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165 HIV-PROTEASE INHIBITOR TREATMENT, A NEW CANINE EXPERIMENTAL MODEL OF INSULIN RESISTANCE
  1. I. F. Liberty,
  2. V. Ionut,
  3. S. P. Kim,
  4. M. Ader,
  5. M. Lottati,
  6. R. N. Bergman
  1. USC, Los Angeles

Abstract

Understanding how insulin resistance develops βcell compensation is essential for understanding the development of IGT and Type 2 diabetes. Comparing different models of insulin resistance can help understand the secretion/sensitivity interaction. Treatment with the Highly Active Antiretroviral Therapy (HAART) can cause insulin resistance accompanied with changes in fat deposition. The aim of the present study was to develop a canine model of insulin resistance caused by the HPI- Indinavir (IDV) and test its effects on fat deposition, insulin sensitivity and insulin secretion compared to other models of insulin resistance:

The fat fed dog treated with an isocaloric moderate fat diet (IMFD) or treated with the atypical antipsychotic Olanzapine (OLZ). 2 normal dogs were given IDV 800mg/TID for 6 weeks and assessed at week 0 and 6 for fat distribution (MRI), insulin sensitivity (euglycemic clamp), and insulin secretion (hyperglycemic (150 mg/dl) clamp). With IDV, total fat increased by 34%; reflecting subcutaneous fat (≠ 50%) and visceral fat (≠ 22.4%). In contrast fat feeding and OLZ doubled fat but favored visceral fat accumulation. Insulin sensitivity decreased on average with IDV, and replicated effects with fat feeding and olanzapine. (Table)

Fat fed dogs and IDV compensated for insulin resistance by increasing insulin secretion as measured by hyperglycemic clamp. But, dogs treated with OLZ exhibited no change in insulin secretion. In conclusion we can see that treatment with IDV causes fat accumulation dominated by increase in subcutaneous fat. It causes decrease in insulin sensitivity and demonstrated insulin compensation. Comparing the IDV model to other insulin resistant models demonstrates the many ways insulin resistance develops with a different degree of compensation.

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