Four grams of glucose

Abstract

Four grams of glucose circulates in the blood of a person weighing 70 kg. This glucose is critical for normal function in many cell types. In accordance with the importance of these 4 g of glucose, a sophisticated control system is in place to maintain blood glucose constant. Our focus has been on the mechanisms by which the flux of glucose from liver to blood and from blood to skeletal muscle is regulated. The body has a remarkable capacity to satisfy the nutritional need for glucose, while still maintaining blood glucose homeostasis. The essential role of glucagon and insulin and the importance of distributed control of glucose fluxes are highlighted in this review. With regard to the latter, studies are presented that show how regulation of muscle glucose uptake is regulated by glucose delivery to muscle, glucose transport into muscle, and glucose phosphorylation within muscle.

Fig. 1.

Lines of communication form a complex network. Much has been learned and remains to be learned about glucose metabolism by assessing organs, tissues, and cells independently. Understanding factors that protect blood glucose and maintain glucose homeostasis requires the communication between organs and integration of signals that is evident in in vivo model systems. Organs can exert effects by direct control of glucose flux (black lines) or indirectly by humoral and neural signals (blue lines).

Fig. 2.

In the short-term, fasted healthy 70-kg human, liver, and muscle store ∼100 and 400 g glycogen, respectively. Four grams of glucose is present in the blood. During exercise, glucose is preserved at the expense of glycogen reservoirs. Carbohydrate (CHO) oxidation by the working muscle is increased in response to exercise. However, after 1 h, 4 g of glucose is maintained. Blood glucose is maintained at the expense of liver and muscle glycogen. The amount of glucose in the blood can still be constant after 2 h of exercise. Only after exercise of extremely long duration does blood glucose fall to concentrations that result in hypoglycemia severe enough to cause neuroglycopenia.

Fig. 3.

Rates of endogenous glucose production in 3 protocols conducted in catheterized dogs. Glucagon and insulin were clamped in all protocols using somatostatin to suppress the endogenous release of these hormones. Glucagon and insulin were replaced at basal rates in the hepatic portal vein during rest. Glucagon and insulin responses to exercise were simulated (green), glucagon response to exercise was simulated and insulin was kept at basal (red), or glucagon and insulin concentrations were both maintained at basal (blue) during exercise. Data are means ± SE. Data are from Wasserman et al. (14, 99).

Fig. 4.

An overview of the circulation is shown at top. In human subjects, blood is sampled from a peripheral vein, an arterialized hand vein, or an artery. Since the tissues of the splanchnic bed (including pancreas) consume and release hormones and metabolites, the content of the blood from these vessels does not reflect the content in portal vein blood. Glucagon and insulin are secreted by the pancreas into the portal vein (via pancreatic veins) and extracted from the portal vein by the liver. Data from a dog model show that arterial glucagon underestimates the glucagon concentration perfusing the liver (bottom left). Conversely, arterial epinephrine overestimates the epinephrine concentration perfusing the liver (bottom right). Data are means ± SE.

Fig. 5.

Endogenous glucose production response to a 2-fold increase in glucagon during rest and exercise in catheterized dogs. Rates represent the peak response under each condition. It is important to note that the response to exercise was not only 5-fold higher, but it was also sustained compared with the transient response at rest. Data are means ± SE. Data were calculated from the data of Stevenson et al. (84) and Wasserman et al. (99).

Fig. 6.

Distributed control of muscle glucose uptake; modified from Wasserman and Halseth (92) and Wasserman et al. (101).

Fig. 7.

Estimated muscle extracellular (R_extracell), transport (R_transport), and phoshorylation (R_phos) resistances to muscle glucose uptake (MGU) during insulin clamps, exercise, and during insulin clamps in rats fed a high-fat (HF) diet. Glucose gradients were calculated using the countertransport method, and the index of MGU (R_g) was calculating using 2-deoxy-[³H]glucose (2[³H]DG; Ref. 65). Values are expressed as %total resistance to MGU. G_a, arterial glucose; G_e, extracellular glucose; G_i, intracellular glucose.

Fig. 8.

Mouse models for assessing distributed control of MGU are depicted by segments of an electrical circuit. WT, GLUT4^Tg, HK^Tg, and GLUT4^TgHK^Tg: wild-type, GLUT4 overexpressing, HK II overexpressing, and combined GLUT4 and HK II overexpressors, respectively. Resistances to transport and phosphorylation are reduced by overexpression of GLUT4 and HK II proteins. Glucose influx was estimated using R_g measured with 2[³H]DG in these mouse models.

Fig. 9.

Fractional 2[³H]DG uptake in gastrocnemius of mice expressing 0, 0.5, 1.0 and ∼3.5 fold WT GLUT4 levels during the steady state period of a 4.0 mU·kg⁻¹·min⁻¹ insulin clamp or during an equal duration saline infusion (top). The same comparisons are made for sedentary (Sed) and exercised mice (bottom). HK II content was either normal (WT) or the protein was overexpressed. GLUT4 only affected fractional 2[³H]DG uptake during saline infusion when it was overexpressed. On the other hand, the absence of GLUT4 caused a marked attenuation of fractional 2[³H]DG uptake during insulin stimulation regardless of whether HK II was overexpressed. HK II overexpression had no effect on the response during saline infusion but increased the maximal response to insulin. Each point is means ± SE for 8–11 in vivo mouse experiments. Data are from Fueger and colleagues (25, 31).

Fig. 10.

Glucose metabolic index measured using 2[³H]DG was measured for the gastrocnemius and superficial vastus lateralis (SVL) during the last 30 min of a 120-min saline infusion or hyperinsulinemic euglycemic clamp (4.0 mU·kg⁻¹·min⁻¹) experiment on 5-h-fasted conscious, unrestrained mice. WT or HK^Tg mice were fed either a standard diet or a high-fat diet up to 4 mo of age and fasted for 5 h. Data are means ± SE for 7–14 mice/group. *P < 0.05 vs. saline condition; †P < 0.05 vs. WT standard diet fed; ‡P < 0.05 vs. HK^Tg standard diet fed. Data are from Fueger et al. (24).

Fig. 11.

Hyperinsulinemic-euglycemic clamps on 5-h-fasted, conscious, unrestrained C57BL/6J mice chronically treated with either vehicle or sildenafil plus arginine subcutaneously for 3 mo. Glucose metabolic index measured using 2[³H]DG is shown for soleus, gastrocnemius, and SVL. Data are means ± SE for 7–8 mice/group. *P ≤ 0.05 vs. vehicle. Data are from Ayala et al. (4).