Causes of type 2 Diabetes

Insulin Resistance

Insulin resistance is a common condition in people who are overweight or obese, have excess abdominal fat, and are not physically active. Muscle, fat, and liver cells stop responding properly to insulin, forcing the pancreas to compensate by producing extra insulin. As long as beta cells are able to produce enough insulin, blood glucose levels stay in the normal range. But when insulin production falters because of beta cell dysfunction, glucose levels rise, leading to prediabetes or diabetes.
Abnormal Glucose Production by the Liver
In some people with diabetes, an abnormal increase in glucose production by the liver also contributes to high blood glucose levels. Normally, the pancreas releases the hormone glucagon when blood glucose and insulin levels are low. Glucagon stimulates the liver to produce glucose and release it into the bloodstream. But when blood glucose and insulin levels are high after a meal, glucagon levels drop, and the liver stores excess glucose for later, when it is needed. For reasons not completely understood, in many people with diabetes, glucagon levels stay higher than needed. High glucagon levels cause the liver to produce unneeded glucose, which contributes to high blood glucose levels. Metformin, the most commonly used drug to treat type 2 diabetes, reduces glucose production by the liver.
The Roles of Insulin and Glucagon in Normal Blood Glucose Regulation
A healthy person’s body keeps blood glucose levels in a normal range through several complex mechanisms. Insulin and glucagon, two hormones made in the pancreas, help regulate blood glucose levels:
Insulin, made by beta cells, lowers elevated blood glucose levels.
Glucagon, made by alpha cells, raises low blood glucose levels.
When blood glucose levels rise after a meal, the pancreas releases insulin into the blood.
Insulin helps muscle, fat, and liver cells absorb glucose from the bloodstream, lowering blood glucose levels.
Insulin stimulates the liver and muscle tissue to store excess glucose. The stored form of glucose is called glycogen.
Insulin also lowers blood glucose levels by reducing glucose production in the liver.
When blood glucose levels drop overnight or due to a skipped meal or heavy exercise, the pancreas releases glucagon into the blood.
Glucagon signals the liver and muscle tissue to break down glycogen into glucose, which enters the bloodstream and raises blood glucose levels.
If the body needs more glucose, glucagon stimulates the liver to make glucose from amino acids.
Drawing showing two cutaway images of blood vessels at the top and one cutaway image of a blood vessel at the bottom, each containing different amounts of small circles representing glucose. The blood vessel at the top left with only a few glucose circles is labeled Low blood glucose, and the vessel at the top right, which contains many glucose circles, is labeled High blood glucose. The vessel at the bottom, with an intermediate number of glucose circles, is labeled Normal blood glucose levels. A solid arrow points from the top left vessel to an image of a labeled pancreas below. An outlined arrow points from the top right vessel to the pancreas image below. Below the pancreas on the left is the label Glucagon released by pancreas and a solid arrow going to a drawing of the liver. Below the pancreas on the right is the label Insulin released by pancreas and an outlined arrow going to a cluster of cells. Below the liver on the left side is the label Liver releases glucose into blood and a solid arrow surrounded by glucose circles pointing to the blood vessel labeled Normal blood glucose levels. Below the cluster of cells on the right is the label Body’s cells absorb glucose from blood and an outlined arrow pointing to the blood vessel labeled Normal blood glucose levels.
Insulin and glucagon help regulate blood
glucose levels.

Metabolic Syndrome

Metabolic syndrome, also called insulin resistance syndrome, refers to a group of conditions common in people with insulin resistance, including
higher than normal blood glucose levels
increased waist size due to excess abdominal fat
high blood pressure
abnormal levels of cholesterol and triglycerides in the blood
People with metabolic syndrome have an increased risk of developing type 2 diabetes and CVD. Many studies have found that lifestyle changes, such as being physically active and losing excess weight, are the best ways to reverse metabolic syndrome, improve the body’s response to insulin, and reduce risk for type 2 diabetes and CVD.
Cell Signaling and Regulation
Cells communicate through a complex network of molecular signaling pathways. For example, on cell surfaces, insulin receptor molecules capture, or bind, insulin molecules circulating in the bloodstream. This interaction between insulin and its receptor prompts the biochemical signals that enable the cells to absorb glucose from the blood and use it for energy.
Problems in cell signaling systems can set off a chain reaction that leads to diabetes or other diseases. Many studies have focused on how insulin signals cells to communicate and regulate action. Researchers have identified proteins and pathways that transmit the insulin signal and have mapped interactions between insulin and body tissues, including the way insulin helps the liver control blood glucose levels. Researchers have also found that key signals also come from fat cells, which produce substances that cause inflammation and insulin resistance.
This work holds the key to combating insulin resistance and diabetes. As scientists learn more about cell signaling systems involved in glucose regulation, they will have more opportunities to develop effective treatments.

Beta Cell Dysfunction

Scientists think beta cell dysfunction is a key contributor to type 2 diabetes. Beta cell impairment can cause inadequate or abnormal patterns of insulin release. Also, beta cells may be damaged by high blood glucose itself, a condition called glucose toxicity.
Scientists have not determined the causes of beta cell dysfunction in most cases. Single gene defects lead to specific forms of diabetes called maturity-onset diabetes of the young (MODY). The genes involved regulate insulin production in the beta cells. Although these forms of diabetes are rare, they provide clues as to how beta cell function may be affected by key regulatory factors. Other gene variants are involved in determining the number and function of beta cells. But these variants account for only a small percentage of type 2 diabetes cases. Malnutrition early in life is also being investigated as a cause of beta cell dysfunction. The metabolic environment of the developing fetus may also create a predisposition for diabetes later in life.