Alternate-day fasting and hormone regulation -
gov , ID NCT Type 2 diabetes is a disease with increasing incidence that carries long-term complications and premature death. Key factors in the pathogenesis of type 2 diabetes are a combination of insulin resistance, insufficient insulin secretory capacity, and genetic disposition combined with excess energy intake and physical inactivity.
For patients with obesity and type 2 diabetes, increased physical activity and weight loss are the first-line of treatment. If unsuccessful, the treatment regimen proceeds with pharmacological therapy.
The goal is to achieve good glycemic control and prevent long-term complications. For lifestyle approaches, physical training Dela et al. via gastric bypass surgery Hansen et al. The effect of physical training on insulin secretion in patients with type 2 diabetes is less well studied, but a few studies have found that the insulin secretory capacity may increase Krotkiewski et al.
With weight loss by gastric bypass or diet, insulin secretory capacity increases in the sub-set of patients who have the shortest duration of the disease and the best preoperative β-cell function Lund et al. The mechanism for restoration of the insulin secretory capacity is believed to be a lessened gluco-lipotoxicity stress on the β-cells which will discontinue β-cell dedifferentiation Poitout et al.
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, which includes alternate-day fasting ADF Harvie and Howell, , but the effect of ADF on weight loss is not better than everyday reduced caloric intake Trepanowski et al. For normal-weight people or patients with obesity, a general health benefit of ADF with or without concomitant weight loss has not been established Mattson et al.
Likewise, the effect of ADF on glucose homeostasis and diabetes risk indicators has been questioned Heilbronn et al. In addition to the positive effect of weight loss, ADF may per se i. without weight loss have positive effects on glucose homeostasis in patients with type 2 diabetes.
These patients are characterized by an elevated average blood glucose concentration, and therefore the β-cells are constantly exposed to a secretagogue. However, in consequence of zero caloric intake every other day, the secretory stimulus to the β-cells will be substantially reduced and therefore lessen the burden on the β-cells, which—in turn - may regain a higher secretory capacity.
In addition, ADF may also reduce ectopic fat deposits in the pancreas and the liver Kelley et al. Specific therapies aiming at reversing the β-cell dysfunction and improving insulin sensitivity in patients with type 2 diabetes are needed.
Here we tested a diet regimen with 3 weeks of ADF without concomitant weight loss i. on feast days the double amount of food 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 se , would 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 ± SD , and 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 6 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 of 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 1 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 baseline , body composition dual-energy X-ray absorptiometry DXA scan , fasting blood sampling, resting energy expenditure REE , intravenous glucose tolerance test IVGTT , and 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 1 , and 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 B , muscle biopsies were obtained before the IVGTT and after the clamp, in addition to the other procedures described.
Maximal oxygen uptake VO 2 max was measured at the study start to document a similar level of physical activity among all study participants. Subsequently, an alternate day fasting ADF intervention was carried out for 6 weeks.
The fasting 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 followed 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. Primary 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 curve with ADF.
Changes in energy store levels were secondary outcome measures. Plasma concentrations of substrates and metabolites glucose, free fatty acids FFA , glycerol, ß-hydroxybutyrate, cholesterol, triglyceride, high-sensitive C-reactive peptide hsCRP , alanine aminotranferase ALAT , asparatate aminotransferase ASAT were measured by spectrophotometry Cobas c , Roche, Glostrup, Denmark.
HbA1c was analyzed on a DCA Vantage Analyser Siemens Healthcare Diagnostics Inc. Tarrytown NY, United States. Applied methods for resting energy 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 as previously described Dohlmann et al. See Supplementary Material for the detailed protocols. Citrate synthase CS activity was measured as previously described Larsen et 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 the 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 random , the 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 diabetes 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 weight loss was allowed. Plasma concentrations of insulin and C-peptide were as expected elevated on the double diet day Table 2.
β-hydroxybutyrate representing ketone bodies were increased after 30 h Fasting, and higher in T2DM vs. Total cholesterol, LDL, and HDL cholesterol were not different between the groups and did not change with the intervention Table 2.
Plasma glycerol concentrations displayed a similar pattern, however, with no group differences, and only OB displayed a significant increase with fasting Table 2. Plasma hsCRP values were generally very low, and no changes were seen Table 2. The interventions did not change the insulin response in the control group.
FIGURE 2. In column graphs are shown area under the curve AUC for insulin E and glucose F. Data are shown as mean ± SD. T2DM patients displayed insulin resistance glucose infusion rate compared with OB Table 1. the insulin sensitivity increased as a main effect and not with ADF alone.
Glucose rate of appearance Ra after an overnight fast in the baseline test was increased in T2DM compared with OB 3. Glucose Ra was unchanged in the fasting state following 3 weeks of ADF T2DM: 3. Muscle glycogen content Table 2 was also measured in the evening after a double diet day and in the morning after a fasting day after 30 h fasting see protocol, Figure 1.
No significant difference was seen with the analysis of the OB and T2DM group separately. The purpose was to monitor adherence to the fasting, double diet and ad libitum diet days and all subjects followed the intervention.
Glucose levels were higher in T2DM compared with OB at all times Figure 3. During ADF, CGM data from weeks one to three illustrates that eating on double diet days increased after the first week, probably also due to encouragement to the patients based upon the daily home-based weighing.
No hypoglycemic events were recorded. FIGURE 3. Continuous glucose monitoring CGM traces in patients with obesity OB and type 2 diabetes T2DM. Data are shown as mean values. FIGURE 4. Intrahepatic triglyceride content measured by 1 H-magnetic resonance spectroscopy in eleven subjects with obesity OB and eleven patients with type 2 diabetes T2DM.
Experiments were performed at baseline, after 3 weeks of alternate-day fasting with double diet on non-fasting days ADF , and after 3 weeks of alternate-day fasting with ad libitum diet, i.
Triglyceride content in m. psoas major by 1 H-MRS was not different between the groups and did not change with the intervention baseline: 5.
Muscle lipid droplet density, size of droplets, or the fractional area of the droplets did not differ between T2DM and OB, and no change with ADF was seen Figure 5A, B, C, F. These data were confirmed by analysis of intramuscular triglyceride IMTG content Figure 5D.
In addition, IMTG content was also measured in Tru-Cut biopsies obtained in the evening after a double diet day and in the morgen after 30 h fasting Figure 5E.
after an overnight fast , but this could not be detected in OB Figure 5E. No difference in IMTG between double diet day and 30 h fasting could be seen in either group Figure 5E.
FIGURE 5. Lipid droplets LD density per area of muscle fibre A. LD size B. Intramuscular triglyceride IMTG content in muscle at baseline clamp and at the clamp after ADF D. IMTG content in muscle after one double diet day and after 30 h fasting E.
Representative images of Bodipy staining F. OB, Obese subjects, T2DM, patients with type 2 diabetes. In figure f, scale bars represent µm top and 25 µm bottom. The expression of proteins relevant for insulin-mediated glucose metabolism is shown in Supplementary Figure S1A-I.
Proteins involved in glucose transport GLUT4 and glycolysis hexokinase and pyruvate kinase and glycogen storage glycogen synthase and phosphorylase were similar between the two groups and did not change with ADF.
Proteins relevant for GLUT4 vesicle formation showed minor changes. Thus, Akt was significantly higher in OB compared with T2DM, and AMPKα1 increased significantly with ADF in OB, but not in T2DM. AS and PKCθ remained unchanged and similar in the two groups. The expression of proteins relevant to lipid metabolism is shown in Supplementary Figure S1J-S.
Proteins involved in fatty acids transport into muscle cells were studied by analysis of proteins located in the plasma membrane. This was carried out to determine if alternate day fasting had any effect on fatty acid transport in healthy or diabetic skeletal muscle tissue. Fatty acid translocase FAT or CD36 binds long-chain fatty acids and is a key player in fatty acid transport across the plasma membrane.
Fatty acid transport protein 4 FATP4 esterifies long-chain fatty acids and has a role in fatty acid transport across the plasma membrane. Plasma membrane fatty acid binding protein FABPpm is also involved in myocellular uptake of long-chain fatty acids.
No change was observed in the T2DM group or between the two groups for all fatty acid transporters. Citrate synthase CS activity was used as an index for mitochondrial mass Larsen et al. Oxygen consumption ex vivo was measured with a sequential substrate protocol, with state 2 respiration complex I; malate and glutamate followed by state 3 respiration with increasing concentrations of ADP complex I and dual electron input to complex I and II glutamate, malate, succinate, and ADP , ending with uncoupled respiration FCCP as protonophore Supplementary Figure S2A.
First of all, there were no differences in respiration between T2DM and OB, and no significant effect of ADF was observed Supplementary Figure S2A. Reactive oxygen species ROS displayed no difference between the groups and no effect of ADF was observed Supplementary Figure S2B.
ADP sensitivity and maximal oxygen flux Vmax was calculated from the oxygen flux during increasing ADP concentrations, and no differences between groups or effects of ADF were seen Supplementary Figures S2C, D. The present study represents a comprehensive characterization of the effects of alternate-day fasting regimens on the human metabolism, studied in obese patients with and without type 2 diabetes.
The energy balance is essential in every attempt to lose bodyweight, and if weight loss is the primary focus it is fundamental to achieve a negative energy balance, no matter how this is brought about. This was not the primary focus here.
With the present study protocol, we aimed to study the metabolic effects of oscillations in energy intake and thus energy balance. An improvement of the insulin secretory capacity in patients with type 2 diabetes is a therapeutic goal that is difficult to achieve non-pharmacologically, and only a few studies in patients with type 2 diabetes have reported improvements in β-cell secretion following physical training Krotkiewski et al.
The purpose of the present study was to mimic the oscillations that occur in energy stores with frequent exercise training, but at the same time avoid the physiological impact on metabolism that takes place with exercise training i.
muscle contractions. ADF would largely accomplish this, but from previous studies, it is known that weight loss often follows ADF. Therefore, we divided the study into two 3-week periods of ADF, where weight loss was allowed in the latter period, as would be the every day practice.
The first-phase insulin response in the patients with type 2 diabetes was, however, not restored albeit the insulin response curve displayed a more marked first phase profile compared with baseline Figure 2C.
An indication that time-restricted feeding i. not the same protocol as used in the present study without weight loss may increase ß-cell responsiveness in pre-diabetic people has been published Sutton et al.
The mechanism for improvements in insulin secretion has been attributed to a decrease in intrapancreatic triacylglycerol Lim et al. This is also a likely explanation in the present study, where we observed large decreases in visceral fat Table 1 and intrahepatic triglyceride content Figure 4 where the latter correlated significantly with the improvement in insulin secretion.
The elevated plasma concentrations of FFA, glycerol, and β-hydroxybutyrate during fasting Table 2 testified to an increased lipolytic rate during fasting, contributing to the marked decrease of adipose tissue during the interventions Table 1. An additional mechanism for the improvement in insulin secretion could also be due to an overall reduced glycemic load on the β-cells i.
reduced glucotoxicity. Apart from documenting the adherence to the protocol, the continuous glucose monitoring Figure 3 revealed a lessened glycemic burden, which in itself reduces the stress on the β-cells.
It is important to note that the duration of type 2 diabetes, or at least the time since diagnosis, was short among the included patients 2.
This means that the patients had a relatively well-preserved β-cell function, but of course, diminished compared with the obese subjects without type 2 diabetes Figure 2. We have previously shown that patients with a high pre-operative β-cell function experience a superior outcome to gastric bypass surgery compared with those patients with the lowest pre-operative β-cell function Lund et al.
Most likely, patients with severely reduced insulin secretory capacity which can be easily estimated by a 6 min glucagon test Dela et al. Many studies have shown positive effects of training on insulin-mediated glucose uptake in skeletal muscle in patients with type 2 diabetes Dela et al.
For muscle glycogen Table 2 this aim was achieved, but the oscillations did not translate into an improvement of insulin-mediated glucose clearance with ADF alone, which is in contrast to earlier findings in young, healthy subjects Halberg et al.
However, the data are in line with findings in obese people, using a calculated index for insulin sensitivity S I from an intravenous glucose tolerance test Catenacci et al. Insulin action at the hepatic level, i. inhibition of endogenous glucose Ra, did not change with ADF.
This finding is in line with the lack of effect of ADF on peripheral insulin action. It may require an extended period of starvation 3—4 days before a reduction of insulin-induced suppression of hepatic glucose output is seen Fery et al.
This indicates a general improvement in hepatic function elicited by dietary regimen. The lack of increases in insulin sensitivity with ADF is in line with the general lack of increases in proteins relevant for skeletal muscle insulin action, e. GLUT4, hexokinase, glycogen synthase Supplementary Figure S1.
In rodents, a similar lack of change in hexokinase after intermittent fasting has been reported Real-Hohn et al. The amount of intramyocellular lipids is inversely correlated with insulin sensitivity Pan et al. psoas major fit well with the lack of changes in insulin sensitivity.
A similar amount of lipid content in the muscle in T2DM and OB has been shown before Hansen et al. The latter is in line with earlier findings that demonstrated that it requires prolonged fasting e.
Lipolysis increases at the beginning of a fasting period here evidenced by increased FFA and glycerol after 30 h fasting; Table 2. The more so, because the anti-lipolytic effect of insulin diminishes with fasting Jensen et al.
Support for an ADF-induced triglyceride-lowering effect is found in low-calorie refeeding studies that demonstrated increased triglyceride turnover and removal efficiency Streja et al. During the fasting days in the present ADF protocol, it would be reasonable to assume that a large part of the substrates for energy production comes from lipids.
If not from intramuscular stores, of which a decrease could not be detected, then from extramyocellular stores, i. adipose tissue. The amount of adipose tissue decreased Table 1 during the 6-week intervention, which in turn give rise to the increased availability of fatty acids Table 2 that facilitates an increased fatty acid transport across the sarcolemma.
To this end, we measured fatty acid translocase CD36 , fatty acids transport protein 4 FATP4 , and plasma membrane fatty acid binding protein FABPpm which are important players in the transport of fatty acids across the plasma membrane.
A mixed result was seen, with CD36 increasing significantly in the OB group, FATP4 decreasing in T2DM, and decreasing in FABPpm main effect Supplementary Figure S1. The changes were small, and the data cannot support the notion that fatty acid transport was increased.
Most likely, the oscillation of carbohydrate and lipid substrates every other day blurred a potential marked increase in these proteins. Once inside the muscle cell, fatty acids can be stored as triglycerides and the final step in the synthesis is catalyzed by diglyceride acyltransferase 1 DGAT1.
DGAT1 protein expression did not change with the intervention Supplementary Figure S2M , but even though we did not detect a difference in lipid content between the two groups, DGAT1 was significantly higher expressed in T2DM compared with OB.
To our knowledge, DGAT1 protein expression in skeletal muscle of patients with type 2 diabetes has only been measured in one other study, in which no change was found compared with obese people and athletes Bergman et al.
Our data suggest that T2DM have the capacity to synthesize greater amounts of intramuscular lipids. We measured two proteins involved in lipolysis adipose triglyceride lipase ATGL , monoacylglyceride lipase MGLL and in lipid storage Perilipin 2 adipophilin , perilipin 3 TIP47 , and perilipin 5 OXPAT and in line with the unchanged lipid content in the muscles Figure 5 we found no effect of the intervention on these proteins Supplementary Figure S1.
An increase in medium-chain acyl-CoA dehydrogenase MCAD might have been seen because MCAD is involved in medium-chain fatty acid beta-oxidation, which would be expected to increase with increased fatty acid availability but not with increased lipid storage.
However, no change was detected Supplementary Figure S1. The expression of proteins involved in lipid transport, synthesis and storage presented here, are in line with data on gene expression mRNA of many of these proteins in a study on females undergoing an intermittent fasting regimen with the muscle biopsies obtained in the same condition i.
after an overnight h fast Liu et al. However, in that study Liu et al. Others have also found that CD36 mRNA remains unchanged with a zero-calorie ADF regimen Heilbronn et al. This is especially true when it comes to health and fitness trends, like Intermittent Fasting.
Research shows that this popular diet can have powerful effects on the brain and body. Intermittent Fasting is an eating pattern that alternates between periods of eating and fasting.
So, the longer you go between meals, the more your body exhausts its insulin supply. This is when you start burning fat. It is recommended that the starting time be earlier in the day to optimize metabolism and avoid eating at the end of the day or late at night, which is linked to increased fat storage and inefficient use of food.
Like most things in life, there are pros and cons. For one, adjusting to the fasting stage of the program might come along with side effects like fatigue, dehydration, heartburn, or anemia.
No one knows you like you know you. If you think Intermittent Fasting is right for your body, consult with your doctor before diving in. By Author Name Apr 20, Updated Nov 17, 5 minute read. First Thing First: What exactly is Intermittent Fasting?
Introduction: Intermittent fasting, regu,ation alternate Altrnate-day fasting ADFhas grown rgulation popularity as it can produce clinically significant metabolic benefits and is often considered to be easier Promote gut health naturally adhere to than other Forskolin and herbal medicine of diets such Alternate-dday chronic calorie restriction. However, the regupation of Alternate-day fasting and hormone regulation on diabetes-associated vascular dysfunction, and the role of adipose-derived hormones, i. Objective: We aimed to test the hypothesis that ADF protects against diabetes-associated endothelial dysfunction, at least partly through modulating adipokine profiles. Methods: Control mice m Lepr db and diabetic mice Lepr db were treated with weeks of ADF. Glucose metabolism, endothelial function, and adipokine profile were assessed. Results: ADF reduced fasting blood glucose level and homeostatic model assessment for insulin resistance HOMA-IRand improved insulin sensitivity. ADF improved endothelium-dependent vasorelaxation of small mesenteric arteries SMA of Lepr db mice. A new study led by Krista HormonfAlternate-day fasting and hormone regulation of Tips for lowering cholesterol levels, found that intermittent fasting did not change Hormome levels of certain kinds of female reproductive hormones and caused hoemone decrease anv normal ranges Body image well-being another hormone. The study Altfrnate-day a group of pre- and Alternate-day fasting and hormone regulation obese fastung who maintained an intermittent fasting diet that involved eating during a four-hour or six-hour period each day without calorie limits, then consuming only water until the same time next day. The researchers compared the differences in hormone levels with those of a control group that followed no diet restrictions. They found that levels of a protein that carries reproductive hormones throughout the body was unchanged in the dieters after eight weeks. The same was true for steroid hormones related to the production of testosterone and estrogen. The dieters also saw a drop in insulin resistance and biomarkers of oxidative stress.
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