When we consume food our small intestine configures its modality and converts it into a simpler form of carbohydrates such as glucose, fructose, and galactose. Glucose in particular is absorbed by the small intestine and released into the bloodstream – its main objective is to reach the target cells and supply energy. The mediator which enables it to do so is “ Insulin”. A hormone that is released by the pancreas acts as a key for glucose to enter the door which is your cells by binding to the insulin receptors in cells and granting entry for glucose to pass through.(At instances where energy is not immediately required but blood sugar levels are high the insulin instructs glucose to be converted into glycogen for energy storage purposes).
When our pancreas produces a very insignificant amount of insulin or not at all it ultimately leads to a chronic metabolic endocrine disorder called “Diabetes mellitus”. First documented in Egypt it was described by rapid weight loss and polyuria, which as of now has manifested as a global epidemic claiming an estimated of 1 life every 10 seconds per year. Recent surveys have predicted an astounding rise in diabetes, from 2003 (194 diagnosed) to 2025 ( nearly 380 million diagnosed). Additionally, almost 50% of putative diabetes are not diagnosed until 10 years after the onset of the disease hence the leading amount for prevailing diabetes may be higher.
There are predominantly 2 types of diabetes :
● Type 1 diabetes: It is an autoimmune disease in which your immune system for unknown reasons destroys the insulin-producing pancreatic cells. It affects up to 10% of people diagnosed with diabetes
● Type 2 diabetes:It occurs when the body does not produce enough insulin or becomes unresponsive to it (insulin resistance). This occurs in 90%-95% of the population diagnosed with diabetes and is the most common type.
In this article, we will be discussing how excessive ketogenesis accounts for type 1 and type 2 diabetes.
Ketogenesis is a metabolic process in which the liver converts fatty acids into ketone bodies at times when glucose levels are low allowing mammals to survive a period of prolonged fasting. It occurs in the mitochondria of hepatocytes (liver cells) where enzymes convert Acetyl CoA (a compound derived from fatty acids) into ketone.
The ketones are then taken up by other cells and oxidized to produce ATP. Insulin usually inhibits lipolysis (breakdown of fat) and proteolysis ( breakdown of protein) hoover the depleted levels due to diabetes encourage the breakdown of fatty acids into acetyl CoA through β-oxidation. Moreover, its decreased levels also give rise to gluconeogenesis which consumes oxaloacetate preventing it from combining with acetyl CoA for the release of energy (decreases the occurrence of Krebs cycle )ultimately contributing to the inflation of ketogenesis.
Physiological ketogenesis is essential for providing an alternate source of energy when glucose is not readily available. Pathological ketogenesis however can be life-threatening as it leads to uncontrolled and continuous production of ketone bodies that lower the blood pH or acidify it (Diabetic ketoacidosis). People who have undergone pancreatectomy or are diagnosed with diabetes (it has been reported to be more prevalent in type 1 diabetes as 2-4% of the diabetics are diagnosed with it ) tend to be vulnerable to such diseases. Likewise, illnesses such as heart attacks, urinary tract infections, stroke, and medications containing sodium-glucose-co-transporter-2 have also been shown to cause Diabetic ketoacidosis (DKA) although it is a very rare occurrence.
Severe acidity in the blood can lead to coma in extreme cases. Enzymes, which are highly sensitive to changes in pH, may undergo alterations in shape and function, resulting in decreased efficiency of cellular processes. Elevated hydrogen ion levels in the blood also disrupt the electron transport chain, which relies on the pH gradient for ATP production. Furthermore, these changes affect the ion gradients in cells that are essential for cell signaling and nutrient transport.
For instance, when blood becomes excessively acidic, some hydrogen ions enter cells to help buffer the acidity. To maintain electrical balance, potassium ions exit the cells, leading to a deviation from the cell's resting potential and resulting in depolarization (where the inside of the cell becomes less negative compared to the outside). This depolarization causes ion channels to open, increasing the influx of Ca²⁺ ions into the cell. While calcium ions are crucial for cell signaling, excessive amounts can lead to cell damage, inflammation, and cell death.
Additionally, high concentrations of hydrogen ions disrupt hemoglobin's ability to carry oxygen due to the Bohr effect, where the affinity for oxygen decreases as pH levels drop. (This takes place for hemoglobin to release oxygen more readily to metabolically active cells, which may deprive the brain of sufficient oxygen and potentially lead to coma.
To tackle such metabolic crises recent research has stated that it is possible to address DKA through insulin-independent pathways. The unger group from Germany discovered that using leptin (a hormone that is involved in energy regulation ) monotherapy can normalize high levels of ketone as it impacts particular neurons in the hypothalamus increasing the level of proteins called S100A9 (protein part of the protein family that can bind to calcium ions and known to promote inflammation) that can interact with other proteins such as S100A8 which together (when overexpressed during insulin-deficient states) activate Toll-like receptor - 4(TLR-4) protein regulating normalization of hypoketonemia and promoting survival pathways in cells in order to protect from damaging effects of ketone and other metabolic stresses).
Although this field of research is as extensive, clinical trials regarding in-vivo S100A9 protein have shown promising results for its effectiveness which inspires optimism for advancements.
In conclusion, while ketogenesis is an eminent source of energy during glucose scarcity, excessive production of ketones can potentially be an etiological factor for diabetic ketoacidosis. Moreover exponential decrease in pH levels of blood disrupts metabolic homeostasis and worst case scenario can lead to COMA. Apart from insulin therapies, there are insulin-independent pathways to balance ketone concentrations in the blood that do show favorable outcomes through clinical trials but have not been expanded to humans just yet.
Written By: Tisa Tamala
REFERENCES :
https://medlineplus.gov/lab-tests/ketones-in-blood/#:~:text=High%20ketone%20levels%20 make%20your,coma%20and%20be%20life%2Dthreatening.
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