greek.doctor

21. Molecular mechanisms of glucose uptake

GLUT transporters

Glucose doesn’t freely diffuse across the cell membrane – it has to be transported into the cell with the help of transport proteins called glucose transporters (GLUT). These transporters transport glucose into cells by facilitated diffusion.

There are many subtypes of GLUT transporters, but only five of them are important for us. The different subtypes have different properties.

GLUT1

GLUT1 is found on almost every cell in the body. It is especially abundant on RBCs and in the brain. It has a high affinity for glucose, so it ensures that RBCs and the brain always receives a steady influx of glucose. Because GLUT1 is present on almost every cell in the body, GLUT1 ensures that all cells receive at least a little glucose; we say that GLUT1 ensures “basal transport” of glucose into most cells.

GLUT2

GLUT2 is found most importantly on liver cells and on beta cells in the Langerhans islets. This glucose transporter has low affinity for glucose, meaning that it only transports glucose when the glucose concentration is high. GLUT2 has different functions in the liver and in beta cells.

GLUT2 functions as a sort of “glucose sensor” in both the liver and in beta cells; the proteins allows these cells to sense the glucose concentration of the blood. Because GLUT2 has a low affinity for glucose, glucose will only enter these cells when the blood glucose concentration is high. Thus, when glucose is transported into the liver and into the beta cells, these cells “know” that the blood glucose concentration is high.

For the beta cells, this is important as it allows the beta cells to sense when the blood glucose concentration is high, and release insulin in response. For hepatocytes, this is important so that the liver doesn’t perform gluconeogenesis when the blood glucose level is already high.

GLUT2 has another property which is important for the liver; it’s a bidirectional transporter. Most cells in the body don’t need the ability to release glucose; only the liver (and to some degree the kidney). When the liver senses that the blood glucose level is low, it will initiate gluconeogenesis. When the glucose concentration in the hepatocyte becomes higher than the glucose concentration in the blood, glucose will leave the hepatocyte into the blood through GLUT2.

GLUT3

GLUT3 is similar to GLUT1 with regards to properties. Both have high affinity for glucose. GLUT3 is especially found on neurons, and ensures that neurons receive a steady supply of glucose.

GLUT4

GLUT4 is very special, and it’s probably the only glucose transporter you’ll hear about outside the context of biochemistry and physiology. GLUT4 is only found on adipose tissue, skeletal muscle and heart muscle, but what’s special about GLUT4 is that it is the only glucose transporter which is insulin-dependent. This means that GLUT4 is only active when insulin is being secreted. There is an exception to this, however; GLUT4 is activated during exercise (more specifically, muscle contraction), even in the absence of insulin. The mechanism of GLUT4 will be explained further down.

Activation of GLUT4 via insulin is the major pathway for the body to reduce the blood glucose level. Having a high concentration of glucose in the blood over a longer period of time is really bad, so when the concentration becomes too high, insulin is released. This activates GLUT4, transporting glucose into muscle, where glucose is stored as glycogen, and into adipose tissue, where glucose is stored as fat.

Under “basal” conditions, i.e., when insulin is not being secreted and there is no exercise, the GLUT4 transporter proteins are actually not in the cell membrane but rather inside specialized storage vesicles in the cytoplasm. As long as they are here they obviously aren’t able to transport glucose inside cells. When GLUT4 is “activated”, it is actually moved from these storage vesicles to the cell membrane.

When insulin is secreted, insulin will bind to the insulin receptor on muscle and adipose tissue cells, triggering the insulin signal transduction cascade. As part of the signal transduction, protein kinase B (PKB), also known as Akt, is activated. PKB phosphorylates a protein called AS160. Now that AS160 is phosphorylated, a G-protein called Rab will bind a GTP instead of GDP, which activates it.

Activated Rab will move the storage vesicles containing GLUT4 from the cytoplasm to the cell membrane. The vesicles will fuse with the cell membrane, depositing GLUT4 in the cell membrane.

The mechanism by which muscle contraction activates GLUT4 isn’t described on the lecture so I don’t think it’s important.

GLUT5

GLUT5 is kind of special, because it doesn’t transport glucose but fructose. It’s only found on enterocytes and in spermatocytes. It’s not particularly interesting.

SGLT transporters

SGLT stands for sodium-dependent glucose transporters, which is exactly what they are. Unlike GLUT, SGLT transporters transport glucose into cells with the help of co-transport with sodium. Like GLUT, multiple subtypes exist.

SGLT1 is found in enterocytes and is involved in the absorption of glucose in food into the intestine.

SGLT2 is found in the kidney, more specifically in the early proximal tubule, and is the major transporter involved in the reabsorption of glucose from the filtrate.

Insulin resistance

Insulin resistance refers to the phenomenon where adipose and muscle tissue no longer respond well to insulin. This means that the cells won’t activate GLUT4 as efficiently as they normally do, causing them to be unable to take in as much glucose as normally. This leaves the blood glucose level high, which is not good, for reasons we’ll see below.

Insulin resistance occurs when the blood glucose level is high over longer periods of time, and it decreases the ability of the body to reduce the blood glucose level, causing an evil cycle.

In the beginning of insulin resistance, beta cells will sense that the blood glucose level isn’t dropping as much as it normally does when insulin is secreted, and they will compensate by secreting even more insulin. However, as insulin resistance becomes worse and worse, it eventually reaches a point where the beta cells can’t produce enough insulin to compensate for the insulin resistance, at which point the blood glucose level will really start to increase.

Insulin resistance is a hallmark of type 2 diabetes mellitus, one of the most common causes of morbidity and mortality in the western world. For this reason, it’s important to look at how insulin resistance occurs, and what can be done to prevent it. We already know that GLUT4 can be activated by exercise independently of glucose, so exercise is a great way to prevent and treat type 2 diabetes.

Insulin resistance (like diabetes type 2) occurs primarily in overweight, non-exercising people with diets high in carbohydrates and low in fibre.

Mechanism of insulin resistance

Insulin resistance occurs due to many mechanisms; nothing is ever simple in the world of biochemistry.

The major mechanism of insulin resistance is thought to be dysfunction of IRS-1. IRS-1 is a protein involved in the signal transduction pathway of insulin. When IRS-1 dysfunctions, the signal transduction pathway is interfered with, reducing the cell’s response to insulin. Dysfunction more specifically means “serine phosphorylation”. Many factors can phosphorylate IRS-1 on its serine residue. Serine phosphorylated IRS-1 is less active.

Many factors can cause IRS-1 serine phosphorylation, including:

  • Stress
  • Hyperlipidaemia
  • Inflammation
  • Obesity
  • Hyperglycaemia
  • Excess nutrient intake

The mechanisms by which these factors cause IRS-1 serine phosphorylation is complicated. They’re mediated by many proteins, including JNK (most important, mTOR, IKK, TNFα and protein kinase C.

Chronic hyperglycaemia increases the activity of the mitochondria. Mitochondria invariably produce reactive oxygen species as a byproduct during their function. ROS activate the protein called JNK, which causes serine phosphorylation of IRS-1.

The presence of high levels of fatty acids is also thought to cause dysfunction of IRS-1. This is thought to be mediated by protein kinase C, as PKC is activated (indirectly) by free fatty acids, and PKC causes activates JNK.