as important determinants of dietary behaviour during shifts. The findings support interventions targeting the food environment for shift workers with T2D.

A Cross-Sectional Analysis of Products Marketed as Plant-Based Across the United States, United Kingdom, and Canada Using Online Nutrition Information.

Background: The food industry is responding to a rising demand for plant-based foods by developing and marketing an ever-wider range of vegan and vegetarian products under the banner of "plant-based." Understanding the nutritional properties of these products is critical. Objectives: To assess the number, meal type, and nutritional content of products marketed as plant-based (MaPB) from the perspective of the consumer across multiple sectors in the United States, United Kingdom, and Canada. Methods: An online search for products MaPB was performed across supermarkets, restaurants, food manufacturers, and plant-based meal delivery companies in the United Kingdom, the United States, and Canada using the terms: "vegan," "vegetarian," and "plant-based." Online nutrition data were extracted, and whole meals that comprised >50% of ingredients such as fruits, vegetables, legumes, nuts, and seeds were identified. The nutritional content of dishes MaPB in restaurants was also directly compared with meat-containing dishes. Results: Further, 3488 unique products were identified, of which 962 were whole meals and 1137 were a replacement for the main protein component in a meal, including 771 meat alternatives. Across all sectors, 45% of whole meals had >15-g protein, 70% had <10% kcal from saturated fat; 29% had >10-g fiber per meal, and 86% had <1000 mg sodium. At restaurants, 1507 meat-containing dishes were identified and compared with 191 vegetarian and 81 vegan dishes. The meat-containing dishes were higher in protein [35.4 g (24.0-51.4)] compared with vegetarian [19.0 g (13.0-26.1)] and vegan [16.2 g (10.5-23.2) dishes (P < 0.001)]. The vegan dishes were low in saturated fat and sodium (SFA: 6.3 g ± 6.4, Sodium: 800 mg (545.0-1410.0) compared with both meat [SFA: 11.6 g ± 10.0; Sodium: 1280 mg (820.0-1952.0)] and vegetarian [SFA: 9.4 g ± 7.6; Sodium: 1011 mg (603.0-1560.0)] options (P < 0.001 for all comparisons). Conclusions: Products MaPB tend to have lower concentrations of saturated fat and sodium than their meat-containing counterparts, but improvements are needed to optimize their nutritional composition.

A randomised crossover trial: Exploring the dose-response effect of carbohydrate restriction on glycaemia in people with well-controlled type 2 diabetes.

BACKGROUND: Trials investigating the role of carbohydrate restriction in the management of glycaemia in type 2 diabetes (T2D) have been confounded by multiple factors, including degree of calorie restriction and dietary protein content, as well as by no clear definition of a low-carbohydrate diet. The present study aimed to provide insight into the relationship between carbohydrate restriction and glycaemia by testing the effect of varying doses of carbohydrate on continuous glucose concentrations within a range of intakes defined as low-carbohydrate at the same time as controlling for confounding factors. METHODS: This was a randomised crossover trial in participants with T2D (HbA1c: 6.6 ± 0.6%, 49 ± 0.9 mmol mol-1 ) testing five different 6-day eucaloric dietary treatments with varying carbohydrate content (10%, 15%, 20%, 25%, and 30% kcal). Diets exchanged %kcal from carbohydrate with fat, keeping protein constant at 15% kcal. Daily self-weighing was employed to ensure weight stability throughout each treatment arm. Between dietary treatments, participants underwent a washout period of at least 7 days and were advised to maintain their habitual diet. Glycaemic control was assessed using a continuous glucose monitoring device. RESULTS: Twelve participants completed the study. There were no differences in 24-h and post-prandial sensor glucose concentrations between the 30 and 10%kcal doses (7.4 ± 1.1 mmol L-1 vs. 7.6 ± 1.3 mmol L-1 [p = 0.28] and 8.1 ± 1.5 mmol L-1 vs. 8.5 ± 1.4 mmol L-1 [p = 0.28], respectively). In our exploratory analyses, we did not find any dose-response relationship between carbohydrate intake and glycaemia. A small amount of weight loss occurred in each treatment arm (range: 0.4-1.1 kg over the 6 days) but adjusting for these differences did not influence the primary or secondary outcomes. CONCLUSIONS: Modest changes in dietary carbohydrate content in the absence of weight loss at the same time as keeping dietary protein intake constant do not appear to influence glucose concentrations in people with well-controlled T2D. SUMMARY: This study randomised people with T2D to receive five different doses of carbohydrate from 10% to 30% of calories in random order to see what effect it had on their blood glucose.

Remission of type 2 diabetes: Perspectives of dietitians in Kuwait.

Although many dietary and lifestyle interventions have been proposed, the concept of total dietary replacement (TDR) to achieve remission of type 2 diabetes in the Gulf region is new. With the high levels of obesity and type 2 diabetes in the region, offering TDR to patients for weight loss and remission of type 2 diabetes would assist in achieving health outcomes. The aim of the current study was to explore and understand remission of type 2 diabetes and TDR from the perspectives of dietitians to identify challenges and recommend solutions for implementation in Kuwait. A qualitative approach utilizing focus groups was chosen to explore the topic. Purposive sampling was used to gain experiences from a diverse sample across primary, secondary, and tertiary specialized diabetes centers. Discussions were audio-recorded and transcribed verbatim. Grounded theory using an iterative approach was applied to analyze the data. Three focus groups with a total of 17 participants achieved data saturation. The sample was varied in terms of workplace and years of experience. The three emerging themes were motivation to use the TDR approach, perceived challenges of TDR, and suggestions to improve and adapt approaches for Kuwait. Dietitians reported that remission of type 2 diabetes is a great motivator for patients to undergo TDR, although various factors were identified that may affect uptake including age, level of education, and social and cultural environment. By understanding dietitians' perspectives, it has provided insight on views regarding the implementation of TDR to achieve remission in Kuwait and how best to tailor approaches by focusing on patient support needs and adopting a flexible approach.

A Mobile Phone App for the Prevention of Type 2 Diabetes in Malaysian Women With Gestational Diabetes Mellitus: Protocol for a Feasibility Randomized Controlled Trial.

BACKGROUND: Over 50% of women with a history of gestational diabetes mellitus (GDM) will develop type 2 diabetes (T2D) in later life. Asian women experience a disproportionate risk of both GDM and T2D compared to women from other ethnic backgrounds. Lifestyle interventions and behavior change can delay or even prevent the onset of T2D. We have developed a digitalized diabetes prevention intervention for the prevention of T2D in Malaysian women with GDM. OBJECTIVE: The protocol describes a randomized controlled trial (RCT) to test the feasibility of undertaking a definitive trial of a diabetes prevention intervention, including a smartphone app and group support. Secondary aims are to summarize anthropometric, biomedical, psychological, and lifestyle outcomes overall and by allocation group, and to undertake a process evaluation. METHODS: This is a two-arm parallel feasibility RCT. A total of 60 Malaysian women with GDM will be randomized in the antenatal period to receive the intervention or standard care until 12 months post partum. The intervention is a diabetes prevention intervention delivered via a smartphone app developed based on the Information-Motivation-Behavioral Skills model of behavior change and group support using motivational interviewing. The intervention provides women with tailored information and support to encourage weight loss through adapted dietary intake and physical activity. Women in the control arm will receive standard care. The Malaysian Ministry of Health's Medical Research and Ethics Committee has approved the trial (NMRR-21-1667-60212). RESULTS: Recruitment and enrollment began in February 2022. Future outcomes will be published in peer-reviewed health-related research journals and presented at national, regional, or state professional meetings and conferences. This publication is based on protocol version 2, January 19, 2022. CONCLUSIONS: To our knowledge, this will be the first study in Malaysia that aims to determine the feasibility of a digital intervention in T2D prevention among women with GDM. Findings from this feasibility study will inform the design of a full-scale RCT in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT05204706; https://clinicaltrials.gov/ct2/show/NCT05204706. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37288.

Reversal and Remission of T2DM - An Update for Practitioners.

Over the past 50 years, many countries around the world have faced an unchecked pandemic of obesity and type 2 diabetes (T2DM). As best practice treatment of T2DM has done very little to check its growth, the pandemic of diabesity now threatens to make health-care systems economically more difficult for governments and individuals to manage within their budgets. The conventional view has been that T2DM is irreversible and progressive. However, in 2016, the World Health Organization (WHO) global report on diabetes added for the first time a section on diabetes reversal and acknowledged that it could be achieved through a number of therapeutic approaches. Many studies indicate that diabetes reversal, and possibly even long-term remission, is achievable, belying the conventional view. However, T2DM reversal is not yet a standardized area of practice and some questions remain about long-term outcomes. Diabetes reversal through diet is not articulated or discussed as a first-line target (or even goal) of treatment by any internationally recognized guidelines, which are mostly silent on the topic beyond encouraging lifestyle interventions in general. This review paper examines all the sustainable, practical, and scalable approaches to T2DM reversal, highlighting the evidence base, and serves as an interim update for practitioners looking to fill the practical knowledge gap on this topic in conventional diabetes guidelines.

Could Dietary Modification Independent of Energy Balance Influence the Underlying Pathophysiology of Type 2 Diabetes? Implications for Type 2 Diabetes Remission.

High-quality clinical trial data demonstrate that remission is possible for people living with type 2 diabetes (T2D) if they lose a large amount of weight (≥ 10 kg). Durable remission appears predicated on the long-term maintenance of weight loss. Unfortunately, long-term follow-up data from lifestyle-based weight loss programmes show that, on average, most people regain at least some of the weight lost. In addition, restoration of a diminished first-phase insulin response also appears necessary for durable remission, and this becomes less likely as T2D progresses. A pragmatic approach to enhance the effects of weight loss on durable remission is to consider whether dietary components could help control blood glucose, independent of caloric balance. This manuscript reviews current evidence on weight-neutral effects of diet on blood glucose, including high-protein, low-carbohydrate, high-fibre and plant-based diets, with a particular focus on the effect of nutrition on the underlying pathophysiology of T2D, including the first-phase insulin response. The importance of mechanistic data in enhancing our understanding of dietary strategies in T2D remission is described, and suggestions are made for future advances in remission research.

Towards targeted dietary support for shift workers with type 2 diabetes (Shift-Diabetes study): A mixed-methods case study protocol.

BACKGROUND: Blood glucose is higher in people working night shifts compared to day workers. Changes to eating behaviour, activity and sleep patterns in addition to circadian disruption are likely to impact glucose management in night-shift workers with type 2 diabetes. AIM: To investigate current dietary intake and glucose variability during night work, including barriers and facilitators to dietary behaviour in this context. METHODS: A mixed-methods case study will be conducted. Shift workers with type 2 diabetes working in a hospital setting will be recruited to this two-part study. Part 1: 70 participants will complete a 10-day observational study collecting data on continuous glucose, diet (self-report diary), sleep and physical activity during a period covering night work, rest days and non-night workdays. Mean glucose concentration and variability, and the mean healthy diet index score, will be compared between days of night work, non-night work and rest, after adjusting for other individual factors (sleep/physical activity/demographics). Part 2: A sample (n~13) will complete semi-structured interviews based on behavioural science frameworks to explore barriers/enablers to dietary behaviour when working night shifts. This will inform a quantitative survey to explore the generalisability of interview findings. DISCUSSION: Findings from Part 1 and 2 will be triangulated to identify potential intervention strategies to address key barriers and enablers to healthier eating, and in turn improved glucose control, in shift workers with type 2 diabetes. This will be facilitated through stakeholder consultation and application of behavioural science frameworks. Shift-Diabetes study registration: ISRCTN11764942.

Renal function in patients following a low carbohydrate diet for type 2 diabetes: a review of the literature and analysis of routine clinical data from a primary care service over 7 years.

PURPOSE OF REVIEW: People with T2 Diabetes (T2D) who follow a low carbohydrate diet (LCD) may increase their dietary protein intake. Dietary protein can modulate renal function so there is debate about its role in renal disease. There is concern that higher protein intakes may promote renal damage, and that LCDs themselves may impact on cardiovascular risk. We review the evidence around LCDs, renal and cardiovascular risk factors and compare to results obtained in a real-world, primary care setting. RECENT FINDINGS: Chronic kidney disease (CKD) is a well-recognised microvascular complication of T2D caused in part by; chronically increased glomerular pressure, hyperfiltration, increased blood pressure and advanced glycation end products. Hyperglycemia can be seen as central to all of these factors. A LCD is an effective first step in its correction as we demonstrate in our real-world cohort. SUMMARY: We found evidence that LCDs for people with T2D may improve many renal and cardiovascular risk factors. In our own LCD cohort of 143 patients with normal renal function or only mild CKD, over an average of 30 months the serum creatinine improved by a significant mean of 4.7 (14.9) µmol/L. What remains to be shown is the effect of the approach on people with T2D and moderate/severe CKD.

Protocol for a qualitative study exploring the perception of need, importance and acceptability of a digital diabetes prevention intervention for women with gestational diabetes mellitus during and after pregnancy in Malaysia (Explore-MYGODDESS).

INTRODUCTION: Women who develop gestational diabetes mellitus (GDM) have an increased risk of developing type 2 diabetes, and to reduce this risk the women have to adopt healthy behaviour changes. Although previous studies have explored the challenges and facilitators to initiate behaviour change among women with GDM, there is limited data from Malaysian women. Thus, this study will explore the factors affecting the uptake of healthy behaviour changes and the use of digital technology among women and their healthcare providers (HCPs) to support healthy behaviour changes in women with GDM. METHODS AND ANALYSIS: The study will be modelled according to the Capability, Opportunity, Motivation and Behaviour and Behaviour Change Wheel techniques, and use the DoTTI framework to identify needs, solutions and testing of a preliminary mobile app, respectively. In phase 1 (design and development), a focus group discussion (FGDs) of 5-8 individuals will be conducted with an estimated 60 women with GDM and 40 HCPs (doctors, dietitians and nurses). Synthesised data from the FGDs will then be combined with content from an expert committee to inform the development of the mobile app. In phase 2 (testing of early iterations), a preview of the mobile app will undergo alpha testing among the team members and the app developers, and beta testing among 30 women with GDM or with a history of GDM, and 15 HCPs using semi-structured interviews. The outcome will enable us to optimise an intervention using the mobile app as a diabetes prevention intervention which will then be evaluated in a randomised controlled trial. ETHICS AND DISSEMINATION: The project has been approved by the Malaysia Research Ethics Committee. Informed consent will be obtained from all participants. Outcomes will be presented at both local and international conferences and submitted for publications in peer-reviewed journals.

Does high dietary protein intake contribute to the increased risk of developing prediabetes and type 2 diabetes?

Insulin resistance is a complex metabolic disorder implicated in the development of many chronic diseases. While it is generally accepted that body mass loss should be the primary approach for the management of insulin resistance-related disorders in overweight and obese individuals, there is no consensus among researchers regarding optimal protein intake during dietary restriction. Recently, it has been suggested that increased plasma branched-chain amino acids concentrations are associated with the development of insulin resistance and type 2 diabetes. The exact mechanism by which excessive amino acid availability may contribute to insulin resistance has not been fully investigated. However, it has been hypothesised that mammalian target of rapamycin (mTOR) complex 1 hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake because of insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. In addition, the long-term effects of high-protein diets on insulin sensitivity during both weight-stable and weight-loss conditions require more research. This review focusses on the effects of high-protein diets on insulin sensitivity and discusses the potential mechanisms by which dietary amino acids can affect insulin signalling. Novelty: Excess amino acids may over-activate mTOR, resulting in desensitisation of IRS-1 and reduced insulin-mediated glucose uptake.

Correction to: Protocol for a randomised controlled trial to investigate the effect of home- and gym-based resistance exercise training on glycaemic control, body composition and muscle strength.

An amendment to this paper has been published and can be accessed via the original article.