Metabolic Switch On Fasting in Risky People

Anton SD, Moehl K, Donahoo WT, et al. Flipping the Metabolic Switch:
Understanding and Applying the Health Benefits of Fasting. Obesity (Silver
Spring). 2018;26(2):254-268. doi:10.1002/oby.22065. [Cited April 1, 2022]
Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783752/

Here we focus on the physiological responses of major organ systems,

including the musculoskeletal system, to the onset of the metabolic
switch – the point of negative energy balance at which liver glycogen
stores are depleted and fatty acids are mobilized (typically beyond 12
hours after cessation of food intake). Emerging findings suggest the
metabolic switch from glucose to fatty acid-derived ketones
represents an evolutionarily conserved trigger point that shifts
metabolism from lipid/cholesterol synthesis and fat storage to
mobilization of fat through fatty acid oxidation and fatty-acid derived
ketones, which serve to preserve muscle mass and function. Thus, IF
regimens that induce the metabolic switch have the potential to
improve body composition in overweight individuals. Calorie
restriction (CR), a reduction in caloric intake without malnutrition,
has consistently been found to produce reductions in body weight and
extend healthy life span across a variety of species,(1) including non-
human primates.(2) Studies conducted in overweight humans indicate
short-term CR (6-months) can significantly improve several
cardiovascular risk factors, insulin-sensitivity, and mitochondrial
function

 For example, IF regimens have been shown to improve cardio-

metabolic risk factors (such as insulin resistance, dyslipidemia and
inflammation cytokines),(13) decrease visceral fat mass,(6) and
produce similar levels of weight loss as CR regimens.(8) In addition to
the weight loss effects and metabolic improvements, several other
beneficial effects of therapeutic fasting have been described including
improvements in lipid profiles,(14) osteoarthritis,(15) healing of
thrombophlebitis,(15) healing of refractory dermal ulcers, (16) and
tolerance of elective surgery.(17)
 Gambar switch metabolik
AcAc, acetoacetate; ATP, adenosine triphosphate; FFA, free fatty acids; TCA, tricarboxylic acid.

Initial scientific studies conducted in 1914 utilized fasting for the

treatment of both type 1 and type 2 diabetes.(36),(37) Subsequently,
numerous studies suggested fasting as a treatment for type 2 diabetes.
Genuth(38) described a case report of a severely obese woman who
had resolution of her diabetes following four weeks of fasting;
significantly, her glucose tolerance remained normal for over a year
after she regained the lost weight. Jackson et al.(39) found an
improvement in glucose tolerance following 17–99 days of fasting,
and the improvement in glucose and insulin metabolism was not
related to the weight lost during the fast or the weight regained
following the fast. Several additional studies found an improved
insulin sensitivity and glucose tolerance in people with diabetes
immediately following a fast.(40) (41–46)
The observed reduction in body fat and elevation of ketone levels in
these mice strongly indicates the metabolic switch occurs in animals
on 30–40% CR.

Early studies of TRF were aimed at understanding how the timing of

food intake affects circadian rhythms.(67, 68) TRF (4 hour feeding
period every day) normalized circadian rhythms, improved glucose
regulation and reduced weight gain in mice.(68) Similarly, 8
hours/day TRF prevented high fat diet-induced obesity in mice,(65)
and 9 hours/day TRF lowered glucose levels, increased insulin levels
and insulin sensitivity in a rat model of type I diabetes
In mice fed a high fat diet, TRF normalizes the expression of genes
involved in fatty acid metabolism (Fasn), β-oxidation (Pparγ) and
antioxidant defenses (Sod1) in the liver.(61) TRF accentuates diurnal
rhythms in the expression of many different genes in liver cells
including those encoding Per2, Bmal1 and Cry1. TRF also completely
prevents the adverse effects of a high fat diet on the circadian rhythm
of phosphorylation CREB (cyclic AMP response element-binding
 protein), a transcription factor that plays a critical role in
gluconeogenesis during fasting.(61) TRF also completely prevents the
accumulation of lipids in the liver that occurs in mice maintained on a
high fat diet.(61) Moreover, multiple markers of inflammation (TNF-α,
IL-6 and IL-1β) are reduced in livers of mice on TRF, and metabolomic
analyses indicate multiple alterations in liver metabolites (palmitate,
oleate and palmitoleate), bioenergetic pathway molecules (glucose-6-
phosphate, citrate and opthalmate), and the antioxidant reduced
glutathione, caused by a high fat diet are reversed by TRF
The transition in transcriptional programs that occurs in liver cells in
response to the metabolic switch is regulated, in part, by sirtuins.(71)
SIRT1 suppresses glucose production through inhibiting CRTC2 -
mediated gluconeogenesis. Time-course analyses during the fasting
period showed SIRT1 is activated during the metabolic switch from
glycogenolysis to ketone production, which leads to deacetylation and
degradation of CRTC2.(29) In addition, SIRT1 represses lipolysis and
cholesterol synthesis by regulating the activity of cholesterol catabolic
pathways.(29) SIRT1 acts as a positive regulator of liver oxidation of
fatty acids. It increases the rate of fatty acid oxidation by deacetylating
PGC-1α(72) and by activating peroxisome proliferators-activated
receptor α (PPARα).(73) PPARα promotes fatty acid β oxidation in
both the mitochondria and peroxisomes. In addition, SIRT1 interacts
with the hepatocyte-derived hormone fibroblast growth factor 21
(FGF21) to coordinate an adaptive response to fasting by inducing
ketogenesis, preventing hepatic steatosis and controlling energy
expenditure
 Data also suggest fasting stimulates autophagy in muscle cells by
mechanisms involving AMPK-mediated inhibition of mTOR signaling
and up-regulation of the autophagy-promoting proteins FOXO3a and
ULK1.
In most studies, IF regimens have been shown to reduce overall fat
mass and visceral fat both of which have been linked to increased
diabetes risk.(139) IF regimens ranging in duration from 8 to 24
weeks have consistently been found to decrease insulin resistance
 In line with this, IF regimens (both TRF and ADMF) have been found
to decrease fasting glucose levels by 3 to 6% in individuals with
prediabetes.(12, 123, 134) IF regimens, however, do not appear to
affect fasting glucose levels in healthy individuals.
In most studies, IF regimens have been shown to reduce traditional
cardiovascular risk factors. Reductions in total cholesterol typically
range from 6 to 21%, with LDL cholesterol decreasing by 7 to 32%
following IF interventions.(12, 115, 118, 122, 123, 134) Similarly, IF
regimens have also been shown to decrease triglyceride levels by
between 16 to 42% in the majority of studies tested.
(12, 115, 118, 119, 122, 123, 131, 132, 134, 140) Significant
reductions in systolic (3 to 8%) and diastolic blood pressure (6 to
10%) have also been reported following 6 to 24 weeks of IF, though
these changes appear to be driven by weight loss as significant
reductions in blood pressure were only reported in studies in which
participants lost 6% or more of their body weight.
While our review suggests IF results in both weight and fat loss (even
when caloric intake is not limited), as well as increased insulin
sensitivity in overweight subjects, there remains an important need
for randomized controlled trials (RCTs) of IF in normal weight
subjects. Emerging findings indicate that IF when combined with
resistance training can produce beneficial changes in body
composition and strength in young, healthy males. Additional studies
are needed to better understand the effects of combining IF with
resistance training on body composition and strength outcomes in
other populations.

1. Safety, health improvement and

well-being during a 4 to 21-day fasting
period in an observational study
including 1422 subjects
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209353
The shift from carbohydrates and glucose to fatty acids and ketones as the major cellular fuel source
for body and brain seems to play a key role. It has recently been referred to as intermittent metabolic
switching (IMS) and glucose-to-ketone (G-to-K) switch. The reverse step–ketone-to-glucose (K-to-G)
switch–happens upon refeeding [2]. The G-to-K switch includes reduction in blood glucose, insulin
and IGF-1 levels, depletion or reduction of glycogen stores, and an increase in lipolysis and
ketogenesis [2, 5, 10]. Fasting has been shown to induce differential cellular stress resistance [11]
and autophagy [12, 13], as well as triggering the synthesis of detoxification enzymes [9, 14]. Fasting
seems to modify the intestinal microbiome [9, 15].  Finally, in the K-to-G switch, fasting has been
found to activate stem cells and multiple system regeneration in the refeeding period [4, 18, 19] and to
increase the mitochondrial biogenesis in neurons and other body cells.

Fasting periods with various patterns are found in most religions [23]. For instance, Ramadan
intermittent fasting was linked with improvements in cardiometabolic risk factors 

TG values of women were lower than the values of men. Fasting reduced TG levels by 0.44 mmol/L
on average (fasting intervention: p<0.001) (S2 Table). TG levels at the end of the fasting were similar
in all groups, suggesting a floor effect (Fig 5A). The decrease in TC was significant (fasting
intervention: p<0.001) and higher in the groups who fasted for longer (fasting duration group-by-
fasting intervention: p<0.001). Fig 5B indicates that F15d and F20d had similar post-values. There
was no difference in TC changes during fasting between men and women. 
Regarding liver function, GOT and GPT levels rose significantly during the course of the fast (fasting
intervention: each p<0.001) without difference between groups. The values at baseline and at the end
remained within norm ranges (<0.8 μkat/L) increasing for GOT in average from 0.4 to 0.6 μkat/L and
GPT from 0.5 to 0.7 μkat/L
Urea concentrations decreased significantly in all groups (fasting intervention: p<0.001), but the
decrease was stronger in the groups with longer fasting periods (fasting duration group-by-fasting
intervention: p<0.001). Creatinine levels increased significantly (fasting intervention: p<0.001) with
differences between the sexes (fasting intervention-by-sex: p<0.001) but without differences between
groups.

Sodium concentrations remained in norm range but showed a significant reduction (fasting
intervention: p<0.001) from a mean of 140.1±0.1 to 138.7±0.1 mmol/L. Calcium levels increased
significantly (fasting intervention: p<0.001), with an effect of groups (fasting duration group-by-fasting
intervention: p<0.001) but not of gender. Potassium showed a reduction during fasting (fasting
intervention: p = 0.001) and magnesium levels remained stable. All values pre- and post-fasting
remained in norm range. Blood pressure showed a significant decrease, whereby mean values did not
fall below the lower norm range, indicating a floor effect. Accordingly, serious hypotensive
complications were not reported. Blood pressure reduction might be triggered by factors such as the
increase of parasympathetic activity due to the release of brain-derived neurotrophic factor (BDNF)
[2, 41, 42], increased renal Na excretion [43] and enhanced receptor sensitivity of natriuretic peptides
and insulin [44]. Earlier studies on zero calorie diets and very-low-calorie diets (VLCD)

 Furthermore, the reduction of insulin and leptin levels appears to act on the hypothalamic-pituitary-
adrenal axis, thereby impacting mood positively [58]. Endogenous opioid (β-endorphin) could also
contribute to well-being, as documented in a 10-day fasting trial in men [59]. In our study, the reported
improvement of a major health complaint, often accompanied by pain relief, could possibly contribute
to the increase of well-being. Moreover, it appears likely that a successful completion of a longer
fasting period improves the feeling of self-efficacy, thereby enhancing subjective well-being [37].

 IF boosts levels of antioxidants and reduces levels of pro-inflammatory cytokines TNF-α, IL-1β and
IL-6 [72]. Serum markers of oxidative damage and inflammation are reduced in asthma patients
maintained on an alternate day fast [62]. Moreover, the reduction of abdominal circumference which
was significant in our study is also associated with a decrease in pro-inflammatory activity

2. Hanif S, Ali SN, Hassanein M, Khunti K, Hanif W. Managing People with Diabetes
Fasting for Ramadan During the COVID-19 Pandemic: A South Asian Health
Foundation Update. Diabet Med. 2020 Jul;37(7):1094-1102. doi: 10.1111/dme.14312.
Epub 2020 Jun 5. PMID: 32333691; PMCID: PMC7267620.
https://pubmed.ncbi.nlm.nih.gov/32333691/
the UK experience has shown diabetes and COVID-19 is associated with dehydration,
starvation ketosis, diabetic ketoacidosis and hyperosmolar hyperglycaemic state. This makes
fasting in Ramadan particularly challenging for those Muslims with diabetes.

Muslims around the world fast for the holy month of Ramadan. This involves abstaining from
food and drink from dawn (suhoor) to dusk (iftar), for the entire month, and is fundamental to
the faith as one of the five pillars of Islam. While fasting is considered compulsory for all
adult Muslims, there are exemptions for those who are pregnant, lactating, travelling, or have
any acute or chronic health conditions (where fasting may place them at risk of ill-health).
Although this means fasting is not mandatory for Muslims with diabetes, many will still
choose to fast for spiritual as well as social and cultural reasons; the Epidemiology of
Diabetes and Ramadan (EPIDIAR) survey of over 12,000 people with diabetes in 13 Islamic
countries, indicated that approximately 43% of people with type 1 diabetes mellitus and 79%
of people with type 2 diabetes mellitus fast during Ramadan [1]. Similarly, Muslims who
develop any acute illness, including COVID-19, are exempt from fasting, but may choose to
do so regardless

We recommend that people in the high risk category during the current COVID-19 pandemic
must not fast. Those in the moderate risk category should not fast. People in the low risk
should take adequate precautions if they choose to fast.
or people with diabetes choosing to fast for Ramadan, frequent blood glucose monitoring is
imperative to mitigate the risk of complications, particularly with the high incidence of
COVID-19 infection. It is well-established that concurrent infection, including COVID-19, may
precipitate hyperglycaemia, DKA and dehydration, hypoglycaemia, or alter their presentation
[14]. We recommend, therefore, that people with diabetes; check their capillary blood
glucose at least four times a day during fasting – at suhoor time, two hours into the fast, just
before breaking the fast at iftar and two hours after breaking the fast. People with diabetes
who demonstrate COVID-19 symptoms; check their blood glucose every 4-6 hours, along
with ketone levels. Additionally, if they experience any symptoms of hypo- or hyperglycaemia
or become unwell, they check their blood glucose.
If blood glucose during fasting is <3.9 mmol/L or >16.6 mmol/L, people with diabetes need to
break their fast, whether or not they have any symptoms [13]. For those using insulin or
sulfonylureas, the fast should be broken if blood glucose is <3.9 mmol/L at the beginning of
the fast 

Alongside these measures, people with type 1 diabetes should ensure adequate fluid intake
of 2-3L of water or unsweetened beverages during non-fasting hours, and close adherence
to infection control measures including frequent hand-washing and social distancing.

People with type 2 diabetes should follow an individualised nutrition plan, taking into account
their age, cultural norms and comorbidities. At mealtimes, people with diabetes should
incorporate foods with a low glycaemic index, and ensure a balanced macronutrient profile,
avoiding the large meals containing highly processed carbohydrates and sugars that are
often seen at iftar. People with diabetes need to eat their suhoor meal as late as possible, to
avoid hypoglycaemia towards the end of the fast. This is especially important during
prolonged fasts. To avoid dehydration, people with type 2 diabetes need to drink 2-3 litres of
water or unsweetened beverages over the course of the non-fasting hours, particularly as
any concurrent COVID-19 infection can be worsened by dehydration and hypovolaemic
acute AKI. For many Muslims, physical activity is reduced during Ramadan [16], particularly
voluntary exercise (compared to physical labour for work, for example), as a result of altered
sleeping patterns, lethargy associated with fasting and increased priority of socio-religious
practices. However, performing light exercise may be beneficial in avoiding weight gain,
maintaining fitness and improving mood and sleep 

3. Park C, Guallar E, Linton JA, et al. Fasting glucose level and the risk of incident
atherosclerotic cardiovascular diseases. Diabetes Care. 2013;36(7):1988-1993.
doi:10.2337/dc12-1577. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687304/

4. The impact of Ramadan fasting on

glucose variability in type 2 diabetes
mellitus patients on oral anti diabetic
agents.
https://journals.plos.org/plosone/article?
id=10.1371/journal.pone.0234443
5. Anton SD, Moehl K, Donahoo WT, et al. Flipping the Metabolic Switch: Understanding and
Applying the Health Benefits of Fasting. Obesity (Silver Spring). 2018;26(2):254-268.
doi:10.1002/oby.22065. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783752/

Puasa Ramadhan dan Penyakit Ginjal Kroning Sedang-Berat

6. Bakhit AA, Kurdi AM, Wadera JJ, Alsuwaida AO. Effects of Ramadan fasting on moderate to
severe chronic kidney disease. A prospective observational study. Saudi Med J.
2017;38(1):48-52. doi:10.15537/smj.2017.1.17566.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278065/
7. Volume 41, Issue 6, December 2015, Pages 456-462.
https://www.sciencedirect.com/science/article/abs/pii/S1262363615001202
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732905/