10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

EFFECTS OF IGF-1/IGFBP-3 TREATMENT ON GLUCOSE METABOLISM AND FAT DISTRIBUTION IN HIV-INFECTED PATIENTS WITH ABDOMINAL OBESITY AND INSULIN RESISTANCE

Antiviral Therapy 2008; 13(Suppl. 4):A5 (abstract no. O-04)

MN Rao¹, K Mulligan¹, J-M Schwarz^1,2, VW Tai¹, M Wen¹, M Weinberg¹, A Dyachenko², T Lang¹ and M Schambelan^1
1University of California San Francisco, San Francisco, CA, USA; ²Touro University, Vallejo, CA, USA

OBJECTIVE: Growth hormone (GH) treatment decreased visceral fat and improved lipid profiles in HIV-positive patients with visceral adiposity. However, GH also worsened glucose metabolism. Insulin-like growth factor (IGF)-1, which mediates many of the effects of GH, improved insulin sensitivity and lipid profiles in HIV-negative individuals. We performed a pilot, open-label study to determine whether IGF-1, complexed to its major binding protein (IGFBP-3), would improve glucose metabolism and alter body fat distribution in HIV-positive patients with abdominal obesity and insulin resistance.

METHODS: Ten HIV-positive men with waist circumference >100 cm and HOMA-IR>2.77 received IGF-1/IGFBP-3 (Insmed, Inc.) for 3 months; seven received 0.5 mg/kg/day and three received 1.0 mg/kg/day, given SQ. Glucose metabolism was assessed under fasting conditions, and during both an oral glucose tolerance test (OGTT) and hyperinsulinaemic euglycaemic clamp. Endogenous glucose production (EGP) and gluconeogenesis (GNG) were measured with stable isotope infusions. Body composition was assessed by DEXA and single-slice computerized tomography scan. Data are means ±se at baseline and month 3. Because the change in free IGF-1 levels achieved with the two doses were not significantly different (3.9 and 3.3 ng/ml, respectively), results were combined in this pilot study. Results were analysed by paired t-test.

RESULTS: HOMA-IR decreased (5.45 ±0.69 to 3.69 ±0.54, P=0.04), reflecting a decrease in both fasting insulin (21 ±3 to 16 ±2 µIU/ml, P=0.039) and glucose (105 ±3 to 98 ±2 mg/dl, P=0.005) levels. During OGTT, both glucose AUC (481 ±24 to 433 ±23 mg•h/dl, P=0.04), and insulin AUC (391 ±74 to 233 ±39 µIU•h/ml, P=0.02) decreased. Insulin-mediated glucose uptake (clamp) increased (3.60 ±0.46 to 5.86 ±0.86 mg/kg•min•µIU/ml, P=0.02). Fasting EGP increased (2.03 ±0.26 to 2.21 ±0.28 mg/kg/min, P=0.007) and during hyperinsulinemic euglycaemic clamp, suppression of EGP was blunted with IGF-1/IGFBP-3 treatment (0.35 ±0.16 to 0.52 ±0.18 mg/kg•min, P=0.011). An increase in GNG (0.53 ±0.12 to 0.65 ±0.13 mg/kg/min, P=0.011) explained most of the observed increase in fasting EGP. Lean body mass increased (1.04 ±0.35 kg, P=0.015, and total body fat and truncal fat decreased (-1.72 ±0.74 kg, P=0.045 and -1.08 ±0.44 kg, P=0.04); changes in limb fat were small and not significant. Visceral adipose tissue and both fasting triglyceride and total cholesterol levels did not change significantly.

CONCLUSIONS: In this pilot study, treatment with IGF-1/ IGFBP-3 was associated with improvement in whole body glucose uptake and oral glucose tolerance. However, an increase in fasting EGP and blunted suppression during hyperinsulinemic euglycaemic clamp were also observed. Although lean body mass increased and total body fat decreased, visceral fat and lipid profiles were unchanged.

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2008-11-06
O-04

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