By acknowledging the hyperbolic relationship, measuring both insulin action and insulin secretion, plotting them together and evaluating the disposition index, beta cell function is evaluated more accurately than when analyzed in isolation. The model is illustrated in Fig. 1. It shows that during the development of insulin resistance, insulin secretion is increased. As long as the compensation is adequate, i.e. the disposition index remains normal, the glucose tolerance is normal. When the increase of insulin secretion becomes inadequate in relation to insulin resistance, i.e. when the disposition index drops, glucose intolerance and type 2 diabetes develop. This model thus focuses on the islet beta cell as the important target of defect in the disease.
The model may be illustrated in obesity, which is known to be accompanied by insulin resistance which is compensated by increased insulin secretion. To evaluate whether obese subjects with glucose intolerance have defective islet compensation, insulin sensitivity and insulin secretion were evaluated together in the same individuals by the euglycemic clamp and the glucose-dependent arginine stimulation tests. It was found that those exhibiting glucose intolerance had a lower insulin secretion than those having normal glucose tolerance, in spite of having the same insulin sensitivity (40). Nevertheless, insulin secretion in the obese subjects with impaired glucose tolerance was higher than in non-obese subjects with normal insulin sensitivity and normal glucose tolerance. If insulin secretion had been analyzed in isolation, the conclusion would therefore be that the beta cells were functioning normally. However, when analyzed in relation to the insulin insensitivity, it is obvious that beta cell function is inadequate for the degree of insulin resistance. Another group at risk of developing glucose intolerance are subjects treated with glucocorticoids. An experimental study has shown that the induction of insulin resistance by short-term exogenous administration of dexamethasone is followed by a compensatory increase in insulin secretion (41). In the subjects where the islet compensation was adequate, glycemia remained normal. However, in subjects where the islet compensation was inadequate in relation to the induced insulin resistance, i.e. when the disposition index was reduced, fasting hyperglycemia increased. Also in these subjects, insulin secretion per se was increased, thus again illustrating that the defective islet function as the cause of fasting hyperglycemia after dexamethasone would have been overlooked if the two variables had not been analyzed together. Moreover, cross-sectional studies in subjects with impaired glucose tolerance have shown a defective insulin secretion in relation to insulin sensitivity (15) by plotting the two variables together (Fig. 2). The importance of evaluating a defective insulin secretion in relation to insulin resistance for correctly validating pathophysiology of type 2 diabetes is also evident from prospective studies. An important study has been presented in Pima Indians, where insulin secretion and insulin sensitivity have been judged from FSIGTs performed every fifth year in subjects maintaining normal glucose tolerance vs those progressing through impaired glucose tolerance to type 2 diabetes (42).
A defective insulin secretion in relation to insulin sensitivity, i.e. reduced disposition index, has been shown not only to be associated with impaired glucose tolerance and type 2 diabetes, but also with conditions having increased risk of developing type 2 diabetes. Thus, first-degree relatives of diabetics and women with gestational diabetes or polycystic ovary syndrome have a low disposition index (43). A low disposition index per se is also associated with future worsening of glucose tolerance, as demonstrated in a prospective 3-year study (14).
A consequence of the hyperbolic relationship is that increased insulin sensitivity is compensated by reduction, or down-regulation, of beta cell function, which may be a mechanism to avoid hypoglycemic episodes. This has been demonstrated as a reduced insulin response to arginine when insulin sensitivity is increased during weight reduction in severely obese subjects undergoing standardized weight reduction by bariatric surgery (16). That study also demonstrated that the reduction in insulin secretion was quantitatively not as prominent as the increase in insulin sensitivity, which increased the disposition index along with weight reduction. This was followed by improvement of glucose tolerance, in support of the model that glucose tolerance is governed by the hyperbolic relationship between insulin secretion and action. Similarly, in a group of elite sportsmen having extremely high insulin sensitivity, the insulin response to arginine was reduced along a hyperbolic line in comparison with a group of sedentary subjects (44). Hence, both increases and decreases of insulin sensitivity are associated with compensatory reciprocal changes in insulin secretion.