Effect of insulin on fat metabolism
Insulin has many effects that lead to fat storage in adipose tissue. First, insulin increases glucose utilization in most tissues, which automatically reduces fat utilization, thus functioning as fat storage.
Although not quite as clear as the rapid effect of insulin on carbohydrate metabolism, the effect of insulin on fat metabolism is long-term and equally important. Particularly impressive is the long-term effect of insulin deficiency in causing atherosclerosis, which often leads to heart attacks, strokes, and other vascular accidents. First, however, let's discuss the rapid effects of insulin on fat metabolism.
Insulin increases fat synthesis and storage
Insulin has many effects that lead to fat storage in adipose tissue. First, insulin increases glucose utilization in most tissues, which automatically reduces fat utilization, thus functioning as fat storage. However, insulin also increases fatty acid synthesis, especially when more carbohydrates are absorbed than needed to provide energy and fuel for fat synthesis. Almost all of this synthesis begins in cells entering the liver, and fatty acids are then transported from the liver to storage in fat cells by lipoproteins in the blood. The following factors lead to increased fatty acid synthesis in the liver:
1. Insulin increases glucose transport into liver cells. After the concentration of glycogen in the liver increases by 5-6%, glycogen synthesis is inhibited. All glucose is further transported to the liver as fat. Glucose is broken down into pyruvate molecules during glycolysis, and then pyruvate is converted to acetyl coenzyme A (acetyl-CoA), the raw material for fatty acid synthesis.
2. Excess citrate and isocitrate ions are formed by the citric acid cycle when too much glucose is used for energy. These ions then directly activate the enzyme acetyl-CoA carboxylase, the enzyme needed to convert acetyl-CoA to malonyl-CoA, the first stage of fatty acid synthesis.
3. Most fatty acids are synthesized in the liver and used to form triglycerides, the normal storage form of fat. They are released from liver cells into the bloodstream as lipoproteins. Insulin activates lipoprotein lipase in the capillary walls of adipose tissue, cleaving triglycerides back into fatty acids, necessary for their absorption into adipocytes, where they are converted back to triglycerides and stored.
The role of insulin in fat storage in adipocytes
1. Insulin inhibits the activity of hormone-sensitive lipase. Lipase is an enzyme that hydrolyzes stored triglycerides in fat cells. Thus, inhibiting the release of fatty acids from adipose tissue into the circulation.
2. Insulin enhances glucose transport across cell membranes into fat cells in the same way that it increases glucose transport into muscle cells. A small portion of glucose is used to synthesize small amounts of fatty acids, but more importantly, it is also used to form large amounts of α-glycerol phosphate. This molecule provides glycerol to combine with fatty acids to form triglycerides, which are stored in fat cells. Therefore, in the absence of insulin, the storage of large amounts of fatty acids transported from the liver in lipoproteins is virtually blocked.
Insulin deficiency increases the use of fat for energy
All of these ways of breaking down fat for energy are greatly enhanced in conditions of insulin deficiency. Even normally, this occurs between meals when insulin secretion is very small, but it becomes stronger in people with diabetes when insulin secretion is close to zero. The results of this effect are described in the following section.
Insulin deficiency causes degradation of stored fat and release of free fatty acids
In insulin-deficient conditions, all of the insulin effects noted above are reversed in fat storage. The most important effect is that the hormone-sensitive lipase enzyme in fat cells becomes more active. This hydrolyzes stored triglycerides, releasing large amounts of fatty acids and glycerol into the bloodstream. As a result, the concentration of free fatty acids begins to increase. These free fatty acids become the main source of energy used by all tissues in the body except the brain.
The figure shows the effect of insulin deficiency on plasma free fatty acid concentrations. It appears that immediately after removal of the pancreas, plasma free fatty acid concentrations begin to increase, even faster than glucose concentrations.
Insulin deficiency increases plasma cholesterol and phospholipid concentrations
Excess plasma fatty acids associated with insulin deficiency increase hepatic conversion of certain fatty acids to phospholipids and cholesterol, the two major products of fat metabolism. These two molecules, in parallel with an excess of triglycerides, are synthesized in the liver at the same time, and then released into the blood as lipoproteins. Randomly, plasma lipoproteins are increased about 3-fold in insulin deficiency, representing a few percent of total plasma lipid concentrations rather than the normal 0.6%. High lipid levels, especially high cholesterol levels, increase the progression of atherosclerosis in patients with diabetes.
Excess use of fat in insulin deficiency causes ketosis and acidosis
Insulin deficiency also causes an excess of acetoacetic acid to be formed in hepatocytes. This excess is the result of the following effect: Insulin deficiency, but in the face of excess fatty acids in hepatocytes, the carnitine transport mechanism that helps transport fatty acids into the mitochondria becomes hyperactive. In mitochondria, beta-oxidation of fatty acids occurs rapidly, releasing large amounts of acetyl-CoA. Much of this excess acetyl-CoA is then converted to acetoacetic acid. Then released into the bloodstream. Most of the acetoacetic acid goes to the peripheral cells, where it is converted back to acetyl-CoA and used for energy as usual.
At the same time, insulin deficiency also reduces acetoacetic acid utilization in peripheral tissues. Therefore, much of the acetoacetic acid released from the liver cannot be completely metabolized in tissues. As shown in the figure, the concentration of acetoacetic acid increases for several days after stopping insulin secretion, sometimes, the level increases to 10 mEq/l or more, which is a severe acidosis of the body fluids.
Figure. Effect of pancreatic excision on approximate concentrations of blood glucose, plasma free fatty acids and acetoacetic acid.
As discussed in section 69, some of the acetoacetic acids is also converted to β-hydroxybutyric acid and acetone. These two molecules, in tandem with acetoacetic acid, are called ketone bodies, and their presence in large amounts in body fluids is termed ketosis. We will see them again in severe diabetes, where acetoacetic acid and β-hydroxybutyric acid can lead to severe acidosis and coma, which can lead to death.