Insulin resistance, defective insulin-mediated fatty acid suppression, and coronary artery calcification in subjects with and without type 1 diabetes: The CACTI study

Irene E Schauer, Janet K Snell-Bergeon, Bryan C Bergman, David M Maahs, Adam Kretowski, Robert H Eckel, Marian Rewers, Irene E Schauer, Janet K Snell-Bergeon, Bryan C Bergman, David M Maahs, Adam Kretowski, Robert H Eckel, Marian Rewers

Abstract

Objective: To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls.

Research design and methods: Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m²/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female).

Results: Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m²/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = -0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22-0.93, P = 0.03; OR = 2.4, 95% CI = 1.08-5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters.

Conclusions: Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes.

Figures

FIG. 1.
FIG. 1.
Correlation of insulin sensitivity to triglycerides and BMI is retained, but left-shifted, in type 1 diabetes. For the relationship of GIR to triglycerides (top panel) the regression equation in type 1 diabetes is GIR = 8.478 – 0.038 (triglycerides), P = 0.022; for nondiabetic subjects GIR = 17.14–0.037 (triglycerides), P = 0.011. In combined analysis, P = 0.966 for an interaction by diabetes and P = 0.002 for the difference in y intercept. For BMI (bottom panel) in type 1 diabetes, GIR = 14.732–0.33 (BMI), P = 0.008; for nondiabetic subjects, GIR = 23.87–0.41(BMI), P = 0.05. In combined analysis, P = 0.734 for an interaction by diabetes, P = 0.156 for the difference in the y intercept.
FIG. 2.
FIG. 2.
Insulin-mediated NEFA and glycerol suppression are impaired in type 1 diabetic subjects. NEFA and glycerol values are μM. Data are least squares mean ± SE (adjusted for age, sex, BMI, fasting glucose, and time point insulin). ■, type 1 diabetic subjects; ▴, nondiabetic controls; *P < 0.0001, †P < 0.05.
FIG. 3.
FIG. 3.
Plot of raw data for CAC volume at 6-year follow-up visit as a function of GIR (n = 87). Open (white) squares = nondiabetic subjects, black triangles = type 1 diabetic subjects.
FIG. 4.
FIG. 4.
Insulin resistance does not correlate with poor glycemic control. Insulin sensitivity is expressed as glucose infusion rate per fat-free mass (GIR, mg/kg FFM/min) and shown by quartile of GHb measured 3 days before the clamp study day. GHb range for each quartile is shown and n = 10 for each quartile. Analysis by ANOVA yields a P value of 0.89 for differences between quartiles. Pairwise comparisons are all nonsignificant with P values ranging from 0.49 (2nd and 4th quartiles) to 0.96 (1st and 4th quartiles).

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