Growth hormone (GH) causes insulin resistance primarily by increasing free fatty acid (FFA) flux and promoting lipotoxicity.
Mechanisms of GH-Induced Insulin Resistance
Growth hormone antagonizes the action of insulin through various molecular pathways. Here's a breakdown of the key mechanisms:
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Increased Lipolysis: GH stimulates the breakdown of triglycerides (fats) stored in adipose tissue (lipolysis).
- This leads to an elevated release of FFAs into the bloodstream.
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Suppression of Insulin's Anti-Lipolytic Action: Chronically elevated GH levels blunt insulin's ability to suppress lipolysis. This means insulin becomes less effective at preventing the release of FFAs from fat cells.
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Lipotoxicity: The increased flux of FFAs into circulation results in lipotoxicity. This means that excessive fat accumulates in non-adipose tissues like muscle and liver.
- Muscle: Intramuscular lipid accumulation interferes with insulin signaling pathways, impairing glucose uptake by muscle cells.
- Liver: Hepatic steatosis (fatty liver) impairs insulin's ability to suppress glucose production by the liver.
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Interference with Insulin Signaling: GH can directly interfere with insulin signaling at the cellular level.
- GH may reduce the expression of insulin receptors on cell surfaces, making cells less responsive to insulin.
- GH can also interfere with downstream signaling molecules in the insulin signaling cascade, such as IRS-1 (Insulin Receptor Substrate 1).
The Role of FFAs
The elevated FFAs play a crucial role in driving insulin resistance. Here's how:
- Impaired Glucose Uptake: FFAs impair glucose uptake in muscle tissue, a major site of glucose disposal.
- Increased Hepatic Glucose Production: FFAs promote increased glucose production by the liver, further contributing to hyperglycemia (high blood sugar).
- Reduced Glycogen Synthesis: FFAs can inhibit glycogen synthesis in both muscle and liver, meaning less glucose is stored for later use.
- Inflammation: Elevated FFAs can trigger inflammatory pathways, contributing to systemic inflammation and insulin resistance.
Summary
In essence, GH disrupts the delicate balance of lipid metabolism. Chronic exposure to high GH levels promotes fat breakdown and increases FFA levels. These elevated FFAs then impair insulin signaling in key tissues like muscle and liver, leading to insulin resistance and ultimately contributing to metabolic dysfunction.
