The maintenance of normal glucose homeostasis depends on a finely balanced dynamic interaction between tissue (muscle, liver, and fat) sensitivity to insulin and insulin secretion. Even in the presence of severe insulin resistance, a perfectly normal β-cell is capable of secreting sufficient amounts of insulin to offset the defect in insulin action. Thus, the evolution of type 2 diabetes requires the presence of defects in both insulin secretion and insulin action, and both of these defects can have a genetic as well as an acquired component. When type 2 diabetic patients initially present to the physician, they will have had their diabetes for many years, and defects in insulin action (in muscle, liver, and adipocytes) and insulin secretion will be well established (1
). At this stage, it is not possible to define which defect came first in the natural history of the disease and which tissue is the primary defect responsible for the insulin resistance. Although insulin resistance represents the earliest detectable abnormality in the great majority of type 2 diabetic people, in a minority of individuals (i.e., glucokinase deficiency), it is clear that a β-cell defect initiates the disturbance in glucose homeostasis. Nevertheless, it is now clear that in any given diabetic patient, whatever defect (insulin resistance or impaired insulin secretion) initiates the disturbance in glucose metabolism, it will eventually be followed by the emergence of its counterpart (Fig. A14).
Insulin resistance is a nearly universal finding in patients with established type 2 diabetes. In normal-weight and obese individuals with IGT and in type 2 diabetic subjects with mild fasting hyperglycemia (110–140 mg/dl, 6.1–7.8 mmol/l), both the basal and glucose-stimulated plasma insulin levels are increased. Although the first-phase insulin response may be decreased in some, but not all, of these subjects, the first phase consistently is increased in the NGT offspring of two type 2 diabetic parents and the total insulin response is increased in NGT offspring and in IGT subjects. In each of these groups, tissue sensitivity to insulin, measured with the insulin clamp technique, has been shown to be diminished. Prospective studies conclusively have demonstrated that hyperinsulinemia and insulin resistance precede the development of IGT and that IGT represents the forerunner of type 2 diabetes. This scenario has been well documented in Pima Indians, Mexican Americans, and Pacific Islanders. It is noteworthy that all of these populations are characterized by obesity and a younger age at onset of diabetes. Such results provide conclusive evidence that insulin resistance is the inherited defect that initiates the diabetic condition in the majority of type 2 diabetic patients. Studies in NGT first-degree relatives of diabetic individuals and in the offspring of two diabetic parents indicate that the inherited defect in insulin action results from an abnormality in the glycogen synthetic pathway in muscle and more proximal defects in glucose transport/phosphorylation and insulin signal transduction. As the insulin resistance progresses and muscle glucose uptake becomes further impaired, the postprandial rise in plasma glucose concentration becomes excessive, but the increase in basal hyperinsulinemia is sufficient to maintain the fasting plasma glucose concentration and HGP within the normal range. Nonetheless, there is an excessive postprandial rise in plasma glucose concentration, and a longer time is required to restore normoglycemia after each meal. Eventually, however, the insulin resistance becomes so severe that the compensatory hyperinsulinemia is no longer sufficient to maintain the fasting glucose concentration at the basal level. The development of hyperglycemia further stimulates β-cell secretion of insulin, and the resultant hyperinsulinemia causes a downregulation of insulin receptor number and of the intracellular events involved in insulin action, thus exacerbating the insulin resistance. Initially, the hyperglycemia-induced increase in insulin secretion serves a compensatory function to maintain near-NGT. In some individuals, the persistent stimulus to the β-cell to oversecrete insulin leads to a progressive loss of β-cell function. Chronic hyperglycemia (glucose toxicity) and/or disturbances in lipid metabolism (lipotoxicity) may contribute to the defect in insulin secretion. The resultant insulinopenia leads to the emergence/exacerbation of postreceptor defects in insulin action. Many of the intracellular events involved in glucose metabolism depend on the surge of insulin that occurs three to four times per day in response to nutrient ingestion. When the insulin response becomes deficient, the activity of the glucose transport system becomes severely impaired and a number of key intracellular enzymatic steps involved in glucose metabolism become depressed. Additionally, when severe insulinopenia ensues, plasma FFA levels rise, further contributing to the defects in intracellular glucose disposal. There is also compelling evidence that hyperglycemia per se can downregulate the glucose transport system, as well as a number of other intracellular events involved in insulin action (glucose toxicity), and a similar argument can be made concerning the intracellular derangement in lipid metabolism. This pathogenetic sequence can explain all of the clinical and laboratory features observed in type 2 diabetic patients. Insofar as the cellular defect is generalized, both hepatic and peripheral tissues (skeletal muscle and adipocytes), and possibly the β-cells themselves, would manifest insulin resistance, and the numerous metabolic alterations characteristic of the diabetic state could be related to one and the same primary defect.
The NGT offspring of two type 2 diabetic parents also manifest marked adipocyte resistance to the suppressive effects of insulin on lipolysis. One could argue, therefore, that the adipocyte represents the primary tissue responsible for the insulin resistance. According to this scenario, the elevated plasma FFA levels produce insulin resistance in muscle and liver and impair β-cell function. Adipocytes in the NGT offspring of two type 2 diabetic parents also secrete excessive amounts of inflammatory and insulin resistance producing adipocytokines that could initiate/exacerbate the insulin resistance in skeletal muscle. As reviewed by Iozzo in this symposium, the adipocyte insulin resistance could be genetic in origin or induced in utero during the third trimester by nutritional deprivation or overfeeding.
There is less evidence to support a role for the liver as the organ responsible for the insulin resistance. However, the NGT offspring of two type 2 diabetic parents have a normal rate of HGP in the presence of fasting hyperinsulinemia, suggesting the presence of hepatic resistance to the suppressive effect of insulin on glucose production. Therefore, one could argue that the resultant fasting hyperinsulinemia leads to the development of insulin resistance in skeletal muscle.