Insulin secretion and action in noninsulin-dependent diabetes mellitus. Is insulin resistance secondary to hypoinsulinemia?

The insulin-stimulated glucose metabolic clearance rate, assessed by the insulin clamp technique, was compared in 40 normal subjects and 40 age- and weight-matched patients with noninsulin-dependent diabetes mellitus. These studies were conducted at steady-state plasma insulin levels of approximately 100 microU/ml, and the mean (+/- standard error of the mean) glucose metabolic clearance rate of patients with noninsulin-dependent diabetes mellitus was 81 +/- 9 ml/m2 per minute, as compared with a value of 235 +/- 14 ml/m2 per minute for normal subjects. This difference was highly statistically significant (p less than 0.001) and documents the extreme resistance to insulin-stimulated glucose utilization seen in noninsulin-dependent diabetes mellitus. Patients with noninsulin-dependent diabetes mellitus were also shown to have a lower than normal plasma insulin response to an oral glucose challenge. In contrast, ambient plasma insulin concentrations of normal subjects and patients with noninsulin-dependent diabetes mellitus were found to be quite comparable when measured throughout the day in response to the ingestion of conventional mixed meals. Consequently, absolute hypoinsulinemia is not characteristic of patients with noninsulin-dependent diabetes mellitus under conditions of daily living. Finally, the ability of intensive insulin treatment to improve insulin resistance was studied after one and six weeks of therapy. These results indicated that successful control of hyperglycemia led to a significant improvement in insulin action as early as one week after the initiation of insulin therapy, with no further changes noted after prolonged insulin administration. The degree to which insulin action approached normal values was greater when studies were carried out at circulating insulin levels of approximately 2,000 microU/ml as compared with insulin levels of approximately 100 microU/ml, but in both instances insulin-treated diabetic patients remained insulin-resistant as compared with normal subjects. These results have corroborated the fact that abnormalities of both insulin action and secretion can be documented in patients with noninsulin-dependent diabetes mellitus. However, patients with noninsulin-dependent diabetes mellitus were not found to be absolutely hypoinsulinemic in their daily existence, and control of their hyperglycemia with exogenous insulin did not restore insulin-stimulated glucose utilization to normal. Consequently, these data are not consistent with the view that the insulin resistance in noninsulin-dependent diabetes mellitus is entirely a secondary consequence of the hypoinsulinemia presumed to be present in these patients.