Insulin Resistance Vs Betacell Dysfunction

One of the most controversial issues during the 1980s and 1990s was whether insulin resistance or B-cell dysfunction was the main cause of type 2 diabetes. The fact that persons with type 2 diabetes, and also those with IGT, invariably have both defects fueled the debate. Several highly discussed studies of people at presumed high-risk for type 2 diabetes, but still normoglycemic (high risk ethnic groups such as Pima Indians, those with both parents having type 2 diabetes, and women with prior gestational diabetes), attempted to identify the operative pathogenic elements before glucose values become abnormal. These studies generally reported that insulin resistance was present, but not B-cell dysfunction (45), resulting in a common belief at the time that insulin resistance was the earlier (and thus dominant) defect in this disease.

These conclusions were based on an experimental measure of B-cell function that was later shown to be misinterpreted: the 2-hour insulin value postmeal or during an oral glucose tolerance test (OGTT). Insulin resistance was relatively easily measured, either by using the euglycemic glucose clamp, which is labor intensive and usually done with a limited number of subjects, or computer models that can be applied to large experimental groups. In contrast, the measurement of B-cell function is highly complex. The insulin response to a meal normally is biphasic, with the amount released depending on many factors, such as the size and composition of the meal, prevailing glycemia, the subject's insulin sensitivity, etc. As glucose tolerance moves from normal to impaired, insulin release during the first 30 minutes of eating ("first phase") falls, and is absent by the time fasting glucose exceeds 115 mg/dL (46). The later insulin secretion ("second phase") paradoxically becomes greater than normal in response to the hyperglycemia. The early studies concluded that the supernormal 2-hour insulin value, attributed to insulin resistance, proved that there was no B-cell dysfunction at that stage. This misinterpretation was corrected by later studies that found reduced 30-minute and elevated 2-hour postmeal insulin values in IGT and early type 2 diabetes (47), and others demonstrating that defective first phase insulin responses to intravenous glucose is a characteristic feature of type 2 diabetes (48).

Investigators next turned to cross-sectional and natural history studies of 6-cell function versus insulin resistance. They confirmed that insulin resistance is already present when glucose values are within the normal glucose tolerance range (49,50). There are a number of potential reasons: in some people this is presumably owing to a genetic abnormality that affects insulin sensitivity, and in others lifestyle factors, such as obesity, lack of exercise, high fat diets, aging, etc., may play a major role. Thereafter, insulin resistance is relatively unchanging. Therefore, a change in the degree of insulin resistance could not explain blood glucose values progressing from normal to IGT to diabetes. Instead, worsening 6-cell function is causative. These natural history studies observed a biphasic pattern: initial hyperinsulinemia, with blood glucose values maintained in the normal range or only mildly impaired, and, subsequently a falling insulin level ("P-cell failure"), resulting in rising glycemia (49,50). Thus, the concept of type 2 diabetes began to change, with insulin resistance being an important risk factor for type 2 diabetes, but 6-cell function determining glycemia in persons genetically at risk for the disease.

The most recent studies have returned to the question of the priority of these abnormalities, in part reflecting better techniques to assess 6-cell function. One of the most used is the disposition index, based on the understanding that 6-cell function is dependent on the degree of insulin sensitivity. In other words, the insulin response to a meal or other stimulus is normally less in an insulin sensitive person such as a marathon runner than for a normoglycemic insulin resistant subject (51). Thus, in normoglycemic subjects, insulin levels are more reflective of insulin sensitivity than 6-cell function. The relationship between experimentally measured insulin sensitivity and first phase insulin secretion as a measure of 6-cell function has been mapped out in a large number of normoglycemic subjects to derive the normal curve that is called the "disposition index" (52,53) (in Fig. 2, the hyperbolic curved lines are the experimentally derived normal curve). It is important to realize this is the normal system - everyone experiences insulin resistance at some time (puberty, pregnancy, aging), with most maintaining normoglycemia because of this 6-cell compensation. Indeed, many consider diabetes a failure of 6-cell compensation (54). It is a commonly used research technique to plot where subjects with varying degrees of glucose tolerance fall on the disposition index to identify the relative roles of insulin resistance versus 6-cell dysfunction (55).

A well-known study that used this method was performed in 48 normally glucose tolerant Pima Indians (a population with the highest worldwide incidence of type 2 diabetes), who were studied over an average of 5 years

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