Effect of Insulin Therapy on Insulin Resistance in Type II Diabetic Subjects: Evidence for Heterogeneity

Abstract

Insulin resistance has been demonstrated previously in both glucose-intolerant and untreated type II diabetics. Although the former group had hyperinsulinemia in the fasting state and after an oral glucose load, the hyperglycemic type II subjects were relatively insulin deficient after carbohydrate ingestion. In an attempt to define the role that insulin deficiency might have played in the pathophysiology of insulin resistance in this latter group, we measured the steadystate plasma glucose level (SSPG) during a constant infusion of glucose (6 mg/kg/min) and insulin (80 mU/min) in 15 nonobese insulin-deficient type II diabetics before and after insulin replacement therapy. Hepatic glucose output (HGO) and plasma clearance of glucose (PCG) during these studies were also determined using an infusion of 3-3H-glucose. Before insulin treatment, 13 of 15 subjects had SSPG levels above the range reported in normal subjects. Two type II patients appeared to be normally sensitive to insulin. Although all subjects were more sensitive to insulin after 1–8 wk of insulin therapy, they could be clearly divided into two groups. Thus, five patients were now normally sensitive to insulin (SSPG:75 ± 5.3 mg/dl) while 10 patients were still significantly resistant (SSPG: 227±11.3 mg/dl). HGO during the infusion studies was high in the resistant group pretreatment and did not change posttreatment (3.54 ± 0.32 vs. 3.14 ± 0.78 mg/kg/min). HGO was lower before insulin therapy and decreased by > 50% after therapy in the sensitive group (1.93 ± 0.07 vs. 0.71 ± 0.32 mg/kg/min). PCG determinations revealed a similar pattern of response. Retrospective analysis of the two groups revealed no significant differences in their baseline characteristics. Fasting plasma glucose and hemoglobin A1c levels also did not differ between the two groups before or after insulin therapy. These results indicate that heterogeneity exists among subjects with type II diabetes mellitus. One-third of the subjects studied appear to have only insulin deficiency as the basis of their diabetes, while two-thirds seem to have an underlying resistance to insulin that is not corrected by insulin therapy.