Physiology of Systemic Glucose Homeostasis
Whole-body glucose homeostasis represents a balance between glucose supply and glucose disposal (or utilization). When the supply of glucose exceeds its disposal, blood glucose concentration rises; when utilization exceeds supply, glucose levels fall. In normal individuals, this balance is intricately maintained so that blood glucose remains stable, typically between 60 and 140 mg/dL, even in the setting of such disparate stressors as the ingestion of a large, simple carbohydrate load or a prolonged fast.2 In contradistinction, marked metabolic abnormalities occur when this balance is perturbed, such as in diabetes mellitus or insulinoma. The sources of blood glucose include gastrointestinal carbohydrate absorption and de novo hepatic production in the form of glycogenolysis and gluconeogenesis. The major source of glucose at any particular time depends on the phase of the meal cycle. In the postprandial phase, hepatic glucose production is suppressed, with new glucose appearance primarily due to absorption of digested carbohydrates. Glucose absorption generally lasts for 2 to 5 hours after a meal, depending on the caloric content and composition of the meal. The tissues responsible for glucose utilization include those that require insulin and those that are insulin independent. The brain is the organ responsible for most of the insulin-independent glucose utilization in the fasting state, with erythrocytes and the renal medulla involved to a lesser extent.
In the postprandial phase, insulin-requiring glucose disposal occurs in many body tissues, most prominently in the liver and muscle. After nutrient ingestion, insulin secretion is stimulated directly by a rise in both plasma glucose and amino acids and indirectly through the action of a variety of incretins, or intestinal factors that promote insulin secretion.3 In liver and muscle, insulin stimulates storage of glucose into glycogen and amino acids into protein. In adipose tissue, insulin stimulates free fatty acid (FFA) incorporation into triglycerides (TGs). Insulin action is balanced by the effects of counter-regulatory hormones, most notably glucagon and catecholamines.24 Both hormones stimulate hepatic glycogenolysis and gluconeogenesis in the liver, whereas catecholamines have additional effects on the pancreas to inhibit insulin release and on muscle to inhibit insulin action. In the postabsorptive or fasting phase, the liver becomes an organ of net glucose production; glycogenolysis contributes approximately 40% of the new glucose supply and gluconeogenesis contributes approximately 60%. As the fast progresses, the percentage of gluconeogenesis contribution rises. By day 3, gluconeogenesis accounts for virtually all glucose production.5 Substrates for gluconeogenesis include amino acids from catabolized muscle protein, lactate, pyruvate, and glycerol. In general, the liver is the major gluconeogenic organ in the body. However, under certain circumstances such as prolonged fasting (lasting longer than several weeks), the kidney can supply up to 40% of whole body glucose production.6 In the postabsorptive phase, circulating insulin levels are low. At this time, insulin-independent organs consume about half of the body's glucose production, whereas other tissues derive most of their energy needs from fat oxidation (ketone bodies).
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