Metabolic dysregulation and interventions in type 2 diabetes mellitus and HIV-lipodystrophy

Abstract

The focus of this thesis is on two aspects of metabolic dysregulation, type 2 diabetes mellitus and HIV-lipodystrophy, and the effects of insulin-sensitizing agents.

Thiazolidinediones (TZDs) have received increasing attenttion for the treatment of hyperglycemia in type 2 diabetes. Currently, there are two TZDs available: rosiglitazone and pioglitazone. Chapter 2 gives a summary analysis of published double-blind, placebo-controlled studies evaluating the effects of rosiglitazone and pioglitazone on blood lipids in patients with type 2 diabetes. We reported that studies with pioglitazone show greater benefits on fasting plasma TG, LDL-cholesterol and HDL-cholesterol than studies with rosiglitazone. Whether the magnitude of these differences are sufficient to produce clinically relevant cardiovascular benefits is an open question.

Since humans are non-fasting most part of the day, this period may be of particular importance in the pathogenesis of atherosclerosis. In chapter 3, the effects of rosiglitazone on postprandial TG and FFA metabolism are described. Rosiglitazone did not change fasting plasma TG levels, but decreased the postprandial TG rise in plasma (-37%), chylomicrons (-20%) and VLDL1 (-27%). These effects may contribute to cardiovascular risk reduction.

One of the potential mechanisms by which postprandial lipemia may promote atherosclerosis is inflammation and oxidative stress, leading to endothelial dysfunction. In chapter 4, we also determined the effects of rosiglitazone on postprandial leukocytes, pro-inflammatory cytokines (IL-6 and IL-8), CRP and MCP-1 in patients with type 2 diabetes. Compared with placebo, rosiglitazone attenuated the postprandial rise of neutrophils (-39%), IL-6 (-63%) and IL-8 (-18%). A reduced inflammatory response after a meal may contribute to cardiovascular risk reduction.

Highly active antiretroviral combinationtherapy (HAART) improves the survival of patients with HIV infection, but is associated with changes in body fat distribution (lipodystrophy) and metabolic risk factors. In chapter 6, we postulated that patients with HIV-lipodystrophy have impaired adipocyte FFA trapping. We found that postprandial concentrations of FFA, hydroxybutyric acid (HBA), as a measure of hepatic FFA oxidation, and TG were higher in the patients with lipodystrophy compared with the other groups, suggesting impaired adipocyte FFA trapping that contributes to postprandial lipemia in these patients.

In chapter 7, we determined functional and structural markers of atherosclerosis in HIV-infected patients. Remarkably, HIV-infected patients without the metabolic syndrome showed endothelial dysfunction comparable to that of age-matched type 2 diabetic patients, suggesting increased cardiovascular risk in HIV-infected patients, even in the absence of metabolic risk variable clustering. As expected, the presence of the metabolic syndrome in HIV-infected patients was associated with more severe endothelial dysfunction, as well as increased intima-media thickness, in our cohort of HIV-infected males.

In chapter 8, we compared the effects of rosiglitazone and metformin on insulin sensitivity and body fat distribution in patients with HIV-lipodystrophy in a randomized clinical trial. Rosiglitazone increased subcutaneous abdominal fat in patients with HIV-lipodystrophy, while metformin reduced subcutaneous and visceral abdominal fat. Metformin and rosiglitazone showed similar benefits on insulin sensitivity. Despite increased insulin sensitivity, a detrimental effect on fasting lipid profile was seen in some rosiglitazone-treated patients. Metformin, but not rosiglitazone, improved endothelial function. These results reinforce the importance of individualized care in HIV-infected patients. Metformin may be best for the viscerally obese, overweight, dyslipidemic patient, whereas rosiglitazone may be best for lipoatrophic patients.