The Role of the Liver in Glucose Homeostasis

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The liver, under the influence of insulin reaching it in high concentration in the portal vein after ingestion of a meal, switches from being a net exporter to net importer of glucose from the glucose pool. Any insulin not extracted and degraded by the liver passes through the heart and lungs to reach peripheral tissues, notably muscle, adipose tissue, and skin, where, providing the concentration of insulin in blood is sufficiently high, it promotes glucose uptake.

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Figure 1 Schematic representation of homeostatic control of blood glucose level and mechanism of hypoglycemia. Hypoglycemia results whenever inflow of glucose from the gut and/or liver fails to meet the outflow of glucose from the glucose pool, which consists of glucose dissolved in the extracellular water only. Imbalance arises from: (1) excessive outflow into the tissues due to insulin (or very rarely IGF-II) overproduction or activity; or (2) in the fasting state, an inability of the liver to liberate or produce glucose at a rate sufficient to meet the non-insulin-dependent, and obligatory, requirements of the brain and red blood cells for glucose.

Figure 1 Schematic representation of homeostatic control of blood glucose level and mechanism of hypoglycemia. Hypoglycemia results whenever inflow of glucose from the gut and/or liver fails to meet the outflow of glucose from the glucose pool, which consists of glucose dissolved in the extracellular water only. Imbalance arises from: (1) excessive outflow into the tissues due to insulin (or very rarely IGF-II) overproduction or activity; or (2) in the fasting state, an inability of the liver to liberate or produce glucose at a rate sufficient to meet the non-insulin-dependent, and obligatory, requirements of the brain and red blood cells for glucose.

Except in disease, the glucose pool, amounting to just 5-15 g, rarely expands by more than 100% even after ingestion of a meal providing up to 300 g of carbohydrate as starch or glucose. Nor does it shrink to less than 4g even after many days of fasting.

Entry of glucose into the glucose pool is limited by the rate at which it can be absorbed from the intestine. This is normally in the region of 25-50 gh^1. In people with normal glucose tolerance, venous blood glucose levels generally return to overnight fasting values within 2 h of eating a meal regardless of how much carbohydrate it contains. Arterial blood glucose levels take somewhat longer to return to preingestion levels but they too are always within the normal fasting range by 3 h, even though the evidence provided by measurement of the gut hormones Glucose-Dependent Insulinotrophic Peptide (GIP), the main incretin, indicate that absorption of large meals continues for much longer. Absorption of a 200-g liquid glucose meal by normal healthy subjects, for example, is still incomplete after 5 h even though both their venous and arterial blood glucose levels have long since returned to normal.

The outflow of glucose into the tissues, on the other hand, depends upon many factors; the two most important are the plasma insulin concentration and the blood concentration itself. Under maximum insulin stimulation - and at 'normal' blood glucose levels - glucose can disappear from the glucose pool at a rate of up to 40-50 gh-1 but these conditions are rarely encountered except experimentally or in cases of gross insulin overdose.

Onset of insulin action is almost instantaneous and persists for as long as insulin remains bound to insulin receptors. This is generally slightly longer than insulin levels in the blood themselves remain elevated. In other words glucose continues to enter insulin-dependent cells for up to 30 min after plasma insulin levels have returned to 'fasting' levels. During this time the glucose pool may shrink sufficiently to produce hypoglycemia unless replenished by glucose continuing to enter from the intestine (or experimentally/therapeutically by intravenous infusion) or from the liver, once it has switched from the glycogenic to glycogenolytic mode.

Small, and always temporary, imbalances between the rate at which insulin action declines and glucose enters the glucose pool can occur in healthy subjects after ingestion of a large dose of glucose in solution on an empty stomach, but is rare following the ingestion of an ordinary mixed meal.

A slight delay in stimulating insulin release in response to a meal is the earliest and most characteristic abnormality observed in patients with non-insulin-dependent diabetes mellitus (NIDDM) who may secrete more insulin in total than people of comparable age, though not of body mass index. They are, however, generally insulin resistant, which explains why, despite the larger amounts of insulin secreted in response to meals in the early stages of their illness, they do not suffer from meal-induced hypoglycemia.

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