Caloric restriction and insulin levels -
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J Clin Endocrinol Metab 89 6 — Download references. Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA. You can also search for this author in PubMed Google Scholar.
Correspondence to Meera Shah. School of Life Sciences, University of Westminster, London, UK. Reprints and permissions. Shah, M. Calorie Restriction and Insulin Sensitivity in Obesity. In: Preedy, V. eds Handbook of Famine, Starvation, and Nutrient Deprivation. Springer, Cham.
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Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Abstract Caloric restriction has long been shown to improve insulin action and glucose control. Keywords Caloric restriction Insulin sensitivity Glucose control Weight loss.
Buying options Chapter EUR eBook EUR Hardcover Book EUR Tax calculation will be finalised at checkout Purchases are for personal use only Learn about institutional subscriptions. References Amar J, Chabo C, Waget A, Klopp P, Vachoux C, Bermudez-Humaran LG, Smirnova N, Berge M, Sulpice T, Lahtinen S, Ouwehand A, Langella P, Rautonen N, Sansonetti PJ, Burcelin R a Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment.
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This animal study was reviewed and approved by the institutional animal care and use committee of Kagawa Medical University Kagawa, Japan. MC, AN, DN, and RO conceived and designed research. MC, JN, JC, and BE performed experiments and analyzed data.
MC, JN, JC, BE, AN, DN, and RO interpreted results of experiments and approved final version of manuscript. MC prepared figures and drafted manuscript. RO edited and revised manuscript.
MC was supported in part by doctoral fellowship UC MEXUS-CONACYT and by National Institute on Minority Health and Health Disparities grant 9TMD 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.
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Citation: Cornejo MA, Nguyen J, Cazares J, Escobedo B, Nishiyama A, Nakano D and Ortiz RM Partial Body Mass Recovery After Caloric Restriction Abolishes Improved Glucose Tolerance in Obese, Insulin Resistant Rats. Received: 09 March ; Accepted: 11 May ; Published: 10 June Copyright © Cornejo, Nguyen, Cazares, Escobedo, Nishiyama, Nakano and Ortiz.
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Cxloric with caloric restriction and insulin levels who combined calorie restriction with restroction for weight loss had Natural vitamin sources improvements in insulin restrivtion than those who only restricted calories or Sweet Citrus Oranges exercised, according to research in Diabetes Care. Study results caloric restriction and insulin levels revealed that calorie restriction alone improved glucoregulation, with postprandial glucagon-like peptide-1 concentrations decreased in response to calorie restriction, but not to matched weight loss from exercise, according to researchers. Edward P. Weiss, PhD, associate professor in the department of nutrition and dietetics at Saint Louis University, and colleagues at other institutions analyzed data from 52 men and women with overweight aged 45 to 65 years from the St. Louis metropolitan area.Caloric restriction and insulin levels -
Transcript levels of synthesized cDNA Quanta Biosciences, Gaithersburg, MD, USA were measured with SYBR green chemistry on a StepOnePlus Real-time PCR System Applied Biosystems. Ct values were normalized by a standard curve and presented as relative expression of beta-actin islets or TBP fat.
qPCR primers are listed in Supplementary Table 1 see section on supplementary data given at the end of this article. Gene expression analysis was performed by multiple t -tests between the ad libitum -fed group and the CR group within each adipose depot. CR has been reported to improve metabolic health span and delay aging Fontana et al.
In contrast to results from a previous short-term CR study Mitchell et al. However, 8 weeks of significantly improved glucose homeostasis, seen as a reduction of fasted glucose levels Fig.
This improved glucose tolerance occurred despite a lack of observable differences in glucose-stimulated insulin secretion under the conditions we used to assess it Fig. All mice with reduced glucose levels due to CR responded without the typical drop in glucose after an exogenous insulin injection of 0.
Collectively, these results suggested that despite no observed changes in the insulin secretion profile of CR-fed wildtype animals, their glucose tolerance is still improved.
Citation: Journal of Endocrinology , 1; Ten weeks of CR in these mice resulted in a significant reduction body weight Fig. Other major organs such as heart and kidney were not affected by the diet treatment Fig.
Histochemical analysis revealed no significant differences in adipocyte size within all different fat pads representative pictures in Fig.
The recently proposed hypothesis that CR promotes the development of functional beige fat Fabbiano et al. If anything, there was a consistent trend toward a decrease in the expression of Ucp1 , a mitochondrial membrane protein that contributes to non-shivering thermogenesis Fig.
Interestingly, Insr expression of scWAT was significantly increased after a CR diet, suggesting the possibility of increased insulin sensitivity of this adipose depot. Interestingly, BAT size was not changed after CR in these mice, but changes were seen in the gene expression profile Fig.
Expression of Ucp1, Cox4 and Prdm16 , genes involved in thermogenesis, tended to be decreased, as well as genes involved in lipogenesis and adipogenesis such as Pparg, Fas and Acaca Fig. Despite their lower insulin reservoir, we have shown previously that these animals are healthy without significant impairment of glucose-insulin homeostasis Leroux et al.
Nevertheless, as in our previous work, CR reduced lowered fasting glucose levels Fig. Indeed, insulin tolerance tests, using exogenous insulin injection of 0. This flat pattern can be interpreted as partial insulin resistance.
However, this improved glucose tolerance is not associated with improved whole-body insulin sensitivity under the conditions we tested. As expected, body weight dropped after 10 weeks of CR Fig. BAT size was unchanged after CR; however, genes involved in thermogenesis, like Ucp1 and Prdm16 , were significantly downregulated.
Decreased expression levels of lipogenic genes, like Fasn and Acaca , Ppargc1a a coregulator of mitochondrial biogenesis and apoptosis marker Ddit3 were also observed in the BAT of CR mice Fig.
Matsusue Analysis of three different white adipose fat tissues at the levels of mRNA expression showed increased expression of Fasn and Acaca , genes that are both involved in lipogenesis. We also observed significantly increased levels of both Ppargc1a and Cidea gWAT Fig.
Together, these data suggest that CR leads to an adaptation of WAT size and gene expression. Sex-specific regulation of glucose metabolism, insulin resistance and energy expenditure has been previously reported Widdowson , Valle et al.
Thus, we next assessed the effects of CR on female with low insulin gene dosage at 20, 45 and 70 weeks of age after 8 weeks of CR. We set out to test the hypothesis that short-term CR is still beneficial for energy metabolism during different life stages and might have different metabolic effects when comparing mice lacking 2 alleles vs mice lacking 3 insulin alleles.
In all three age groups, body weight dropped significantly Fig. Compared to their original weight, the weight loss in the oldest females was slightly greater compared to the males at the same stage of life. Islets isolated from these mice had significantly reduced insulin content at all ages tested Fig.
We did not observe statistically significant differences in fasting insulin levels between CR mice and their controls Fig. CR mice released less insulin in response to a glucose bolus at 20 weeks and 45 weeks of age, but not at 70 weeks of age Fig.
Interestingly, these CR mice had improved glucose tolerance at 45 and 70 weeks of age Fig. At 20 weeks, the CR-induced improvement in glucose tolerance was not observed, demonstrating non-additivity in these young female mice with reduced insulin gene dosage Fig.
Insulin tolerance tests also revealed a similar pattern of apparent insulin resistance in the CR mice to what was observed in the males Fig. Thus, our data demonstrate that in the context of reduced insulin gene dosage, short-term CR improves glucose homeostasis associated with paradoxical reduction in insulin secretion and insulin sensitivity.
These phenomena are relatively consistent through the age range we tested. LOD, limit of detection. In contrast to our findings in males, week-old female mice showed more pronounced changes in WAT and BAT gene expression.
All white fat depots measured gonadal, subcutaneous and mesenteric were significantly smaller Fig. In the postprandial state, all fat depots of CR mice showed increased expression of lipogenic genes like Fas and Acaca consistent with the optimization of energy storage Fig.
Markers involved in browning of white adipose tissue were increased in the scWAT and mWAT depots, specifically Adrb3, Ppargc1a, Prmd16, Cidea and Cox4 expression.
These genes would be predicted to stimulate Ucp1 activity and thermogenesis Okita et al. However, differences in Ucp1 expression were not significant Fig.
CR females also exhibited a slight increase in BAT mass, although this was also not statistically significant Fig. The aim of this study was to investigate the effects of short-term CR on glucose metabolism and adipose tissue in the contexts of age and genetically lowered insulin.
One of the most consistent findings in animal models of CR is a significant improvement in glucose homeostasis Colman et al. Others have observed improvement in glucose tolerance, together with reduced levels of leptin, insulin and IGF1, after only 3 months of CR Mitchell et al.
In the present study, we confirmed the expected rapid improvement in glucose tolerance with CR, except in young female mice with reduced insulin gene dosage. The interpretation of the role of circulating insulin on the effects of CR is complicated by the fact that fasting insulin levels were not dramatically different between the different strains of mice and at the different ages tested, despite a significant reduction in insulin content in the mice with reduced insulin gene dosage.
Fasting insulin averaged 0. This compensation for reduced insulin gene dosage is consistent with previous studies, and we have found that this compensation is more robust in male mice Leroux et al. Interestingly, it was only at the lowest circulating level in the week-old female mice where CR did not further improve glucose tolerance.
This non-additive effect suggests that CR and extreme insulin reduction act on glucose homeostasis via at least some common mechanisms in young mice.
Other effects of CR, including the expected weight loss were maintained at all ages, indicating that the mechanisms controlling glucose homeostasis and weight loss in CR are distinct. The molecular mechanisms underlying these differences require further study and are beyond the scope of this investigation.
Our current study demonstrated beneficial effects of CR in aged mice, regardless of genotype. Furthermore, the physiological mechanisms by which CR improves glucose homeostasis remain to be fully elucidated.
We did not observe differences in fasting insulin or glucose-stimulated insulin secretion in our wild-type mice as shown previously Mitchell et al. The insulin tolerance tests changed the profile of blood glucose after a bolus insulin injection.
Differences in metabolic parameters between our study and others could possibly be the result of our feeding protocol of 3 small meals during the dark phase, which reduces the time of fasting in the CR animals compared to standard protocol of 1 meal a day.
In all cases, the significantly lower fasting glucose complicates the interpretation of these data, and we do not have data on counter-regulatory signals that are likely robust under these conditions. It should also be noted that the insulin tolerance test is not ideal for a full assessment of insulin sensitivity.
Additional studies to further elucidate these phenomena will require hyperinsulinemic—euglycemic clamp experiments. Our study identified possible sex differences in the metabolic response to short-term CR.
We documented the expected rapid decrease in body weight and blood glucose levels after CR treatment, but found that it was more pronounced in females than in males. Some authors have argued that females conserve their energy more efficiently and are more resistant to CR because of their relative importance for reproduction and the survival of the species Widdowson , Valle et al.
However, in our study, the female CR mice lose an equal percentage of their starting body weight. Furthermore, upregulation of genes involved in lipogenesis and thermogenesis in scWAT are more pronounced in females.
The molecular mechanisms underlying the sex differences in the metabolic responses to CR require further study. In female mice with reduced insulin, CR reduced the size of white adipocytes, which has been linked to alterations in altered adipokine secretion.
Hypertrophic adipocytes, possessing more triglycerides, have been proposed to secrete less adiponectin and more pro-inflammatory cytokines, whereas small adipocytes are generally found to be more sensitive to insulin and act as a powerful buffer taking up free fatty acids during the postprandial period.
For this reason, reducing adipocyte size by CR is considered beneficial for a healthy lifespan Okita et al. It has been proposed that the activation of BAT and the browning of WAT play important roles in the effects of CR.
Originally, it was believed that WAT and BAT had distinct morphology and function, with WAT being a major source for triglyceride storage and adiponectin secretion to enhance insulin sensitivity, and BAT playing an important role in energy expenditure and thermogenesis Saely et al.
Lately, the distinction between BAT and WAT has become less rigid, with observations of browning of WAT i. We examined the expression levels of Ucp1 mRNA, which is critical for thermogenic activity Puigserver et al.
We did not observe an increase in Ucp1 mRNA, and in fact, there were robust reductions under some conditions. Nevertheless, we observed tendencies for increases in genes known to control Ucp1 expression and thermogenesis, such as Ppargc1a , Nrf1 and Cox4.
The molecular mechanisms mediating the possible functional remodeling of adipose tissue in the context of short-term CR require further study.
A previous study suggested that CR downregulated the mitochondrial electron transport chain but enhanced fatty acid biosynthesis in BAT, suggesting that in CR animals, BAT may change its function from an energy-consuming system to an energy reservoir system Okita et al. Is time-restricted eating or intermittent fasting better at controlling Type 2 diabetes than following a low calorie diet?
Explaining the study, Dr Atul Luthra, Director and HOD, Fortis C-DOC, Centre of Excellence for Diabetes and Metabolic Diseases, at the Fortis Memorial Research Institute, Gurugram, says that the process of fasting has always been known to flush toxins out of the body. However, early time-restricted eating along with intermittent fasting is better than total caloric restriction because the former compresses the meal timing and prevents a late evening binge.
Early time-restricted eating or calorie restriction, which is better for reducing the risk of diabetes? I would like to share two historical facts. Religious fasting has been practised over centuries for body cleansing and ridding it of toxins. Our forefathers followed the circadian rhythms for eating, prioritising heavier food intake in the early part of the day and finishing all meals by sunset.
Now we talk of similar concepts and call them either intermittent fasting, time-restricted eating or calorie restriction. Time-restricted eating means eating or energy intake within a specific time window or compressed meal timings.
On the other hand, we have a continuous caloric restriction known as CR, where you restrict the total number of calories you consume in the day, bringing it down to 70 per cent of your normal allowance without any restricted timing.
Both are good strategies but we have to understand what is good for whom. Caloric restriction is basically a method of reducing the intake of calories and burning them more through physical activity and exercise.
The purpose could be weight management, changing the body composition or reducing the fat mass. So caloric restriction can be used for weight management, fat burning and change in body composition. Intermittent fasting is for a subset of people who have a high risk of diabetes in the future, either due to genetic factors or because of certain clinical parameters.
Why does this work? As our activity level decreases during this time of the day and our unspent calories get stored, insulin resistance goes up. Also, we have more cravings in the evening because of a change in our nutrient-signalling pathways.
So leptin, the satiety hormone, goes down and ghrelin, the appetite-stimulating hormone, goes up. With metabolic rate and exercise levels dipping, nutrient cravings increase and insulin resistance becomes higher, factors not conducive for diabetics.
So if you compress the meal timings within a specific window of eight hours or so, having your first meal at 10 am and your last meal at 6 pm, commonly known as time-restricted eating, you can avoid a late evening calorie load from building up.
The other method is alternate day fasting where one day you have ad libitum food and the other day you just take 30 per cent of your normal calories, that too in a four-hour window.
As far as diabetes prevention or glucose metabolism is concerned, definitely time-restricted eating is better than total caloric restriction in suppressing insulin resistance factors.
So, diabetes patients should avoid eating late in the evening. This not only applies to people who have diabetes but also people who are predisposed to developing diabetes later or are pre-diabetic. For someone who is an adolescent, has no diabetes or cholesterol issue but just wants to lose weight, they must focus on total caloric restriction.
The caloric intake is determined by your body weight and your activity level. Once you figure that out, you have to take only 70 per cent of your required calorie count.
The kinases that phosphorylate S are unknown; thus far, JNK and IKK have been reported to phosphorylate this site. CR caused a significant reduction in kinase activity toward S in lean rats; however, this was not seen in obese Zucker rats.
The answer for this phenomenon is unknown. We speculate that the combination of opposing kinase activities may lead to this unusual activity pattern. GSK3B is a serine kinase that is negatively regulated by insulin Richter et al.
GSK3B is also thought to be involved in insulin resistance. In type 2 diabetics, GSK3B activity is elevated twofold in both basal muscle and insulin-stimulated muscle Nikoulina et al. Additionally, inhibition of GSK3B improves insulin's action and glucose metabolism in human smooth muscle Nikoulina et al.
In our system, we detected slightly reduced phosphorylation of GSK3B in obese rats, indicating mild activation; these data, however, did not reach statistical significance. Consistent with GSK3B activity, obese rats showed mild increased phosphorylation of S, but again, this did not attain statistical significance.
However, CR had no effect on phosphorylation of GSK3B and IRS1 at S, suggesting a lack of association of GSK3B activity with insulin resistance based on our two-criterion approach.
Thus, this enzyme may not have a critical role in controlling insulin sensitivity in obese Zucker rats or in modulating insulin signaling during CR. Although our in vitro kinase assay provides an easy and reproducible way to examine the IRS protein kinases in TEs because of a well-controlled condition, it does have its limitations.
First, due to the large sample numbers, all the in vitro kinase assays were carried out in the same condition. Second, although phosphorylation sites for many serine kinases are determined by few adjacent amino acids, some serine kinases do require binding to their substrates before phosphorylation can take place.
Therefore, we could not rule out the possibility that negative results such as S, S, and S may simply suggest that these sites are not phosphorylated in our condition. Future study with full-length IRS1 proteins in a kinase-specific reaction buffer should verify these results.
We provide further evidence that ERK is likely the primary kinase responsible, in liver, for the phosphorylation of IRS1 and possibly IRS-2 as well, since these phosphorylation sites are well conserved between the two isoforms in obesity-induced insulin resistance.
Given the central role of the liver in mediating glucose metabolism, combined with the fact that loss of insulin-regulated glucose output is a principle factor driving chronic hyperglycemia in the metabolic syndrome and type 2 diabetes, restraining ERK activity may have important implications for future therapies.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Journal of Biological Chemistry — American Journal of Physiology.
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Advanced Search Help. Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70 S6K activities in the liver of obese Zucker rats in Journal of Endocrinology.
Authors: Yanbin Zheng Yanbin Zheng Search for other papers by Yanbin Zheng in Current site Google Scholar PubMed Close. Wenshuo Zhang Wenshuo Zhang Search for other papers by Wenshuo Zhang in Current site Google Scholar PubMed Close. Elisha Pendleton Elisha Pendleton Search for other papers by Elisha Pendleton in Current site Google Scholar PubMed Close.
Sanhua Leng Sanhua Leng Search for other papers by Sanhua Leng in Current site Google Scholar PubMed Close. Jiong Wu Jiong Wu Section of Endocrinology, HumanZyme, Cell Signaling Technology, The University of Chicago, E 57th Street, KCBD Room , Chicago, Illinois , USA Search for other papers by Jiong Wu in Current site Google Scholar PubMed Close.
Ridong Chen Ridong Chen Section of Endocrinology, HumanZyme, Cell Signaling Technology, The University of Chicago, E 57th Street, KCBD Room , Chicago, Illinois , USA Search for other papers by Ridong Chen in Current site Google Scholar PubMed Close. Xiao Jian Sun Xiao Jian Sun Search for other papers by Xiao Jian Sun in Current site Google Scholar PubMed Close.
Page Range: — Online Publication Date: Dec Copyright: © Society for Endocrinology Free access. Download PDF. Check for updates. Abstract Calorie restriction CR improves obesity-related insulin resistance through undefined molecular mechanisms.
Introduction Calorie restriction CR may improve the outcome of obesity-associated diseases, including diabetes and cardiovascular disease. Tissue extract preparations Liver tissue extracts TEs were prepared as described previously Qiao et al. Subcloning of IRS1 Glutathione-S-transferase GST —IRS1 2— , GST—IRS1 — , and GST—IRS1 — were prepared as described previously Qiao et al.
Statistical analysis ANOVA was performed to compare differences among three or more groups. Figure 1 Average daily food intake and body weight of obese and lean Zucker rats. Figure 2 Insulin tolerance test ITT in the four experimental groups following 20 weeks of ad libitum or restricted CR feeding.
Effect of obesity and CR on IRS1 kinase profiles CR-induced improvements in insulin sensitivity in obese Zucker rats provided a good animal model for investigating the association between abnormal activation of IRS1 serine kinases and phosphorylation of IRS1 with respect to insulin sensitivity.
Metrics details. Caloric Thermogenic weight loss CR caloric restriction and insulin levels become increasingly restrictuon in the treatment levvels type caloriic diabetes mellitus T2DM because of the caloric restriction and insulin levels common high-calorie diet and sedentary lifestyle. This study aimed to evaluate the role of CR in T2DM treatment and further explore its potential molecular mechanisms. Sixty male Sprague—Dawley rats were used in this study. Meanwhile, normal rats fed a free standard chow diet served as the vehicle control. Body mass, plasma glucose levels, and lipid profiles were monitored. Calorie restriction CR improves reetriction caloric restriction and insulin levels resistance through valoric molecular mechanisms. CR in obese rats significantly reduced body weight leveos increased insulin sensitivity compared restricton AL controls. Concomitantly, obesity increased and CR caloric restriction and insulin levels the activity of hepatic Restriciton and Chitosan for nail health S6K against IRS1. The close association between the activity of hepatic ERK and p70 S6K with insulin resistance suggests an important role for ERK and p70 S6K in the development of insulin resistance, presumably via phosphorylation of IRS proteins. Calorie restriction CR may improve the outcome of obesity-associated diseases, including diabetes and cardiovascular disease. At the whole-body level, CR has been shown to reduce visceral fat Barzilai et al. The underlying molecular mechanisms mediating these effects are not very clear.
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