Submission statement: MD-PhD Robert Cywes looked at the claim in the foundational literature that linked saturated fat to diabetes. This paper was published in 1963, and there were key advances in the understanding of energy regulation that were not available to the authors at the time.

Trigger Warning: High fat, carnivore MD-PhD opinions.

Ep: 276 The Randle Cycle Explained and Demystified by MD-Phd Robert Cywes

Citation to Paper discussed: RANDLE PJ, GARLAND PB, HALES CN, NEWSHOLME EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785-9. doi: 10.1016/s0140-6736(63)91500-9. PMID: 13990765

Summary of Findings and Historical Context:

• Muscle Cells - including the heart - prefer to use fats as a fuel..
• The use of fat shunts glucose to glycogen formation.
• When glycogen stores are full, glucose is converted into pyurvate and lactate, which are then released into the bloodstream vice being converted to ATP in the mitocondria. Lactate is fuel used by some tissues, but the bulk of the free pyurvate and lactate are reassembled into glucose by the liver.
• The erroneous conclusion in 1963 was that this release of pyurvate & lactate was an abnormal energy process. Not discussed and purely my conjecture, but if pyurvate and lactate are more benign substances to have in the blood stream, this seems like a great way to mitigate excessive blood sugar and also ensure that the main glycogen store, the liver, is topped off.
• All of the process "caused by fat" are mediated by glucagon - the release of pyruvate & lactate, of the release of fat from body stores, the production of ketones, and the release of glucose from glycogen from stores in the liver. Glucagon was identified at the time of publication, but subsequently mechanistically studied after the publication of this paper.
  
• Dr. Cywes then explains that glucagon and insulin balance each other in a feeback system so that energy is stored when insulin is dominant after meals and utilized when glucagon is dominate during fasting.
• The two missing pieces of information at the time were the existence of Glucagon and the Glut-4 insulin receptor. Without knowledge of the Glut-4 receptor then positing the down regulation due to hyperinsuilinemia and subsequent insulin resistance were then assigned to fat utilization instead of elevate blood glucose levels.
  
• A history of Glucagon discovery, from 1922-1976 the tools were not available to determine glucagon's actual function.

Ep: 378 Glucose Knowledge to be Healthy - Your Doctor doesn't understand this! by MD-PhD Robert Cywes

I think that the title for this one should be "Energy detection and regulation in the human body."

The main point being is that the release of insulin occurs in response to two factors:

1. The release of "gut hormones" in response to a meal: GLP 1, GIP, Peptide YY, and also Lectin.
2. When high blood glucose concentrations are detected by the beta cells in the pancreas. Note that the pancreas is one of the last tissues to receive blood - the Liver, Heart, and Lungs all get fed by the flow of blood from the intestines before the rest of the body system sees the sugar.

Insulin resistance of the alpha cells in the pancreas, which is also "last in line", creates an inability to clear glucose into the alpha cells, which are then energy deficient. Therefore glucagon is released for fat and glycogen release, dumping more fuel in an already over full system... So insulin resistance typified by T2 Diabetes is self perpetuating to a certain extent if it effects the alpha cells of the pancreas.

Lastly, for a modern, heavily carnivore biased Professor's take on the Randle Cycle: "Dangers of Mixing Carbs and Fat | Randle Cycle Discussion - Bary Kay" The short summary is that there is a cellular feedback mechanism that allows a cell to cease the uptake of energy substrates, glucose or fats, when the cells energy needs are met - which blocks the action of insulin.

The worst thing one can do is continually swap fuel substrates as burning one substrate inhibits the uptake of another.