In RMS severe insulin resistance is caused by defective insulin receptors. This patient (Diabetes 43:1096, 1994) lacks insulin receptor binding due to a truncation of one allele and a point mutation of the other allele of the α subunit. He developed pulmonary hypertension and cor pulmonale and was considered for lung transplantation. A trial of Prednisone 1.2 mg/kg/day was initiated to determine if he could tolerate immunosuppressive therapy. We studied carbohydrate metabolism at baseline (BL) and after four days of glucocorticoid therapy (GC). Each study was preceeded by 24 hr of intravenous insulin to maintain plasma glucose (PG) at 150-200 mg/dl and a 12 hr fast. A primed (26.7 μmol/kg) continuous infusion (0.33 μmol/kg/min) of 6,6-2H2-glucose was started 2 hr before each study following which insulin was off for 2 hr (OFF) and resumed at 7 units/kg/hr for 2 hr. Dextrose was infused as needed to maintain PG at 170 mg/dl (CLAMP). Samples were obtained every 10 min during the last 30 min of OFF and CLAMP for PG, free insulin, C-peptide(C-P), β-OH butyrate (βOHb), and plasma 6,6-2H2-glucose isotopic enrichment by electron impact mass spectroscopy. During BL-OFF, PG rose to 245±7 mg/dl, C-P=10.29 ng/ml and βOHb=159 μM. During BL-CLAMP, glucose infusion rate was 3.80 mg/kg/min to maintain PG at 169±1 mg/dl, C-P=8.20 ng/ml. Tracer-determined glucose utilization rate (Rd) did not rise during CLAMP (OFF vs. CLAMP 7.71 vs. 5.30 mg/kg/min), but hepatic glucose production rate (HGP) fell (7.85 vs. 1.48 mg/kg/min). During GC, PG was 138±8 mg/dl during OFF, C-P=5.98 ng/ml. During GC-CLAMP, the glucose infusion rate was only 0.39 mg/kg/min to maintain PG at 169±3, C-P 10.93 ng/ml. Rd and HGP were similar (Rd: 5.14 vs. 4.71 mg/kg/min; HGP: 5.31 vs. 4.19 mg/kg/min; GC-OFF vs. GC-CLAMP). Free insulin concentrations were>400 μU/ml and βOHb concentrations remained low (<160mM) throughout both studies.
Total glucose utilization did not change in response to large doses of exogenous insulin at BL or GC, indicating complete peripheral insulin resistance. HGP was partially suppressed during BL-CLAMP, indicating partial hepatic sensitivity to insulin. During GC, HGP failed to suppress despite similar free insulin levels, indicating that GC worsened hepatic insulin resistance. The effect of insulin on the liver in this insulin resistant state may be due to residual activity of the patient's defective insulin receptor, cross reactivity with the IGF-1 receptor or a non-insulin-mediated process. Regardless, this process appears to be blocked by glucocorticoids.
