Hypothesis: Nutrient Off-Loading and Ectopic Fat Reduction Reverse Insulin Resistance and Improve Cardiovascular Outcomes in Type 2 Diabetes—A Narrative Review

Figure 1. (A) The insulin receptor pathway in individuals with normal insulin receptor sensitivity. Activation of the insulin receptor results in parallel and balanced insulin signaling to the PI3KAkt pathway (metabolic arm) and the Ras-MAPK pathway (mitogenic arm). The metabolic pathway stimulates glucose uptake, glycogen synthesis, protein synthesis and inhibits lipolysis, apoptosis, inflammation and oxidative stress. Consequently, normal insulin receptor sensitivity is associated with normoglycemia and normal triglycerides. The mitogenic pathway stimulate growth, proliferation, and differentiation. In individuals with normal insulin receptor sensitivity insulin promotes a normal glucose metabolism, cell metabolism and a healthy cardiovascular system. (B) The insulin receptor pathway in individuals with insulin receptor resistance. Insulin resistance is characterized by a specific impairment in PI3K-dependent signaling pathway. This results in a decreased activation of the insulin receptor resulting in low glucose uptake, glycogen synthesis, protein synthesis and anti-lipolytic effects. Consequently, insulin resistance may cause hyperglycemia and hypertriglyceridemia. Simultaneously the…

Figure 2. The traditional model vs. the alternative model. (A) In the traditional model, insulin resistance is the primary driver of metabolic syndrome, prediabetes, type 2 diabetes, cardiovascular disease, cancer, and premature mortality. Through feedback, hyperinsulinemia may further contribute to an increase in insulin resistance. (B) In recent years, a shift from this traditional insulin resistance-centered paradigm has occurred toward an alternative model in which hyperinsulinemia may act as a primary driver of metabolic disease. In the alternative model, hyperinsulinemia due to (over)nutrition, genetics, and/or the environment is the primary cause of secondary insulin resistance. Through feedback, insulin resistance may further contribute to an increase in hyperinsulinemia.

Figure 3. Molecular mechanism of ectopic lipid-induced muscle insulin resistance. An increased intramyocellular content of diacylglycerol (DAG), a metabolic intermediate of lipid metabolism, has been postulated to play a major role in causing insulin resistance. An increase in the DAG content is caused by an imbalance of intracellular fluxes: the rates of DAG synthesis (owing to increased fatty acid delivery and uptake into the skeletal muscle cells) exceed the rates of mitochondrial long-chain CoA oxidation and the incorporation of DAG into neutral lipids (triacylglycerol [TAG]) (which are stored in lipid droplets). The increased intracellular accumulation of DAG content results in the activation of the theta isoform of protein kinase C (PKC ϴ). The activation of PKC ϴ leads to the increased serine phosphorylation of insulin receptor substrate 1 (IRS-1) on critical sites (e.g., Ser 1101), which in turn blocks the insulin-stimulated tyrosine phosphorylation of IRS-1 and the subsequent binding and activation of phosphatidylinositol (PI) 3-kinase (PI3K). This, in turn, leads to decreased insulin-stimulated glucose transport activity by glucose transporter type 4 (GLUT 4), resulting in…

Figure 4. Model explaining how mitochondrial superoxide acts as a nutrient sensor and forms the nexus between intracellular metabolism and the control of insulin action. The ratio of nutrient supply and ATP demand is at the center of this model. When the nutrient supply/ATP demand ratio of the cell is high due to overnutrition/physical inactivity, the cell can rapidly respond to the correct energy surplus by controlling the glucose entry into the cell. A high nutrient supply/ATP demand ratio causes an increased mitochondrial superoxide production in the cells. The increased mitochondrial superoxide production is the signal for the cell to dampen glucose uptake by inhibiting the recruitment of glucose transporter 4 (Glut 4), although the exact mechanism is unknown. As a direct consequence, the glucose uptake by the muscle and fat cells decreases. In contrast, in the opposite situation, when the nutrient supply/ATP demand ratio in the cells is low due to the nutrient off-loading/physical exercise (right), the concomitant increase in the AMP/ATP ratio leads to the activation of AMPK and subsequently the increase in the insulin-mediated glucose uptake by the cells (modified from [90], with…

Figure 5. Scheme showing how the Western diet, overnutrition, and physical inactivity are involved in the development of hyperinsulinemia, ectopic fat depositions, excessive ROS production, and insulin resistance. Hyperinsulinemia is caused by the hyper-responsiveness of pancreatic β-cells to a hostile environment and drastic changes in lifestyle (Westernized diet, overnutrition, and a lack of physical activity). The combination of hyperinsulinemia and overnutrition initially stores excess fuel as fat in the subcutaneous fat stores. Consequently, the subcutaneous fat mass initially increases. However, when energy intake is chronically greater than energy expenditure, the maximum capacity of an individual’s subcutaneous fat cells to store excessive fuel as fat is exceeded, and there will be a spillover of free fatty acids into the bloodstream. Excessive fatty acids are then transported to the liver, pancreas, heart, and skeletal muscles and stored in these tissues as ectopic fat. Independent from this mechanism, it has been hypothesized that impaired mitochondrial fat oxidation (due to excessive fuel supply unmatched to (higher than) the actual energy demands) leads to increased ectopic fat…

Figure 6. Scheme of energy metabolism in the cardiomyocytes of a healthy heart and in type 2 diabetes. (A) In the healthy heart, the rates of glucose and fatty acid uptake by the heart exactly match the rates of substrate utilization. In the healthy state, fatty acids are the major sources of cardiac energy. Most fatty acids undergo rapid oxidation and induce adenosine triphosphate (ATP) production to maintain an adequate cardiac function. Supply and demand of energy-providing substrates is well balanced to meet the energy needs. (B) In type 2 diabetes, the substrate availability is increased, and higher levels of fatty acids are preferentially used by the heart as substrates relative to glucose. The development of cardiac insulin resistance causes an increased reliance of the heart on free fatty acid oxidation as an energy source and a simultaneous decrease in glucose oxidation This results in increased fatty acid uptake and fatty acid oxidation in cardiomyocytes. Increased fatty acid oxidation causes reduced ATP production and work efficiency of the heart, possibly as more oxygen is needed per ATP molecule generated and cardiac energy metabolism is reduced. In addition, when fatty acid…

Figure 7. Effects of bariatric surgery, GLP-1 receptor agonists, and SGLT2 inhibitors on cardiovascular disease in type 2 diabetes. Nolan et al. previously predicted that glucose-lowering approaches that simultaneously off-load nutrients to the myocardium and vascular endothelium had the greatest potential to improve the cardiovascular outcomes of insulin-resistant patients with type 2 diabetes [72]. The treatment with bariatric surgery, GLP-1 receptor agonists, or SGLT2 inhibitors normalizes whole-body energy balance by nutrient off-loading: this reduces body weight, ectopic fat depositions, intracellular diacylglycerol (DAG), and reactive oxygen species (ROS), which improves insulin sensitivity and decreases glucose toxicity. All these effects contribute to the dramatic reduction in cardiovascular disease in type 2 diabetes observed after treatment with bariatric surgery, GLP-1 receptor agonists, or SGLT2 inhibitors (see the main text for more details).