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Leptin Replacement Therapy Improves Insulin Resistance in Highly Active Antiretroviral Therapy (HAART)

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Title: Leptin Replacement Therapy Improves Insulin Resistance in Highly Active Antiretroviral Therapy (HAART)


1
Leptin Replacement Therapy Improves Insulin
Resistance in Highly Active Antiretroviral
Therapy (HAART) Induced Lipodystrophy and
Metabolic Syndrome in HIV PatientsJennifer H.
Lee1, Jean L. Chan1, Robyn Murphy2, Alex M.
DePaoli2, Christos S. Mantzoros11Beth Israel
Deaconess Medical Center, Harvard Medical School,
Boston, MA, 2Amgen Inc., Thousand Oaks, CA
Absolute Changes in Insulin Sensitivity, Body Composition Lipids Absolute Changes in Insulin Sensitivity, Body Composition Lipids Absolute Changes in Insulin Sensitivity, Body Composition Lipids Absolute Changes in Insulin Sensitivity, Body Composition Lipids Absolute Changes in Insulin Sensitivity, Body Composition Lipids Absolute Changes in Insulin Sensitivity, Body Composition Lipids Absolute Changes in Insulin Sensitivity, Body Composition Lipids Absolute Changes in Insulin Sensitivity, Body Composition Lipids
Main Model1 (LSM SE) Main Model1 (LSM SE) Main Model1 (LSM SE) VFat Model2 (LSM SE) VFat Model2 (LSM SE) VFat Model2 (LSM SE)
Leptin Placebo p-value Leptin Placebo p-value
Insulin Sensitivity Fasting Insulin -4.90 3.77 5.69 4.22 0.103 -4.89 2.86 6.78 3.22 0.035
Insulin Sensitivity Fasting Glucose 1.50 2.45 3.25 2.74 0.648 1.50 2.64 3.24 2.98 0.679
Insulin Sensitivity HOMA-B -83.04 43.49 44.98 48.62 0.091 -82.96 31.25 58.07 35.26 0.024
Insulin Sensitivity HOMA-IR -1.03 0.82 1.31 0.92 0.099 -1.03 0.62 1.54 0.71 0.035
Body Composition Weight (kg) -1.30 0.81 2.20 0.90 0.024
Body Composition Fat mass (gm) -598.30 98.91 257.08 110.59 lt0.001
Body Composition Visceral Fat (gm) -12.50 18.72 -5.00 20.93 0.797
Body Composition Liver Fat (mL) 0.06 0.69 -0.16 0.77 0.839
Body Composition Liver Volume (mL) -174.50 101.1 -5.42 113.03 0.302
Lipids Cholesterol (mg/dL) 24.08 9.30 -15.67 10.40 0.025
Lipids Triglycerides (mg/dL) 100.92 104.24 71.13 116.54 0.854
Lipids HDL (mg/dL) 3.78 2.19 -3.52 2.45 0.062
Lipids LDL (md/dL) 4.03 14.36 -11.98 16.06 0.482
Background Highly active antiretroviral therapy
(HAART) for HIV infection may cause a metabolic
syndrome characterized by insulin resistance,
hyperlipidemia and lipodystrophy. A previously
published uncontrolled study showed that leptin
replacement therapy dramatically improves the
metabolic syndrome associated with congenital or
acquired non-HIV lipoatrophy. We conducted a
double-blinded, randomized, placebo-controlled,
cross-over study to test the hypothesis that
leptin replacement to physiologic levels would
improve the metabolic abnormalities associated
with HAART-induced HIV lipoatrophy.
Baseline Characteristics
Mean (SE) Range
Age (yrs) 45.8 (2.0) 39 - 53
Sex (male) 7 N/A
BMI (kg/m2) 21.8 (0.8) 19.4 24.8
Fasting insulin (?IU/ml) 11.5 (2.7) 1.7 19.5
Fasting glucose (mg/dl) 81.1 (6.7) 60-108
HbA1c () 5.1 (0.3) 4.2 6.9
Leptin (ng/ml) 1.34 (0.2) 0.89 2.59
Triglyceride (mg/dl) 530 (53.8) 305 - 669
CD4 count (cells/ ?l) 454 (94) 80 - 820
HIV viral load (copies/ml) 24,524 (13,693) lt50 80,500
Leptin
Placebo
Methods 7 HIV-1-infected lipoatrophic and
leptin-deficient adults on HAART were randomized
to receive recombinant-methionyl human leptin at
a physiologic dose or placebo for 2 months.
After a one-month washout period, the subjects
were crossed-over to the alternate therapy for 2
additional months. We determined the effect of
leptin therapy on insulin resistance (Boost
challenge test and insulin suppression test),
lipid and apolipoprotein levels, lipoprotein
particle size, hormone levels (insulin, TNF-a,
IL-6, CRP, adiponectin), glycemia, free fatty
acids, body composition (anthropometry, BIA,
DEXA, abdominal CT scan), HIV viral load,
lymphocyte subsets, blood pressure. Repeated-meas
ures ANOVA and linear models with independent
factors controlling for treatment, period,
treatment-by-period interaction, and visceral fat
mass were used.
1 contains effects for treatment, period, and
treatment-by-period interaction 2 contains
effects for treatment, period,
treatment-by-period interaction, and change in
visceral fat mass.
P0.04
P0.24
  • Summary
  • Baseline insulin levels decline significantly
    after 2 months of leptin therapy compared to
    placebo
  • HOMA also decreases significantly on leptin
    therapy.
  • Leptin therapy causes a decrease in fat mass and
    weight.
  • There were no significant changes in triglyceride
    levels, liver fat or visceral fat content.
  • Conclusion
  • Leptin replacement therapy mildly improves
    insulin resistance in HIV-1-infected adults with
    HAART-induced lipoatrophy and metabolic syndrome.

Rpt-measures ANOVA
Leptin
Placebo
Plt0.03
P0.22
Rpt-measures ANOVA
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