Monday, January 16, 2006

High-fat diet and type 2 diabetes

Diabetes (which appears in several different forms) has been a difficult disease to understand in detail. The main diagnostic indication of diabetes is poor regulation of levels of glucose in the blood -- either too much glucose (hyperglycemia) or too little (hypoglycemia). From these conditions (if not treated) follow various other seriously harmful effects, including arterial disease, nerve damage, kidney failure, damage to the eyes, and gangrene in the extremities.

Insulin is the hormone which is most responsible for proper regulation of glucose levels. The body produces insulin only in the beta cells of the pancreas. Its primary function is to get glucose out of the blood by causing it to be taken up by cells, where the glucose is either stored or used for energy production.

This process can fail in two different ways. In the first case, a persistent excess of glucose can cause overproduction of insulin by the beta cells if those cells themselves are undamaged. This in turn leads to insulin resistance, in which other body cells do not take up glucose properly even in the presence of insulin. A common cause of this is excessive amounts of carbohydrates in a person's diet.

In the second case, not enough isulin is proudced, either because the beta cells have been damaged or else because they are inhibited in some way. One way that beta cells can actually be destroyed is in an autoimmune condition. Typically, but not necessarily, this occurs before adulthood, and so this has been called juvenile onset diabetes or (more commonly now) type 1 diabetes.

Diabetes that occurs (usually in adulthood) without major damage to beta cells is referred to as type 2 diabetes (formerly called adult onset diabetes). If this type isn't the result of insulin resistance (the first case above), it is due to underproduction of insulin in the beta cells. This circumstance has been the hardest to understand. Sometimes it appears to be genetic, but may also be triggered by obesity and/or a high-fat diet. New research is beginning to illuminate how this comes about.

Researchers Discover Mechanistic Link Between High-Fat Diet and Type 2 Diabetes
Howard Hughes Medical Institute researchers have discovered a molecular link between a high-fat, Western-style diet, and the onset of type 2 diabetes. In studies in mice, the scientists showed that a high-fat diet interferes with a genetic mechanism they discovered that promotes insulin production, resulting in the classic signs of type 2 diabetes.

In an article published in the December 29, 2005, issue of the journal Cell , the researchers report that knocking out a single gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a) disrupts insulin production. Importantly, the scientists showed that a high-fat diet suppresses the activity of GnT-4a and leads to type 2 diabetes due to failure of the pancreatic beta cells.

The enzyme GnT-4a was suspected of being involved in the problem because it is highly expressed in the pancreas. The same enzyme is also found in mice, so researchers studied mice in which the gene for GnT-4a was disabled.

The studies showed that GnT-4a has an important effect on another protein, called Glut-2, which is important in beta cells. Glut-2 normally occurs on the surface of a beta cell, and it enables the cell to sense the amount of glucose in the blood. The cell produces insulin in proportion to the blood glucose level. What GnT-4a does is to attach a sugar-like molecule called a glycan to Glut-2 -- a process called glycosylation. If there's not enough GnT-4a, the process doesn't occur, and Glut-2 is unable to situate on the beta cell membrane, which makes the cell unresponsive to glucose, which inhibits insulin production. It was already known that a deficiency of Glut-2 on beta cell surfaces occurs in patients with type 2 diabetes.

This fact alone indicates why diabetes can be a genetic condition: If both parents have diabetes as a result of defective GnT-4a genes, their offspring may have the same problem. (It would be a recessive trait.)

But what was really interesting was that the researchers found that when mice with normal GnT-4a genes were fed a high-fat diet, the levels of GnT-4a enzyme were also decreased. Somehow a high-fat diet inhibits the expression of GnT-4a genes, but the exact mechanism is still not clear.

As far as obesity is concerned, it's often the result of a diet that is too high in fat, but it's not clear whether obesity per se also affects GnT-4a. So it seems still undetermined whether the association of obesity with diabetes is because the two conditions have a common cause (too much fat), or whether something extra is going on.

But in any case, there's now more evidence that high-fat diets are not a good thing.

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