To determine whether early gestational diabetes (GDM) differs from later GDM in maternal characteristics and perinatal outcomes. This is a secondary analysis of an energy-restricted dietary intervention in GDM (DiGest) randomized controlled trial. We compared maternal weight, glycemia, and pregnancy/neonatal outcomes between the early GDM (< 20 weeks, n = 118) and standard GDM diagnosis (21–28 weeks, n = 299) groups. Early GDM was associated with higher antenatal (40 vs. 38 mmol/mol; p = 0.017) and postnatal HbA1c (38 vs. 36 mmol/mol; p = 0.002) and higher risk of diabetes/prediabetes postnatally (19 vs. 6

This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt "fatty pancreas" as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta-cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high-quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence-based clinical practice in this emerging field.

The development of magnetic resonance methods for quantifying intra-organ metabolites has permitted advances in the understanding of fasting and post-prandial carbohydrate and lipid handling in people with and without type 2 diabetes. Insulin resistance in the liver was shown to be related to excess intra-organ fat and was able to be returned to normal by weight loss. The practical effect of having muscle insulin sensitivity in the lower part of the wide normal range resulted in the obligatory shunting of carbohydrates via de novo lipogenesis into saturated fat. These observations provided the basis for the Twin Cycle Hypothesis of the aetiology of type 2 diabetes. Subsequent studies on people with type 2 diabetes confirmed the postulated pathophysiological abnormalities and demonstrated their reversibility by dietary weight loss of 10-15 kg. Overall, the fundamental understanding of the mechanisms causing type 2 diabetes has bridged physiological and clinical perspectives. Large population-based randomised controlled trials confirmed the practical clinical application of the method of achieving substantial weight loss, and an NHS programme is now in place offering potential remission to people within 6 years of diagnosis.

OBJECTIVE: Continuous glucose monitoring (CGM) is increasingly used in gestational diabetes mellitus (GDM) but optimal metrics, ranges and targets in this population are undefined. We assessed associations between CGM metrics and pregnancy outcomes in gestational diabetes. RESEARCH DESIGN AND METHODS: During the DiGest study, 425 women with GDM (diagnosed at median (IQR) 25.1 (18.3- 27.7) weeks) and BMI ≥25kg/m2 received a dietary intervention, with masked Dexcom G6 CGM at 29 (n=361), 32 (n=215) and 36 weeks (n=227) gestation. For this secondary analysis, we used logistic regression, receiver-operator-curves and Youden index to assess associations and predictive ability of CGM metrics including pregnancy-specific time-in-range (TIRp; 63-140mg/dL; 3.5-7.8mmol/L) and pregnancy outcomes. RESULTS: CGM metrics at 29 weeks were significantly associated with LGA and SGA. Participants achieving mean glucose <110mg/dL (6.1mmol/L), TIRp ≥90% or pregnancy-specific time-above-range (TARp) <10% at 29 weeks had a significantly lower risk of LGA (OR 0.41 (95%CI 0.22-0.77); OR 0.38 (0.20-0.70); OR 0.39 (0.20-0.73) and SGA (OR 0.26 (0.08-0.79); OR 0.30 (0.10-0.91); OR 0.19 (0.06-0.62)). TARp<10% and mean nocturnal glucose <110mg/dL were associated with reduced odds of preterm birth (OR 0.40 (0.17-0.94); OR 0.42 (0.19-0.97)). A stricter range (63-120mg/dL; 3.5-6.7mmol/L) had similar performance overall, but had no single statistically-robust TIR/TAR target across all outcomes. CONCLUSIONS: In women with GDM, CGM mean glucose <110mg/dL (6.1mmol/L), ≥90% TIRp or <10% TARp using a range of 63-140mg/dL (3.5-7.8mmol/L) at 29 weeks of gestation was associated with a low risk of suboptimal offspring outcomes.

Reduced-energy diets promote weight loss and improve long-term outcomes in type 2 diabetes but are untested in gestational diabetes. We aimed to identify if weight loss in pregnancy improves perinatal outcomes in gestational diabetes. We performed a multicentre parallel, randomized, controlled, double-blind trial of energy restriction in women with singleton pregnancies, gestational diabetes and body mass index >= 25 kg m(-)(2). Participants were randomized to receive a standard-energy control diet (2,000 kcal d(-1)) or reduced-energy intervention diet (1,200 kcal d(-1)) from enrollment (29 weeks) until delivery, provided as weekly diet boxes (40% carbohydrate, 35% fat, 25% protein). The randomization was performed in a 1:1 ratio, stratified by center and blinded to the participants and study team. Primary outcomes were maternal weight change from enrollment to 36 weeks and offspring birth weight. In total, 425 participants were randomized to the control (n = 211) or intervention (n = 214). Outcome data were available for 388 of 425 (90.1%) participants at 36 weeks and 382 of 425 (89.8%) at delivery. There was no evidence of a difference in maternal weight change to 36 weeks between groups (intervention effect -0.20 (95% confidence interval -1.01, 0.61); P > 0.1) and offspring standardized birth weight (intervention effect 0.005 (-0.19, 0.20); P > 0.1). A reduced-energy diet was safe in pregnancy. ISRCTN registration no. 65152174.

Intentional weight loss improves cardiometabolic risk factors, which by associated neuroprotective effects may reduce dementia risk. However, assessing change in dementia risk directly demands long-term follow-up. In this study, we assessed whether a recently validated 25-protein signature for dementia risk could detect changes in dementia risk in response to an intentional weight loss program in people with type 2 diabetes (T2D) and associated cardiometabolic features. A potential impact of intentional weight loss on dementia risk was explored in two randomized controlled clinical trials in patients with obesity and T2D, DiRECT and DIADEM-I; both demonstrated that a diet program to induce and maintain weight loss led to diabetes remissions of 46% and 61% at 1 year. The proteomic dementia risk test (derived from the SomaScan™ assay, predicting the probability of incident dementia diagnosis within 20-years of blood draw) was applied to plasma samples at baseline and 1-year in intervention (DiRECT n=118; DIADEM-I n=56) and control (DiRECT n=144; DIADEM-I n=66) participants. This model includes measurements of 25 plasma proteins, but not HbA1c, which might otherwise dominate a prediction of dementia risk in people with T2D. Dementia risk scores were compared within and between trial arms and the association between weight loss amount and the magnitude of dementia risk score change was explored. In both DiRECT and DIADEM-I a significant difference in the change in dementia risk score from baseline to 1-year between the trial arms was observed ( p =1.8x10 -7 and p =8.79x10 -8, respectively), with risk scores either remaining stable or decreasing in the intervention arm over the trial duration. Furthermore, in DiRECT there was a significant ( p =9.06x10 -3 ) association between the amount of weight lost and the reduction in dementia risk in the intervention arm with greater weight loss associating with a greater reduction in dementia risk. These results support epidemiological evidence that non-pharmacological weight loss may protect against dementia risk, particularly in those with cardiometabolic features. Furthermore, the proteomic dementia risk test was robust to identifying changes in dementia risk in response to intentional weight loss. These findings suggest that the proteomic model has value to evaluate pharmacologic and non-pharmacological interventions to reduce dementia.

OBJECTIVE:We aimed to assess whether energy restriction, weight loss, or maternal glycemia in late pregnancy were associated with breastfeeding outcomes. RESEARCH DESIGN AND METHODS:This is a secondary analysis of the Dietary Intervention in Gestational Diabetes (DiGest) randomized controlled trial, which included 425 participants with gestational diabetes who were randomly assigned to receive a standard-energy (2,000 kcal/day) or reduced-energy (1,200 kcal/day) diet box from 29 weeks until delivery, with masked continuous glucose monitoring. Breastfeeding intentions and outcomes were documented (n = 304 of 425) and analyzed using regression models. RESULTS:Energy restriction in late pregnancy did not affect breastfeeding outcomes. Achieving ≥90% time in range (3.5-6.7 mmol/L; 63-120 mg/dL) with a low glycemic variability (coefficient of variation and SD), but not weight loss, were associated with any breastfeeding at 3 months postnatally. CONCLUSIONS:Improved late pregnancy glycemia and decreased glucose variability, but not weight loss or energy restriction, were associated with breastfeeding after gestational diabetes.

Standard lifestyle interventions prove ineffective in preventing type 2 diabetes among individuals with isolated impaired fasting glucose, a highly prevalent prediabetes phenotype globally. Here, we propose low-calorie diets as a promising strategy for diabetes prevention in this high-risk population. Thirunavukkarasu et al. discuss how standard lifestyle interventions prove ineffective in preventing type 2 diabetes in individuals with isolated impaired fasting glucose, a highly prevalent prediabetes phenotype globally. They propose low-calorie diets as a promising strategy for diabetes prevention in this high-risk population.

BackgroundIn DiRECT, a randomised controlled effectiveness trial, weight management intervention after 2 years resulted in mean weight loss of 7·6 kg, with 36% of participants in remission of type 2 diabetes. Of 36 in the intervention group who maintained over 10 kg weight loss at 2 years, 29 (81%) were in remission. Continued low-intensity dietary support was then offered up to 5 years from baseline to intervention participants, aiming to maintain weight loss and gain clinical benefits. This extension study was designed to provide observed outcomes at 5 years.MethodsThe DiRECT trial took place in primary care practices in the UK. Participants were individuals aged 20–65 years who had less than 6 years’ duration of type 2 diabetes, a BMI greater than 27 kg/m2, and were not on insulin. The intervention consisted of withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825–853 kcal per day formula diet for 12–20 weeks), stepped food reintroduction (2–8 weeks), and then structured support for weight-loss maintenance. After sharing the 2-year results with all participants, UK National Health Service data were collected annually until year 5 from remaining intervention participants who received low-intensity dietary support, intervention withdrawals, and the original randomly allocated groups. The primary outcome was remission of type 2 diabetes; having established in the DiRECT trial that sustained weight loss was the dominant driver of remission, this was assumed for the Extension study. The trial is registered with the ISRCTN registry, number 03267836.FindingsBetween July 25, 2014, and Aug 5, 2016, 149 participants were randomly assigned to the intervention group and 149 were assigned to the control group in the original DiRECT study. After 2 years, all intervention participants still in the trial (101 [68%] of 149) were approached to receive low-intensity support for a further 3 years. 95 (94%) of 101 were able to continue and consented and were allocated to the DiRECT extension group. 54 participants were allocated to the non-extension group, where intervention was withdrawn. At 5 years, DiRECT extension participants (n=85) lost an average of 6·1 kg, with 11 (13%) of 85 in remission. Compared with the non-extension group, DiRECT extension participants had more visits with HbA1c <48 mmol/mol (<6·5%; 36% vs 17%, p=0·0004), without glucose-lowering medication (62% vs 30%, p<0·0001), and in remission (34% vs 12%, p<0·0001). Original control participants (n=149) had mean weight loss 4·6 kg (n=82), and 5 (5%) of 93 were in remission. Compared with control participants, original intervention participants had more visits with weight more than 5% below baseline (61% vs 29%, p<0·0001), HbA1c below 48 mmol/mol (29% vs 15%, p=0·0002), without antidiabetic medication (51% vs 16%, p<0·0001), and in remission (27% vs 4%, p<0·0001). Of those in remission at year 2, 26% remained in remission at 5 years. Serious adverse events in the original intervention group (4·8 events per 100 patient-years) were under half those in the control group (10·2 per 100 patient-years, p=0·0080).InterpretationThe extended DiRECT intervention was associated with greater aggregated and absolute weight loss, and suggested improved health status over 5 years.FundingDiabetes UK.

Management of type 2 diabetes has now been simplified by the understanding that the condition is caused by excess fat in the liver together with suppression of beta cell function by the associated excess liver export of fat. These factors can be reversed by substantial weight loss leading to remission in the early years after diagnosis, or at least major decrease in cardiovascular risks and improvement in glucose control for all. Weight loss by any means is successful, but it is most easily achieved by rapid action using a low or very low calorie diet of around 800 kcal/day followed by sustained modest restraint of dietary habits. Oral hypoglycaemic agents and one antihypertensive drug can be withdrawn on day 1 of the weight loss diet, raising the importance of appropriate deprescribing.

Background: Reduced-energy diets improve clinical outcomes in type 2 diabetes but are untested in gestational diabetes. Methods: In a randomized, controlled, double-blind, whole-diet replacement trial (ISRCTN; 37866), women with gestational diabetes and BMI >25 kg/m2 were assigned (1:1) to receive a standard-energy (2000 kcal/day) (control) or a reduced-energy diet (1200 kcal/day) (intervention) until delivery, provided as weekly dietboxes containing 40% carbohydrate, 35% fat and 25% protein. Diagnosis used the National Institute of Health and Care Excellence (NICE) and interim UK Covid-19 criteria. Primary outcomes were maternal weight change (enrolment to 36wks) and offspring standardized birthweight. Secondary outcomes included maternal glycemia, treatment requirements and neonatal outcomes. Results: 423 women were randomized at 29wks gestation; (n=211 control; n=212 intervention). Outcome data were available for 386 (91.3%) participants at 36wks and 358 (84.6%) at delivery. Intervention and control groups had similar maternal weight change to 36wks (mean 0.41(SD 4.25) vs 0.50(4.15) kg; baseline-adjusted difference intervention vs control -0.148 (95%CI -0.95 to 0.68); p=0.741). The intervention reduced requirements for short-acting (odds ratio 0.37 (0.14 to 0.97); p=0.044) and long-acting (0.38 (0.19 to 0.75); p=0.006) insulin therapy at 36wks. Offspring had similar standardized birthweight (0.44(1.03) vs 0.44(0.85) SDS; 0.004(-0.20 to 0.19) p=0.967) and comparable rates of large-for-gestational-age and neonatal intensive care admission. Serious adverse events and withdrawals were similar between groups. Weight loss in late pregnancy appeared safe. Conclusions: The protocol did not result in differences in weight gain or primary outcomes between groups but the provision of a reduced energy diet was associated with a reduced requirement for insulin therapy. Disclosure L.C. Kusinski: None. D. Jones: None. N. Atta: None. E. Turner: None. L.M. Oude Griep: None. K.L. Rennie: None. E. De Lucia Rolfe: None. S. Sharp: Consultant; Shionogi & Co., Ltd. H.R. Murphy: Advisory Panel; Medtronic. Research Support; Abbott, Dexcom, Inc. Speaker's Bureau; Ypsomed AG, Eli Lilly and Company, Dexcom, Inc. R. Taylor: Advisory Panel; Fast800. C.L. Meek: Research Support; Dexcom, Inc. Funding Diabetes UK 17/0005712EFSD - NNF NNF19SA058974

BACKGROUND:Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. METHODS:Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. FINDINGS:Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67-0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78-0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. INTERPRETATION:Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk. FUNDING:The main sources of funding for this work were Diabetes UK, Cancer Research UK, World Cancer Research Fund, and Wellcome.

Type 2 diabetes has long been thought to have heterogenous causes, even though epidemiological studies uniformly show a tight relationship with overnutrition. The twin cycle hypothesis postulated that interaction of self-reinforcing cycles of fat accumulation inside the liver and pancreas, driven by modest but chronic positive calorie balance, could explain the development of type 2 diabetes. This hypothesis predicted that substantial weight loss would bring about a return to the non-diabetic state, permitting observation of the pathophysiology determining the transition. These changes were postulated to reflect the basic mechanisms of causation in reverse. A series of studies over the past 15 years has elucidated these underlying mechanisms. Together with other research, the interaction of environmental and genetic factors has been clarified. This knowledge has led to successful implementation of a national programme for remission of type 2 diabetes. This Review discusses the paucity of evidence for heterogeneity in causes of type 2 diabetes and summarises the in vivo pathophysiological changes, which cause this disease of overnutrition. Type 2 diabetes has a homogenous cause expressed in genetically heterogenous individuals.

Background Randomised controlled trials have shown that total diet replacement (TDR) can lead to remission of type 2 diabetes. In 2019, the English National Health Service (NHS) committed to establishing a TDR-based interventional programme delivered at scale within real-world environments; development followed of the NHS Type 2 Diabetes Path to Remission (T2DR) programme, a 12-month behavioural intervention to support weight loss involving an initial 3-month period of TDR. We assessed remission of type 2 diabetes for programme participants. Methods In this national prospective service evaluation of programme implementation, people in England aged 18–65 years and diagnosed with type 2 diabetes in the last 6 years were referred to the programme between programme launch on Sept 1, 2020, and Dec 31, 2022. Programme data were linked to the National Diabetes Audit to ascertain HbA1c measurements and glucose-lowering medication prescriptions. The primary outcome was remission of type 2 diabetes at 1 year, defined as two HbA1c measurements of less than 48 mmol/mol recorded at least 3 months apart with no glucose-lowering medications prescribed from 3 months before the first HbA1c measurement, and the second HbA1c measurement recorded 11–15 months after the programme start date. Outcomes were assessed in two ways: for all participants who started TDR on the 12-month programme before January, 2022, for whom there were no missing data; and for all participants who started TDR on the 12-month programme before January, 2022, and had completed the programme (ie, had a valid weight recorded at month 12) by Dec 31, 2022, for whom there were no missing data. Findings Between Sept 1, 2020, and Dec 31, 2022, 7540 people were referred to the programme; of those, 1740 started TDR before January, 2022, and therefore had a full 12-month opportunity to undertake the programme by the time of data extraction at the end of December, 2022. Of those who started TDR before January, 2022, 960 (55%) completed the programme (defined as having a weight recorded at 12 months). The mean weight loss for the 1710 participants who started the programme before January, 2022 and had no missing data was 8·3% (95% CI 7·9–8·6) or 9·4 kg (8·9–9·8), and the mean weight loss for the 945 participants who completed the programme and had no missing data was 9·3% (8·8–9·8) or 10·3 kg (9·7–10·9). For the subgroup of 710 (42%) of 1710 participants who started the programme before January, 2022, and also had two HbA1c measurements recorded, 190 (27%) had remission, with mean weight loss of 13·4% (12·3–14·5) or 14·8 kg (13·4–16·3). Of the 945 participants who completed the programme, 450 (48%) had two HbA1c measurements recorded; of these, 145 (32%) had remission, with mean weight loss of 14·4% (13·2–15·5) or 15·9 kg (14·3–17·4). Interpretation Findings from the NHS T2DR programme show that remission of type 2 diabetes is possible outside of research settings, through at-scale service delivery. However, the rate of remission achieved is lower and the ascertainment of data is more limited with implementation in the real world than in randomised controlled trial settings. Funding None.

Background: Continuous glucose monitoring (CGM) is increasingly used in gestational diabetes but the optimal metrics and targets in this population are undefined. We assessed if CGM metrics were associated with pregnancy outcomes in gestational diabetes. Methods: 432 women with gestational diabetes (BMI >25 kg/m2) received a dietary intervention (DiGest trial; ISRCTN; 37866), with masked CGM (Dexcom G6) at 29 (n=332) and 36wks (n=225) respectively. We used logistic regression, adjusted for trial arm, to assess the associations between standardized CGM metrics and pregnancy outcomes, including preeclampsia, preterm delivery, large-for-gestational-age (LGA), admission to the neonatal intensive care unit (NICU) and neonatal hypoglycemia. Time in range (TIR) was defined using 63-120 mg/dl. Results: At 29wks, mean glucose, TIR and time-above-range (TAR) were significantly associated with multiple outcomes, including pre-eclampsia, LGA, NICU admission and neonatal hypoglycemia (table 1). TIR and TAR recalculated using range 63-140mg/dl (3.5-7.8 mmol/l) performed similarly. Glucose SD at 29 and 36wks was significantly associated with LGA. Time-below-range at 36wks was associated with neonatal hypoglycemia (table 1). Conclusions: CGM metrics are strong predictors of multiple relevant pregnancy outcomes in gestational diabetes. Disclosure L.C. Kusinski: None. D. Jones: None. N. Atta: None. E. Turner: None. L.M. Oude Griep: None. K.L. Rennie: None. E. De Lucia Rolfe: None. H.R. Murphy: Advisory Panel; Medtronic. Research Support; Abbott, Dexcom, Inc. Speaker's Bureau; Ypsomed AG, Eli Lilly and Company, Dexcom, Inc. R. Taylor: Advisory Panel; Fast800. C.L. Meek: Research Support; Dexcom, Inc. Funding Diabetes UK 17/0005712EFSD - NNF NNF19SA058974

Thousands of proteins circulate in the bloodstream; identifying those which associate with weight and intervention-induced weight loss may help explain mechanisms of diseases associated with adiposity. We aimed to identify consistent protein signatures of weight loss across independent studies capturing changes in body mass index (BMI). We analysed proteomic data from studies implementing caloric restriction (Diabetes Remission Clinical trial) and bariatric surgery (By-Band-Sleeve), using SomaLogic and Olink Explore1536 technologies, respectively. Linear mixed models were used to estimate the effect of the interventions on circulating proteins. Twenty-three proteins were altered in a consistent direction after both bariatric surgery and caloric restriction, suggesting that these proteins are modulated by weight change, independent of intervention type. We also integrated Mendelian randomisation (MR) estimates of the effect of BMI on proteins measured by SomaLogic from a UK blood donor cohort as a third line of causal evidence. These MR estimates provided further corroborative evidence for a role of BMI in regulating the levels of six proteins including alcohol dehydrogenase-4, nogo receptor and interleukin-1 receptor antagonist protein. These results indicate the importance of triangulation in interrogating causal relationships; further study into the role of proteins modulated by weight in disease is now warranted.