The insulin sensitiser pioglitazone does not influence skin microcirculatory function in patients with type 2 diabetes treated with insulin

Abstract

Aims/hypothesis: Insulin resistance is associated with abnormal microvascular function. Treatment with insulin sensitisers may provoke oedema, suggesting microvascular effects. The mechanisms underlying the peripheral oedema observed during glucose-lowering treatment with thiazolidinediones are unclear. Therefore we examined the effect of pioglitazone on microvascular variables involved in oedema formation. Methods:: Subjects (40-80 years) with type 2 diabetes and on insulin were randomised to 9 weeks of pioglitazone therapy (30 mg/day; n=14) or placebo (n=15). The following assessments were performed at baseline and 9 weeks: microvascular filtration capacity; isovolumetric venous pressure; capillary pressure; capillary recruitment following venous or arterial occlusion; postural vasoconstriction; and maximum blood flow. A number of haematological variables were also measured including vascular endothelium growth factor (VEGF), IL-6 and C-reactive protein (CRP). Results: Pioglitazone did not significantly influence any microcirculatory variable as compared with placebo (analysis of covariance [ANCOVA] for microvascular filtration capacity for the two groups, p=0.26). Mean VEGF increased with pioglitazone (61.1 pg/ml), but not significantly more than placebo (9.76 pg/ml, p=0.94).HbA 1c levels and the inflammatory markers IL-6 and CRP decreased with pioglitazone compared with placebo (ANCOVA: p=0.009, p=0.001 and p=0.004, respectively). Conclusions/interpretation: Pioglitazone improved glycaemic control and inflammatory markers over 9 weeks but had no effect on microcirculatory variables associated with oedema or insulin resistance in type 2 diabetic patients treated with insulin.

Effects of intensive insulin therapy alone and with added pioglitazone on renal salt/water balance and fluid compartment shifts in type 2 diabetes

“…VEGF is a cytokine which greatly increases vascular permeability. There are reports in the literature that the TZDs either increase or have no effect on VEGF levels [27,28]. In our study, VEGF levels did not change significantly with pioglitazone treatment.…”

Thiazolidinedione insulin sensitizers and the heart: a tale of two organs?

“…Rosiglitazone, meanwhile, has been shown to increase the production of nitric oxide in, and blood flow to, the skin [136], and blood flow to subcutaneous adipose tissue [137] in patients with type 2 diabetes. By contrast, however, Tooke et al [138] found no effect of pioglitazone on a raft of microcirculatory variables in the skin of insulin‐treated patients with type 2 diabetes.…”

Pleiotropic effects of thiazolidinediones on traditional and non-traditional atherosclerotic risk factors

“…2.6 ± 0.5 mg/l (p = 0.01, between‐group difference) (52). In a randomised, parallel‐group, 9‐week study, pioglitazone significantly reduced levels of both CRP and IL‐6 from baseline in insulin‐treated patients with type 2 diabetes ( n = 29) (55). Levels of the angiogenic cytokine, vascular endothelium growth factor (VEGF), were also raised from baseline following pioglitazone treatment, although the difference vs. placebo failed to reach statistical significance.…”

“…Clinical studies of pioglitazone effects on atherogenic biomarkers published since 2001(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68) …”