Last updated on April 4, 2019 at 11:24
This topic describes the biochemical changes in diabetes. The deficiency of insulin explains most of these changes.
Many glucose transporter proteins (GLUT) exist, but GLUT4 is the only one that is insulin dependent. It is found in myocardium, skeletal muscle and adipose tissue. When insulin binds to the insulin receptor on these cells will intracellular vesicles that contain GLUT4 be transported to the membrane, so that the glucose transporter is embedded into the membrane, allowing transport of glucose into the cell. However, insulin isn’t the only factor that activates GLUT4; muscle contractions in both skeletal and cardiac muscle causes translocation of GLUT4 to the cell membrane. This explains how physical activity helps prevent development of diabetes.
However, GLUT4 isn’t the only glucose transporter on muscle cells and adipose tissue. GLUT1 is expressed in basically all cells, including these, ensuring a small transport of glucose even in insulin deficiency.
The metabolic effects of insulin are summarized below.
|Pentose phosphate pathway||Stimulated|
|Fatty acid synthesis||Stimulated|
Insulin is an anabolic hormone, so it stimulates all processes that “build” molecules and inhibit all processes that “break down” molecules.
Pathobiochemistry of 1DM
Before we begin there is something that should be explained. What was previously known as “free fatty acids” are nowadays more correctly called “non-esterified fatty acids” or NEFAs. This is because “free fatty acids” aren’t free (they’re bound to albumin), so the term is inaccurate. Whenever you see the term “NEFA” you should think “free fatty acids”.
Hyperglycaemia develops in DM due to multiple factors:
- Decreased glucose uptake by insulin-dependent tissues
- Increased glycogenolysis in the liver
- Increased gluconeogenesis in the liver
- Decreased inhibition of insulin-antagonist hormones
In 1DM the insulin deficiency means that there is no inhibition of the insulin antagonist hormones glucagon, epinephrine, cortisol, growth hormone and thyroxine. The levels of these hormones may be increased, potentially contributing to the hyperglycaemia.
Diabetes mellitus causes similar intracellular biochemistry as starvation. There exists a lot of energy (glucose) outside the cells, but because the cells can’t take this energy up and utilize it, they’re basically starving.
When there is absolute insulin deficiency (1DM) insulin-dependent tissues will have dramatically reduced glucose uptake. Any glucose that is taken up by these tissues can’t be utilized properly, as many enzymes of the glycolysis and TCA cycle are insulin-dependent as well.
Insulin-dependent tissues still need energy and they must get this energy from somewhere else. Hormone-sensitive lipase is usually inhibited by insulin, but isn’t inhibited in DM. This allows lipolysis, which provides NEFAs which are released into the circulation from the liver and adipose tissue. FFAs are taken up by peripheral cells and the liver, who burn them during β-oxidation. This produces acetyl-CoA, all of which cannot enter the TCA cycle as this cycle is insulin-dependent. Instead the excess acetyl-CoA is converted into ketone bodies in the liver. The brain will not utilize these ketone bodies as it does during starvation, as in DM the brain cells receive more than enough glucose (as they use an insulin-independent glucose transporter).
Insulin-independent tissues like the brain, retina and RBCs take up more than normal amounts of glucose. The surplus amount of glucose in these cells may stimulate unusual pathways, like the polyol pathway.
The polyol pathway consumes approximately 30% of glucose in the body in DM (source), and the pathway is especially active in places where diabetic damage is characteristic, like the retina, kidney and nervous tissues. This pathway is very simple, as it only has two steps: glucose -> sorbitol -> fructose. The first step consumes NADPH and the second consumes NAD+, so excessive activation of this pathway causes NADPH and NAD+ deficiency.
NADPH is essential to recycle glutathione, a very important antioxidant. The deficiency of NADPH causes increased levels of oxidative stress due to reactive oxygen species.
Increased NADH/NAD+ ratio causes a state of pseudohypoxia, a metabolic state very similar to the state of hypoxia but without actual oxygen deficiency. This may damage cells by increased free radical production, decreased Na+/K+ ATPase activity and other mechanisms.
Protein synthesis decreases and protein breakdown increases in 1DM as the anabolic hormone insulin is deficient. The nitrogen balance will be negative.
The formation of advanced glycation end-products (AGEs) is important in diabetes. Glucose binds non-enzymatically not only to haemoglobin but to proteins and lipids all over the body. AGEs are prevalent in the vasculature of diabetic patients and contribute to the development of atherosclerosis. These products are pathogenic by many mechanisms. They bind to a receptor called RAGE (receptor for AGE), which is pro-inflammatory and stimulates NF-κB. They can form cross-links between molecules, altering and/or inhibiting their function.
Pathobiochemistry of 2DM
The biochemical changes are mostly the same as in 1DM, however some aspects are different in 2DM as there is always some effect of insulin. In general the membrane transport of glucose is still impaired, but the intracellular actions of insulin are mostly maintained. The glucose that cells take up through other transporters (like GLUT1) can be effectively utilized. Tissues aren’t forced to use fatty acids, and lipogenesis is stimulated in adipose tissue. Protein catabolism is high.
41. Basic characteristics and forms of diabetes mellitus syndrome
43. Etiology and pathogenesis of 1DM