CLASSIFICATION

Diabetes is classified by underlying cause. The categories are: type 1 diabetesan autoimmune disease in which the body's own immune system attacks the pancreas, rendering it unable to produce insulin; type 2 diabetesin which a resistance to the effects of insulin or a defect in insulin secretion may be seen; gestational diabetes; and "other types". Table 1 compares the presentation (phenotype) of type 1 and type 2 diabetes.

Type 2 diabetes commonly occurs in adults who are obese. There are many underlying factors that contribute to the high blood glucose levels in these individuals. An important factor is the body's resistance to insulin in the body, essentially ignoring its insulin secretions. A second factor is the falling production of insulin by the beta cells of the pancreas. Therefore, an individual with type 2 diabetes may have a combination of deficient secretion and deficient action of insulin.

In contrast to type 2, type 1 diabetes most commonly occurs in children and is a result of the body's immune system attacking and destroying the beta cells. The trigger for this autoimmune attack is not clear, but the result is the end of insulin production.

Glucose is an essential fuel for the body (Figure 1).The amount of glucose in the bloodstream is regulated by many hormones, the most important being insulin.

Insulin is the "hormone of plenty"it is released when glucose is abundant and stimulates the following:

• muscle and fat cells to remove glucose from the blood
• cells to breakdown glucose, releasing its energy in the form of ATP (via glycolysis and the citric acid cycle)
• the liver and muscle to store glucose as glycogen (short-term energy reserve)
• adipose tissue to store glucose as fat (long-term energy reserve)
• cells to use glucose in protein synthesis

Glucagon is the main hormone opposing the action of insulin and is released when food is scarce. Whereas insulin triggers the formation of glycogen (an energy-requiring process, or an anabolic effect), glucagon triggers glycogen breakdown, which releases energy (a catabolic effect). Glucagon also helps the body to switch to using resources other than glucose, such as fat and protein (Figure 2).

Regulation of Blood Glucose

Blood glucose levels are not constantthey rise and fall depending on the body's needs, regulated by hormones. This results in glucose levels normally ranging from 70 to 110 mg/dl.

The blood glucose level can rise for three reasons: diet, breakdown of glycogen, or through hepatic synthesis of glucose.

Eating produces a rise in blood glucose, the extent of which depends on a number of factors such as the amount and the type of carbohydrate eaten (i.e., the glycemic index), the rate of digestion, and the rate of absorption. Because glucose is a polar molecule, its absorption across the hydrophobic gut wall requires specialized glucose transporters (GLUTS) of which there are five types. In the gut, GLUT2 and GLUT5 are the most common.

The liver is a major producer of glucoseit releases glucose from the breakdown of glycogen and also makes glucose from intermediates of carbohydrate, protein, and fat metabolism. The liver is also a major consumer of glucose and can buffer glucose levels (see Box 1). It receives glucose-rich blood directly from the digestive tract via the portal vein (Figure 3). The liver quickly removes large amounts of glucose from the circulation so that even after a meal, the blood glucose levels rarely rise above 110 mg/dl in a non-diabetic.

After a Mealthe Role of Insulin

The rise in blood glucose following a meal is detected by the pancreatic beta cells, which respond by releasing insulin. Insulin increases the uptake and use of glucose by tissues such as skeletal muscle and fat cells. This rise in glucose also inhibits the release of glucagon, inhibiting the production of glucose from other sources, e.g., glycogen break down (Figure 4).

1. Use Glucose

Once inside the cell, some of the glucose is used immediately via glycolysis. This is a central pathway of carbohydrate metabolism because it occurs in all cells in the body, and because all sugars can be converted into glucose and enter this pathway. During the well-fed state, the high levels of insulin and low levels of glucagon stimulate glycolysis, which releases energy and produces carbohydrate intermediates that can be used in other metabolic pathways.

2. Make Glycogen

Any glucose that is not used immediately is taken up by the liver and muscle where it can be converted into glycogen (glycogenesis). Insulin stimulates glycogenesis in the liver by:

• stimulating hepatic glycogen synthetase (the enzyme that catalyzes glycogen synthesis in the liver)
• inhibiting hepatic glycogen phosphorylase (the enzyme that catalyzes glycogen breakdown in the liver)
• inhibiting glucose synthesis from other sources (inhibits gluconeogenesis)

Insulin also encourages glycogen formation in muscle, but by a different method. Here it increases the number of glucose transporters (GLUT4) on the cell surface. This leads to a rapid uptake of glucose that is converted into muscle glycogen.

3. Make Fat

When glycogen stores are fully replenished, excess glucose is converted into fat in a process called lipogenesis. Glucose is converted into fatty acids that are stored as triglycerides (three fatty acid molecules attached to one glycerol molecule) for storage. Insulin promotes lipogenesis by:

• increasing the number of glucose transporters (GLUT4) expressed on the surface of the fat cell, causing a rapid uptake of glucose
• increasing lipoprotein lipase activity, which frees up more fatty acids for triglyceride synthesis

In addition to promoting fat synthesis, insulin also inhibits fat breakdown by inhibiting hormone-sensitive lipase (an enzyme that breaks down fat stores). As a result, there are lower levels of fatty acids in the blood stream.

Insulin also has an anabolic effect on protein metabolism. It stimulates the entry of amino acids into cells and stimulates protein production from amino acids.

Fastingthe Role of Glucagon

Fasting is defined as more than eight hours without food. The resulting fall in blood sugar levels inhibits insulin secretion and stimulates glucagon release. Glucagon opposes many actions of insulin. Most importantly, glucagon raises blood sugar levels by stimulating the mobilization of glycogen stores in the liver, providing a rapid burst of glucose. In 1018 hours, the glycogen stores are depleted, and if fasting continues, glucagon continues to stimulate glucose production by favoring the hepatic uptake of amino acids, the carbon skeletons of which are used to make glucose.

In addition to low blood glucose levels, many other stimuli stimulate glucagon release including eating a protein-rich meal (the presence of amino acids in the stomach stimulates the release of both insulin and glucagon, glucagon prevents hypoglycemia that could result from unopposed insulin) and stress (the body anticipates an increased glucose demand in times of stress).

Starvation

The metabolic state of starvation in the USA is more commonly found in people trying to lose weight rapidly or in those who are too unwell to eat. After a couple of days without food, the liver will have exhausted its stores of glycogen but continues to make glucose from protein (amino acids) and fat (glycerol).

The metabolism of fatty acids (from adipose tissue) is a major source of energy for organs such as the liver. Fatty acids are broken down to acetyl-CoA, which is channeled into the citric acid cycle and generates ATP. As starvation continues, the levels of acetyl-CoA increase until the oxidative capacity of the citric acid cycle is exceeded. The liver processes these excess fatty acids into ketone bodies (3-hydroxybutyrate) to be used by many tissues as an energy source.

The most important organ that relies on ketone production is the brain because it is unable to metabolize fatty acids. During the first few days of starvation, the brain uses glucose as a fuel. If starvation continues for more than two weeks, the level of circulating ketone bodies is high enough to be used by the brain. This slows down the need for glucose production from amino acid skeletons, thus slowing down the loss of essential proteins.

"Starvation in the Midst of Plenty"

Diabetes is often referred to as "starvation in the midst of plenty" because the intracellular levels of glucose are low, although the extracellular levels may be extremely high.

As in starvation, type 1 diabetics use non-glucose sources of energy, such as fatty acids and ketone bodies, in their peripheral tissues. But in contrast to the starvation state, the production of ketone bodies can spiral out of control. Because the ketones are weak acids, they acidify the blood. The result is the metabolic state of diabetic ketoacidosis (DKA). Hyperglycemia and ketoacidosis are the hallmark of type 1 diabetes (Figure 5).

Hypertriglyceridemia is also seen in DKA. The liver combines triglycerol with protein to form very low density lipoprotein (VLDL). It then releases VLDL into the blood. In diabetics, the enzyme that normally degrades lipoproteins (lipoprotein lipase) is inhibited by the low level of insulin and the high level of glucagon. As a result, the levels of VLDL and chylomicrons (made from lipid from the diet) are high in DKA.

Low-Carbohydrate Diet

Low-carbohydrate diets, such as the "Atkins" and "South Beach" diets, are currently popular ways to lose weight. Such diet plans involve restricting the type and amount of carbohydrate eaten.

One of the earliest descriptions of a low-carbohydrate diet was by William Banting in the 1860s in England. At the age of 66, Banting found success in following a carbohydrate-restricted diet: in the course of one year, he lost 46 pounds of his initial weight of 202 pounds. His impression was that "any starchy or saccharine matter tends to the disease of corpulence in advanced life". He claimed he was never hungry and that "the great charms and comfort of the system are that its effects are palpable within a week of trial and creates a natural stimulus to persevere for a few weeks more".

In a recent small trial, 63 obese men and women were assigned to either a low-carbohydrate diet or a low-fat diet ( 1). People on both diets lost weight. The carbohydrate-restricted group initially lost weight at a faster rate, but when reviewed at the end of the year there was no significant difference in weight loss between the two groups ( 1). It was found that low-carbohydrate dieters (who were allowed unrestricted amounts of protein and fat) actually had a lower energy intake than the low-fat diets (who were limited in their calorie intake). It may be that when carbohydrates are restricted, weight loss is due to a lower calorie intake due to the monotony of the diet. It is also possible that the lower calorie intake may be because of a change in peripheral or central saiety signals, leaving people feeling more full after a meal.

A second study compared the effects of a carbohydrate-restricted diet on the risk of developing atherosclerosis ( 2). 132 severely obese men and women were assigned to either a low-carbohydrate or low-fat diet. Again, after a 6-month period both groups lost weight. They became more sensitive to insulin, and their triglyceride (TG) levels, a type of fat that is a risk factor for atherosclerosis, improved. However, the carbohydrate-restricted group lost more weight and showed a greater improvement in insulin sensitivity and TG levels. After one year, the weight loss between the two groups was similar, but the cardiogenic risk factors were improved in the low-carbohydrate dieters, TG levels were lower, and levels of HDL cholesterol, a type of fat that protects against atherosclerosis, were higher ( 3). Also, long-term sugar control, which can be measured by checking for the amount of glycosylated hemoglobin (HbA1c), was better in people on the low-carbohydrate diet. However, it remains unclear whether these beneficial effects would continue after 1 year.

At present, the risks of obesity are well known, and the benefits of weight loss by traditional low-calorie, low-fat, and high-complex carbohydrate diets are also well documented. Future research will clarify the long-term outcomes of a low-carbohydrate diet for achieving and maintaing a healthy weight together with the effects on the heart and other systems of the body.