At any point in time, the glycemic response to exogenous glucose is the balance between the rate at which glucose appears in the systemic circulation (from oral as well as endogenous sources) and the rate at which glucose is disposed of. Oral glucose appearance in the peripheral circulation depends on: (a) the rate at which the gastric contents are passed on to the small intestine; (b) the rate of intestinal glucose absorption; (c) the extent of gut glucose utilization; (d) the degree of hepatic glucose trapping; and (e) the dynamics of glucose transfer through gut, liver, and posthepatic circulation on to the right heart. The contribution of endogenous glucose to the glycemic response to feeding depends on the extent and rate of change of hepatic glucose production. Finally, glucose disposal depends on changes in the pattern of hormonal stimuli and substrate availability.
Being a summation phenomenon, the response to oral glucose explores the whole of glucose tolerance, not the individual contribution of the various components. The rate-limiting step in the transfer of ingested glucose from the stomach to the liver is the rate of gastric emptying. This depends on the volume, temperature, and osmolarity of the glucose solution in the case in which glucose alone is ingested. Glucose absorption through the intestinal lining cells is rapid and efficient, the capacity of the whole small intestine being far in excess of ordinary needs. The presence of sodium chloride in the glucose drink enhances glucose absorption. Glucose utilization by intestinal tissues is small when glucose is presented on the vascular side, that is, when there is no oral glucose (Table 14.1).
The possibility also exists that systemic hyperglycemia and/or hyperinsulinemia may interfere with intestinal glucose absorption. Experimentally induced hyperglycemia impairs gastric motility and slows down gastric emptying, thereby delaying the absorption of oral antidiabetic drugs.
Glucose uptake by the liver is stimulated by portal hyperglycemia (see later), but traversing the hepatic space is unlikely to significantly delay the appearance of oral glucose in the systemic circulation. On the whole, the dynamics of oral glucose appearance are essentially driven by gastric emptying, while intestinal transit, crossing of the mucosa to enter portal blood, and transhepatic passage together introduce only a small time delay. In other words, if neither gut nor liver tissues used glucose, the time course of oral glucose appearance would only follow gastric emptying, with a time shift of a few minutes. For this reason, the absorption step is a major component of the shape of the glycemic response to glucose. Figure 14.18 shows the pattern of appearance of ingested glucose in the systemic circulation in healthy individuals, as reconstructed by a double tracer technique . Glucose arrival peaks within 30–45 min, declines slowly thereafter, and is still significantly above zero 210 min after glucose ingestion. A secondary rise in oral glucose appearance is sometimes seen between 2 and 3h after ingestion. Figure 14.18 also shows the time course of suppression of endogenous glucose release by oral glucose. A sustained nadir between 45 and 135 min is followed by a slow return toward fasting rates; hepatic glucose production is still significantly inhibited 210 min after the glucose challenge. Overall suppression of endogenous glucose production during 3 – 4 h after ingestion averages 50%, surprisingly less than what would be expected on the basis of the combined portal hyper- glycemia and hyperinsulinemia (see Figure 14.4). Relative to intravenous glucose/ insulin administration, glucose ingestion evidently reinforces counterregulatory influences which keep liver glucose outflow open.
In Figure 14.19 the observed arterial plasma glucose concentration is broken down into the component contributed by oral glucose appearance and that provided by hepatic glucose production. While the resemblance of oral Ra to the plasma glucose curve is evident (especially during the first 60 – 90 min), less appreciated is the fact that absorption is still incomplete 3 – 4 h after ingestion. Figure 14.18 depicts the time course of total glucose disposal (Rd) following oral glucose: with a lag of some 30 min, glucose uptake is stimulated by 50 – 110% throughout the period of observation. Hyperglycemia contributes more to whole-body glucose disposal during the first half of the test; thereafter, hyperinsulinemia predominates. Oral glucose elicits vasodilation of the splanchnic vascular bed; this, too, is a change that persists for at least 4 h . Thus, both the metabolic and the hemodynamic perturbations induced by oral glucose extend beyond the time of return of plasma glucose to pre-ingestion levels. The tissue destination of absorbed glucose has been the subject of intense investigation. While the liver classically was reputed to be responsible for the eventual disposal of the majority of oral glucose , the weight of more recent evidence [33,36,110] favors the view that peripheral tissues are responsible for between one half and two thirds of glucose uptake, while the splanchnic tissues account for the remainder.
A robust insulin secretory response directs more posthepatic glucose to the periphery, while a large increase in splanchnic blood flow increases the delivery of incoming sugar to the liver. In humans, for example, a glucose drink sipped over 3.5 h rather than swallowed in one bolus generates the same overall glucose curve but a 50% smaller endogenous insulin response .
The route of administration seems to influence the metabolic fate of glucose [33,36,113,114], in that the portosystemic glucose gradient per se enhances liver glucose uptake independently of portal glycemia and total glucose delivery to the organ [33,36,112,113] (as previously discussed).
Limited information is available on the intracellular fate of ingested glucose. While glucose oxidation in the brain continues unabated during the absorptive period, some 50% of the glucose taken up by peripheral tissues (muscle) is oxidized, the remainder being stored as muscle glycogen or as lactate in the lactate pool . During absorption, there is an increase in lactate release by both the splanchnic area as a whole and the intestine [28–30]. In the latter, it has been estimated that some 5% of the ingested load is converted into three-carbon precursors of glucose (lactate, pyruvate, and alanine) and passed on to the liver [28,115]. The net release of lactate by the splanchnic area indicates that the sum of hepatic lactate production and gut lactate formation exceeds hepatic lactate extraction. Liver glycogen formation during absorption of oral glucose certainly occurs both directly from glucose and indirectly via gluconeogenesis. The relative contribution of the direct versus indirect pathway to hepatic glycogen synthesis is somewhat uncertain owing to methodological difficulties. Current data  suggest that gluconeogenesis participates in liver glycogen repletion to a lesser extent in humans than in rats [117,118].
Following glucose ingestion, the plasma insulin response is two- to threefold greater than that observed when the same glucose profile is created by intravenous glucose . This incretin effect is due to the release of glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), which are secreted by the K cells of the early small intestine and L cells of the distal small bowel/large intestine [119,120]. GLP-1 and GLP are released within 2 – 3 min following glucose ingestion. Since gastric emptying takes 10–15min to begin, it is clear that the nutrients cannot have reached the duodenum and certainly not the large bowel. The release of GLP-1 and GIP is mediated via neural connections to the brain and back via the vagus nerve . Although activation of the neural pathway within minutes leads to the release of GLP-1 and GIP, insulin secretion is not increased since the stimulatory effect of GLP-1 and GIP on the β cell is glucose dependent and only occurs when gastric emptying begins and the plasma glucose concentration rises. Approximately half of all insulin that is secreted in response to oral glucose is dependent upon GLP-1/GIP in healthy subjects. A direct effect of GLP-1 to augment hepatic glucose uptake, beyond its stimulatory effect on insulin secretion, has been proposed . The inhibition of glucagon secretion and simultaneous stimulation of insulin secretion conspire to suppress hepatic glucose production. GLP-1 also has a direct effect on the liver to enhance hepatic glucose uptake .