The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT).

AIMS/HYPOTHESIS: High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. METHODS: We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. RESULTS: Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. CONCLUSIONS/INTERPRETATION: We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes. DATA AVAILABILITY: The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .

Aetiology of Type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis.

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to ß cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on ß-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of ß-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Physical activity, inactivity and sleep during the Diabetes Remission Clinical Trial (DiRECT).

AIMS: As sustained weight loss is vital for achieving remission of type 2 diabetes, we explored whether randomisation to weight loss plus maintenance in the DiRECT trial was associated with physical activity, inactivity or sleep. METHODS: Participants were randomised to either a dietary weight management programme or best-practice care. The weight management group were encouraged to increase daily physical activity to their sustainable maximum. Objective measurement was achieved using a wrist-worn GENEActiv accelerometer for 7 days at baseline, 12 and 24 months in both groups. RESULTS: Despite average weight loss of 10 kg at 12 months in the intervention (n = 66) group, there were no differences in total physical activity or inactivity compared with the control (n = 104) at any time point. However, in our exploratory analysis, those who lost more than 10% of their baseline body weight performed on average 11 mins/day more light activity than the <10% group at 24 months (p = 0.033) and had significantly lower bouts of Inactivity30min (interaction, p = 0.005) across 12 and 24 months. At 24 months, the ≥10% group had higher daily acceleration (38.5 ± 12.1 vs. 33.2 ± 11.1 mg, p = 0.020), and higher accelerations in the most active 5-hour period (59.4 ± 21.8 vs. 50.6 ± 18.3 mg, p = 0.023). Wakefulness after sleep onset decreased in the intervention group compared with the control group and also in the ≥10% weight loss group at 12 and 24 months. CONCLUSIONS: Randomisation to a successful intensive weight loss intervention, including regular physical activity encouragement, was not associated with increased physical activity although sleep parameters improved. Physical activity was greater, and night-time waking reduced in those who maintained >10% weight loss at 12 and 24 months. TRIAL REGISTRATION ISRCTN03267836.

Sex differences in intraorgan fat levels and hepatic lipid metabolism: implications for cardiovascular health and remission of type 2 diabetes after dietary weight loss.

AIMS/HYPOTHESIS: Type 2 diabetes confers a greater relative increase in CVD risk in women compared with men. We examined sex differences in intraorgan fat and hepatic VLDL1-triacylglycerol (VLDL1-TG) export before and after major dietary weight loss. METHODS: A group with type 2 diabetes (n = 64, 30 male/34 female) and a group of healthy individuals (n = 25, 13 male/12 female) were studied. Intraorgan and visceral fat were quantified by magnetic resonance and VLDL1-TG export by intralipid infusion techniques. RESULTS: Triacylglycerol content of the liver and pancreas was elevated in people with diabetes with no sex differences (liver 16.4% [9.3-25.0%] in women vs 11.9% [7.0-23.1%] in men, p = 0.57, and pancreas 8.3 ± 0.5% vs 8.5 ± 0.4%, p = 0.83, respectively). In the absence of diabetes, fat levels in both organs were lower in women than men (1.0% [0.9-1.7%] vs 4.5% [1.9-8.0%], p = 0.005, and 4.7 ± 0.4% vs 7.6 ± 0.5%, p< 0.0001, respectively). Women with diabetes had higher hepatic VLDL1-TG production rate and plasma VLDL1-TG than healthy women (559.3 ± 32.9 vs 403.2 ± 45.7 mg kg-1 day-1, p = 0.01, and 0.45 [0.26-0.77] vs 0.25 [0.13-0.33] mmol/l, p = 0.02), whereas there were no differences in men (548.8 ± 39.8 vs 506.7 ± 29.2 mg kg-1 day-1, p = 0.34, and 0.72 [0.53-1.15] vs 0.50 [0.32-0.68] mmol/l, p = 0.26). Weight loss decreased intraorgan fat and VLDL1-TG production rates regardless of sex, and these changes were accompanied by similar rates of diabetes remission (65.4% vs 71.0%) and CVD risk reduction (59.8% vs 41.5%) in women and men, respectively. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, women have liver and pancreas fat levels as high as those of men, associated with raised hepatic VLDL1-TG production rates. Dynamics of triacylglycerol turnover differ between sexes in type 2 diabetes and following weight loss. These changes may contribute to the disproportionately raised cardiovascular risk of women with diabetes.

Delivering the Diabetes Remission Clinical Trial (DiRECT) in primary care: Experiences of healthcare professionals.

OBJECTIVE: The Diabetes Remission Clinical Trial (DiRECT) used a formula total diet replacement programme followed by structured weight loss maintenance to induce and sustain weight loss and remission of type 2 diabetes (T2D) in 36% of participants after 2 years. Nurses and dietitians delivering DiRECT in 22 primary care practices in Tyneside and Scotland provided behavioural support to participants. Participant experiences with DiRECT highlighted the key role of support by healthcare professionals (HCPs). We evaluated HCPs' experiences with DiRECT. RESEARCH DESIGN AND METHODS: Healthcare professionals delivering DiRECT were interviewed at 12 months, while general practices (GPs) were sent an implementation questionnaire. The interviews were analysed thematically. The questionnaires were analysed using frequencies and a narrative synthesis. RESULTS: Healthcare professionals representing 11 of 22 intervention practices were interviewed and 10 of 22 GPs completed questionnaires. HCPs' initial concerns over perceived potential negative intervention effects, particularly withdrawing anti-diabetes and anti-hypertensive medications, were barriers to engagement. Trust of HCPs towards the research team and perceived credibility of the study facilitated engagement and adoption. Ongoing support by research dietitians was key to the management of participants. Involvement in DiRECT inspired more focus on behaviour modification in the treatment of other people living with T2D in routine practice. CONCLUSIONS: Diabetes Remission Clinical Trial was considered highly appropriate for the management of T2D in primary care when supported by trained dietitians. Addressing limitations, including varying training needs of HCPs may improve intervention scale-up and tailoring to clinical contexts.

Consensus report: Definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Participant experiences in the Diabetes REmission Clinical Trial (DiRECT).

INTRODUCTION: The Diabetes REmission Clinical Trial (DiRECT) has shown that sustained remission of type 2 diabetes in primary care is achievable through weight loss using total diet replacement (TDR) with continued behavioural support. Understanding participants' experiences can help optimise the intervention, support implementation into healthcare, and understand the process of behaviour change. METHODS: Thirty-four DiRECT participants were recruited into this embedded qualitative evaluation study. In-person and telephone interviews were conducted before the TDR; at week 6-8 of the TDR; 2 weeks into food reintroduction (FR); and at 1 year, to learn about participant experiences with the programme. Transcribed narratives were analysed thematically, and we used interpretation to develop overarching themes. RESULTS: Initiation of the TDR and transition to FR were challenging and required increased behavioural support. In general, adhering to TDR proved easier than the participants had anticipated. Some participants chose the optional extension of TDR. Rapid weight loss and changes in diabetes markers provided ongoing motivation. Further weight loss, behavioural support and occasional use of TDR facilitated weight loss maintenance (WLM). A process of behaviour adaptation to change following regime disruption was identified in three stages: (1) expectations of the new, (2) overcoming difficulties with adherence, and (3) acceptance of continuous effort and establishment of routines. CONCLUSIONS: The DiRECT intervention was acceptable and regularity, continuity, and tailoring of behavioural support was instrumental in its implementation in primary care. The adaptation process accounts for some of the individual variability of experiences with the intervention and highlights the need for programme flexibility.

Lower carbohydrate diets for adults with type 2 diabetes.

In May 2021, the Scientific Advisory Committee on Nutrition (SACN) published a risk assessment on lower carbohydrate diets for adults with type 2 diabetes (T2D)(). The purpose of the report was to review the evidence on 'low'-carbohydrate diets compared with the current UK government advice on carbohydrate intake for adults with T2D. However, since there is no agreed and widely utilised definition of a 'low'-carbohydrate diet, comparisons in the report were between lower and higher carbohydrate diets. SACN's remit is to assess the risks and benefits of nutrients, dietary patterns, food or food components for health by evaluating scientific evidence and to make dietary recommendations for the UK based on its assessment(). SACN has a public health focus and only considers evidence in healthy populations unless specifically requested to do otherwise. Since the Committee does not usually make recommendations relating to clinical conditions, a joint working group (WG) was established in 2017 to consider this issue. The WG comprised members of SACN and members nominated by Diabetes UK, the British Dietetic Association, Royal College of Physicians and Royal College of General Practitioners. Representatives from NHS England and NHS Health Improvement, the National Institute for Health and Care Excellence and devolved health departments were also invited to observe the WG. The WG was jointly chaired by SACN and Diabetes UK.

Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT).

AIMS/HYPOTHESIS: Our aim was to evaluate the safety and efficacy of a planned therapeutic withdrawal of all antihypertensive and diuretic medications, on commencing a formula low-energy diet replacement, targeting remission of type 2 diabetes. METHODS: Post hoc analysis of changes in BP, antihypertensive medication prescriptions and symptoms during the initial total diet replacement phase was performed in the intervention arm of the Diabetes Remission Clinical Trial (n = 143) and in the subset (n = 69) who discontinued antihypertensive medications at the start of total diet replacement. The Counterweight-Plus total diet replacement provided about 3470 kJ/day (830 kcal) with automatic reductions in all nutrients, including sodium, to achieve marked negative energy balance and rapid weight loss over 12-20 weeks, with regular BP monitoring and an antihypertensive reintroduction protocol based on current clinical guidelines. RESULTS: Of 143 intervention group participants who commenced total diet replacement, 78 (55%) were on treatment for hypertension at baseline. The overall mean BP fell significantly from the start of total diet replacement (week 1) and was significantly lower at week 20, after total diet replacement finished, and also at 12 and 24 months. Of the 78 participants previously on treatment for hypertension, 65 (83%) stopped all antihypertensive and diuretic medications as per protocol, and four (5%) stopped some drugs. These 69 participants experienced no immediate (within the first week) change in BP, but their mean BP fell significantly from 9 weeks. No excessive rises in BP were recorded in individuals, but antihypertensive medications were reintroduced during total diet replacement to manage raised BP for 19/69 (27.5%) participants, mostly within the first 3-7 weeks, despite some weight loss. Reintroduction of antihypertensive medications was necessary for 5/19 participants previously on one drug, and for 14/19 previously on two or more drugs. Of the 69 who stopped antihypertensives, 19 (28%) remained off medications at 24 months. Among the 53 participants who achieved sustained remissions of diabetes at 24 months (with a mean weight loss of 11.4 kg), 31 had been previously treated for hypertension. Twenty-seven stopped medication at baseline, and 15/27 required reintroduction of antihypertensive medications. Mild to moderate dizziness, suggesting some postural hypotension, was reported during total diet replacement by 51 participants, 15 of whom had recorded dizziness at baseline prior to starting total diet replacement, with nine of these on antihypertensive or diuretic medications. CONCLUSIONS/INTERPRETATION: Replacing antihypertensive medications with a 3470 kJ/day (830 kcal) diet to induce weight loss reduces BP substantially and may increase mild dizziness. It is safe to stop antihypertensives, but BP should be monitored regularly, particularly for those taking two or more antihypertensives, as over two-thirds will require reintroduction of some medications. Long-term support to maintain weight loss is vital. TRIAL REGISTRATION: ISRCTN registry, number 03267836.

Consensus report: definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks vs benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed 'remission' as the most appropriate descriptive term, and HbA1c <48 mmol/mol (6.5%) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Type 2 diabetes and remission: practical management guided by pathophysiology.

The twin cycle hypothesis postulated that type 2 diabetes was a result of excess liver fat causing excess supply of fat to the pancreas with resulting dysfunction of both organs. If this was so, the condition should be able to be returned to normal by calorie restriction. The Counterpoint study tested this prediction in short-duration type 2 diabetes and showed that liver glucose handling returned to normal within 7 days and that beta-cell function returned close to normal over 8 weeks. Subsequent studies have demonstrated the durability of remission from type 2 diabetes. Remarkably, during the first 12 months of remission, the maximum functional beta-cell mass returns completely to normal and remains so for at least 24 months, consistent with regain of insulin secretory function of beta cells which had dedifferentiated in the face of chronic nutrient oversupply. The likelihood of achieving remission after 15% weight loss has been shown to be mainly determined by the duration of diabetes, with responders having better beta-cell function at baseline. Remission is independent of BMI, underscoring the personal fat threshold concept that type 2 diabetes develops when an individual acquires more fat than can be individually tolerated even at a BMI which in the nonobese range. Observations on people of South Asian or Afro-American ethnicity confirm that substantial weight loss achieves remission in the same way as in the largely White Europeans studied in detail. Diagnosis of type 2 diabetes can now be regarded as an urgent signal that weight loss must be achieved to avoid a progressive decline of health.

Brief formula low-energy-diet for relapse management during weight loss maintenance in the Diabetes Remission Clinical Trial (DiRECT).

BACKGROUND: Weight loss maintenance (WLM) is critical for sustaining type 2 diabetes (T2D) remission, but poorly evidenced. We evaluated brief return to formula low-energy-diet (LED) as relapse treatments (RTs) during the WLM phase of the Diabetes Remission Clinical Trial (DiRECT). METHODS: This post-hoc evaluation included all participants commencing the WLM phase of DiRECT. The protocol offered RT when regain of >2 kg occurred. RESULTS: In total, 123/149 (83%) DiRECT intervention participants commenced the WLM phase after 26 (17%) had withdrawn prior to the WLM phase. Most participants [99/123 (80%)] regained >2 kg during the WLM phase, among whom 60/99 (61%) were recorded as using RT and 39/99 (39%) not using any RT. At baseline, RT users had a higher mean (SD) body mass index [35.8 (4.9) kg m-2 vs. 33.8 (3.9) kg m-2 , p = 0.0231] and had greater social deprivation (P = 0.0003) than non-users, although otherwise the groups were similar. Weight loss ≥ 2k g was achieved in 30/93 (32%) of RT attempts. At 2 years, those regaining >2 kg and using RT (n = 60) had mean (SD) weight losses of 7.4 (6.1) kg, with 25 (42%) remissions and 7 (12%) programme withdrawals. Those regaining >2 kg but not using RT (n = 39) had weight losses of 8.8 (6.0) kg, with 21 (54%) remissions and 4 (10%) programme withdrawals (all not significant). Twelve participants were never recorded as having regained >2 kg or using RTs and, at 2 years, their weight losses were 12.9 (9.2) kg, with 4 (33%) remissions and 8 (67%) programme withdrawals. CONCLUSIONS: Most people with T2D experience weight regain >2 kg during the 2 years after substantial weight loss with a LED. Only one-third of RTs corrected their 2-kg regain, resulting in similar weight losses, remissions and programme withdrawals at 2 years compared to those not using RTs; however, both groups had weight losses below those not recorded as regaining >2 kg during WLM.

Type 2 diabetes remission: 2 year within-trial and lifetime-horizon cost-effectiveness of the Diabetes Remission Clinical Trial (DiRECT)/Counterweight-Plus weight management programme.

AIMS/HYPOTHESIS: Approximately 10% of total healthcare budgets worldwide are spent on treating diabetes and its complications, and budgets are increasing globally because of ageing populations and more expensive second-line medications. The aims of the study were to estimate the within-trial and lifetime cost-effectiveness of the weight management programme, which achieved 46% remissions of type 2 diabetes at year 1 and 36% at year 2 in the Diabetes Remission Clinical Trial (DiRECT). METHODS: Within-trial analysis assessed costs of the Counterweight-Plus intervention in DiRECT (including training, programme materials, practitioner appointments and low-energy diet), along with glucose-lowering and antihypertensive medications, and all routine healthcare contacts. Lifetime cost per quality-adjusted life-year (QALY) was estimated according to projected durations of remissions, assuming continued relapse rates as seen in year 2 of DiRECT and consequent life expectancy, quality of life and healthcare costs. RESULTS: Mean total 2 year healthcare costs for the intervention and control groups were £3036 and £2420, respectively: an incremental cost of £616 (95% CI -£45, £1269). Intervention costs (£1411; 95% CI £1308, £1511) were partially offset by lower other healthcare costs (£796; 95% CI £150, £1465), including reduced oral glucose-lowering medications by £231 (95% CI £148, £314). Net remission at 2 years was 32.3% (95% CI 23.5%, 40.3%), and cost per remission achieved was £1907 (lower 95% CI: intervention dominates; upper 95% CI: £4212). Over a lifetime horizon, the intervention was modelled to achieve a mean 0.06 (95% CI 0.04, 0.09) QALY gain for the DiRECT population and mean total lifetime cost savings per participant of £1337 (95% CI £674, £2081), with the intervention becoming cost-saving within 6 years. CONCLUSIONS/INTERPRETATION: Incorporating the lifetime healthcare cost savings due to periods of remission from diabetes and its complications, the DiRECT intervention is predicted to be both more effective (QALY gain) and cost-saving in adults with type 2 diabetes compared with standard care. This conclusion appears robust to various less favourable model scenarios, providing strong evidence that resources could be shifted cost-effectively to support achieving remissions with the DiRECT intervention. TRIAL REGISTRATION: ISRCTN03267836 Graphical abstract.

Weight loss induced increase in fasting ghrelin concentration is a predictor of weight regain: evidence from the Diabetes Remission Clinical Trial.

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomised clinical trial designed to assess the effect of weight-loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (aged 53.6±7.5 years, BMI 34.7±4.4 kg/m2, 59% males). Intervention participants received a 24-month weight-management programme and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, GLP-1, and PYY were measured at baseline, 12 and 24-months in all participants, and at 5-months in a subset of interventions (n=56) and controls (n=22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3±6.0% body-weight at 5-months but regained over time, with weight-losses of 10.0±7.5% at 12-months and 7.6±6.3% at 24-months. Weight-loss in controls was 1.1±3.7% and 2.1±5.0% at 12 and 24-months, respectively. Body-weight increased by 2.3% [95% CI: 0.4,4.1]; p=0.019) between 12 and 24-months for every 1 ng/ml increase in ghrelin between baseline and 12-months, and weight regain between 12 and 24-months was increased by 1.1% (95% CI: 0.2,2.0; p=0.023) body-weight for every 1 ng/ml increase in ghrelin at 12-months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight-loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve WLM. This article is protected by copyright. All rights reserved.

Weight loss-induced increase in fasting ghrelin concentration is a predictor of weight regain: Evidence from the Diabetes Remission Clinical Trial (DiRECT).

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomized clinical trial, designed to assess the effect of weight loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (age 53.6 ± 7.5 years, body mass index 34.7 ± 4.4 kg/m2 , 59% men). Intervention participants received a 24-month weight management programme, and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, glucagon-like peptide-1 and peptide YY were measured at baseline, 12 months and 24 months in all participants, and at 5 months in a subset of participants in the intervention (n = 56) and control groups (n = 22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3 ± 6.0% body weight at 5 months but regained weight over time, with weight losses of 10.0 ± 7.5% at 12 months and 7.6 ± 6.3% at 24 months. Weight loss in controls was 1.1 ± 3.7% and 2.1 ± 5.0% at 12 and 24 months, respectively. Body weight increased by 2.3% (95% confidence interval [CI] 0.4, 4.1; P = 0.019) between 12 and 24 months for every 1-ng/mL increase in ghrelin between baseline and 12 months, and weight regain between 12 and 24 months was increased by 1.1% (95% CI 0.2, 2.0; P = 0.023) body weight for every 1-ng/mL increase in ghrelin at 12 months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve weight-loss maintenance.

Treatment of periodontitis reduces systemic inflammation in type 2 diabetes.

AIMS: To assess the impact of periodontal treatment on systemic inflammation in type 2 diabetes. MATERIALS AND METHODS: Adults with type 2 diabetes (n = 83) and without diabetes (controls, n = 75) were recruited, and participants with periodontitis received periodontal treatment and 12 months' follow-up. Biomarkers for periodontal inflammation (gingival crevicular fluid interleukin-6, tumour necrosis factor-α, interleukin-1ß, interferon-γ, matrix metalloproteinase-8, matrix metalloproteinase-9, adiponectin) and serum markers of inflammation and diabetes control (glycated haemoglobin, high sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-α, interleukin-1ß, interferon-γ, leptin, adiponectin) were measured. Structural equation modelling was used to evaluate periodontal treatment effects on oral and systemic inflammation. RESULTS: Periodontal treatment resulted in significant improvements in clinical status and reductions in gingival crevicular fluid biomarkers from baseline to month 12. Structural equation modelling identified that, at baseline, individuals with diabetes and periodontitis had significantly higher systemic inflammation than non-diabetic controls with periodontitis (Δ = 0.20, p = .002), with no significant differences between groups for oral inflammation. There was a greater reduction in systemic inflammation following periodontal treatment in individuals with diabetes and periodontitis compared to those with periodontitis but not diabetes (Δ = -0.25, p = .01). CONCLUSIONS: Diabetes and periodontitis together appear to increase systemic inflammation, with evidence of reductions following periodontal treatment.

The degree of hepatic steatosis associates with impaired cardiac and autonomic function.

BACKGROUND & AIMS: Cardiovascular disease is the principle cause of death in patients with elevated liver fat unrelated to alcohol consumption, more so than liver-related morbidity and mortality. The aim of this study was to evaluate the relationship between liver fat and cardiac and autonomic function, as well as to assess how impairment in cardiac and autonomic function is influenced by metabolic risk factors. METHODS: Cardiovascular and autonomic function were assessed in 96 sedentary individuals: i) non-alcoholic fatty liver disease (NAFLD) (n = 46, hepatic steatosis >5% by magnetic resonance spectroscopy), ii) Hepatic steatosis and alcohol (dual aetiology fatty liver disease [DAFLD]) (n = 16, hepatic steatosis >5%, consuming >20 g/day of alcohol) and iii) CONTROL (n = 34, no cardiac, liver or metabolic disorders, <20 g/day of alcohol). RESULTS: Patients with NAFLD and DAFLD had significantly impaired cardiac and autonomic function when compared with controls. Diastolic variability and systolic variability (LF/HF-sBP [n/1]; 2.3 (1.7) and 2.3 (1.5) vs. 3.4 (1.5), p <0.01) were impaired in patients with NAFLD and DAFLD when compared to controls, with DAFLD individuals showing a decrease in diastolic variability relative to NAFLD patients. Hepatic steatosis and fasting glucose were negatively correlated with stroke volume index. Fibrosis stage was significantly negatively associated with mean blood pressure (r = -0.47, p = 0.02), diastolic variability (r = -0.58, p ≤0.01) and systolic variability (r = -0.42, p = 0.04). Hepatic steatosis was independently associated with cardiac function (p ≤0.01); TNF-α (p ≤0.05) and CK-18 (p ≤0.05) were independently associated with autonomic function. CONCLUSION: Cardiac and autonomic impairments appear to be dependent on level of liver fat, metabolic dysfunction, inflammation and fibrosis staging, and to a lesser extent alcohol intake. Interventions should be sought to moderate the excess cardiovascular risk in patients with NAFLD or DAFLD. LAY SUMMARY: Increased levels of fat in the liver impair the ability of the cardiovascular system to work properly. The amount of fat in the liver, metabolic control, inflammation and alcohol are all linked to the degree that the cardiovascular system is affected.

Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial.

BACKGROUND: Type 2 diabetes is a chronic disorder that requires lifelong treatment. We aimed to assess whether intensive weight management within routine primary care would achieve remission of type 2 diabetes. METHODS: We did this open-label, cluster-randomised trial (DiRECT) at 49 primary care practices in Scotland and the Tyneside region of England. Practices were randomly assigned (1:1), via a computer-generated list, to provide either a weight management programme (intervention) or best-practice care by guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700). Participants, carers, and research assistants who collected outcome data were aware of group allocation; however, allocation was concealed from the study statistician. We recruited individuals aged 20-65 years who had been diagnosed with type 2 diabetes within the past 6 years, had a body-mass index of 27-45 kg/m2, and were not receiving insulin. The intervention comprised withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal/day formula diet for 3-5 months), stepped food reintroduction (2-8 weeks), and structured support for long-term weight loss maintenance. Co-primary outcomes were weight loss of 15 kg or more, and remission of diabetes, defined as glycated haemoglobin (HbA1c) of less than 6·5% (<48 mmol/mol) after at least 2 months off all antidiabetic medications, from baseline to 12 months. These outcomes were analysed hierarchically. This trial is registered with the ISRCTN registry, number 03267836. FINDINGS: Between July 25, 2014, and Aug 5, 2017, we recruited 306 individuals from 49 intervention (n=23) and control (n=26) general practices; 149 participants per group comprised the intention-to-treat population. At 12 months, we recorded weight loss of 15 kg or more in 36 (24%) participants in the intervention group and no participants in the control group (p<0·0001). Diabetes remission was achieved in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19·7, 95% CI 7·8-49·8; p<0·0001). Remission varied with weight loss in the whole study population, with achievement in none of 76 participants who gained weight, six (7%) of 89 participants who maintained 0-5 kg weight loss, 19 (34%) of 56 participants with 5-10 kg loss, 16 (57%) of 28 participants with 10-15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more. Mean bodyweight fell by 10·0 kg (SD 8·0) in the intervention group and 1·0 kg (3·7) in the control group (adjusted difference -8·8 kg, 95% CI -10·3 to -7·3; p<0·0001). Quality of life, as measured by the EuroQol 5 Dimensions visual analogue scale, improved by 7·2 points (SD 21·3) in the intervention group, and decreased by 2·9 points (15·5) in the control group (adjusted difference 6·4 points, 95% CI 2·5-10·3; p=0·0012). Nine serious adverse events were reported by seven (4%) of 157 participants in the intervention group and two were reported by two (1%) participants in the control group. Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention. No serious adverse events led to withdrawal from the study. INTERPRETATION: Our findings show that, at 12 months, almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs. Remission of type 2 diabetes is a practical target for primary care. FUNDING: Diabetes UK.

Translating aetiological insight into sustainable management of type 2 diabetes.

Using a low-energy diet as a tool, it has been possible to elucidate the sequence of pathophysiological changes that lead to the onset of type 2 diabetes. Negative energy balance in type 2 diabetes causes a profound fall in liver fat content resulting in normalisation of hepatic insulin sensitivity within 7 days. As the period of negative energy balance extends and liver fat levels fall to low normal, the rate of export of triacylglycerol from the liver falls. Consequent to this, the raised pancreas fat content falls and in early type 2 diabetes, normal first-phase insulin secretion becomes re-established with normal plasma glucose control. This research, driven by the predictions of the 2008 twin cycle hypothesis, has led to a paradigm shift in understanding. Studying the reversed sequence of pathophysiological changes, the linked abnormalities in liver and pancreas have been revealed. Early type 2 diabetes is a potentially reversible condition. Surprisingly, it was observed that the diet devised as an experimental tool was actually liked by research participants. It was associated neither with hunger nor tiredness in most people, but with rapidly increased wellbeing. A defined period of weight loss followed by carefully planned weight maintenance-the 'One, Two' approach-has since been applied in clinical practice. Motivated individuals can reverse their type 2 diabetes and remain normoglycaemic over years. A large study is underway to evaluate the applicability of this general approach to routine primary care practice as a long-term management strategy.