Publications by authors named "Taylor Roy"

123 Publications

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

Diabet Med 2021 Sep 14:e14689. Epub 2021 Sep 14.

Policy Research Unit Behavioural Science, Population Health Sciences Institute, Newcastle University, UK.

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, allow 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 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 3 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.
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http://dx.doi.org/10.1111/dme.14689DOI Listing
September 2021

Genes and lifestyle: Which of the two is more relevant in driving NAFLD progression?

Dig Liver Dis 2021 Sep 8. Epub 2021 Sep 8.

Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, NE4 5PL, UK.

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http://dx.doi.org/10.1016/j.dld.2021.08.011DOI Listing
September 2021

Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes.

Diabetes Care 2021 Aug 30. Epub 2021 Aug 30.

Diabetes UK, London, U.K.

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.
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http://dx.doi.org/10.2337/dci21-0034DOI Listing
August 2021

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

Diabet Med 2021 Aug 30:e14669. Epub 2021 Aug 30.

Diabetes UK, London, UK.

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.
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http://dx.doi.org/10.1111/dme.14669DOI Listing
August 2021

Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes.

J Clin Endocrinol Metab 2021 Aug 30. Epub 2021 Aug 30.

Diabetes UK, London, U.K.

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.
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http://dx.doi.org/10.1210/clinem/dgab585DOI Listing
August 2021

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

Diabetologia 2021 Aug 30. Epub 2021 Aug 30.

Diabetes UK, London, UK.

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 HbA <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.
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http://dx.doi.org/10.1007/s00125-021-05542-zDOI Listing
August 2021

Nutritional basis of type 2 diabetes remission.

BMJ 2021 07 7;374:n1449. Epub 2021 Jul 7.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

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http://dx.doi.org/10.1136/bmj.n1449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261662PMC
July 2021

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

Diabetologia 2021 Sep 31;64(9):1927-1938. Epub 2021 May 31.

Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.

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.
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http://dx.doi.org/10.1007/s00125-021-05471-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382659PMC
September 2021

Effect of Weight Loss by Low-Calorie Diet on Cardiovascular Health in Type 2 Diabetes: An Interventional Cohort Study.

Nutrients 2021 Apr 26;13(5). Epub 2021 Apr 26.

Translational and Clinical Research Institute, Magnetic Resonance Centre, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.

Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes (T2DM), and the leading cause of death worldwide. We aimed to determine cardiovascular benefits of weight loss with or without remission of diabetes, and to assess utility of plasma biomarkers. 29 people with T2DM were studied at baseline and after dietary weight loss. Change in plasma adipokines and lipid related markers was examined in relation to weight loss, diabetes remission, 10-year cardiovascular risk (QRISK), and duration of diabetes. QRISK decreased markedly after weight loss (18.9 ± 2.2 to 11.2 ± 1.6%, < 0.0001) in both responders and non-responders, but non-responders remained at higher risk (15.0 ± 2.0 vs. 5.8 ± 1.6%, < 0.0001). At baseline, plasma GDF-15 was higher in longer diabetes duration (1.19 ± 0.14 vs. 0.82 ± 0.09 ng/mL, = 0.034), as was the QRISK (22.8 ± 2.6 vs. 15.3 ± 3.4%, = 0.031). Leptin, GDF-15 and FGF-21 decreased whereases adiponectin increased after weight loss in responders and non-responders. However, the level of FGF-21 remained higher in non-responders (0.58 [0.28-0.71] vs. 0.25 [0.15-0.42] ng/mL, = 0.007). QRISK change correlated with change in plasma VLDL1-TG (r = 0.489, = 0.007). There was a positive correlation between rise in HDL cholesterol and the decrease in leptin (r = 0.57, = 0.001), or rise in adiponectin (r = 0.58, = 0.001) levels. In conclusion, weight loss markedly decreases cardiometabolic risk particularly when remission of diabetes is achieved. Leptin, adiponectin, GDF-15 and FGF-21 changes were related to weight loss not remission of diabetes. Normalization of 10-year cardiovascular risk and heart age is possible after substantial dietary weight loss and remission of T2DM.
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http://dx.doi.org/10.3390/nu13051465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146720PMC
April 2021

Voices: Insulin and beyond.

Cell Metab 2021 Apr;33(4):692-699

Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph.
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http://dx.doi.org/10.1016/j.cmet.2021.03.017DOI Listing
April 2021

Measurement of intraorgan fat and hepatic output of triglycerides in human type 2 diabetes by magnetic resonance and intralipid infusion techniques.

STAR Protoc 2021 Mar 2;2(1):100355. Epub 2021 Mar 2.

Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.

Liver fat content and the linked rate of export of triglyceride are central to the etiology of type 2 diabetes, as well as to the cardiovascular effects of fatty liver disease. Measurement in humans of intrahepatic and intrapancreatic fat content is described using magnetic resonance techniques and quantification of the rate of hepatic secretion of very low density lipoprotein using a non-isotopic competitive blocking of tissue uptake. This protocol is non-invasive, can be repeated sequentially, and does not involve ionizing radiation. For complete details on the use and execution of this protocol, please refer to (Taylor et al., 2018) and (Al-Mrabeh et al., 2020b).
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http://dx.doi.org/10.1016/j.xpro.2021.100355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937826PMC
March 2021

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

J Hum Nutr Diet 2021 06 6;34(3):472-479. Epub 2021 Jan 6.

Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.

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 vs. 33.8 (3.9) kg m , 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.
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http://dx.doi.org/10.1111/jhn.12839DOI Listing
June 2021

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

Diabetes Obes Metab 2020 Dec 2. Epub 2020 Dec 2.

Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.

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/m , 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.
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http://dx.doi.org/10.1111/dom.14274DOI Listing
December 2020

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

Diabetes Obes Metab 2020 Dec 2. Epub 2020 Dec 2.

Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK.

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/m, 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.
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http://dx.doi.org/10.1111/dom.14274DOI Listing
December 2020

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

Authors:
Roy Taylor

J Intern Med 2021 Jun 27;289(6):754-770. Epub 2020 Dec 27.

Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.

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.
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http://dx.doi.org/10.1111/joim.13214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247294PMC
June 2021

2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECT open-label, cluster-randomised trial.

Lancet Diabetes Endocrinol 2020 12 5;8(12):939-948. Epub 2020 Oct 5.

Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Background: The pancreas is small and irregular in shape in people with type 2 diabetes. If these abnormalities are caused by the disease state itself rather than being a predisposing factor, remission of type 2 diabetes should restore normal pancreas morphology. The objective of this study was to determine whether changes in pancreas volume and shape occurred during 2 years of remission.

Methods: For this post-hoc analysis, we included a subset of adult participants of the Diabetes Remission Clinical Trial (DiRECT), who had type 2 diabetes and were randomly assigned to a weight management intervention or routine diabetes management. Intervention group participants were categorised as responders (HbA <6·5% [48 mmol/mol] and fasting blood glucose <7·0 mmol/L, off all anti-diabetes medication) and non-responders, who were classified as remaining diabetic. Data on pancreas volume and irregularity of pancreas border at baseline, 5 months, 12 months, and 24 months after intervention were compared between responders and non-responders; additional comparisons were made between control group participants with type 2 diabetes and a non-diabetic comparator (NDC) group, who were matched to the intervention group by age, sex, and post-weight-loss weight, to determine the extent of any normalisation. We used a mixed-effects regression model based on repeated measures ANOVA with correction for potential confounding. Magnetic resonance techniques were employed to quantify pancreas volume, the irregularity of the pancreas borders, and intrapancreatic fat content. β-cell function and biomarkers of tissue growth were also measured.

Findings: Between July 25, 2015, and Aug 5, 2016, 90 participants with type 2 diabetes in the DiRECT subset were randomly assigned to intervention (n=64) or control (n=26) and were assessed at baseline; a further 25 non-diabetic participants were enrolled into the NDC group. At baseline, mean pancreas volume was 61·7 cm (SD 16·0) in all participants with type 2 diabetes and 79·8 cm (14·3) in the NDC group (p<0·0001). At 24 months, pancreas volume had increased by 9·4 cm (95% CI 6·1 to 12·8) in responders compared with 6·4 cm (2·5 to 10·3) in non-responders (p=0·0008). Pancreas borders at baseline were more irregular in participants with type 2 diabetes than in the NDC group (fractal dimension 1·138 [SD 0·027] vs 1·097 [0·025]; p<0·0001) and had normalised by 24 months in responders only (1·099 [0·028]). Intrapancreatic fat declined by 1·02 percentage points (95% CI 0·53 to 1·51) in 32 responders and 0·51% (-0·17 to 1·19) in 13 non-responders (p=0·23).

Interpretation: These data show for the first time, to our knowledge, reversibility of the abnormal pancreas morphology of type 2 diabetes by weight loss-induced remission.

Funding: Diabetes UK.
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http://dx.doi.org/10.1016/S2213-8587(20)30303-XDOI Listing
December 2020

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.

Diabetologia 2020 10 10;63(10):2112-2122. Epub 2020 Aug 10.

Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Level 2, New Lister Building, Glasgow Royal Infirmary, 8-16 Alexandra Parade, Glasgow, G31 2ER, UK.

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.
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http://dx.doi.org/10.1007/s00125-020-05224-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476973PMC
October 2020

Evidence for a Growth Zone for Deep-Subsurface Microbial Clades in Near-Surface Anoxic Sediments.

Appl Environ Microbiol 2020 09 17;86(19). Epub 2020 Sep 17.

University of Tennessee, Knoxville, Tennessee, USA.

Global marine sediments harbor a large and highly diverse microbial biosphere, but the mechanism by which this biosphere is established during sediment burial is largely unknown. During burial in marine sediments, concentrations of easily metabolized organic compounds and total microbial cell abundance decrease. However, it is unknown whether some microbial clades increase with depth. We show total population increases in 38 microbial families over 3 cm of sediment depth in the upper 7.5 cm of White Oak River (WOR) estuary sediments. Clades that increased with depth were more often associated with one or more of the following: anaerobes, uncultured, or common in deep marine sediments relative to those that decreased. Maximum doubling times ( steady-state growth rates could be faster to balance cell decay) were estimated as 2 to 25 years by combining sedimentation rate with either quantitative PCR (qPCR) or the product of the fraction read abundance of 16S rRNA genes and total cell counts (FRAxC). Doubling times were within an order of magnitude of each other in two adjacent cores, as well as in two laboratory enrichments of Cape Lookout Bight (CLB), NC, sediments (average difference of 28% ± 19%). qPCR and FRAxC in sediment cores and laboratory enrichments produced similar doubling times for key deep subsurface uncultured clades (8.7 ± 1.9 years) and /MBG-D (4.1 ± 0.7 years). We conclude that common deep subsurface microbial clades experience a narrow zone of growth in shallow sediments, offering an opportunity for selection of long-term subsistence traits after resuspension events. Many studies show that the uncultured microbes that dominate global marine sediments do not actually increase in population size as they are buried in marine sediments; rather, they exist in a sort of prolonged torpor for thousands of years. This is because, although studies have shown biomass turnover in these clades, no evidence has ever been found that deeper sediments have larger populations for specific clades than shallower layers. We discovered that they actually do increase population sizes during burial, but only in the upper few centimeters. This suggests that marine sediments may be a vast repository of mostly nongrowing microbes with a thin and relatively rapid area of cell abundance increase in the upper 10 cm, offering a chance for subsurface organisms to undergo natural selection.
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http://dx.doi.org/10.1128/AEM.00877-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499048PMC
September 2020

Erratum: Dietary Intervention in Pregnant Women with Gestational Diabetes; Protocol for the DiGest Randomised Controlled Trial; 2020, , 1165.

Nutrients 2020 Jun 17;12(6). Epub 2020 Jun 17.

Institute of Metabolic Science, University of Cambridge, CB2 0QQ, UK.

The authors would like to correct an error in a recent published paper [...].
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http://dx.doi.org/10.3390/nu12061793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353399PMC
June 2020

Remission of type 2 diabetes by weight loss in a non-white population.

Authors:
Roy Taylor

Lancet Diabetes Endocrinol 2020 06;8(6):458-459

Translational and Clinical Research Insitute, Magnetic Resonance Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30147-9DOI Listing
June 2020

Dietary Intervention in Pregnant Women with Gestational Diabetes; Protocol for the DiGest Randomised Controlled Trial.

Nutrients 2020 Apr 22;12(4). Epub 2020 Apr 22.

Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.

Gestational diabetes mellitus (GDM) annually affects 35,000 pregnancies in the United Kingdom, causing suboptimal health outcomes to the mother and child. Obesity and excessive gestational weight gain are risk factors for GDM. The Institute of Medicine recommends weight targets for women that are overweight and obese, however, there are no clear guidelines for women with GDM. Observational data suggest that modest weight loss (0.6-2 kg) after 28 weeks may reduce risk of caesarean section, large-for-gestational-age (LGA), and maternal postnatal glycaemia. This protocol for a multicentre randomised double-blind controlled trial aims to identify if a fully controlled reduced energy diet in GDM pregnancy improves infant birthweight and reduces maternal weight gain (primary outcomes). A total of 500 women with GDM (National Institute of Health and Care Excellence (NICE) 2015 criteria) and body mass index (BMI) ≥25 kg/m will be randomised to receive a standard (2000 kcal/day) or reduced energy (1200 kcal/day) diet box containing all meals and snacks from 28 weeks to delivery. Women and caregivers will be blinded to the allocations. Food diaries, continuous glucose monitoring, and anthropometry will measure dietary compliance, glucose levels, and weight changes. Women will receive standard antenatal GDM management (insulin/metformin) according to NICE guidelines. The secondary endpoints include caesarean section rates, LGA, and maternal postnatal glucose concentrations.
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http://dx.doi.org/10.3390/nu12041165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230897PMC
April 2020

Treatment of periodontitis reduces systemic inflammation in type 2 diabetes.

J Clin Periodontol 2020 06 12;47(6):737-746. Epub 2020 May 12.

School of Dental Sciences, Newcastle University, Newcastle upon Tyne, UK.

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-1β, 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-1β, 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.
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http://dx.doi.org/10.1111/jcpe.13274DOI Listing
June 2020

Time Course of Normalization of Functional β-Cell Capacity in the Diabetes Remission Clinical Trial After Weight Loss in Type 2 Diabetes.

Diabetes Care 2020 04 14;43(4):813-820. Epub 2020 Feb 14.

Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K.

Objective: To assess functional β-cell capacity in type 2 diabetes during 2 years of remission induced by dietary weight loss.

Research Design And Methods: A Stepped Insulin Secretion Test with Arginine was used to quantify functional β-cell capacity by hyperglycemia and arginine stimulation. Thirty-nine of 57 participants initially achieved remission (HbA <6.5% [<48 mmol/mol] and fasting plasma glucose <7 mmol/L on no antidiabetic drug therapy) with a 16.4 ± 7.7 kg weight loss and were followed up with supportive advice on avoidance of weight regain. At 2 years, 20 participants remained in remission in the study. A nondiabetic control (NDC) group, matched for age, sex, and weight after weight loss with the intervention group, was studied once.

Results: During remission, median (interquartile range) maximal rate of insulin secretion increased from 581 (480-811) pmol/min/m at baseline to 736 (542-998) pmol/min/m at 5 months, 942 (565-1,240) pmol/min/m at 12 months ( = 0.028 from baseline), and 936 (635-1,435) pmol/min/m at 24 months ( = 0.023 from baseline; = 20 of 39 of those initially in remission). This was comparable to the NDC group (1,016 [857-1,507] pmol/min/m) by 12 ( = 0.064) and 24 ( = 0.244) months. Median first-phase insulin response increased from baseline to 5 months (42 [4-67] to 107 [59-163] pmol/min/m; < 0.0001) and then remained stable at 12 and 24 months (110 [59-201] and 125 [65-166] pmol/min/m, respectively; < 0.0001 vs. baseline) but lower than that of the NDC group (250 [226-429] pmol/min/m; < 0.0001).

Conclusions: A gradual increase in assessed functional β-cell capacity occurred after weight loss, becoming similar to that of NDC group participants by 12 months. This result was unchanged at 2 years with continuing remission of type 2 diabetes.
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http://dx.doi.org/10.2337/dc19-0371DOI Listing
April 2020

Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss.

Cell Metab 2020 02 19;31(2):233-249.e4. Epub 2019 Dec 19.

Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Electronic address:

The role of hepatic lipoprotein metabolism in diet-induced remission of type 2 diabetes is currently unclear. Here, we determined the contributions of hepatic VLDL1-triglyceride production rate and VLDL1-palmitic acid content to changes in intra-pancreatic fat and return of first phase insulin response in a subgroup of the Diabetes Remission Clinical Trial. Liver fat, VLDL1-triglyceride production, and intra-pancreatic fat decreased after weight loss and remained normalized after 24 months of remission. First-phase insulin response remained increased only in those maintaining diabetes remission. Compared with those in remission at 24 months, individuals who relapsed after initial remission had a greater rise in the content of VLDL1-triglyceride and VLDL1-palmitic acid, re-accumulated intra-pancreatic fat, and lost first-phase response by 24 months. Thus, we observed temporal relationships between VLDL1-triglyceride production, hepatic palmitic acid flux, intra-pancreatic fat, and β-cell function. Weight-related disordered fat metabolism appears to drive development and reversal of type 2 diabetes.
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http://dx.doi.org/10.1016/j.cmet.2019.11.018DOI Listing
February 2020

Understanding the mechanisms of reversal of type 2 diabetes.

Lancet Diabetes Endocrinol 2019 09 13;7(9):726-736. Epub 2019 May 13.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Clinical and pathophysiological studies have shown type 2 diabetes to be a condition mainly caused by excess, yet reversible, fat accumulation in the liver and pancreas. Within the liver, excess fat worsens hepatic responsiveness to insulin, leading to increased glucose production. Within the pancreas, the β cell seems to enter a survival mode and fails to function because of the fat-induced metabolic stress. Removal of excess fat from these organs via substantial weight loss can normalise hepatic insulin responsiveness and, in the early years post-diagnosis, is associated with β-cell recovery of acute insulin secretion in many individuals, possibly by redifferentiation. Collectively, these changes can normalise blood glucose levels. Importantly, the primary care-based Diabetes Remission Clinical Trial (DiRECT) showed that 46% of people with type 2 diabetes could achieve remission at 12 months, and 36% at 24 months, mediated by weight loss. This major change in our understanding of the underlying mechanisms of disease permits a reassessment of advice for people with type 2 diabetes.
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http://dx.doi.org/10.1016/S2213-8587(19)30076-2DOI Listing
September 2019

An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling.

Dev Cell 2019 05 18;49(4):574-589.e5. Epub 2019 Apr 18.

Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

The effect of intracellular vesicle trafficking on stem-cell behavior is largely unexplored. We screened the Drosophila sorting nexins (SNXs) and discovered that one, SH3PX1, profoundly affects gut homeostasis and lifespan. SH3PX1 restrains intestinal stem cell (ISC) division through an endocytosis-autophagy network that includes Dynamin, Rab5, Rab7, Atg1, 5, 6, 7, 8a, 9, 12, 16, and Syx17. Blockages in this network stabilize ligand-activated EGFRs, recycling them via Rab11-dependent endosomes to the plasma membrane. This hyperactivated ERK, calcium signaling, and ER stress, autonomously stimulating ISC proliferation. The excess divisions induced epithelial stress, Yki activity, and Upd3 and Rhomboid production in enterocytes, catalyzing feedforward ISC hyperplasia. Similarly, blocking autophagy increased ERK activity in human cells. Many endocytosis-autophagy genes are mutated in cancers, most notably those enriched in microsatellite instable-high and KRAS-wild-type colorectal cancers. Disruptions in endocytosis and autophagy may provide an alternative route to RAS-ERK activation, resulting in EGFR-dependent cancers.
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http://dx.doi.org/10.1016/j.devcel.2019.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542281PMC
May 2019

Corrigendum: Calorie restriction for long-term remission of type 2 diabetes.

Authors:
Roy Taylor

Clin Med (Lond) 2019 03;19(2):192

Newcastle University, Newcastle upon Tyne, UK

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http://dx.doi.org/10.7861/clinmedicine.19-2-192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454376PMC
March 2019

Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial.

Lancet Diabetes Endocrinol 2019 05 6;7(5):344-355. Epub 2019 Mar 6.

Newcastle Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Electronic address:

Background: The DiRECT trial assessed remission of type 2 diabetes during a primary care-led weight-management programme. At 1 year, 68 (46%) of 149 intervention participants were in remission and 36 (24%) had achieved at least 15 kg weight loss. The aim of this 2-year analysis is to assess the durability of the intervention effect.

Methods: DiRECT is an open-label, cluster-randomised, controlled trial done at primary care practices in the UK. Practices were randomly assigned (1:1) via a computer-generated list to provide an integrated structured weight-management programme (intervention) or best-practice care in accordance with guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700 people). Allocation was concealed from the study statisticians; participants, carers, and study research assistants were aware of allocation. We recruited individuals aged 20-65 years, with less than 6 years' duration of type 2 diabetes, BMI 27-45 kg/m, and not receiving insulin between July 25, 2014, and Aug 5, 2016. The intervention consisted of withdrawal of antidiabetes 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. The coprimary outcomes, analysed hierarchically in the intention-to-treat population at 24 months, were weight loss of at least 15 kg, and remission of diabetes, defined as HbA less than 6·5% (48 mmol/mol) after withdrawal of antidiabetes drugs at baseline (remission was determined independently at 12 and 24 months). The trial is registered with the ISRCTN registry, number 03267836, and follow-up is ongoing.

Findings: The intention-to-treat population consisted of 149 participants per group. At 24 months, 17 (11%) intervention participants and three (2%) control participants had weight loss of at least 15 kg (adjusted odds ratio [aOR] 7·49, 95% CI 2·05 to 27·32; p=0·0023) and 53 (36%) intervention participants and five (3%) control participants had remission of diabetes (aOR 25·82, 8·25 to 80·84; p<0·0001). The adjusted mean difference between the control and intervention groups in change in bodyweight was -5·4 kg (95% CI -6·9 to -4·0; p<0·0001) and in HbA was -4·8 mmol/mol (-8·3 to -1·4 [-0·44% (-0·76 to -0·13)]; p=0·0063), despite only 51 (40%) of 129 patients in the intervention group using anti-diabetes medication compared with 120 (84%) of 143 in the control group. In a post-hoc analysis of the whole study population, of those participants who maintained at least 10 kg weight loss (45 of 272 with data), 29 (64%) achieved remission; 36 (24%) of 149 participants in the intervention group maintained at least 10 kg weight loss. Serious adverse events were similar to those reported at 12 months, but were fewer in the intervention group than in the control group in the second year of the study (nine vs 22).

Interpretation: The DiRECT programme sustained remissions at 24 months for more than a third of people with type 2 diabetes. Sustained remission was linked to the extent of sustained weight loss.

Funding: Diabetes UK.
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http://dx.doi.org/10.1016/S2213-8587(19)30068-3DOI Listing
May 2019

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

J Hepatol 2019 06 13;70(6):1203-1213. Epub 2019 Feb 13.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jhep.2019.01.035DOI Listing
June 2019
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