Diabetes and Fasting

Diabetes and Fasting

“JUST BLAME IT ON BREAKFAST”

Over the last few weeks, our class has received a general refresher on diabetes – its causes, symptoms, and treatments. As we have all learned, diabetes is an extremely prevalent disease that has an extraordinary impact on many peoples’ lives across the globe. It seems that the current trend of diabetes prevalence is on an upward slope, with more and more people being diagnosed with the disease with each passing year. Costing our healthcare system billions of dollars and imposing broad lifestyle restrictions on patients with the disease, diabetes is certainly a malady that could use a remedy. While we have learned about some current drugs and treatment regimens aimed at managing diabetes, the world is still seeking the next revolutionary discovery which hopefully has a higher efficacy. However, the research surrounding diabetes treatment can lead down two paths: treatments for the existing diabetic condition, and precautionary measures aimed at preventing the disease altogether. In this paper, I wish to bore all of you greatly by expanding on a topic that I believe will be a prominent preventative measure for diabetes in the future: intermittent fasting.

            The discussion about fasting and diabetes begins a few years ago, when I was a fresh high school graduate who decided it may finally be time to lose weight and get into shape. My family grew up without a lot of money, and so I developed poor eating habits at a young age. I was all too used to junk food, fast food, and eating whenever I felt like it. I eventually reached a certain point of self-loathing where I decided that I should show more respect to myself and my body, and I started to research weight loss and weight lifting. I began eating more nutritious foods, restricting my calories, and curling as many dumbbells as I could find. I became very interested in researching these topics and trying to figure out what behaviors and protocols had real-world results: after all, something you read in one study will likely be directly contradicted in another study. However, one topic that I have learned about, practiced myself, and have seen supported time and time again is the topic of intermittent fasting.

            So, what exactly is fasting? In the simplest terms, fasting can be defined as the complete avoidance of caloric intake. By avoiding calories for a certain length of time, the body enters a fasted state where insulin levels are at their lowest, catecholamine levels (e.g. adrenaline) are high, and endogenous energy sources (fat stores, glycogen, etc.) are utilized instead of exogenous sources (the cheeseburger sitting in your small intestine). Now, fasting is certainly not a healthy continuous long-term practice. If you cease eating altogether, your body will begin to break itself down for energy and you will eventually die. Intermittent fasting aims to avoid this negative side-effect by taking advantage of the fasted state for a specified duration, and then exiting the fasted state well before your body begins to break itself down. While some intermittent fasters choose to consume meals only every other day, a method known as alternate-day fasting, many people choose to continue eating daily while still entering a fasted state. In practice, this is accomplished by permitting yourself a limited daily eating window in which calories are consumed, with the majority of a 24-hour period having no caloric intake. In simpler terms: don’t eat breakfast. In fact, many practitioners of intermittent fasting only consume their meals between noon and 8PM, resulting in 16 hours of caloric avoidance every day.

            While this may seem like a small behavioral change, fasting can cause a multitude of beneficial effects across a wide range of domains. For example, fasting is one of the only dietary practices shown to increase mammalian lifespan (Carlson and Hoelzel 1946; Goodrick et al. 1982; Heilbronn et al. 2005; Mair and Dillin 2008; Uno et al. 2013; Weindruch and Walford 1982; Wolf 2006). In regards to exercise and fat loss, fasting primes the body for lipolysis and increased energy expenditure via higher levels of catecholamines and low levels of insulin.  However, fasting also causes a plethora of metabolic and physiological changes that would be valuable for the diabetic patient. An example of such changes would be an increase in insulin sensitivity, lower levels of inflammation, and lower blood pressure (Andersson et al. 1988; Anson et al. 2003; Mattson and Wan 2005). While these effects may be more targeted for patients with Type 2 diabetes (e.g. increased insulin sensitivity), fasting also has beneficial effects on patients with Type 1 diabetes (Mojaddidi et al. 2006; Reiter et al. 2007) though insulin dosages may need to be adjusted to the new meal timing. Overall, fasting seems to be a safe practice for diabetic patients and the aforementioned effects are certainly advantageous to a maladjusted metabolic response (AlAlwan and Al Banyan 2010; Hui et al. 2010; Sheikh and Wallia 2007).

            It’s not hard to see that the physiological changes produced by fasting could serve as part of a treatment plan for an existing diabetic condition. However, I believe that fasting would also be an important practice in preventing the onset of diabetes altogether. As previously mentioned, fasting basically primes the body for the next visit to the gym: low insulin levels prevent the body from entering storage mode. High catecholamine levels increase the magnitude of the fight or flight response while simultaneously increasing blood flow to adipose tissue. Exiting the fasted state on a daily basis means your body will maintain its leptin levels and not enter a weight loss plateau. Exercise is one of the best precautionary measures to prevent the onset of diabetes, and fasting acts synergistically with exercise. However, I don’t think acting as an exercise primer is the only reason why fasting may act as a preventative treatment for diabetes.

A few weeks ago, our class discussed how the inhibition of GSK-3 produced beneficial effects in regards to pancreatic beta cell proliferation and survival. This prompted me to research whether the metabolic pathways affected by fasting also affect GSK-3 expression or not. Through some brief research, I found that while GSK-3 has a broad variety of inhibitors, a very notable and effective inhibitor is Protein Kinase A (Fang et al. 2000). PKA phosphorylates both the alpha and beta forms of GSK-3, resulting in the total deactivation of the molecule.  It turns out that both glucagon and epinephrine stimulate the production of PKA (Johnson 2003).  Glucagon release can be increased by the activation of both alpha-1 and alpha-2 adrenoceptors, something that normally occurs during periods of fasting via raised catecholamine levels (Layden et al. 2010; Skoglund et al. 1987). Furthermore, PKA activity is dependent on cAMP; without cAMP, PKA cannot perform its function (Fang et al. 2000).  Conveniently enough, both fasting and increased glucagon expression result in higher plasma concentrations of cAMP (Chang et al. 2002; Liljenquist et al. 1974; Mjoos et al. 1977). By consolidating all of this information, we can see the following physiological changes (theoretically) brought about by fasting:

Now, the inhibition of GSK-3 via entering a fasted state is a purely hypothetical pathway that I inferred from the meta-analysis of the previously mentioned studies. I could not find any studies that explicitly stated an increase in GSK-3 inhibition from a fasted state, but I wouldn’t be surprised if this is actually the case. As previously mentioned, fasting produces a broad multitude of beneficial effects without many known causes or mechanisms of action. Perhaps the inhibition of GSK-3 is just one of the causes of fasting’s beneficial effects, but more research would be needed before this could be relied upon.

            Piecing this all together, I believe that intermittent fasting has great potential in both preventing and treating diabetes. For current patients, intermittent fasting produces metabolic changes that may help curb the disease with the help of exercise and other drugs. As a preventative measure, fasting allows exercise to more easily exhibit its beneficial effects which are known to prevent the onset of diabetes. More importantly, however, the increased catecholamine levels seen during the fasted state may allow you to pump out one or two more curls on your last set. 

References

AlAlwan I and Al Banyan A. 2010. Effects of Ramadan fasting on children with Type 1 diabetes. International Journal of Diabetes Mellitus 2:127-129.

Andersson B, Wallin G, Hedner T, Ahlberg AC, Andersson OK. 1988. Acute effects of short-term fasting on blood pressure, circulating noradrenaline and efferent sympathetic nerve activity. Acta Med Scand. 223:485-490.

Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, and Mattson MP. 2003. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. PNAS 100:6216-6220.

Carlson AJ and Hoelzel F. 1946. Apparent Prolongation of the Life Span of Rats by Intermittent Fasting. J. Nutr 31:363-375.

Chang LL, Kau MM, Wun WS, Ho LT, and Wang PS. 2002. Effects of fasting on corticosterone production by zona fasciculata-reticularis cells in ovariectomized rats. Journal of Investigative Medicine 50:86-94.

Fang X, Yu SX, Lu Y, Bast RC Jr, Woodgett JR, and Mills GB. 2000. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci USA 97:11960-11965.

Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. 1982. Effects of Intermittent Feeding Upon Growth and Life Span in Rats. Gerontology 28:233-241.

Heilbronn LK, Smith SR, Martin CK, Anton SD, and Ravussin E. 2005. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr 81:69-73.

Hui E, Bravis V, Hassanein M, Hanif W, Malik R, Chowdhury TA, Suliman M, and Devendra D. 2010. Management of people with diabetes wanting to fast during Ramadan. British Medical Journal 340:1407-1411.

Johnson L. 2003. Essential Medical Physiology. Academic Press. Page 643 – ISBN 978-0-12-387584-6.

Layden BT, Durai V and Lowe WL. 2010. G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes. Nature Education 3:13.

Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, and Liddle GW. 1974. Effect of glucagon on net splanchnic cyclic AMP production in normal and diabetic men. The Journal of Clinical Investigation 53:198-204.

Mair W and Dillin A. 2008. Aging and Survival: The Genetics of Life Span Extension by Dietary Restriction. Annual Review of Biochemistry 77:727-754.

Mattson MP and Wan R. 2005. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. The Journal of Nutritional Biochemistry 16:129-137.

Mjoos OD, Vik-Mo H, Henden T, and Wang H. 1977. Increased plasma cyclic AMP concentrations in fasting man. Scandinavian Journal of Clinical and Laboratory Investigation 37:439-442.

Mojaddidi M, Hassanein M, and Malik RA. 2006. Ramadan and diabetes: evidence-based guidelines. Prescriber 17:38-43.

Reiter J, Wexler ID, Shehadeh N, Tzur A, and Zangen D. 2007. Type 1 diabetes and prolonged fasting. Diabetic Medicine 24:436-439.

Sheikh A and Wallia S. 2007. Ramadan fasting and diabetes. British Medical Journal 335:613-614.

Skoglund G, Lundquist I, and Ahren B. 1987. Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse. European Journal of Pharmacology 143:83-88.

Uno M, Honjoh S, Matsuda M, Hoshikawa H, Hishimoto S, Yamamoto T, Ebisuya M, Yamamoto T, Matsumoto K, and Nishida E. 2013. A Fasting-Responsive Signaling Pathway that Extends Life Span in C. elegans. Cell Reports 3:79-91.

Weindruch R and Walford RL. 1982. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215:1415-1418.

Wolf G. 2006. Calorie Restriction Increases Life Span: A Molecular Mechanism. Nutrition Reviews 64:89-92.

so many references i am very smart www.mensa.org/mike