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Philip Randle described the Randle Cycle (aka Randle Effect) in 1963 as an explanation of how the human physiology determines glucose or fat metabolism, which determined by the body being in either a fasted or fed state. When in insulin levels are low, the body is in a fasted state and conversely, when insulin levels are high, the body is in a fed state. When the body is in fed state, the mitochondria favour glucose metabolism and inhibits fat metabolism. When the body is in a fasted state, the body favours fat metabolism and inhibits glucose metabolism.

I became aware of the effect of the Randle Cycle after I stopped taking Dapagliflozin (Forxiga/Farxiga). After being off of Forxiga for two weeks, I noticed that the Dawn Phenomenon became more pronounced and took longer to wear off. Others on a fat-adapted (eg, ketogenic) diet have also reported a similar situation and some describe it as psysiological insulin resistance. This occurs because the liver responds to waking hormonal changes and "dumps" glucose into the bloodstream, which significantly boosts serum glucose. Dr Ben Bikman (see Diet Doctor Podcast #35 @ 13:04) states he believes this situation is "glucose intolerance" rather than insulin resistance because psysiologially the body will respond to an influx of insulin. With this glucose intolerance (aka carbohydrate intolerance), hyperinsulinemia is NOT present and the pancreas does not appear to be responding to the endogenous glucose produced by the liver. This has also been described as "Adaptive Glucose Sparing" because, although the liver raises serum glucose from the Dawn Phenomenon, tissues have been adapted to using ketones and no-longer require as much glucose for fuel. It appears that high morning glucose on a low-carb diet is normal and healthy.

There are numerous benefits to being in a fasted state from a the perspective of mitochondrial health and exercise has similar benefits. Having healthy mitochondria is absolutely essential to good health and impaired mitochondrial function is linked to many chronic diseases. Neurons are particularly susepticible to dyfunctional mitochondria. The fasted state is characterized by low insulin and the presence of ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone), which are a produced by the liver from triglycerides.  Most cells with mitochondria readily use ketones for fuel.  The presence of ketones will cause uncoupling of adipose mitochondria so that they generate heat in addition to producing ATP, which increases the body's metabolic rate.  Ketones help the muscle mitochondria become more coupled so that they are more energy efficient in producing ATP. Benefits of being in the fasted state are:

  • Increased mitochondrial biogenenis (more mitochondria)
  • Increased mitochondrial fusion (enhanced ATP production)
  • Favourable mitochondrial function (less oxidative stress, enhanced ATP production, umcoupling of adipose tissue while maintaining coupling of muscle tissue)

It appears that metabolizing longer-chain saturated fats promotes mitochondrial biogenesis though reverse electron transport via Reactive Oxygen Species (signaling molecules) in the mitochondria's electron transport chain. Increased low-level ROS synthesis causes localized insulin resistance at the cellular level, which prevents the uptake of glucose. Basically, the higher the ratio of FADH2 to NADH (F/N ratio), the greater the amount of reverse electron transport (RET), which in turn encourages the mitochondrial biosynthesis. Reverse electron transport occurs marginally with F/N=0.46 and not at all with F/N<0.46. Fat oxidation generates greater amounts of FADH2 than glucose oxiation and fat metabolism generates ketones. Because ketones deactive the cell's insulin receptor, they also help prevent the glucose uptake in adipose tissue. Since Linoleic Acid has no RET effect, it acts like a supercharged carbohydrate because it contains 9 calories/gram vs 4 for glucose and it is likely a significant contributor to the obesity epidemic. Industrial seed oils (eg, canola/rapeseed, corn, cotton, peanut, safflower, soybean, sunflower) are a key component of processed foods.

Fatty Acid Carbon
Chain
Length
Carbon
Double
Bonds
(Saturation)
F/N
Ratio
Drives
RET?
Stearic Acid
(eg, beef tallow & other animal fats, cocoa & shea butter)
C18 0 0.49 ↑ ↑ ↑
Palmitic Acid
(eg, palm oil, meats, dairy products, cocoa butter)
C16 0 0.48 ↑ ↑
Caprylic Acid
(eg, goats milk, coconut & palm oil)
C8 0 0.47
Oleic Acid
(eg, olive & sunflower oil, poultry fat & lard)
C18 1 0.46
Palmitoleic Acid
(eg, macadamia oil)
C16 1 0.45
Butyric Acid
(eg, butter & other dairy products, human breast milk)
C4 0 0.43
Linoleic Acid
(eg, industrial seed oils)
C18 2 0.43
Glucose C6 (ring) N/A 0.20

With my blood sugar now staying primarily in the healthy range (3.9-6.9 mM) and steady, it has become easy to defer breakfast as the Dawn Phenomenon typically takes until early afternoon to wear off. As a result, I've been deferring breakfast until mid afternoon or until late afternoon / early evening (one meal a day). Without eating, my blood tends to gradually fall into the low 4 range by late afternoon.I monitor my blood glucose with my FreeStyle Libre to help me determine the best time to eat. Since gluconeogenesis is demand-driven, I expect that the Dawn Phenomenon may possibly diminish over time with decreasing hepatic insulin resistance. As my focus is to become insulin sensitive and this can only be done by minimizing insulin levels, I am going to continue with time-restricted, LCHF diet and see where it takes me.

To minimize the Dawn Effect, it appears that not consuming food and having low-intensity exercise (eg, walking) after supper are helpful. It also appears that having high-intensity exercise (compared with walking) in the morning does not quickly drive down serum glucose but seems to have somewhat of an opposite effect. This may be because the high-intensity exercise demands glucose from gluconeogenesis.

References: