The hyperbola defining the inverse relationship between insulin sensitivity and insulin secretion indicates that it is impossible to judge insulin secretion in a given individual without knowing the ambient insulin sensitivity. Most importantly, the hyperbola has convincingly demonstrated the critical and fundamental importance of beta cell dysfunction for the development of type 2 diabetes, as it was initially proposed in the classic work of Cerasi & Luft in 1967 (45) and exploited in detail by Porte, Kahn and collaborators (43, 46).
Now we need to establish the mechanism of the hyperbolic relationship, both in the organism and in the beta cells, i.e. which factors signal to the beta cells to augment insulin secretion when insulin resistance worsens. Several factors are candidates for being such signals. One possible candidate is glucose, which may increase during the development of insulin resistance thereby signaling to the beta cells to increase insulin secretion. However, glucose is probably not a key signal in this respect because glucose levels are usually not increased when insulin resistance develops if the beta cells are functioning adequately. Also, a study has shown that when insulin sensitivity is improved by exercise, a reduced insulin secretion is observed in association with increased, not reduced, glucose levels and another study using nicotinic acid has shown that insulin resistance is followed by increased insulin secretion but a reduced circulating glucose (43).
Other candidates would be circulating lipids, because free fatty acids (FFAs) are known to be increased in insulin resistance due to reduced antilipolytic action of insulin, and FFAs might then stimulate insulin secretion (47). However, whether FFAs stimulate insulin secretion at the concentrations seen under these conditions is not known. Another possible candidate for mediating the increased insulin secretion in insulin resistance is the autonomic nervous system (48). It has thus been demonstrated that the hyperinsulinemia in the insulin-resistant ob/ob mouse is sensitive to cholinergic blockade and that in insulin-resistant high-fat-fed mice insulin secretion is very sensitive to cholinergic activation (48). This could be explained by increased activity in the vagal nerves due to insulin resistance, and in support of this notion, the circulating levels of pancreatic polypeptide, a marker of cholinergic activation, are increased in insulin-resistant Pima Indians (49). Also other candidates might contribute, however, and recently it has been suggested that circulating levels of the gut incretin, glucagon-like peptide-1 (GLP-1) as well as the expression of GLP-1 receptors in the pancreas were increased in insulin-resistant high-fat-fed dogs (50). Hence, GLP-1 might contribute to hyperinsulinemia in insulin resistance. However, the relative contribution of these tentative candidates is not known, and needs now to be established.
Conversely, possible signals from the beta cells regulating insulin sensitivity need also to be examined. We also need knowledge as to why and when the hyperbolic relationship fails, in order to target physiologically relevant processes when exploring new treatment modalities for type 2 diabetes.