BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL STUDENTS - E. S. Severin - 2004

CHAPTER 7. CARBOHYDRATE METABOLISM

XI. Regulation of Blood Glucose Levels

The ultimate goal of regulating metabolic pathways involving glucose is to maintain a constant Blood glucose concentration.

The concentration of glucose in arterial blood is maintained at a steady level of 60-100 mg/dL (3.3-5.5 mmol/L) throughout the day. Following a carbohydrate-rich meal, glucose levels rise over the course of about 1 hour to reach 150 mg/dL (~8 mmol/L, alimentary hyperglycemia), before gradually returning to normal within approximately 2 hours. Figure 7-59 illustrates the 24-hour fluctuations in blood glucose concentration under a three-meal-a-day regimen.

Class="center">Fig. 7-59. Diurnal fluctuations in blood glucose concentration. A, B — absorptive period; C, D — postabsorptive period. The arrow indicates mealtime, and the dashed line represents the normal Blood Glucose Level.

A. Regulation of Blood Glucose Levels During the Absorptive and Postabsorptive Periods

To prevent an excessive spike in blood glucose levels following a meal, uptake of glucose by The Liver and Muscles—and, to a lesser extent, by adipose tissue—plays a primary role. It is worth recalling that more than half of all dietary glucose (60%) entering the portal vein from the intestine is captured by the liver. Approximately two-thirds of this amount is stored in the liver as Glycogen, while the remainder is converted into Lipids or oxidized to drive ATP synthesis. These processes are rapidly accelerated by an elevated Insulin-Glucagon ratio. The remaining portion of dietary glucose enters the systemic Circulation. Roughly two-thirds of this fraction is taken up by Muscle and adipose tissue, driven by an increase in Cell membrane permeability to glucose in response to high insulin concentrations. In Skeletal Muscle, glucose is stored as glycogen, whereas in adipocytes, it is converted into triglycerides. The rest of the glucose circulating in the bloodstream is cleared by other Cells (insulin-independent Tissues).

Under normal dietary habits and a balanced nutritional intake, blood glucose levels and the glucose supply to all Organs are primarily sustained through glycogen Synthesis and Breakdown. Only toward the end of a night's Sleep—that is, following the longest fasting interval between meals—does THE CONTRIBUTION OF Gluconeogenesis increase slightly. This role becomes even more prominent if breakfast is skipped and fasting continues (Fig. 7-60).

Fig. 7-60. Sources of blood glucose during Digestion and fasting. 1 — dietary CARBOHYDRATES serve as the primary source of blood glucose during the absorptive period; 2 — in the postabsorptive period, the liver supplies glucose to the blood via Glycogenolysis and gluconeogenesis, with glycogen breakdown accounting for the maintenance of blood glucose levels over an 8-12 hour window; 3 — hepatic glycogenolysis and gluconeogenesis contribute equally to maintaining normal glucose concentrations; 4 — over the course of the day, liver glycogen stores are nearly depleted, leading to an upregulation of gluconeogenesis; 5 — during prolonged fasting (1 week or more), The rate of gluconeogenesis decreases slightly, yet it remains the sole source of blood glucose.

B. Regulation of Blood Glucose Levels During Prolonged Fasting

During the first 24 hours of fasting, the body's glycogen stores are depleted, after which gluconeogenesis becomes the exclusive source of glucose (derived from lactate, glycerol, and Amino Acids). Consequently, gluconeogenesis is accelerated, while Glycolysis is downregulated due to low insulin and high glucagon levels (The Mechanism of this phenomenon was described previously). Furthermore, after 1-2 days, another regulatory mechanism comes into significant play: the Induction and Repression of specific enzyme synthesis. The levels of glycolytic Enzymes decline, whereas the concentrations of gluconeogenic enzymes increase. These shifts in enzyme synthesis are likewise mediated by insulin and glucagon (the underlying mechanism is discussed in Chapter 11).

Starting on the second day of fasting, gluconeogenesis from Amino Acids and glycerol reaches its maximal rate, while the rate of lactate-derived gluconeogenesis remains constant. As a result, approximately 100 g of glucose is synthesized daily, primarily within the liver.

It should be noted that during fasting, glucose is not utilized by muscle or adipose tissue because, in the absence of insulin, it cannot enter these cells, thereby sparing glucose for the Brain and other glucose-dependent tissues. Since muscles normally act as one of the primary glucose consumers, halting glucose uptake in skeletal muscle during starvation is crucial for ensuring an adequate glucose supply to the brain. During extended periods of fasting (several days or more), the brain begins to utilize alternative Energy Sources as well (see Chapter 8).

A specific variant of fasting is unbalanced Nutrition, particularly diets deficient in carbohydrates—often referred to as carbohydrate starvation. Under these conditions, gluconeogenesis is similarly activated, utilizing amino acids and glycerol derived from dietary Proteins and fats to synthesize glucose.

C. Regulation of Blood Glucose Levels at Rest and During Physical Exercise

Both at rest and during sustained physical exertion, the immediate source of glucose for working muscles is the glycogen stored within the muscles themselves, followed subsequently by blood glucose. It is well established that running consumes roughly 100 g of glycogen in about 15 minutes, whereas muscle glycogen reserves following a carbohydrate-rich meal can reach 200-300 g. Figure 7-61 illustrates the respective contributions of hepatic glycogen and gluconeogenesis in supplying glucose to muscles across varying intensities and durations of exercise. The Regulation of Glycogen mobilization in muscles and the liver, as well as hepatic gluconeogenesis, has been outlined previously (Chapters VII, X).

Fig. 7-61. Contribution of liver glycogen and gluconeogenesis to maintaining blood glucose levels at rest and during prolonged physical exercise. The dark portion of the bar represents the contribution of liver glycogen to maintaining blood glucose; the light portion represents the contribution of gluconeogenesis. As the duration of physical activity increases from 40 min (2) to 210 min (3), glycogenolysis and gluconeogenesis contribute nearly equally to supplying the blood with glucose. 1 — resting state (postabsorptive period); 2, 3 — physical exercise.

In summary, the evidence discussed above leads to the Conclusion that the Coordinated regulation of the rates of glycolysis, gluconeogenesis, glycogen synthesis, and glycogen breakdown by Hormones ensures:

✵ Prevention of an excessive rise in postprandial blood glucose concentration;

✵ storage of glycogen and its mobilization during the intervals between meals;

✵ an adequate supply of glucose to skeletal muscles, whose energy demands increase rapidly during physical activity.

✵ supply of glucose to cells that preferentially use glucose as an energy source during starvation (Nerve Cells, erythrocytes, renal medulla, Testes).