Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes

Preeti Kanikarla-Marie, Sushil K Jain, Preeti Kanikarla-Marie, Sushil K Jain

Abstract

Diets that boost ketone production are increasingly used for treating several neurological disorders. Elevation in ketones in most cases is considered favorable, as they provide energy and are efficient in fueling the body's energy needs. Despite all the benefits from ketones, the above normal elevation in the concentration of ketones in the circulation tend to illicit various pathological complications by activating injurious pathways leading to cellular damage. Recent literature demonstrates a plausible link between elevated levels of circulating ketones and oxidative stress, linking hyperketonemia to innumerable morbid conditions. Ketone bodies are produced by the oxidation of fatty acids in the liver as a source of alternative energy that generally occurs in glucose limiting conditions. Regulation of ketogenesis and ketolysis plays an important role in dictating ketone concentrations in the blood. Hyperketonemia is a condition with elevated blood levels of acetoacetate, 3-β-hydroxybutyrate, and acetone. Several physiological and pathological triggers, such as fasting, ketogenic diet, and diabetes cause an accumulation and elevation of circulating ketones. Complications of the brain, kidney, liver, and microvasculature were found to be elevated in diabetic patients who had elevated ketones compared to those diabetics with normal ketone levels. This review summarizes the mechanisms by which hyperketonemia and ketoacidosis cause an increase in redox imbalance and thereby increase the risk of morbidity and mortality in patients.

Keywords: Diabetic ketoacidosis (DKA); Hyperketonemia; Ketogenic diet (KD); Ketones; Oxidative stress.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
In normal conditions glucose gets converted to acetyl CoA and enters tricarboxylic acid (TCA) cycle to yield energy. When glucose becomes limiting, glucagon levels rise facilitating free fatty acid (FFA) transport into the liver, fatty acid oxidation is carried out by the liver to generate ketone bodies that can keep up with the brain’s energy demands. Ketogenesis increases as the availability of oxaloacetate (OA) becomes limited forcing the acetyl CoA pools towards ketone production. The ketones get converted to acetyl CoA in the extra hepatic tissues and enter into the TCA cycle providing with energy.
Figure 2
Figure 2
Conditions that induce the upregulation of ketone synthesis or cause the accumulation of ketones in the blood. In individuals during normal physiological conditions such as fasting and pregnancy along with infancy, the concentration of ketones rises in the blood. Other states such as diabetes, also known as an insulin deficient state, alcoholism, and certain mutations in the genes that are required in the breakdown of ketones also increase ketone levels in the blood.
Figure 3
Figure 3
Literature has shown that ketones can increase oxidative stress by several mechanisms, and upregulation of NADPH oxidases is one such example. The increase in the production of superoxide radicals, mediated by ketones, can upregulate signaling mechanisms inducing the expression of adhesion molecules. It has been shown in the endothelial cells where the increased adhesion molecule expression can cause the monocytes to adhere that could potentially lead to lesion or plaque initiation or tissue infiltration contributing to tissue damage [31].

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