Review articlePathogenesis of Type 2 Diabetes Mellitus
Introduction
Type 2 diabetes is a worldwide health crisis. The figures in the U.S. are disturbing—18.1 million affected at a cost of $132 billion in 2002 (1)—and likely to get much worse. The Centers for Disease Control and Prevention estimates there are 40 million people in the U.S. with prediabetes, and the Diabetes Prevention Program (U.S. study that investigated the effect of lifestyle intervention or metformin to prevent progression of impaired glucose tolerance (IGT) to diabetes) showed an 11% conversion per year of IGT going to diabetes (2), which means 2 to 4 million new diabetes cases each year. Furthermore, the incidence of type 2 diabetes is increasing worldwide, often in countries that cannot meet the resulting medical and financial burdens (3), with a recent study predicting the worldwide prevalence of diabetes will increase from 2.8% in 2000 to 4.4% in 2030, resulting in 366 million affected people (4).
Much of the current crisis stems from our modern lifestyle with the abundance of high calorie foods along with lowered energy expenditure because of the wide availability of cars, TV watching, fewer outside activities, etc. Also, the worldwide trend of developing societies shifting away from an agrarian existence to city living and less physically demanding office and factory jobs also is taking its toll. In the U.S., these changes have been most evident for children and countless papers have reported on the epidemic of childhood obesity (5) and its root causes of TV watching, eating fast food, etc. 6, 7.
One can predict that returning to healthy lifestyles would reverse the rising incidence of type 2 diabetes. Unfortunately, that is not a practical solution. Instead, the current approach is to better understand the pathogenesis of type 2 diabetes, hopefully followed by the development of pharmaceuticals that reverse the key pathogenic elements. We entered the 1990s knowing that type 2 diabetes was characterized by the classic triad of β-cell dysfunction, excess glucose production from the liver, and insulin resistance defined as impaired insulin-mediated glucose clearance into skeletal muscle (8). However, knowledge at that time provided no physiological connection between these organs. Another conundrum was how excess adiposity, i.e., being fat, caused insulin resistance, which again is a defect in skeletal muscle physiology.
Considerable progress has occurred over the last decade in our understanding of type 2 diabetes although all of the answers are not in yet. This review will provide an overview of the current understanding of how this disease develops, with Figure 1 showing the main pathogenic factors to be discussed.
Section snippets
Genetic Predisposition
The fact that type 2 diabetes is a genetic disease is well known to clinicians by how it occurs in families, and by there being ethnic populations who are particularly high risk. The genetic link was clearly shown more than two decades ago by a famous study of identical twins in the U.K. that found essentially a 100% concordance rate for this disease—if one twin developed type 2 diabetes, then the other one invariably developed it (9). However, this kind of study provides no insight into how
Environment
The second factor in Figure 1 is environmental aspects. An important concept is the diabetes genotype typically causes only a predisposition for glucose intolerance (note the terminology susceptibility gene was used in the preceding paragraphs). Whether one develops the diabetes phenotype depends on environmental factors, some obvious in how they act, others less so. For instance, the Nurses Health Survey showed positive associations between obesity and lack of physical activity in the
Acquired Organ Dysfunction
The third element on the top of Figure 1 is acquired defects. This refers to additional defects in glucose homeostasis that occur as the diabetes metabolic environment develops. This concept was first identified by studies that intensively treated persons with type 2 diabetes to bring blood glucose values as close to normal as possible, and noted improved beta-cell function (20), with later studies also showing some reversal of insulin resistance. This reversal effect is unrelated to the type
Insulin Resistance vs. Beta-Cell Dysfunction
Figure 1 (bottom) shows one of the most controversial topics within the field of type 2 diabetes over many years—is this a disease of insulin resistance or beta-cell dysfunction? The confusion for many years was both defects were invariably present when persons with type 2 diabetes were investigated and also when persons with IGT were studied. Attempts to go earlier in the course of the disease by studying persons at high-risk who were still normoglycemic—high-risk ethnic groups such as Pima
Beta-Cell Dysfunction in Type 2 Diabetes
Studies over many years have described the types of beta-cell dysfunction that characterize this disease—Reference (48) is a comprehensive review of the subject. The major defects are that insulin is normally secreted in a pulsatile fashion, with oscillations every 11 to 14 min that are thought necessary for normal regulation of hepatic glucose production (49), and large bursts (termed ultradian oscillations) several times a day, especially after meals, to maximize the efficiency of nutrient
Lowered Beta-Cell Mass in Type 2 Diabetes
The prior discussion was of beta-cell functional abnormalities in type 2 diabetes. A more recent research focus concerns abnormalities in the mass of beta cells. The measurement of beta-cell mass in humans is extremely difficult and must be done on autopsy specimens. Until recently there were few studies of this topic, and all with only a few subjects. Further confusing the issue was a lack of appropriately matching subjects with type 2 diabetes to weight-matched controls in many of the
Cellular Mechanisms of Beta-Cell Dysfunction
There has been intense study of potential cellular mechanisms of the beta-cell dysfunction in type 2 diabetes, although for the most part these studies have been carried out in vitro after exposing isolated islets or beta-cell clonal cell lines to abnormally high glucose levels, or by studying isolated islets from diabetic animals. A major impediment in this field has been the inability to get islet tissue from free living humans. Several mechanisms have been proposed, but none definitively
Insulin Resistance in Type 2 Diabetes
Insulin resistance is defined as impaired insulin-mediated glucose clearance into target tissues. Physiology studies many years ago showed most of the insulin-mediated clearance of a glucose load goes into skeletal muscle, plus the insulin response to the meal shuts down hepatic glucose production. We now know that the defect with insulin resistance is at both sites. In the fasting state, the degree of hyperglycemia is directly determined by the rate of glucose overproduction by the liver. With
What Is the Link Between Adiposity and Insulin Resistance?
One of the great questions some years ago was how is insulin resistance caused by becoming fat? A breakthrough in this subject occurred with the discovery that adipose tissue is more complex than simply acting as a storage site for triglyceride. In particular, adipocytes have been shown to produce many proteins (adipokines) that have peripheral effects on many tissues including skeletal muscle and liver and concurrently insulin sensitivity (104).
Of particular interest for skeletal muscle are
Summary
The pathological sequence for type 2 diabetes shown in Figure 1 entails many elements. It is believed to be mandatory to have a genetic predisposition that is currently poorly understood. Whether the diabetes phenotype then occurs is influenced by many environmental factors that share an ability to stress the glucose homeostasis system, either by causing or worsening insulin resistance or impairing insulin secretion. We also propose that a lowered beta-cell mass through genetic or beta-cell
Acknowledgement
The author receives research funds from the American Diabetes Association and the National Institutes of Health (DK-56818, DK-66635, DK-68329).
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