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Interaction Between Type 2 Diabetes Prevention Strategies and Genetic Determinants of Coronary Artery Disease on Cardiometabolic Risk Factors.
Merino, J, Jablonski, KA, Mercader, JM, Kahn, SE, Chen, L, Harden, M, Delahanty, LM, Araneta, MRG, Walford, GA, Jacobs, SBR, et al
Diabetes. 2020;69(1):112-120
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Individual risk of Coronary Artery Disease (CAD) and type 2 diabetes reflects the interplay between lifestyle behaviours acting on a backdrop of genetic predisposition. The aim of this study was to examine whether type 2 diabetes prevention strategies, either an intensive lifestyle intervention (ILS) or metformin treatment (MET), modify the association between CAD genetic risk and cardiometabolic risk factors (CRFs) in participants at high risk of type 2 diabetes. The study is a randomised controlled trial were participants were randomly allocated to one of the three groups; ILS (n = 1,079), MET (850 mg twice daily [n = 1,073]), or placebo (n = 1,082). Results indicate that there weren’t major significant differences in baseline characteristics, except for lower high-density lipoprotein and higher triglyceride in the placebo individuals compared with individuals assigned to MET or ILS. In fact, either an ILS or MET has a beneficial effect on 1-year change in different CRFs. Authors conclude that type 2 diabetes–preventive strategies for individuals at high risk of type 2 diabetes provide beneficial effects on CRFs regardless of CAD genetic risk profile.
Abstract
Coronary artery disease (CAD) is more frequent among individuals with dysglycemia. Preventive interventions for diabetes can improve cardiometabolic risk factors (CRFs), but it is unclear whether the benefits on CRFs are similar for individuals at different genetic risk for CAD. We built a 201-variant polygenic risk score (PRS) for CAD and tested for interaction with diabetes prevention strategies on 1-year changes in CRFs in 2,658 Diabetes Prevention Program (DPP) participants. We also examined whether separate lifestyle behaviors interact with PRS and affect changes in CRFs in each intervention group. Participants in both the lifestyle and metformin interventions had greater improvement in the majority of recognized CRFs compared with placebo (P < 0.001) irrespective of CAD genetic risk (P interaction > 0.05). We detected nominal significant interactions between PRS and dietary quality and physical activity on 1-year change in BMI, fasting glucose, triglycerides, and HDL cholesterol in individuals randomized to metformin or placebo, but none of them achieved the multiple-testing correction for significance. This study confirms that diabetes preventive interventions improve CRFs regardless of CAD genetic risk and delivers hypothesis-generating data on the varying benefit of increasing physical activity and improving diet on intermediate cardiovascular risk factors depending on individual CAD genetic risk profile.
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Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.
Stekovic, S, Hofer, SJ, Tripolt, N, Aon, MA, Royer, P, Pein, L, Stadler, JT, Pendl, T, Prietl, B, Url, J, et al
Cell metabolism. 2019;30(3):462-476.e6
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Intermittent fasting and calorie restriction are believed to reduce cardiometabolic risk factors and increase longevity. Fasting alternate days (ADF) involves fasting for 36 hours and eating ad libitum for 12 hours. Thirty healthy participants were randomly assigned to a long-term ADF intervention group for ≥6 months against sixty participants in the control group. After completing the cross-sectional study arm, sixty healthy participants in the control group were randomly assigned to either a four-week short-term ADF intervention group or a control group with an ad libitum diet. Study participants adhered well to the fasting regimen. Both short-term and long-term ADF intervention groups showed a significant reduction in calorie intake, improvements in anthropometric and cardiovascular parameters including reduced BMI, substantial reduction in trunk fat, lower heart rate, increased serum β-hydroxybutyrate which is cardioprotective and anti-ageing, reduced circulating triiodothyronine (fT3) levels which indicate longevity. Short-term ADF reduced systolic and diastolic pressure, mean arterial pressure, pulse pressure, and pulse wave velocity. Long-term ADF intervention reduced circulating total cholesterol, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and triglycerides, the age-related biomarker sICAM-1 for disease and inflammation, and improved lipid and amino acid metabolites. ADF did not affect insulin sensitivity. Although red blood cells and iron levels were altered, ADF interventions were not associated with iron deficiency. Healthcare professionals can use the results of this study to understand the cardioprotective and anti-ageing properties of ADF. However, further long-term robust studies are required to evaluate the effect of long-term ADF on bone health.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Short duration (<4 weeks) alternate day fasting may be an effective way to implement caloric restriction, improve body composition and reduce cardiovascular disease risk in healthy non-overweight adults.
- >6 months alternate fasting does not appear to be associated with reduced bone mass, bone mineral density of the lumbar spine region, white blood cell counts, ferritin and transferrin when compared to healthy controls.
- Both short term and long term alternate day fasting may reduce triiodothyronine in healthy adults. Low levels of fT3 without thyroid gland dysfunction has been associated with longevity in humans.
- Alternate day fasting should be performed alongside a trained clinician to reduce the risk of adverse effects due to critical medical conditions.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
Animal models have consistently demonstrated the healthspan and lifespan benefits of caloric restriction. However, chronic caloric restriction in humans has proven difficult to maintain.
Intermittent fasting may serve as a more manageable alternative to continuous caloric restriction. This randomised controlled trial and cross sectional analysis aimed to investigate the effects of alternate day fasting (ADF) on heart rate, blood pressure, cholesterol levels, CVD risk, body composition, and the metabolome and proteome of healthy, non-overweight adults (cohort median age between 48 and 52 years).
Methods
Prior to the enrollment of the study a cross sectional analysis was conducted on healthy adults engaged in long term (>6 months) alternate day fasting (n=30) and a control group (n=60).
The 60 participants from the cross sectional analysis control group were then randomised to either a 4 week ADF group or a control group. In both the >6 months and 4 weeks of ADF groups, participants were instructed to eat every second-day ad libitum, but to completely exclude solid and liquid foods and caloric beverages on fasting days.
Results
The cross sectional analysis identified that the alternate day fasting group:
- Consumed fewer calories vs the control group (−28.56%, p=0.0002).
- Had lower levels of circulating total cholesterol (p=0.004), LDL (p=0.011), VLDL (p=0.009), triglycerides (p=0.010) and a lower heart rate (p=0.040) vs the control group.
- Lower levels of soluble intercellular adhesion molecule-1 (sICAM-1) (p value 0.048), an age-associated inflammatory marker.
- Reduced circulating triiodothyronine (p<0.001) compared to the control group.
- In the metabolome, 54 out of 113 detected significantly modified metabolites (p value < 0.05) were at least 20% higher after 36 h of fasting, of which the majority (>95%) were lipids or free fatty acids, including polyunsaturated free fatty acids (PUFAs), α-tocopherol, and a type of vitamin E. 49 metabolites were at least 20% lower, consisting mainly (44.9%) of amino acids or related metabolites. Low levels of circulating amino acids have been found to increase lifespan in model organisms. The authors concluded that the elevation in fatty acids may be due to increased lipolysis from adipose tissue while the reduction in amino acids may be the result of increased gluconeogenesis.
- 13 out of 2,089 significantly (p value < 0.05) modulated protein hits within the PBMC proteome showed an increase of ≥15%, while the remaining proteins were downregulated after 36 h of fasting. Gene set enrichment analysis (GSEA) performed on the PBMC proteome unveiled changes in pathways related to lipid metabolism, pathways related to energy metabolism and stress response.
Following the 4 week intervention the alternate day fasting group demonstrated:
- Reduced caloric intake from baseline vs. the control group (−37.40% vs. −8.22%, p=0.0012).
- Greater reductions in body weight (−3.5kg vs −0.2kg, p<0.0001), BMI (−1.23kg/m2 vs −0.02kg/m2, p<0.0001) and improvements in their fat to lean mass ratio (−6.3% ± 5.0 percentage points, p value < 0.0001).
- Reduced systolic (−4.5mmHg, p=0.006) and diastolic (−2.5mmHg, p=0.03) blood pressure, heart rate (-4.5 b/min, p=0.0019), arterial (−3mmHg, p=0.0087) and pulse pressure (−2.5mmHg, p=0.0088) as well as pulse wave velocity (−1.538%, p=0.0362). Pulse wave velocity measures the rate at which pressure moves down the vessel wall and is a measure of arterial stiffness.
- Reduced circulating triiodothyronine (p<0.001) from baseline values.
Clinical practice applications:
The cross sectional analysis did not identify any differences in the long-term (>6 months) alternate day fasting group and control group in bone mass, bone mineral density of the lumbar spine region, white blood cell counts, ferritin and transferrin when compared to healthy controls. RBC counts and iron metabolism markers in the blood plasma (hematocrit, haemoglobin, iron, and transferrin saturation), were lower in the >6 months of ADF group but stayed within the reference range.
The randomised controlled trial demonstrated that alternate day fasting may be an effective intervention to reduce caloric intake, improve body composition and reduce cardiovascular disease risk in healthy non-overweight adults within 4 weeks.
Compliance rate was high with only 1 drop out in the alternate day fasting group of the randomised controlled trial.
Both the 4 week intervention and long-term (>6 month) analysis identified a reduction in triiodothyronine amongst the ADF groups. Low levels of triiodothyronine in absence of thyroid gland dysfunction has been associated with longevity in humans.
Considerations for future research:
- Future larger studies in non-healthy and/or overweight/obese populations would be useful to determine safety and efficacy of alternate day fasting within that population group.
- Further studies comparing alternate day fasting with continuous caloric restriction would be useful to identify which intervention is most beneficial for body composition and cardioprotection.
- Subgroup analysis of diet composition and diet quality may help to identify the most appropriate/inappropriate diet to compliment alternate day fasting.
- Longer duration randomised controlled trials are needed to identify any health risks or deficiencies which may develop with long term caloric restriction and alternate day fasting.
Abstract
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
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A Pilot Study To Investigate the Immune-Modulatory Effects of Fasting in Steroid-Naive Mild Asthmatics.
Han, K, Nguyen, A, Traba, J, Yao, X, Kaler, M, Huffstutler, RD, Levine, SJ, Sack, MN
Journal of immunology (Baltimore, Md. : 1950). 2018;201(5):1382-1388
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Previous studies have shown that caloric restriction and fasting may modulate immune function and have positive effects in asthmatics. The aim of this pilot study was to evaluate the effects of fasting on specific inflammatory markers that might mediate such benefits. 18 mild asthmatics, 5 of whom were not on steroid inhalers, fasted for 24 hours. Lung function and immune parameters were evaluated at baseline and 2.5 hours after the first meal following the fast. There were significant differences between subjects who were and were not on steroid inhalers. Whilst one day of fasting did not affect lung function, a number of inflammatory parameters were improved by fasting in those not taking steroid inhalers, but not in those who were taking steroids. The authors conclude that caloric restriction might be considered as a strategy to improve systemic and pulmonary inflammation in asthma.
Abstract
A fasting mimetic diet blunts inflammation, and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on the NLRP3 inflammasome, Th2 cell activation, and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study in which pulmonary function testing (PFT) and PBMCextraction was performed 24 h after fasting, with repeated PFT testing and blood draw 2.5 h after refeeding. PFTs were not changed by a prolonged fast. However, steroid-naive mild asthmatics showed fasting-dependent blunting of the NLRP3 inflammasome. Furthermore, PBMCs from these fasted asthmatics cocultured with human epithelial cells resulted in blunting of house dust mite-induced epithelial cell cytokine production and reduced CD4+ T cell Th2 activation compared with refed samples. This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level-dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study as well as the potential development of caloric restriction interventions for the treatment of asthma.
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In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles.
Eitan, E, Tosti, V, Suire, CN, Cava, E, Berkowitz, S, Bertozzi, B, Raefsky, SM, Veronese, N, Spangler, R, Spelta, F, et al
Aging cell. 2017;16(6):1430-1433
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Obesity and insulin resistance are associated with accelerated aging and increased risk of many age-related diseases. The risk of many cancers, including prostate cancer, increases with age and being overweight further increases the risk. The aim of the study is to investigate the inhibition of tumour growth through the effect of protein restriction diets and hence, levels of circulating amino acids. The participants of the study were men (n=38) with prostate cancer awaiting prostatectomy surgery. Most of the subjects were overweight with a BMI of 30.45 ± 5.8. They were randomly assigned to either a control diet or a protein restricted diet. In comparison to the control diet, results show that protein restriction increased the levels of receptors (a protein molecule that receives chemical signals from outside a cell) responsible of leptin, the hormone that controls hunger. The results also show that protein restriction can improve the body’s sensitivity to the effects of the insulin in neurons (a nerve cell specialised to transmit information throughout the body). Authors conclude that protein restriction can counteract major age-related diseases.
Abstract
Obesity, metabolic syndrome, and hyperleptinemia are associated with aging and age-associated diseases including prostate cancer. One experimental approach to inhibit tumor growth is to reduce dietary protein intake and hence levels of circulating amino acids. Dietary protein restriction (PR) increases insulin sensitivity and suppresses prostate cancer cell tumor growth in animal models, providing a rationale for clinical trials. We sought to demonstrate that biomarkers derived from plasma extracellular vesicles (EVs) reflect systemic leptin and insulin signaling and respond to dietary interventions. We studied plasma samples from men with prostate cancer awaiting prostatectomy who participated in a randomized trial of one month of PR or control diet. We found increased levels of leptin receptor in the PR group in total plasma EVs and in a subpopulation of plasma EVs expressing the neuronal marker L1CAM. Protein restriction also shifted the phosphorylation status of the insulin receptor signal transducer protein IRS1 in L1CAM+ EVs in a manner suggestive of improved insulin sensitivity. Dietary PR modifies indicators of leptin and insulin signaling in circulating EVs. These findings are consistent with improved insulin and leptin sensitivity in response to PR and open a new window for following physiologic responses to dietary interventions in humans.
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Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects.
Traba, J, Kwarteng-Siaw, M, Okoli, TC, Li, J, Huffstutler, RD, Bray, A, Waclawiw, MA, Han, K, Pelletier, M, Sauve, AA, et al
The Journal of clinical investigation. 2015;125(12):4592-600
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Intermittent fasting and caloric restriction have been shown to have beneficial effects on a particular inflammatory pathway, called NLRP3 inflammasome, which is associated with insulin resistance and asthma. In this highly technical paper the authors report a study which was conducted to confirm whether the beneficial effect of fasting on the NLRP3 inflammatory pathway is mediated via a particular protein called sirtuin and its effects on mitochondria (the energy producing parts of every cell). 19 healthy subjects fasted for 24 hours followed by a set meal. Bloods were drawn after the fast and 1 hour and 3 hours after the meal and evaluated for a number of inflammatory parameters. The NLRP3 inflammasome was less active in the fasted than in the fed state. The investigators established the involvement of sirtuin and mitochondria, as well as other inflammatory pathways in this fasting induced immune modulation.
Abstract
BACKGROUND Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity. METHODS We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation. RESULTS In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting. CONCLUSIONS Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease. TRIAL REGISTRATION ClinicalTrials.gov NCT02122575 and NCT00442195. FUNDING Division of Intramural Research, NHLBI of the NIH.
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Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
Wing, RR, Bolin, P, Brancati, FL, Bray, GA, Clark, JM, Coday, M, Crow, RS, Curtis, JM, Egan, CM, Espeland, MA, et al
The New England journal of medicine. 2013;369(2):145-54
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Weight loss is recommended for overweight or obese patients with type 2 diabetes as it increases glycaemic control, reduces risk factors of cardiovascular disease and improves overall quality of life. These benefits, however, are based on short-term studies and the long-term effects of weight loss in this population have not been examined. The aim of this randomised trial was to elucidate whether an intensive lifestyle intervention of weight loss and increased physical activity would decrease cardiovascular morbidity and mortality in overweight or obese adults with type 2 diabetes. Participants were either assigned to an intervention group receiving diet and exercise counselling, or a control group receiving diabetes support and education. A total of 5145 patients were enrolled in the study and the median follow-up was nearly 10 years. The findings of this study showed that an intensive lifestyle intervention did not reduce the risk of cardiovascular morbidity and mortality, as compared with a control programme of diabetes support and education, among overweight and obese patients. While this primary outcome was not reduced, participants in the intervention group experienced various clinically beneficial outcomes throughout the follow-up period.
Abstract
BACKGROUND Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.).