Synergistic interactions among metabolic syndrome components and homeostasis model assessment of insulin resistance in a middle-aged general population over time.

BACKGROUND: Insulin resistance is considered a hallmark feature of the metabolic syndrome, but how metabolic syndrome components and insulin resistance measures interact over time is unclear. The homeostasis model assessment of insulin resistance (HOMA-IR) is a static index of insulin resistance typically used in epidemiological studies. We explored how HOMA-IR is affected by clustering metabolic syndrome components over time in a population of middle-aged, healthy subjects. METHODS: A total of 1757 subjects aged 41.3±7.5 years (39% males) free from diabetes at baseline were followed-up for a median of 5.7 years. At baseline and at the end of observation, we determined metabolic syndrome components and HOMA-IR. RESULTS: Cross-sectionally, HOMA-IR was synergistically increased by clustering of at least two to three metabolic syndrome components as determined at baseline and at study end by departure from additivity. Some combinations of metabolic syndrome components were associated with a significant synergic increase in HOMA-IR, and some combinations of two components entailed a synergistic risk of developing metabolic syndrome. Over time, the average change in HOMA-IR was more than additively affected by change in the number of metabolic syndrome components. Baseline HOMA-IR values were predictive of incident metabolic syndrome independent from age, sex, and each metabolic syndrome component. CONCLUSIONS: We show synergistic interaction between clustering metabolic syndrome components and insulin resistance, estimated by HOMA-IR, cross-sectionally and over time. This more than additive effect explains the incremental value of HOMA-IR in predicting metabolic risk.

Short-term statin discontinuation increases endothelial progenitor cells without inflammatory rebound in type 2 diabetic patients.

Type 2 diabetes (T2D) is characterized by impaired vascular regeneration owing to reduced endothelial progenitor cells (EPCs). While statins are known to increase EPCs, the effects of statin withdrawal on EPCs are unknown. Herein, we evaluated the effects of statin discontinuation on EPCs, inflammation and in vivo angiogenesis. Thirty-four T2D patients were randomized to 5-day discontinuation or continuation of statin treatment. At baseline and at day 5, we determined lipid profile, EPC levels, monocyte-macrophage polarization, and concentrations of hsCRP, VEGF, SDF-1α, and G-CSF. Angiogenesis by human circulating cells was assessed in vivo. At day 5, patients who stopped statins showed raised total and LDL cholesterol and EPCs compared to baseline, while no changes were observed in patients who continued statins. No changes were observed in hsCRP, VEGF, SDF-1α, G-CSF, M1 and M2 macrophages and classical, intermediate and nonclassical monocytes in both groups. In vivo angiogenesis by circulating cells was increased in patients who stopped statin treatment. In vitro, cholesterol supplementation stimulated mobilizing signals in human bone marrow mesenchymal stem cells. In conclusion, a brief statin withdrawal increases circulating EPCs and functional proangiogenic cells in T2D. These findings identify statin-sensitive pathways as reverse target mechanisms to stimulate vascular repair in diabetes.

Diabetes impairs stem cell and proangiogenic cell mobilization in humans.

OBJECTIVE: Diabetes mellitus (DM) increases cardiovascular risk, at least in part, through shortage of vascular regenerative cells derived from the bone marrow (BM). In experimental models, DM causes morphological and functional BM alterations, but information on BM function in human DM is missing. Herein, we sought to assay mobilization of stem and proangiogenic cells in subjects with and without DM. RESEARCH DESIGN AND METHODS: In a prospective trial (NCT01102699), we tested BM responsiveness to 5 µg/kg human recombinant granulocyte colony-stimulating factor (hrG-CSF) in 24 individuals with DM (10 type 1 and 14 type 2) and 14 individuals without DM. Before and 24 h after hrG-CSF, we quantified circulating stem/progenitor cells and total and differential white blood cell counts. We also evaluated in vivo the proangiogenic capacity of peripheral blood mononuclear cells using the Matrigel plug assay. RESULTS: In response to hrG-CSF, levels of CD34(+) cells and other progenitor cell phenotypes increased in subjects without DM. Patients with DM had significantly impaired mobilization of CD34(+), CD133(+), and CD34(+)CD133(+) hematopoietic stem cells and CD133(+)KDR(+) endothelial progenitors, independently of potential confounders. The in vivo angiogenic capacity of peripheral blood mononuclear cells significantly increased after hrG-CSF in control subjects without DM, but not in patients with DM. DM was also associated with the inability to upregulate CD26/DPP-4 on CD34(+) cells, which is required for the mobilizing effect of granulocyte colony-stimulating factor. CONCLUSIONS: Stem and proangiogenic cell mobilization in response to hrG-CSF is impaired in DM, possibly because of maladaptive CD26/DPP-4 regulation. These alterations may hamper tissue repair and favor the development of cardiovascular complications.