[HTML][HTML] Treatment of insulin resistance with peroxisome proliferator–activated receptor γ agonists

JM Olefsky - The Journal of clinical investigation, 2000 - Am Soc Clin Investig
The Journal of clinical investigation, 2000Am Soc Clin Investig
On diabetes: insulin resistance insulin-resistant study groups in man. In terms of human
studies, TZDs have been most extensively evaluated in patients with type 2 diabetes. Initial
clinical research studies with TZDs clearly demonstrated that treatment of type 2 diabetic
patients with these agents lowered both fasting and postprandial glucose levels, as well as
circulating insulin levels (15, 16). This combination of findings is consistent with the
presumed action of these compounds as insulin-sensitizing agents, as was directly …
On diabetes: insulin resistance insulin-resistant study groups in man. In terms of human studies, TZDs have been most extensively evaluated in patients with type 2 diabetes. Initial clinical research studies with TZDs clearly demonstrated that treatment of type 2 diabetic patients with these agents lowered both fasting and postprandial glucose levels, as well as circulating insulin levels (15, 16). This combination of findings is consistent with the presumed action of these compounds as insulin-sensitizing agents, as was directly demonstrated by performing glucose clamps in type 2 diabetic patients before and after a period of TZD treatment. These studies showed that essentially all patients exhibited an improvement in insulin-stimulated glucose disposal after the drug treatment period, and on average this amounted to a 30% increase in this action of insulin (15). Elevated hepatic glucose production rates are a characteristic feature of type 2 diabetic patients with fasting hyperglycemia (1), and this is also a manifestation of insulin resistance. The effects of TZD treatment on basal hepatic glucose production rates in type 2 diabetic patients have been somewhat variable. Some studies have shown striking decreases in this abnormality (15), while others have shown either no effect (17) or effects only at higher doses of TZDs (18). Furthermore, it is not clear whether the effects of TZDs to lower hepatic glucose production rates represent direct actions on the liver, or indirect beneficial effects secondary to some other aspect of the improved metabolic environment produced by these drugs. For example, TZD treatment reduces FFA levels, which may secondarily lower hepatic glucose output.
TZDs have also been used in the treatment of nondiabetic human insulin-resistant states. For example, treatment of obese nondiabetic subjects, subjects with impaired glucose tolerance (IGT), and women with PCOS have all demonstrated an improvement in insulin sensitivity (19–21). The mechanisms of insulin resistance are almost certainly heterogeneous across all these human conditions. Thus, these results are consistent with what has been learned from animal studies in that TZDs are effective at ameliorating insulin resistance regardless of the diverse underlying genetic and acquired mechanisms. It is also important to point out that, unlike in the animal studies, the effects of TZDs result in only partial improvement in insulin resistance. Thus, TZD treatment leads to anywhere from a 20–40% improvement in insulin-stimulated glucose disposal in human insulin-resistant states, compared with near normalization in insulin-resistant animals. Therefore, even after effective TZD treatment, patients with type 2 diabetes, obesity, IGT, and PCOS still remain moderately insulin-resistant. Treatment of patients with TZDs seems to have beneficial effects on most, if not all, of the components of syndrome X (see Ginsberg, this Perspective series, ref. 22). For example, not only does TZD treatment
The Journal of Clinical Investigation