Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes.

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.

Using trials of caloric restriction and bariatric surgery to explore the effects of body mass index on the circulating proteome.

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.

What predicts drug-free type 2 diabetes remission? Insights from an 8-year general practice service evaluation of a lower carbohydrate diet with weight loss.

Background: Type 2 diabetes (T2D) is often regarded as a progressive, lifelong disease requiring an increasing number of drugs. Sustained remission of T2D is now well established, but is not yet routinely practised. Norwood surgery has used a low-carbohydrate programme aiming to achieve remission since 2013. Methods: Advice on a lower carbohydrate diet and weight loss was offered routinely to people with T2D between 2013 and 2021, in a suburban practice with 9800 patients. Conventional 'one-to-one' GP consultations were used, supplemented by group consultations and personal phone calls as necessary. Those interested in participating were computer coded for ongoing audit to compare 'baseline' with 'latest follow-up' for relevant parameters. Results: The cohort who chose the low-carbohydrate approach (n=186) equalled 39% of the practice T2D register. After an average of 33 months median (IQR) weight fell from 97 (84-109) to 86 (76-99) kg, giving a mean (SD) weight loss of -10 (8.9)kg. Median (IQR) HbA1c fell from 63 (54-80) to 46 (42-53) mmol/mol. Remission of diabetes was achieved in 77% with T2D duration less than 1 year, falling to 20% for duration greater than 15 years. Overall, remission was achieved in 51% of the cohort. Mean LDL cholesterol decreased by 0.5 mmol/L, mean triglyceride by 0.9 mmol/L and mean systolic blood pressure by 12 mm Hg. There were major prescribing savings; average Norwood surgery spend was £4.94 per patient per year on drugs for diabetes compared with £11.30 for local practices. In the year ending January 2022, Norwood surgery spent £68 353 per year less than the area average. Conclusions: A practical primary care-based method to achieve remission of T2D is described. A low-carbohydrate diet-based approach was able to achieve major weight loss with substantial health and financial benefit. It resulted in 20% of the entire practice T2D population achieving remission. It appears that T2D duration <1 year represents an important window of opportunity for achieving drug-free remission of diabetes. The approach can also give hope to those with poorly controlled T2D who may not achieve remission, this group had the greatest improvements in diabetic control as represented by HbA1c.

A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk.

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.

Intra-pancreatic fat deposition: bringing hidden fat to the fore.

Development of advanced modalities for detection of fat within the pancreas has transformed understanding of the role of intra-pancreatic fat deposition (IPFD) in health and disease. There is now strong evidence for the presence of minimal (but not negligible) IPFD in healthy human pancreas. Diffuse excess IPFD, or fatty pancreas disease (FPD), is more frequent than type 2 diabetes mellitus (T2DM) (the most common disease of the endocrine pancreas) and acute pancreatitis (the most common disease of the exocrine pancreas) combined. FPD is not strictly a function of high BMI; it can result from the excess deposition of fat in the islets of Langerhans, acinar cells, inter-lobular stroma, acinar-to-adipocyte trans-differentiation or replacement of apoptotic acinar cells. This process leads to a wide array of diseases characterized by excess IPFD, including but not limited to acute pancreatitis, chronic pancreatitis, pancreatic cancer, T2DM, diabetes of the exocrine pancreas. There is ample evidence for FPD being potentially reversible. Weight loss-induced decrease of intra-pancreatic fat is tightly associated with remission of T2DM and its re-deposition with recurrence of the disease. Reversing FPD will open up opportunities for preventing or intercepting progression of major diseases of the exocrine pancreas in the future.

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.

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.

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.

Quantification of intrapancreatic fat in type 2 diabetes by MRI.

OBJECTIVES: Accumulation of intrapancreatic fat may be important in type 2 diabetes, but widely varying data have been reported. The standard quantification by MRI in vivo is time consuming and dependent upon a high level of experience. We aimed to develop a new method which would minimise inter-observer variation and to compare this against previously published datasets. METHODS: A technique of 'biopsying' the image to minimise inclusion of non-parenchymal tissues was developed. Additionally, thresholding was applied to exclude both pancreatic ducts and intrusions of visceral fat, with pixels of fat values of <1% or >20% being excluded. The new MR image 'biopsy' (MR-opsy) was compared to the standard method by 6 independent observers with wide experience of image analysis but no experience of pancreas imaging. The effect of the new method was examined on datasets from two studies of weight loss in type 2 diabetes. RESULTS: At low levels of intrapancreatic fat neither the result nor the inter-observer CV was changed by MR-opsy, thresholding or a combination of the methods. However, at higher levels the conventional method exhibited poor inter-observer agreement (coefficient of variation 26.9%) and the new combined method improved the CV to 4.3% (p<0.03). Using either MR-opsy alone or with thresholding, the new methods indicated a closer relationship between decrease in intrapancreatic fat and fall in blood glucose. CONCLUSION: The inter-observer variation for quantifying intrapancreatic fat was substantially improved by the new method when pancreas fat levels were moderately high. The method will improve comparability of pancreas fat measurement between research groups.

Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial.

BACKGROUND & AIMS: Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH. METHODS: Twenty-four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m2) with sedentary lifestyles (<60 min/wk of moderate-vigorous activity) and biopsy-proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks. RESULTS: Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm2 vs an increase of 14 ± 48 cm2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and γ-glutamyltransferase (reduction of 10 ± 28 U/L-1 vs a reduction of 17 ± 38 U/L-1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis. CONCLUSIONS: In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some but not all factors associated with NASH. Clinical care teams should consider exercise as part of a management strategy of NASH, but weight management strategies should be included. Larger and longer-term studies are required to determine the effects of exercise in patients with NASH. ISRCTN registry.com: ISRCTN16070927.

The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial.

BACKGROUND: Despite improving evidence-based practice following clinical guidelines to optimise drug therapy, Type 2 diabetes (T2DM) still exerts a devastating toll from vascular complications and premature death. Biochemical remission of T2DM has been demonstrated with weight loss around 15kg following bariatric surgery and in several small studies of non-surgical energy-restriction treatments. The non-surgical Counterweight-Plus programme, running in Primary Care where obesity and T2DM are routinely managed, produces >15 kg weight loss in 33% of all enrolled patients. The Diabetes UK-funded Counterpoint study suggested that this should be sufficient to reverse T2DM by removing ectopic fat in liver and pancreas, restoring first-phase insulin secretion. The Diabetes Remission Clinical Trial (DiRECT) was designed to determine whether a structured, intensive, weight management programme, delivered in a routine Primary Care setting, is a viable treatment for achieving durable normoglycaemia. Other aims are to understand the mechanistic basis of remission and to identify psychological predictors of response. METHODS/DESIGN: Cluster-randomised design with GP practice as the unit of randomisation: 280 participants from around 30 practices in Scotland and England will be allocated either to continue usual guideline-based care or to add the Counterweight-Plus weight management programme, which includes primary care nurse or dietitian delivery of 12-20weeks low calorie diet replacement, food reintroduction, and long-term weight loss maintenance. Main inclusion criteria: men and women aged 20-65 years, all ethnicities, T2DM 0-6years duration, BMI 27-45 kg/m(2). Tyneside participants will undergo Magnetic Resonance (MR) studies of pancreatic and hepatic fat, and metabolic studies to determine mechanisms underlying T2DM remission. Co-primary endpoints: weight reduction ≥ 15 kg and HbA1c <48 mmol/mol at one year. Further follow-up at 2 years. DISCUSSION: This study will establish whether a structured weight management programme, delivered in Primary Care by practice nurses or dietitians, is a viable treatment to achieve T2DM remission. Results, available from 2018 onwards, will inform future service strategy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03267836 . Date of Registration 20/12/2013.

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes.

OBJECTIVE: This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function. RESEARCH DESIGN AND METHODS: Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using in-phase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal. RESULTS: Weight loss after surgery was similar (NGT: 12.8 ± 0.8% and T2DM: 13.6 ± 0.7%) as was the change in fat mass (56.7 ± 3.3 to 45.4 ± 2.3 vs. 56.6 ± 2.4 to 43.0 ± 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 ± 0.2 to 5.5 ± 0.4%) but decreased in the group with T2DM (6.6 ± 0.5 to 5.4 ± 0.4%; P = 0.007). First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT (0.24 [0.13-0.46] to 0.23 [0.19-0.37] nmol ⋅ min(-1) ⋅ m(-2)) but normalized in T2DM (0.08 [-0.01 to -0.10] to 0.22 [0.07-0.30]) nmol ⋅ min(-1) ⋅ m(-2) at week 8 (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups. CONCLUSIONS: The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.

Altered volume, morphology and composition of the pancreas in type 2 diabetes.

OBJECTIVE: Although impairment in pancreatic insulin secretion is known to precede the clinical diagnosis of type 2 diabetes by up to a decade, fasting blood glucose concentration only rises abnormally once the impairment reaches a critical threshold. Despite its centrality to the pathogenesis of type 2 diabetes, the pancreas is the least studied organ due to its inaccessible anatomical position. Previous ultrasound and CT studies have suggested a possible decrease in pancreatic volume in type 2 diabetes. However, ultrasound techniques are relatively insensitive while CT uses ionizing radiation, making these modalities unsuitable for precise, longitudinal studies designed to explore the underlying mechanisms of type 2 diabetes. Hence there is a need to develop a non-invasive, safe and precise method to quantitate pancreas volume. METHODS: We developed and applied magnetic resonance imaging at 3.0T to obtain balanced turbo field echo (BTFE) structural images of the pancreas, together with 3-point Dixon images to quantify pancreatic triglyceride content. Pancreas volume, morphology and triglyceride content was quantified in a group of 41 subjects with well-controlled type 2 diabetes (HbA1c ≤ 7.6%) taking only metformin (duration of T2DM 5.7 ± 0.7 years), and a control group of 14 normal glucose tolerance subjects matched for age, weight and sex. RESULTS: The mean pancreatic volume was found to be 33% less in type 2 diabetes than in normal glucose tolerant subjects (55.5 ± 2.8 vs. 82.6 ± 4.8 cm3; p < 0.0001). Pancreas volume was positively correlated with HOMA-ß in the type 2 diabetes subjects (r = 0.31; p = 0.03) and controls (r = 0.46; p = 0.05) considered separately; and in the whole population studied (r = 0.37; p = 0.003). In type 2 diabetes, the pancreas was typically involuted with a serrated border. Pancreatic triglyceride content was 23% greater (5.4 ± 0.3 vs. 4.4 ± 0.4%; p = 0.02) in the type 2 diabetes group. CONCLUSION: This study describes for the first time gross abnormalities of the pancreas in early type 2 diabetes and quantifies the decrease in pancreas size, the irregular morphology and increase in fat content.

Cardiac structure and function are altered in type 2 diabetes and non-alcoholic fatty liver disease and associate with glycemic control.

BACKGROUND: Both non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes increase the risk of developing cardiovascular disease. The metabolic processes underlying NAFLD and Type 2 diabetes are part of an integrated mechanism but little is known about how these conditions may differentially affect the heart. We compared the impact of NAFLD and Type 2 diabetes on cardiac structure, function and metabolism. METHODS: 19 adults with Type 2 diabetes (62 ± 8 years), 19 adults with NAFLD (54 ± 15 years) and 19 healthy controls (56 ± 14 years) underwent assessment of cardiac structure, function and metabolism using high resolution magnetic resonance imaging, tagging and spectroscopy at 3.0 T. RESULTS: Adults with NAFLD and Type 2 diabetes demonstrate concentric remodelling with an elevated eccentricity ratio compared to controls (1.05 ± 0.3 vs. 1.12 ± 0.2 vs. 0.89 ± 0.2 g/ml; p < 0.05). Despite this, only the Type 2 diabetes group demonstrate significant systolic and diastolic dysfunction evidenced by a reduced stroke index (31 ± 7vs. controls, 38 ± 10, p < 0.05 ml/m2) and reduced E/A (0.9 ± 0.4 vs. controls, 1.9 ± 1.4, p < 0.05) respectively. The torsion to shortening ratio was higher in Type 2 diabetes compared to NAFLD (0.58 ± 0.16 vs. 0.44 ± 0.13; p < 0.05). Significant associations were observed between fasting blood glucose/HbA1c and diastolic parameters as well as the torsion to shortening ratio (all p < 0.05). Phosphocreatine/adenosine triphosphate ratio was not altered in NAFLD or Type 2 diabetes compared to controls. CONCLUSIONS: Changes in cardiac structure are evident in adults with Type 2 diabetes and NAFLD without overt cardiac disease and without changes in cardiac energy metabolism. Only the Type 2 diabetes group display diastolic and subendocardial dysfunction and glycemic control may be a key mediator of these cardiac changes. Therapies should be explored to target these preclinical cardiac changes to modify cardiovascular risk associated with Type 2 diabetes and NAFLD.

Effect of physical activity on age-related changes in cardiac function and performance in women.

BACKGROUND: Higher levels of physical activity are associated with reduced cardiovascular mortality but its effect on age-related changes in cardiac structure and function is unknown. The present study defines the effect of daily physical activity on age-related changes in cardiac structure, function, metabolism, and performance in healthy women. METHODS AND RESULTS: Sixty-three healthy women were grouped according to age (young, 20-30 years, n=21; middle, 40-50 years, n=22; and older, 65-81 years, n=20) and daily physical activity level (low active<7500 and high active>12,500 steps/d). Participants underwent cardiac MRI including tissue tagging and 31P spectroscopy and exercise testing with noninvasive central hemodynamic measurements. Aging was associated with increased concentric remodeling (P<0.01) and left ventricular torsion (P<0.01), and a decline in diastolic function (P<0.01), cardiac phosphocreatine:ATP ratio (P<0.01), peak exercise cardiac power output (P<0.01), and O2 consumption (P<0.01). Older high-active women demonstrated a phosphocreatine:ATP ratio and relative peak O2 consumption similar to young low-active women, and 23% and 26% higher than older low-active women (phosphocreatine:ATP ratio, 1.9±0.2 versus 1.4±0.1; P<0.05 and O2 consumption, 24.1±3.8 versus 17.8±2.0 mL/[kg·min]; P<0.01). In older women, physical activity had no effect on eccentricity ratio (0.9±0.2 versus 0.8±0.1 g/mL; P=0.19), E/A ratio (1.3±0.5 versus 1.4±0.5; P=0.66), torsion (7.6±1.7 versus 8.0°±2.1°; P=0.20), and peak cardiac power output (3.4±0.7 versus 3.4±0.8 W; P=0.91). CONCLUSIONS: A higher level of daily physical activity preserves cardiac metabolism and exercise capacity with aging but has limited effect on age-related changes in concentric remodeling, diastolic function, and cardiac performance.

Levothyroxine improves abnormal cardiac bioenergetics in subclinical hypothyroidism: a cardiac magnetic resonance spectroscopic study.

CONTEXT: It is well established that subclinical hypothyroidism (SCH) is associated with mild cardiac dysfunction, but it is unknown whether there is an underlying impairment of cardiac bioenergetic function. OBJECTIVE: The objective of the study was to quantify the cardiac phosphocreatine to adenosine triphosphate ratio (PCr to ATP) in SCH, compared with healthy controls, and to measure the effect of 6 months of levothyroxine treatment. DESIGN AND SETTING: This was a 6-month, prospective, case-controlled interventional study. PARTICIPANTS AND MAIN OUTCOME MEASURES: The PCr to ATP ratio was measured using phosphorus-31 magnetic resonance spectroscopy in subjects with SCH at baseline and after levothyroxine therapy (1.6 µg/kg · d) and compared with age- and gender-matched euthyroid controls. All subjects were free of overt heart disease. RESULTS: Twenty-one subjects with SCH (normal free T4 and serum TSH between 4.1 and 10 mIU/L) and 17 controls were matched for age (mean age 40.5 vs 43.3 y) and sex (females 81% vs 82%) but differed in mean TSH (6.5 vs 2.1 mIU/L, P < .001). At baseline the mean (± SD) PCr to ATP ratio in SCH was lower than in controls (1.80 ± 0.26 vs 2.07 ± 0.20, P = .001). In the 16 subjects studied after levothyroxine treatment, the PCr to ATP ratio improved (from 1.74 ± 0.24 to 1.91 ± 0.26, P = .004) and approached controls (borderline loss of significance, P = .051). On multivariate analysis, SCH was independently associated with a reduced PCr to ATP ratio, even after adjusting for confounding variables (body mass index and fasting glucose) (P = .001). CONCLUSION: Our results demonstrate early cardiac bioenergetic impairment in SCH, which is reversible with levothyroxine therapy. This mechanistic insight provides justification for longitudinal trials to determine whether improvement in bioenergetic function improves cardiovascular outcome.

Movement as Medicine for Type 2 Diabetes: protocol for an open pilot study and external pilot clustered randomised controlled trial to assess acceptability, feasibility and fidelity of a multifaceted behavioural intervention targeting physical activity in primary care.

BACKGROUND: Physical activity (PA) and nutrition are the cornerstones of diabetes management. Several reviews and meta-analyses report that PA independently produces clinically important improvements in glucose control in people with Type 2 diabetes. However, it remains unclear what the optimal strategies are to increase PA behaviour in people with Type 2 diabetes in routine primary care. METHODS: This study will determine whether an evidence-informed multifaceted behaviour change intervention (Movement as Medicine for Type 2 Diabetes) targeting both consultation behaviour of primary healthcare professionals and PA behaviour in adults with Type 2 diabetes is both acceptable and feasible in the primary care setting. An open pilot study conducted in two primary care practices (phase one) will assess acceptability, feasibility and fidelity. Ongoing feedback from participating primary healthcare professionals and patients will provide opportunities for systematic adaptation and refinement of the intervention and study procedures. A two-arm parallel group clustered pilot randomised controlled trial with patients from participating primary care practices in North East England will assess acceptability, feasibility, and fidelity of the intervention (versus usual clinical care) and trial processes over a 12-month period. Consultation behaviour involving fidelity of intervention delivery, diabetes and PA related knowledge, attitudes/beliefs, intentions and self-efficacy for delivering a behaviour change intervention targeting PA behaviour will be assessed in primary healthcare professionals. We will rehearse the collection of outcome data (with the focus on data yield and quality) for a future definitive trial, through outcome assessment at baseline, one, six and twelve months. An embedded qualitative process evaluation and treatment fidelity assessment will explore issues around intervention implementation and assess whether intervention components can be reliably and faithfully delivered in routine primary care. DISCUSSION: Movement as Medicine for Type 2 Diabetes will address an important gap in the evidence-base, that is, the need for interventions to increase free-living PA behaviour in adults with Type 2 diabetes. The multifaceted intervention incorporates an online accredited training programme for primary healthcare professionals and represents, to the best of our knowledge, the first of its kind in the United Kingdom. This study will establish whether the multifaceted behavioural intervention is acceptable and feasible in routine primary care. TRIAL REGISTRATION: Movement as Medicine for Type 2 Diabetes (MaMT2D) was registered with Current Controlled Trials on the 14th January 2012: ISRCTN67997502. The first primary care practice was randomised on the 5th October 2012.

Noninvasive in vivo magnetic resonance measures of glutathione synthesis in human and rat liver as an oxidative stress biomarker.

UNLABELLED: Oxidative stress (OS) plays a central role in the progression of liver disease and in damage to liver by toxic xenobiotics. We have developed methods for noninvasive assessment of hepatic OS defenses by measuring flux through the glutathione (GSH) synthesis pathway. (13) C-labeled GSH is endogenously produced and detected by in vivo magnetic resonance after administration of [2-(13) C]-glycine. We report on a successful first-ever human demonstration of this approach as well as preclinical studies demonstrating perturbed GSH metabolism in models of acute and chronic OS. Human studies employed oral administration of [2-(13) C]-glycine and (13) C spectroscopy on a 3T clinical magnetic resonance (MR) imaging scanner and demonstrated detection and quantification of endogenously produced (13) C-GSH after labeled glycine ingestion. Plasma analysis demonstrated that glycine (13) C fractional enrichment achieved steady state during the 6-hour ingestion period. Mean rate of synthesis of hepatic (13) C-labeled GSH was 0.32 ± 0.18 mmole/kg/hour. Preclinical models of acute OS and nonalcoholic steatohepatitis (NASH) comprised CCl4 -treated and high-fat, high-carbohydrate diet-fed Sprague-Dawley rats, respectively, using intravenous administration of [2-(13) C]-glycine and observation of (13) C-label metabolism on a 7T preclinical MR system. Preclinical studies demonstrated a 54% elevation of GSH content and a 31% increase in flux through the GSH synthesis pathway at 12 hours after acute insult caused by CCl4 administration, as well as a 23% decrease in GSH content and evidence of early steatohepatitis in the model of NASH. CONCLUSION: Our data demonstrate in vivo (13) C-labeling and detection of GSH as a biomarker of tissue OS defenses, detecting chronic and acute OS insults. The methods are applicable to clinical research studies of hepatic OS in disease states over time as well as monitoring effects of therapeutic interventions.

Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance.

BACKGROUND & AIMS: Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used (1)H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model. METHODS: Human studies employed cohorts of LAL-deficient patients and NAFLD subjects. Rat experimental groups comprised ex vivo liver samples of wild type, NAFLD, LAL-deficient, and LAL-deficient rats receiving 4weeks of sebelipase alfa treatment. Hepatic (1)H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. RESULTS: CE accumulation was identified in LAL deficiency in both human and preclinical studies. A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa. CONCLUSIONS: We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature associated with a rare genetic cause of fatty liver. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression / treatment monitoring of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.