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Context: Recent data suggest that circulating retinol-binding protein (RBP) might be involved in the pathogenesis of insulin resistance. Moreover, protein C inhibitor (PCI), which specifically binds retinoic acid, was found to be increased in myocardial infarction survivors who are also insulin resistant.Objective: The objective of this study was to investigate the association of insulin resistance with RBP factors and PCI active antigen.Design and Setting: This was a clinical study.Patients: Nondiabetic humans with high (IS; n = 20, 14 females, six males, aged 47.2 ± 1.9 yr, body mass index 26 ± 1 kg/m2) and low (IR; n = 20, 14 females, six males, aged 45.5 ± 1.7 yr, body mass index 28 ± 1 kg/m2) insulin-stimulated glucose-disposal (M) participated in this study.Main Outcome Measures: M was measured by 2-h hyperinsulinemic (40 mU·min−1·m−2)-isoglycemic clamp tests. Measurements of RBP were performed using a nephelometric method and validated using quantitative Western blotting.Results: M (80–120 min) was higher in IS (10.9 ± 0.6 mg·min−1·kg−1) than IR (4.0 ± 0.2; P < 10−12). Fasting plasma RBP concentrations were comparable between IS and IR measured by both nephelometry (IS: 4.4 ± 0.3; IR: 4.6 ± 0.3 mg/dl, P = 0.6) and quantitative Western blot (IS 7.9 ± 0.5, IR 8.3 ± 0.6 mg/dl; P = 0.6). Fasting plasma PCI active antigen was similar in both groups. Plasma RBP and PCI were not significantly related to M. RBP was positively correlated with uric acid (r = 0.488, P = 0.003), triglycerides (r = 0.592, P < 0.001), prealbumin (r = 0.63, P < 0.0001), and vitamin A (r = 0.75, P < 10−6).Conclusions: Our data demonstrate that healthy, insulin-resistant humans do not show altered plasma retinol binding factors, such as RBP and PCI. Both do not significantly correlate with insulin sensitivity. Thus, our findings do not support the hypothesis of insulin sensitivity modulation by proteins involved in retinol transport.

Aims: We investigated long-term mortality and requirement of renal replacement therapy (RRT) in type 1 diabetes mellitus (T1DM) to study risk factors and late complication incidence of T1DM in a prospective cohort study at Lainz Hospital, Vienna, Austria. Methods: In 1983–1984, T1DM patients [n = 648; 47% females, 53% males; age, 30 ± 11 yr; T1DM duration, 15 ± 9 yr; body mass index, 24 ± 4 kg/m2; glycated hemoglobin (HbA1c), 7.6 ± 1.6%] were stratified into HbA1c quartiles [1st, 5.9 ± 0.5% (range, 4.2–6.5%); 2nd, 6.9 ± 0.3% (6.6–7.4%); 3rd, 7.9 ± 0.3% (7.5–8.4%); and 4th, 9.6 ± 1.3% (8.5–14.8%)]. Twenty years later, both endpoints (death and RRT) were investigated by record linkage with national registries. Results: At baseline, creatinine clearance, blood pressure, and body mass index were comparable among the HbA1c quartiles, whereas albuminuria was more frequent in the 4th quartile (+15%; P < 0.03). After the 20-yr follow-up, 13.0% of the patients had died [rate, 708 per 100,000 person-years (95% confidence interval, 557–859)], and 5.6% had received RRT [311 per 100,000 person-years (95% confidence interval, 210–412)]. Patients with the highest HbA1c values (4th quartile) had a higher mortality rate and a greater incidence of RRT (P < 0.04). In the Cox proportional hazards analysis, age, male gender, increased HbA1c, albuminuria, and reduced creatinine clearance were predictors of mortality (P < 0.05). Predictors of RRT were albuminuria (P < 0.001), reduced creatinine clearance (P < 0.001), and belonging to the 4th HbA1c quartile (P = 0.06). In Kaplan-Meier analysis, mortality was linearly associated with poor glycemia, whereas RRT incidence appeared to rise at a HbA1c threshold of approximately 8.5%. Conclusion/Interpretation: In the Lainz T1DM cohort, 13.0% mortality and 5.6% RRT were directly associated with and more frequently found in poor glycemia, showing that good glycemic control is essential for the longevity and quality of life in T1DM.

Endocrine defensive mechanisms provide for energy supply during hypoglycemia. Intramyocellular lipids (IMCL) were recently shown to contribute to energy supply during exercise.The objective of this study was to assess the contribution of IMCL compared with lipolysis and endogenous glucose production (EGP) to insulin-mediated hypoglycemia counterregulation in patients with type 1 diabetes mellitus (T1DM).This was a prospective explorative study performed in a university research facility.Six well-controlled T1DM (age, 29 +/- 4 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 6.3 +/- 0.1%) and six nondiabetic humans (controls; age, 28 +/- 2 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 5.1 +/- 0.1%) were studied.We performed 240-min hypoglycemic (approximately 3 mM)-hyperinsulinemic (0.8 mU/kg x min) clamps on separate days to measure: 1) systemic lipolysis ([2H5]glycerol turnover), EGP ([6,6-(2)H2]glucose), and local lipolysis in abdominal s.c. adipose tissue and gastrocnemius muscle (microdialysis); and 2) IMCL (by 1H nuclear magnetic resonance spectroscopy) in soleus and tibialis anterior muscle.The main outcome measures were changes in IMCL during prolonged hypoglycemia.At baseline, EGP, glycerol turnover, and IMCL were not different between the groups. During hypoglycemia, hormonal counterregulation was blunted in T1DM (peak: glucagon, 68 +/- 4 vs. 170 +/- 37 pg/ml; cortisol, 16 +/- 2 vs. 24 +/- 2 microg/dl; epinephrine, 274 +/- 84 vs. 597 +/- 212 pg/ml; all P0.05 vs. control). T1DM had approximately 50% lower EGP (4.6 +/- 0.6 vs. 10.9 +/- 0.5 micromol/kg x min; P0.005), but approximately 40% higher glycerol turnover (374 +/- 21 vs. 272 +/- 19 micromol/kg x min; P0.01). Glycerol concentrations in muscle (T1DM, 302 +/- 22 control, 346 +/- 17 micromol/liter) and adipose tissue (264 +/- 25 vs. 318 +/- 25 micromol/liter) did not differ between groups. IMCL in soleus and tibialis anterior muscle did not change from baseline during hypoglycemia.In well-controlled T1DM, impaired hypoglycemia counterregulation is associated with decreased glucose production and augmented whole body lipolysis, which cannot be explained by either hydrolysis of muscle triglycerides or increased abdominal s.c. adipose tissue lipolysis.