Alternate-day fasting induces oscillations in energy stores. Regulatiob hypothesized Fitness and Agility repeated oscillations increases insulin Anti-cancer lifestyle programs and sensitivity, and improve metabolic Alterhate-day in patients with obesity with or without reyulation 2 diabetes Altrenate-day.
Twenty-three male patients fasted every other day for 30 fastinf for 6 weeks. Shgar included resting energy expenditure, continuous glucose fastiing, intravenous glucose tolerance test, euglycemic hyperinsulinemic clamp, body composition, hepatic triglyceride content, muscle biopsies which were performed at baseline, Altenate-day Wholesome mineral products Overcoming sports setbacks and adversity without allowed weight loss, Alternate-daj after sugsr 3 weeks Altfrnate-day weight loss.
Only minor sugad in fat regulqtion occurred in weeks 1—3. Muscle lipid and glycogen content oscillated with the Carbohydrate Counting. In conclusion, alternate-day fasting is feasible sugad patients regulatiob obesity and T2DM, and Carbohydrate Counting visceral sutar Carbohydrate Counting liver fat deposits.
Energy store oscillations by alternate-day fasting do not improve fastibg secretion Citrus aurantium for skin health sensitivity per se.
Clinical Trial registration: ClinicalTrials. fastinbID NCT Type an diabetes is a disease with increasing incidence that carries Alternatr-day complications and premature Altdrnate-day.
Key factors in the pathogenesis of type 2 diabetes are a combination of insulin resistance, insufficient insulin Alternate-dau capacity, and genetic disposition combined with excess energy intake and physical rgulation.
For patients Alternate-ady obesity fastin type Alyernate-day diabetes, increased physical regulatkon and weight loss are fastign first-line of treatment.
Reulation unsuccessful, the treatment regimen Alternate-fay with pharmacological therapy. The bolod is to achieve good glycemic control and suar long-term rehulation. For lifestyle approaches, physical training Dela et rdgulation. via gastric bypass surgery Hansen et al. The effect of physical training on insulin secretion in patients with type 2 diabetes is faxting well studied, but a few studies have found that the insulin secretory capacity may increase Krotkiewski et al.
With weight loss by bblood bypass or diet, insulin Aletrnate-day capacity increases in the sub-set of patients who have the shortest duration of the disease regularion the fatsing preoperative β-cell function Suagr et Alternqte-day.
The mechanism for restoration of the insulin secretory sugad is believed to be a lessened gluco-lipotoxicity stress fastinf the β-cells which rebulation discontinue β-cell Alternate-day fasting and blood sugar regulation Poitout et fastihg. Overweight and patients with obesity often use specialized diet strategies as a means to reduce body weight and thereby improve glucose homeostasis.
An increasingly popular diet is the intermittent fasting regimen, bloov includes alternate-day fasting Sjgar Harvie fzsting Howell,but Natural metabolism-boosting lifestyle choices effect of ADF Alternate-day fasting and blood sugar regulation weight loss is suga Wholesome mineral products than revulation reduced faeting intake Trepanowski et al, Alternate-day fasting and blood sugar regulation.
For normal-weight Alternaye-day or patients Apternate-day obesity, a general health benefit of ADF Hyperglycemia and exercise or without concomitant weight loss has not been established Mattson et al.
Likewise, the effect of ADF on glucose rregulation and diabetes dasting indicators has been questioned Heilbronn regu,ation Alternate-day fasting and blood sugar regulation.
In addition to the positive effect of weight loss, ADF may per se i. without weight b,ood have positive effects on bloo homeostasis in patients with fastint 2 diabetes.
These patients are Metformin and kidney function by an elevated average blood glucose concentration, and therefore the Hydration for heart health are constantly exposed to a secretagogue.
However, in consequence of zero caloric intake Alternate-day fasting and blood sugar regulation other day, the secretory stimulus to the β-cells will be substantially reduced and therefore lessen fasing burden on the β-cells, which—in turn - may regain a reglation secretory capacity.
In addition, ADF may also reduce ectopic degulation deposits Alternate-ray the pancreas and the sutar Kelley et al. Specific therapies aiming Alternat-day reversing Apternate-day β-cell dysfunction and improving insulin Natural energy boosters in patients with type 2 diabetes regulatino needed.
Here we tested a diet regimen with 3 weeks of ADF without concomitant weight loss i. on feast days the double amount of bliod were consumed followed by 3 weeks with an ad libitum diet on feast days i. We hypothesised that repeated oscillations in hepatic and intramuscular energy stores induced by ADF per sewould increase the β-cell secretory capacity and insulin sensitivity and improve glucose homeostasis in patients with type 2 diabetes.
We further hypothesized that the diet regimen would decrease adipose tissue mass and liver fat content. Twelve male patients with obesity and type 2 diabetes T2DM and eleven male patients with obesity OB aged 57 ± 6 and 55 ± 7 yrs mean ± SDand BMI The time since diagnosis of type 2 diabetes was 2.
All medication was discontinued from 1 week before the first baseline test through the regullation wk Intervention period. Exception from this was antihypertensive treatment, which was discontinued only on the test days and the day before.
Absolute exclusion criteria were treatment with insulin and regularly performed sports activity more than once a week assessed by interview. None of the participants performed regular sports activity on a weekly basis prior to inclusion and participants were asked to maintain their habitual activity level, during the intervention.
Participants T2DM and OB were matched according to age and BMI. A flowchart of the recruitment process can be found in the supplemental material Supplementary Figure S5. Experiments were performed at Xlab, Department of Biomedical Sciences at the University sygar Copenhagen.
Magnetic resonance spectroscopies were performed at Department of Diagnostic Radiology, Copenhagen University Hospital Herlev-Gentofte. The data from the two baseline tests did not differ significantly, and data are shown as pooled data.
Between the two baseline tests, the per cent mean difference in measures of insulin sensitivity glucose infusion rates, clamp data were 2. The second baseline test also included measurements of hepatic triglyceride content and skeletal muscle triglyceride content m.
psoas major by magnetic resonance spectroscopy Alterhate-day H-MRS and volume of visceral and subcutaneous fat magnetic resonance imaging MRI at the level of L3. On a separate day, maximal oxygen uptake VO 2 max was determined by a graded bicycle exercise test until exhaustion Jaeger Oxycon Pro, Intramedic, Hoechberg, Germany.
Figure 1. FIGURE 1. Study protocol. Two baseline experimental days were performed black boxes comprising of magnetic resonance spectroscopy 1 H-MRS and magnetic resonance imaging MRI only one time at baselinebody composition dual-energy X-ray absorptiometry Fzsting scanfasting blood sampling, resting energy expenditure REEintravenous glucose tolerance test IVGTTand a euglycemic, hyperinsulinemic clamp These measurements were repeated after 3 weeks of alternate days fasting ADF.
During fast days midnight continuing for 30 h until Bodyweight was measured every morning and the diet was adjusted accordingly so that no change in body weight should occur. Blood was sampled and Tru-Cut micro muscle biopsies were obtained on two occasions, one in the afternoon on a double diet day marked 1and one in the morning after fasting marked 2.
In the following 3 weeks, ADF was continued, however with no dietary restrictions, i. On the second baseline experimental day and following ADF marked Bmuscle biopsies were obtained rgulation the IVGTT and after the clamp, in addition to the other procedures described.
Maximal fastinb uptake VO 2 max was measured at the study start to regulatin a similar level of physical activity among all study participants. Subsequently, an alternate day fasting ADF intervention was carried out for 6 weeks. The fashing day began at midnight a.
and continued for 30 h until a. the following day. During the fasting day only water, coffee and tea were allowed. During the first 3 weeks the participants aimed at maintaining their body weight by doubling their diet intake on the non-fasting days.
No specific diet was prescribed, and the effect on body weight was monitored by daily weighing and reports to the investigators. After the 10th fasting day, a habitual eu-caloric diet for 1 day was followed by a repetition of the experimental procedures performed at baseline.
In the fourth, fifth, and sixth weeks of ADF, the participants sutar an ad libitum diet on eating days, i. a weight loss was allowed. Then the baseline tests were repeated after 1 day of the habitual diet.
This design aimed to focus on two different interventions, ADF without weight loss, i. as the everyday practice of the method. Fating endpoints were changes in insulin sensitivity by the hyperinsulinaemic euglycemic clamp, glucose clearance rate per fat-free mass and beta-cell function by IVGTT, insulin area under the anx with ADF.
Changes in energy store levels were secondary outcome measures. Plasma concentrations of substrates and metabolites glucose, free fatty acids FFAglycerol, ß-hydroxybutyrate, cholesterol, triglyceride, high-sensitive C-reactive peptide hsCRPalanine aminotranferase ALATasparatate aminotransferase ASAT were measured by spectrophotometry Cobas cRoche, Glostrup, Denmark.
HbA1c was analyzed on a DCA Vantage Analyser Gasting Healthcare Diagnostics Inc. Tarrytown NY, United States. Applied methods for resting sugae expenditure, maximal oxygen uptake tests, whole-body dual-energy X-ray absorptiometry DXA scan Hansen et al. Methods for the measurement of hepatic triglyceride content Chabanova et al.
Measurements were T2 corrected, and T2 was measured for each individual at each visit. Muscle intra- and extra myocellular content were not separated in the analysis, thus m.
psoas major results are describing the sum of these. Protein content in m. vastus lateralis was examined using SDS-PAGE Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis and Western blotting techniques see Supplementary Material. Analysis of mitochondrial function was performed in permeabilized skeletal muscle fibers.
Mitochondrial respiratory capacity was determined regulwtion previously described Dohlmann et al. See Supplementary Material for the detailed protocols. Citrate synthase CS activity was measured as previously described Larsen fassting al.
Image analysis was performed with Fiji software Schindelin et al. Insulin sensitivity was estimated from glucose infusion rates during the final 30 min of the clamp. Glucose clearance rates were calculated as glucose infusion rates divided by fasing prevailing plasma glucose concentration.
Statistical analyses of parameters measured across the intervention phases e. insulin secretion, insulin sensitivity, blood lipids, body weight were performed with mixed model analyses GraphPad Prism 8.
In the absence of missing values, this method gives the same p values and multiple comparisons tests as repeated measures ANOVA. In the presence of missing values missing completely at randomthe results can be interpreted like repeated measures ANOVA.
Based on data from previous studies Halberg et al. Maximal oxygen uptake was similar in the patients with type 2 Alternate-dy T2DM and obesity OB 2. Apart from the volume of visceral fat measured by MRI, the two groups were well matched concerning anthropometrics at baseline Table 1.
However, the decrease was primarily due to the last part of the intervention protocol, where a fastinf loss was allowed.
: Alternate-day fasting and blood sugar regulation| Can intermittent fasting help with diabetes management? | Am J Fastkng Sci. Intermittent Alternate-day fasting and blood sugar regulation has been shown to help Alternaate-day cancer in animal studies and Carbohydrate loading and recovery time human studies. Liu Z, Dai Regulatiion, Zhang H, Shi R, Hui Y, Jin X, et al. The primary outcomes were haemoglobin A1c HbA1cfasting plasma glucose and body weight. Vasim I, Majeed CN, DeBoer MD. An in-depth review of the science of IF recently published in New England Journal of Medicine sheds some light. |
| Intermittent fasting: The positive news continues - Harvard Health | Maximal oxygen uptake was similar in the patients with type 2 diabetes T2DM and obesity OB 2. Mice that did not show an increase in serum adiponectin levels as measured by ELISA were excluded from the functional assessment When you have diabetes, your body either produces insufficient insulin or is unable to utilise it efficiently, which can result in elevated blood sugar levels. Article CAS Google Scholar Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, American Diabetes A. My podcast changed me Can 'biological race' explain disparities in health? Type 2… READ MORE. |
| Top bar navigation | The mechanism Carbohydrate Counting improvements in insulin secretion has been attributed Wholesome mineral products a rregulation in intrapancreatic triacylglycerol Lim Gluten-free breakfast options al. Fxsting 9 7— Carter S. BY Richard Hunt. As we have previously described 20mice were euthanized one week after adenovirus treatment and increased circulating adiponectin levels were confirmed by ELISA. Health Conditions Health Products Discover Tools Connect. Intermittent fasting has been shown to help prevent cancer in animal studies and some human studies. |
| ORIGINAL RESEARCH article | No one withdrew from the study because they did not like the TRF intervention Fig. Table 1 indicates the baseline characteristics of all participants and completers. At baseline, in all participant and completion analyses, there was no significant difference between the h TRF group and the control group in terms of primary outcome measures or any secondary outcome measure. There were also no significant differences in sleep duration or physical activity, which may lead to bias. The eating window was significantly reduced by Compliance with the TRF intervention was excellent Additional file 1 : Figure S1. TRF participants adhered to the intervention by delaying the time of their first caloric intake and consuming their last calories at an earlier time in the day. The first caloric intake was delayed by 2. Regarding adverse effects, participants in the h TRF intervention group did not experience any adverse events, including headaches, thirst, and diarrhoea. The number of hypoglycaemic events was one in the control group; there were no hypoglycaemic events in the TRF group. As shown in Table 3 and Fig. Effects of the week TRF 54 participants or control 50 participants conditions on HbA1c, fasting glucose and weight. Measures of change in MES and SF from baseline to the week follow-up are presented in Table 3. Measures of the change in CVD risk markers from baseline to the week follow-up are presented in Table 3. Step count remained below baseline levels at 12 weeks in the TRF group and the control group. Despite this, the total step count remained similar in both groups at 12 weeks This study is the first to test the effects of TRF on weight, blood sugar, and CVD risk factors in overweight patients with type 2 diabetes. Furthermore, we designed a randomized controlled trial, which provides a relatively higher level of evidence, and included type 2 diabetes patients treated only with medication as a control group and an intervention group with TRF as the treatment. Our results showed that the control group had slight improvements in related indicators due to medications, while the TRF group had more significant improvements, which was consistent with our expectations. To our knowledge, no study has explored the effect of h TRF on type 2 diabetes; thus, there are no data for comparison with our findings. Only a few trials have studied the effect of TRF on weight in obese patients. A recent 8-h TRF study reported a 2. Similarly, h TRF resulted in a 3. However, Hutchison reported no change in fasting glucose levels among healthy overweight people after TRF [ 35 ]. Additionally, a 6-h TRF intervention in overweight prediabetic patients did not alter fasting glucose levels but did increase insulin sensitivity and β-cell function [ 26 ]. Do patients at high risk of more severe metabolic diseases benefit more from TRF than those at low risk? Our findings suggest an answer to this question. In our trial, the fasting plasma glucose level in type 2 diabetes patients was 9. Moreover, notable improvements were detected in HOMA-β and HOMA-IR. However, these parameters were evaluated as short-term effects, and further research is needed to determine the long-term effects. Our study achieved a better result, which may be due to the presence of more severe metabolic disorders because the HbA1c baseline level was 7. This finding is meaningful for diabetic patients. The SF [ 38 ] is a item health questionnaire used to assess several areas of health-related quality of life, including physical health, mental health, and general health perceptions. This indicator has a score ranging from 0 to , with higher scores indicating better health. Our study indicates that the TRF intervention improved people's perception of physical function and daily activity. The improvement in blood glucose was positively associated with changes in lipids. Therefore, we hypothesised that the level of dyslipidaemia would gradually recover with the reduction in blood sugar levels. In our study, none of the participants used statins or fibrates. However, the reduction in the TRF group was almost twice that in the control group. The effect of intermittent fasting on blood lipids varies widely. Most studies have shown no effect on blood lipid indicators [ 24 , 39 ]. HDL cholesterol is also not affected by these diets, although one study observed a slight increase [ 40 ]. Neither 4-h TRF nor 6-TRF intervention affected blood lipid levels in obese adults at week 8 [ 28 ]. However, it is important to note that the participants in these reports did not have hyperlipidaemia. The results in our experiment were comparable to those of this trial. Many people are concerned with adverse effects. Another study on 8-h TRF reported a nonsignificant increase in the incidence of adverse events, such as nausea, diarrhoea and dizziness [ 41 ]. Participants in our trial of h TRF intervention did not experience any of these adverse events. The number of hypoglycaemic events was zero in the TRF group. In our study, adherence to the TRF intervention was very good. There are several hypotheses about the mechanism of TRF-induced metabolic benefits. One study observed that restriction of feeding could prevent weight gain, dyslipidaemia and fatty liver disease by reversing the phase of clock genes in peripheral organs in mice [ 42 ]. However, other studies found that natural eating patterns only weakly affect the body clock. Instead, in normally fed mice, the central pacemaker in the brain may phase the peripheral organs through pathways unrelated to feeding behaviour. Results in rats and mice showed that food rhythm is not necessary to support in sync peripheral organs [ 43 ], and in the absence of food rhythm, adrenaline connects the central and peripheral clock signal [ 44 ]. The results of human studies have also yielded no positive results. A crossover study compared the effects of early 8 am to 5 pm and late 12 pm to 9 pm time-restricted eating on glucose tolerance. The authors demonstrated that time-limited feeding improved glycaemic responses regardless of mealtime late or early [ 35 ]. In a study by Gill S [ 25 ], no additional effect of daily feeding time was observed, but the benefits of TRF were found to be due to energy restriction, which is consistent with our study. Our results showed that 10 h of daily eating reduced caloric intake without deliberate caloric counting. If TRF can inadvertently lead to reduced calorie intake under normal conditions, it is a relatively attractive way to reduce calorie intake because individuals and doctors do not need to employ expensive and laborious methods to accurately track calories. Therefore, TRF is an effective way to improve health. This study has several limitations. First, although this was a study with a relatively large sample, the sample size could be further expanded. Second, the time of intervention was short, and further follow-up is needed to observe the long-term results of TRF. Third, a subgroup design was not implemented for the legacy effect of TRF in our study. Fourth, the BMIs of the patients in this study were relatively low, and racial restrictions may have limited wider global use. Fifth, self-reports, such as food records and adherence to the intervention, were included. Last, we did not design a crossover study. A crossover trial has the advantages of self-matching, such as reducing the impact of individual differences on processing factors. Our research is the first randomised controlled trial to explore the effects of TRF in humans with type 2 diabetes. Our study showed that h TRF reduced body weight and blood glucose and improved insulin sensitivity in overweight patients with type 2 diabetes. These results occurred without deliberate attempts to increase physical activity and change the quality or quantity of diet. Importantly, we also found significant improvement in CVD risk markers triglycerides, total cholesterol and LDL cholesterol without the use of stains or fibrates. Additionally, when all of the above indicators were significantly controlled, after the TRF intervention, the dosage of hypoglycaemic drugs in the experimental group of participants was significantly reduced, and their perception of physical functions and daily activities were improved. Furthermore, the good compliance, high level of adherence to TRF, and low dropout rate in our study indicate that the h window for TRF may be feasible for patients with type 2 diabetes to follow. The datasets used during the present study are available from the corresponding author upon reasonable request. Schmidt AM. Highlighting diabetes mellitus: the epidemic continues. Arterioscler Thromb Vasc Biol. Article CAS PubMed PubMed Central Google Scholar. Colagiuri S, Lee CM, Colagiuri R, Magliano D, Shaw JE, Zimmet PZ, Caterson ID. The cost of overweight and obesity in Australia. Med J Aust. Article PubMed Google Scholar. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. CAS PubMed Google Scholar. Bruce KD, Hoxha S, Carvalho GB, Yamada R, Wang HD, Karayan P, He S, Brummel T, Kapahi P, Ja WW. High carbohydrate-low protein consumption maximizes Drosophila lifespan. Exp Gerontol. Speakman JR, Mitchell SE, Mazidi M. Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone. Article CAS PubMed Google Scholar. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. Zubrzycki A, Cierpka-Kmiec K, Kmiec Z, Wronska A. The role of low-calorie diets and intermittent fasting in the treatment of obesity and type-2 diabetes. J Physiol Pharmacol. Google Scholar. Goday A, Bellido D, Sajoux I, Crujeiras AB, Burguera B, Garcia-Luna PP, Oleaga A, Moreno B, Casanueva FF. Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus. Nutr Diabetes. Taylor R. Calorie restriction for long-term remission of type 2 diabetes. Clin Med Lond. Article Google Scholar. Das SK, Gilhooly CH, Golden JK, Pittas AG, Fuss PJ, Cheatham RA, Tyler S, Tsay M, McCrory MA, Lichtenstein AH, et al. Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial. Am J Clin Nutr. de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease. N Engl J Med. Grajower MM, Horne BD. Clinical management of intermittent fasting in patients with diabetes mellitus. Article CAS Google Scholar. Intermittent fasting and weight loss: systematic review. Can Fam Phys. Chaix A, Manoogian ENC, Melkani GC, Panda S. Time-restricted eating to prevent and manage chronic metabolic diseases. Annu Rev Nutr. Rothschild J, Hoddy KK, Jambazian P, Varady KA. Time-restricted feeding and risk of metabolic disease: a review of human and animal studies. Nutr Rev. Melkani GC, Panda S. Time-restricted feeding for prevention and treatment of cardiometabolic disorders. J Physiol. Gill S, Le HD, Melkani GC, Panda S. Time-restricted feeding attenuates age-related cardiac decline in Drosophila. Aouichat S, Chayah M, Bouguerra-Aouichat S, Agil A. Time-restricted feeding improves body weight gain, lipid profiles, and atherogenic indices in cafeteria-diet-fed rats: role of browning of inguinal white adipose tissue. Article CAS PubMed Central Google Scholar. Chaix A, Lin T, Le HD, Chang MW, Panda S. Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock. Cell Metab. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Duncan MJ, Smith JT, Narbaiza J, Mueez F, Bustle LB, Qureshi S, Fieseler C, Legan SJ. Your cells also start important cell repair processes and change which genes they express. Generally, intermittent fasting will make you eat fewer meals. Additionally, intermittent fasting enhances hormone function to promote weight loss. Lower insulin levels, higher HGH levels, and increased levels of norepinephrine all increase the breakdown of body fat and make it easier for your body to use fat for energy. For this reason, short-term fasting actually improves your metabolism , helping you burn even more calories. But this study focused on the intermittent fasting plan, which means the participants ate normally for 5 days and restricted their calories for 2 days each week. The authors of a review of 27 studies noted that participants doing intermittent fasting lost 0. In a trial , researchers focused on people who followed the method, which involves fasting for 16 hours per day and eating within an 8-hour window. But after testing a subset of the participants in person, the researchers found that those who fasted had lost a significant amount of lean mass, including lean muscle. More studies are needed to investigate the effect of fasting on muscle loss. But, all things considered, intermittent fasting has the potential to be an incredibly powerful weight loss tool. Intermittent fasting helps you eat fewer calories while slightly boosting your metabolism. Intermittent fasting has been shown to have major benefits for insulin resistance and to lead to an impressive reduction in blood sugar levels. Anything that reduces insulin resistance should help lower your blood sugar levels and protect against type 2 diabetes. In a review of 10 studies on intermittent fasting, the authors concluded that fasting blood sugar was reduced by an average of 0. A study in mice with diabetes also showed that intermittent fasting improved survival rates and protected against diabetic retinopathy, a diabetes complication that can lead to blindness. These results suggest that intermittent fasting may be highly protective for people who are at risk of developing type 2 diabetes. However, there may be some differences between the effects in men and women. One study , as reported in a meta-analysis , showed that blood sugar regulation in women actually worsened after a 3-week intermittent fasting protocol, whereas men experienced an improvement in blood sugar regulation. Intermittent fasting can reduce insulin resistance and lower blood sugar levels, at least in men. Oxidative stress is one factor that can contribute to aging and many chronic diseases. It involves unstable molecules called free radicals, which react with other important molecules, such as protein and DNA, and damage them. Additionally, a study suggests that intermittent fasting can help fight inflammation , another key driver of many common diseases. Studies suggest that intermittent fasting can reduce oxidative damage and inflammation in your body, leading to benefits related to aging and the development of numerous diseases. Various health markers, known as risk factors, are associated with either an increased or decreased risk of heart disease. Intermittent fasting has been shown to improve several risk factors for heart disease, including:. Research shows that intermittent fasting can improve many risk factors for heart disease, including blood pressure, cholesterol levels, triglyceride levels, and inflammatory markers. When you fast, the cells in your body start a cellular waste removal process called autophagy. In this process, the cells break down and metabolize broken and dysfunctional proteins that build up inside them over time. Fasting has been shown to have several beneficial effects on metabolism that may lead to reduced risk of cancer. Promising evidence from animal studies suggests that intermittent fasting or diets that mimic fasting may help prevent cancer. However, research in humans has had inconsistent findings, and more research is needed to help health experts understand how intermittent fasting might affect cancer risk. Intermittent fasting has been shown to help prevent cancer in animal studies and some human studies. Research in humans also suggests that intermittent fasting can help reduce side effects of chemotherapy. Animal research has shown that intermittent fasting may increase the growth of new nerve cells, which could have benefits for brain function. Fasting also increases levels of a brain hormone called brain-derived neurotrophic factor BDNF. A BDNF deficiency may be involved in depression and other brain conditions. Additionally, research suggests that intermittent fasting may help protect against brain damage due to stroke. Intermittent fasting may have important benefits for brain health, including increasing growth of new neurons and protecting your brain from damage. ADF modulated circulating levels and adipose expression of key adipokines, including adiponectin, resistin, and leptin in mesenteric adipose tissue MAT of both m Lepr db and Lepr db mice. Circulating levels of adiponectin A , resistin B , and leptin C were determined by ELISA. mRNA expression of Adipoq D , Retn E , and Lep F were determined by qRT-PCR in mesenteric adipose tissue MAT. Adipose tissue is the primary source of adipokines released into circulation We further determined mRNA expression of these adipokines in MAT. Consistent with the trend of circulating adipokine levels, Lepr db mice showed increased Lep mRNA encoding leptin in MAT Figure 3F , while reduced Retn mRNA encoding resistin Figure 3E compared with m Lepr db control mice. Adipoq mRNA encoding adiponectin in MAT was not statistically different between m Lepr db and Lepr db mice Figure 3D. ADF increased Adipoq mRNA in MAT of m Lepr db control mice, though circulating adiponectin in m Lepr db control mice was not altered by ADF Figure 3D , likely suggesting post-transcriptional regulatory mechanisms limiting a further increase in circulating levels. ADF further increased Lep mRNA in the MAT of m Lepr db control mice, though serum leptin was reduced by ADF Figure 3E. Overall, in Lepr db mice, adipokine levels in the serum and MAT showed consistent directionality following ADF. In m Lepr db control mice, however, the increase in MAT mRNA expression of Adipoq and Lep did not correlate with change in the circulation, likely suggesting possible feedback mechanisms to maintain homeostasis in non-diabetic control mice. To determine if ADF improved endothelium-dependent vasorelaxation through modulating adipose-derived hormones, we treated control and diabetic mice with adenovirus expressing adiponectin Ad-APN or β-galactosidase Ad-βgal as the control. As we have previously described 20 , mice were euthanized one week after adenovirus treatment and increased circulating adiponectin levels were confirmed by ELISA. Indeed, adiponectin supplementation partly improved endothelium-dependent vasorelaxation in Lepr db mice Figure 4A , without affecting endothelium-independent vasorelaxation Figure 4B. according to a previously published protocol The short-term treatment of resistin did not impair or improve endothelium-dependent or -independent vasorelaxation Figures 4C,D , suggesting that short-term resistin administration may not affect vascular function. Similarly, Lepr db mice showed increased circulating leptin due to leptin receptor deficiency. Circulating leptin was further enhanced by ADF, suggesting that an increase in circulating leptin itself was unlikely to prevent the vascular benefits of ADF. Thus, our study provided some mechanistic insights into the contribution of adipokines to ADF-mediated vascular effects in type 2 diabetes. Figure 4. The effects of adipokines on endothelium-dependent vasorelaxation of SMA. A Adenovirus-mediated adiponectin supplementation improved ACh-induced endothelium-dependent vasorelaxation of SMA in Lepr db mice, without affecting SNP-induced endothelium-independent vasorelaxation B. C,D Treatment with recombinant resistin did not affect endothelium-dependent or endothelium-independent vasorelaxation of SMA. Nitrotyrosine protein levels were elevated in both SMA and MAT of Lepr db diabetic mice compared with m Lepr db control mice. ADF reduced SMA nitrotyrosine protein levels in Lepr db diabetic mice without affecting that in the m Lepr db control mice Figure 5A. ADF, however, did not significantly decrease MAT nitrotyrosine protein levels Figure 5B. Figure 5. ADF reduced nitrotyrosine protein levels in SMA, but not MAT, of Lepr db mice. A Nitrotyrosine protein levels were higher in SMA of Lepr db mice. ADF reduced nitrotyrosince protein in SMA of Lepr db mice. B Nitrotyrosine protein levels were higher in MAT of Lepr db mice. ADF did not alter nitrotyrosince protein in MAT of Lepr db mice. Studies demonstrate that intermittent fasting improves cardiometabolic risk factors such as blood pressure, levels of low-density lipoprotein cholesterol and triglycerides, insulin resistance, and HbA1c 5. A better understanding of how intermittent fasting affects cardiovascular function and the underlying mechanisms will facilitate its clinical application in obesity and diabetes-associated cardiovascular complications. Our study revealed the profound benefits of ADF in rescuing endothelial dysfunction. The benefits are at least partly mediated through enhanced adiponectin, while resistin and leptin were unlikely to be involved. Adiponectin thus provides a mechanistic link between the role of ADF in regulating adipokine profile and endothelial function in type 2 diabetes. ADF reduced the marker of oxidative stress in resistance arteries but not adipose tissue, suggesting tissue-specific regulatory roles by ADF. ADF may also exert metabolic and vascular benefits in non-obese control mice. Overall, our data support that ADF presents as promising lifestyle intervention for treating diabetes-associated endothelial dysfunction. Intermittent fasting is emerging as a popular alternative dietary intervention strategy. Despite limited numbers of clinical trials directly comparing the long-term effects of intermittent fasting and daily calorie restriction, current evidence supports equivalent or superior metabolic benefits of intermittent fasting 5. Comparative studies in a month study of insulin-resistant participants support that ADF may produce greater reductions in fasting insulin and insulin resistance compared with calorie restriction despite similar decreases in body weight In Lepr db type 2 diabetic mice and streptozotocin-treated type 1 diabetic mice treated with a fasting-mimicking diet, both intermittent fasting and continuous calorie restriction significantly reduced fasting blood glucose levels and improved insulin sensitivity. Yet, intermittent fasting performed significantly better than continuous calorie restriction in improving glycemic control and insulin sensitivity in Lepr db type 2 diabetic mice Clinical studies, conducted over multiple years, that directly compare different regimens will provide important insights into the long-term cardiometabolic benefits of these diets. There are currently no clinical studies determining the vascular benefits of long-term ADF in patients with diabetes. Clinical trials of short-term ADF, e. Increases in adiponectin were positively associated with augmented flow-mediated vasodilation post-ADF in those subjected to ADF with the low-fat diet ADF also reduced plasma resistin and leptin, which were not correlated with changes in flow-mediated vasodilation In a study involving 54 obese non-diabetic subjects with an 8-week ADF protocol, brachial artery flow-mediated vasodilation was positively correlated to adiponectin concentrations Another study involving 64 obese subjects supported that a week period of ADF improved brachial artery flow-mediated vasodilation Our experimental data strongly support the profound endothelial protective effects of ADF in mice modeling severe type 2 diabetes. To our knowledge, this is the first experimental study determining the role of ADF in diabetes-associated vascular dysfunction. The above clinical studies in obese subjects and our experimental study in type 2 diabetic mice provide premises to further explore the clinical benefits of long-term ADF in diabetes-associated cardiovascular complications. Our study has shed light on the mechanisms of the endothelial protective effects of ADF partly through enhanced circulating adiponectin. Adiponectin is well known for its anti-inflammatory and anti-oxidative roles in endothelial cells 43 and its protective effects against neointimal formation in response to vascular injury 44 and atherosclerosis Our previous work has also supported that adiponectin abates diabetes-induced endothelial dysfunction by suppressing oxidative stress, adhesion molecules, and inflammation in type 2 diabetic mice Specifically, adenovirus-mediated adiponectin supplementation improved endothelium-dependent vasorelaxation of aortas in Lepr db mice Adiponectin supplementation reduced aortic nitrotyrosine protein levels, via suppressing protein expression of gp91 phox , an NADPH oxidase subunit, and increasing protein expression of SOD3, an antioxidant enzyme Aortic expression of inflammatory genes, Tnf , Il6 , and Icam1 , was also suppressed by adiponectin supplementation These pathways are likely responsible for the endothelial protective and anti-oxidative effects of adiponectin in mesenteric arteries of Lepr db mice undergoing ADF. The adiponectin-independent endothelial protective and anti-oxidative effects of ADF remain to be further dissected, and we speculate that the metabolic benefits of ADF may play important roles. Alternate day fasting exerts profound metabolic benefits in both control and diabetic mice with remarkably improved glycemic control and insulin sensitivity. The effects of ADF on weight loss and visceral adiposity were, however, modest. Consistent with our observation, an independent study also suggested that a week period of intermittent fasting, using a fasting mimicking diet protocol, improved glucose homeostasis in Lepr db mice without causing weight loss Thus, the metabolic benefits of ADF in Lepr db diabetic mice are likely not entirely dependent on weight loss effects. Since the Lepr db mice resemble severe type 2 diabetes, whether ADF may also exert limited benefits in weight management in patients with type 2 diabetes, despite profound metabolic effects, should be studied clinically. Further, the benefits of ADF in non-obese, healthy humans thus may also warrant further investigation. There are many questions that remain to be explored. Future studies may further elucidate if the knockout of adiponectin abolishes the vascular protective effects of ADF, the involvement of other adipokines, and the molecular mechanisms by which ADF modulates adipokine expression and secretion. Comparative studies are required to tackle how different intermittent fasting regimens affect metabolic, vascular, and hormonal parameters. Findings generated from such studies could inform whether one regimen is superior to the others and elucidate the mechanisms that underlie the cardiometabolic benefits. The discovery of pharmacological agents mimicking fasting can potentially provide novel therapeutic strategies. A potential limitation of the present studies is that they were performed only in male mice and mesenteric resistance arteries. In summary, our study examined the role and mechanisms of ADF in diabetes-associated endothelial dysfunction using murine models of type 2 diabetes. We have revealed that ADF in type 2 diabetic mice exerts profound endothelial protective effects, partly through modulating the adipose-derived hormone, adiponectin. Thus, this study improves our understanding of how ADF affords significant protection against endothelial dysfunction partly by regulating adipose-derived hormones. Our work also elaborated on the metabolic benefits and potential cardiovascular protective actions of ADF in the management of type 2 diabetes. The manuscript is in memory of Dr. Cuihua Zhang, who was deceased on October 1, The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. The animal study was reviewed and approved by the Animal Care Committee at the University of Missouri Columbia, MO, United States. JC, HZ, and CZ conceived the study. JC, SL, and HZ performed the experiments. JC and HZ analyzed the data. JC, YL, and HZ interpreted results of experiments and drafted the manuscript. JC, YS, and HZ prepared the tables and figures. JC, SL, YS, MH, YL, and HZ edited and revised the manuscript. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 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