The Effects of Intermittent Fasting Related to Metabolic Syndrome

Ariel Lebert 11/19/2012 NTR 415

The Effects of Intermittent Fasting Related to Metabolic Syndrome Introduction Fasting has been an integral part of human history, whether from spiritual obligation or food scarcity. In a state of fasting the body undergoes many changes physiologically from when it is in a fed-state. It is well known that in mice, calorierestriction leads to greater longevity, but perhaps the biochemical changes that occur within the body in a fasting state provide protection against metabolic disease biomarkers apart from the calorie restriction that is associated with intermittent fasting. The following is a discussion, beginning with an overview of metabolic syndrome and the physiological effects of fasting, on the effects of intermittent fasting (IF) relating to biomarkers of metabolic syndrome such as dyslipidemia, insulin resistance, leptin resistance, and obesity. Metabolic Syndrome Metabolic Syndrome is characterized by risk factors that together increase the risk for cardiovascular disease (CVD), stroke, and type 2 diabetes mellitus (T2DM). Some of these conditions are hypertension, high blood sugar, abdominal obesity, dyslipidemia, hypercholesterolemia, and insulin resistance leading to glucose intolerance. According to the National Health Statistics Report, as of 2009, the prevalence of metabolic syndrome for adults 20 years of age and older in the US was 34.4%. The population displayed the following risk factors: abdominal obesity (53.2%), hypertriglyceridemia (31.4&), low HDL-C (24.7%), high blood pressure or medication in use (40.0%), high fasting glucose or medication in use . One risk factor for metabolic syndrome, obesity, is often

attributed to a largely inactive lifestyle and a diet high in saturated fats and added sugars

from processed foods and sugary beverages. Much research has been conducted to discover new ways that these risk factors can be decreased in order to prevent the development of metabolic disease through medicine and lifestyle changes. Physiology of Fasting According to Advanced Nutrition and Human Metabolism in a fasted state, low insulin levels increase lipolysis (this is due mainly to the decrease in insulins action of promoting lipogenesis) and decrease the use of glucose, which contributes to the rise of free fatty acids in . Working alongside this effect is glucagon that increases

during fasting to increase lipolysis. Some free fatty acids metabolized by the liver form ketone bodies that can be used as fuel by muscle and the brain (known as ketosis), while the glycerol backbone from TG can be converted to glucose to maintain a minimal supply for the brain in addition to ketones. In prolonged fasting the muscles begin to use ketones preferred by muscles as fuel so that as little protein as possible is used for gluconeogenesis (a protein-sparing state), even in preference to fatty acids seen in an earlier state of fasting. In summary, the body switches from a predominantly glucose burning and storage state to a fat mobilization and burning state, when the body adapts to using ketones, FFA, and a minimum amount of glucose as fuel by a change in gene transcript section. Fasting Hormones Many of the energy regulating hormones in the body promote fat mobilization and catabolism and only few, such as insulin, promote storage and anabolism. A study by Longuet et al demonstrated the effects of glucagon in a fasting state found that glucagon and the regulation of endocrine hormones discussed in the following

directs FFA mobilized from TG stores toward beta oxidation rather than reesterification into triglyceride and secretion and that disruption of endogenous Gcgr signalling impairs the control of fatty acid oxidation during fastin . Due to the catabolic action of glucagon, it is normally stimulated by hypoglycemia, but as high glucagon levels are normally seen within patients that have T2D , it could be that glucagon production is a

response related to cellular energy status. This cellular energy-sensor is likely related to leptin signalin , another catabolic hormone released from adipose and known as a hunger regulator. A study by Morton and Schwartz on the effect of leptin in glucose metabolism showed the integrative nature of the endocrine hormones such as insulin, leptin and glucago . They suggested that adipose leptin signaling (which induces

lipolysis and inhibits lipogenosis in addition to CNS signaling to suppress hunger) affected insulin sensitivity and that hyperleptinemia seen in obesity can lead to leptin resistance similar to that seen in insulin resistanc . Morton and Schwartz also suggested, based on biomolecular studies, that leptin resistance is result of the inflammation associated with obesit . This impaired signaling of cellular energy status could lead to

over-eating and the presence of both high levels of glucagon and insulin in circulation in type 2 diabetics. Insulin also plays a role in fasting, mainly through reduction of its antilipolytic properties and suppression of gluconeogenesis by the liver, and if insulin is present in large quantities in the blood, it antagonizes glucagon and prevents fat mobilization even during fasting. Possible Benefits of Fasting Ketosis As discussed previously, ketosis occurs when insulin levels are low, allowing for triglycerides (TG) to be metabolized to free fatty acids (FFA) and used as fuel. A study

by Nam-Seok Joo, et al. the presence of ketosis after a minimum of eight hours of fasting was correlated with a lower prevalence of obesity, central obesity and metabolic syndrome as well as improved metabolic parameters such as HDL, TG, FG, insulin including body weight, BMI and waist circumferenc . However only 8.8% of subjects were shown to be in ketosis after simple fasting (>8 hours . A follow-up study showed that serum insulin was negatively correlated with ketosis that occurs in a fasted stat . This very well could be attributed to the fact that insulin promotes storage of FFA and individuals with high fasting insulin levels would be unable to access the FFA from the TG in their adipose tissue, prolonging the time before individuals reach ketosi .

Hyperinsulinemia, that is often associated with obesity as it is a sign of insulin resistance, could be the barrier between individuals that do not reach ketosis and those who do. It is also a reasonable to attribute the benefits observed to the lower insulin levels rather than to ketosis. Improved Insulin Signaling Many new studies have been conducted suggesting that insulin resistance in the brain could lead to mental diseases such as Alzheimer . As discussed by Jianghua Lu

et al. in a study on the effects of IF in mice, repeated fasting and refeeding (RFR) lead to a decrease in plasma insulin as evidenced by insulin signaling pathways in the brain. This decrease in plasma insulin was attributed to an increase in insulin sensitivit . If this

were an accurate conclusion, IR or RFR would prove to provide protective effects against the development of T2DM, CHD and possibly Alzheimers. In addition, a study by Alirezaei et al. in 2010 found that short-term fasting induced neuronal autophagy, a process in which cells degrade and digest their own intercellular compartments as a

defense mechanism believed to be protective against protein aggregates that lead to the development of Alzheimers diseas Religious IF During the Islamic month of Ramadan, Muslims observe a fasting ritual that requires abstinence from food and drink during daylight hours (more devout Muslims will consume food and drink only when the moon is visible). A study conducted by Ezzat Faris et al. shows that in the observance of the religious fasting month of Ramadan, during the fast there is decrease in oxidative stress that accompanies a decrease in body fat and BM . Lipid profiles were also improved during the fast such as lowering LDL . However, many of these .

and raising HDL may contribute to lowering the risk of CH

beneficial effects were not seen after the fast once the subjects returned to their normal routines. Many biomarkers returned to baseline values. The specific biomarker of oxidative stress that was 15FIP, and it was found to be associated with obesit .

Other fasting religious populations, such as the Church of the Latter-Day Saints in Utah, have been associated with decreased risk of CHD manifested as CA . However, these

observations could be due to other lifestyle factors such as limited alcohol intake, spiritual observance, and social support. Weekly IF and Calorie Restriction A study by Kroeger et al. developed dietary interventions for obese women around the Chicago area. The interventional diets were calorie restricted (CR) combined with fasting the last day of the week. The intervention diets were separated into two additional groups, one group consumed a premeasured CR liquid diet for their first two meals of the day and dinner that was not provided, while the other group ate a CR non-

liquid diet that was not provided. Nutritional education was provided to aid in the participants food choices. During the 8-week intervention period participants on the IFCR-Liquid diet showed a decrease in average body weight, fat mass, waist circumference and BMI. Those on the IFCR-Food diet also had an average decrease in these values but to a lesser exten . While the weight loss was a beneficial effect of the

IFCR diets, perhaps more importantly, decreases LDL-C and TG related to reduced waist circumference and circulating leptin levels are favorable changes in reducing risk of CHD. These effects are congruent with those seen in observers of religious I . While

the calorie restriction may speed the process of weight loss, the reduced risk of CHD may be greatly due to fasting. Conclusion It has been suggested by some experts that an intermittent fasting program can have beneficial effects on preventing and treatment metabolic syndrome diseases and risks factors. The strongest evidence is related to weight loss and the risk of CVD. While it is possible that the benefits are contributed by the decrease in calories consumed by those intermittently fasting, it is also likely that the fasting metabolic state is more adapted to than the well-fed state, evolutionarily speaking. Due to the effects of fasting on blood sugar and its regulatory hormones, namely insulin, glucagon and leptin, those who have impaired signaling of these hormones would want to undergo a very controlled fast under medical supervision, or seek to improve their hormone levels through proper diet and exercise before partaking in a fast.

References 1. Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 20032006. National health statistics reports; no 13. Hyattsville, MD: National Center for Health Statistics. 2009. 2. Gropper SAS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism, 5e. Cengage Learning, 2009. 3. Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Ill JY, Olefsky J, Guarente L, Montminy M. A Fasting Inducible Switch Modulates Gluconeogenesis Via Activator-Coactivator Exchange. Nature. 2008 November 13; 456(7219): 269273. 4. Longuet, Christine; The glucagon receptor is required for the adaptive metabolic response to fast. Cell Metab. 2008 November ; 8(5): 359371. 5.Crane C, Akhter N, Johnson BW, Iruthayanathan M, Farhad S, Kudo A, Zhou YH, Childs GV. Fasting and glucose effects on pituitary leptin expression. Is leptin a local signal for nutrient status? J Histochem Cytochem. 2007 October ; 55(10): 10591073. 6. Morton GJ, Schwartz MW. Leptin and the CNS Control of Glucose Metabolism. Physiol Rev. 2011 April ; 91(2): 389411. 7. Scherer T, Buettner C. Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism. Rev Endocr Metab Disord. 2011 September ; 12(3): 235243. 8. Joo NS, Lee DJ, Kim KM, Kim BT, Kim CW, Kim KN, Kim SM. Ketonuria after Fasting may be Related to the Metabolic Superiority. J Korean Med Sci 2010; 25: 17711776. 9. Kim HJ, Joo NS, Kim KM, Lee DJ, Kim SM. Different Response of Body Weight Change According to Ketonuria after Fasting in Healthy Obese. J Korean Med Sci 2012; 27: 250-254. 10. Mohammadiha H. Resistance to ketonuria and ketosis in obese subjects. Am J Clin Nutr 1974; 27: 1212-3. 11. De la Monte, Suzanne M. Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease. Current Alzheimer Research, 2012, 9, 35-66.

12. Lu J, Lezi E, Wang WF, Frontera J, Zhu H, Wang WT, Lee SP, Choi IY, Brooks WM, Burns JM, Aires D, Swerdlow RH. Alternate Day Fasting Impacts the Brain Insulin Signaling Pathway of Young Adult Male C57BL/6 Mice. J Neurochem. 2011 April ; 117(1): 154163. 13. Alirezaei M, Kemball CC, Flynn CT, Wood MR, Whitton JL, Kiosses WB. Shortterm fasting induces profound neuronal autophagy. Autophagy, 2010 August; 6:6, 702710. 14. Ezzat Faris MA, Hussein RN, Al-Kurd RA, Al-Fararjeh MA, Bustanji YK, Mohammad MK. Impact of Ramadan Intermittent Fasting on Oxidative Stress Measured by Urinary 15-F2t-Isoprostane. J Nutr Meta, 2012 September; 2012: 9. 15.Horne BD, May HT, Anderson JL, Kfoury AG, Bailey BM, McClure BS, Renlund DG, Lappe DL, Carlquist JF, Fisher PW, Pearson RR, Bair TL, Adams TD, Muhlestein JB. Usefulness of Routine Periodic Fasting to Lower Risk of Coronary Artery Disease among Patients Undergoing Coronary Angiography. Am J Cardiol. 2008 October 1; 102(7): 814819. 16. Kroeger CM, Sinclair EM, Maida A, Baggio LL, Maziarz M, Charron MJ, Drucker DJ. Improvement in coronary heart disease risk factors during intermittent fasting/calorie restriction regime: relationship to adipokine modulations. Nutrition & Metabolism 2012; 9:98.