MCAT Biochemistry Review

Chapter 9: Carbohydrate Metabolism I: Glycolysis, Glycogen, Gluconeogenesis, and the Pentose Phosphate Pathway

Introduction

Maintaining a constant blood glucose concentration around  is of the utmost importance in the body: high blood sugar causes long-term damage to the retina, kidney, blood vessels, and nerves, while low blood sugar can cause autonomic disturbances, seizures, and even coma. Without the ability to take in glucose constantly, the body must find ways to store and release glucose as it is needed. And given the variety of food we eat on a daily basis, the body must find ways to use all of the various carbohydrates it takes in.

There's a complex interplay between the neurological, endocrine, digestive, and excretory systems to maintain this blood glucose concentration, much of which is discussed in Chapter 12 of MCAT Biochemistry Review. In this chapter, we'll take a look at the metabolic pathways that involve glucose: the methods by which our bodies digest glucose and other monosaccharides, store and release glucose for energy, generate glucose from other biomolecules, and use glucose to create some of the coenzymes and substrates needed for biosynthesis.

This chapter is the first of four that focus on metabolism in MCAT Biochemistry Review. Here, we focus on metabolic processes of glucose that do not require oxygen; in Chapter 10, we'll turn our focus to the processes that only occur under aerobic conditions. In Chapter 11, we'll explore the metabolism of lipids and amino acids. Finally, in Chapter 12, we'll bring all of metabolism together with a focus on bioenergetics and the regulation of metabolism overall.

9.1 Glucose Transport

Glucose entry into most cells is driven by concentration and is independent of sodium, unlike absorption from the digestive tract. Normal glucose concentration in peripheral blood is 5.6 mM (normal range: 4–6 mM). There are four glucose transporters, called GLUT 1 through GLUT 4. GLUT 2 and GLUT 4 are the most significant of these because they are located only in specific cells and are highly regulated.

GLUT 2 is a low-affinity transporter in hepatocytes and pancreatic cells. After a meal, blood traveling through the hepatic portal vein from the intestine is rich in glucose. GLUT 2 captures the excess glucose primarily for storage. When the glucose concentration drops below the Km for the transporter, much of the remainder leaves the liver and enters the peripheral circulation. The Km of GLUT 2 is quite high (~15 mM). This means that the liver will pick up glucose in proportion to its concentration in the blood (first-order kinetics). In other words, the liver will pick up excess glucose and store it only after a meal, when blood glucose levels are high. In the β-islet cells of the pancreas, GLUT 2, along with the glycolytic enzyme glucokinase, serves as the glucose sensor for insulin release.

BRIDGE

The Km is the concentration of substrate when an enzyme is active at half of its maximum velocity (vmax). The lower the Km, the higher the enzyme's affinity for the substrate. See Chapter 2 of MCAT Biochemistry Review for more on Michaelis–Menten enzyme kinetics.

GLUT 4 is in adipose tissue and muscle and responds to the glucose concentration in peripheral blood. The rate of glucose transport in these two tissues is increased by insulin, which stimulates the movement of additional GLUT 4 transporters to the membrane by a mechanism involving exocytosis, as shown in Figure 9.1. The Km of GLUT 4 is close to the normal glucose levels in blood (~5 mM). This means that the transporter is saturated when blood glucose levels are just a bit higher than normal. When a person has high blood sugar concentrations, these transporters will still permit only a constant rate of glucose influx because they will be saturated (zero-order kinetics). Then how can cells with GLUT 4 transporters increase their intake of glucose? By increasing the number of GLUT 4 transporters on their surface.

Figure 9.1. Insulin Regulation of Glucose Transport in Muscle and Adipose Cells

REAL WORLD

Diabetes mellitus is caused by a disruption of the insulin/GLUT 4 mechanism. In type 1 diabetes, insulin is absent and cannot stimulate the insulin receptor. In type 2 diabetes, the receptor becomes insensitive to insulin and fails to bring GLUT 4 transporters to the cell surface. In both cases, blood glucose rises, leading to immediate symptoms (increased urination, increased thirst, ketoacidosis) and long-term symptoms (blindness, heart attacks, strokes, nerve damage).

Although basal levels of transport occur in all cells independently of insulin, the transport rate increases in adipose tissue and muscle when insulin levels rise. Muscle stores excess glucose as glycogen, and adipose tissue requires glucose to form dihydroxyacetone phosphate (DHAP), which is converted to glycerol phosphate to store incoming fatty acids as triacylglycerols.

MCAT Concept Check 9.1:

Before you move on, assess your understanding of the material with these questions.

1.    Compare and contrast GLUT 2 and GLUT 4:

 

GLUT 2

GLUT 2

Important tissues

   

Km

   

Saturated at normal glucose levels?

   

Responsive to insulin?

   

2.    How does insulin promote glucose entry into cells?