Glucose Homeostasis

Circulating glucose levels are primarily regulated by Insulin and Glucagon. These hormones control the expression and activity of cellular uptake transporters and the balance between glycogen synthesis and breakdown.

The cellular uptake and efflux of glucose is mediated by multipass transporters which are differentially expressed between tissues.

Glut family transporters are required for importing glucose into cells. They are most highly expressed in glucose-dependent organs such as brain, skeletal muscle, and kidney.

SGLT transporters are highly expressed in the kidney or small intestine. SGLT2 mediates glucose reabsorption from the renal glomerular filtrate and is an important pharmaceutical target for treatment of hyperglycemia.

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Glucose Transport

Insulin is an anabolic peptide hormone that is secreted by pancreatic beta cells and promotes cellular glucose uptake and glycogen storage. It binds to the Insulin R which triggers signaling through IRS1 and IRS2. Dysregulation of Insulin production or action is the defining characteristic of type 1 and type 2 diabetes, respectively.

Glucagon is a catabolic peptide hormone secreted by pancreatic alpha cells during times of fasting. It signals through Glucagon R and counterbalances Insulin’s effects by limiting Insulin secretion and promoting hepatic glycogenolysis.

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Hormonal Control

Internalized glucose is catabolized through glycolysis or converted to glycogen for energy storage, primarily in the liver. The expression of glucose and glycogen-metabolizing enzymes is controlled by transcription factors that are responsive to intracellular glucose levels.

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Intracellular Glucose Metabolism

Proteins and lipids can be non-enzymatically modified by glycation to generate advanced glycation end products (AGEs) such as carboxymethyl lysine (CML). The binding of AGE-modified macromolecules to RAGE and scavenger receptors triggers widespread inflammatory reactions. Glycation is accelerated by hyperglycemia, oxidative stress, and aging.

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