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Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
Address all correspondence and requests for reprints to: Eugenio Cersosimo, M.D., Ph.D., Division of Diabetes, Department of Medicine, Mail Code 7886, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900. E-mail: Eugenio.Cersosimo{at}uhs-sa.com.
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Abstract |
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Objective: The objective of this study was to examine the association between inflammation, glucose, and lipid metabolism and vascular dysfunction.
Design and Setting: We conducted a randomized, double-blind, controlled trial of pioglitazone vs. placebo and other therapies aimed at equal glycemic control for 24 wk at an academic tertiary referral clinic.
Patients and Interventions: Mexican-American subjects with T2DM and no complications were randomly assigned to pioglitazone 45 mg daily (PIO, n = 16) or placebo (CON, n = 15) and matched for age, gender, body mass index, diabetes duration, and glycemic control. All subjects completed the study.
Main Outcome Measure: We looked for improved vascular reactivity independent of glycemic control but closely related to plasma adiponectin, lipids, and insulin sensitivity.
Results: After 24 wk, there was an equal decrease in fasting plasma glucose (
135 mg/dl), glycosylated hemoglobin (7.0%), and glucose production (15%). The decrease in free fatty acids (30 vs. 10%) and increase in glucose disposal (40 vs. 25%) were greater in PIO vs. CON (P < 0.05). In PIO, plasma high-density lipoprotein rose by 15% (P < 0.05), and low-density lipoprotein and high-density lipoprotein particle size rose significantly (P < 0.01). Plasma adiponectin doubled in PIO (from 6.1 ± 0.8 to 12.7 ± 2.1 µg/ml). Forearm blood flow rose equally (130%) during reactive hyperemia in both groups, although after therapy, the increase was greater (P < 0.001) in PIO (153%) than in CON (137%); vasodilation was greater (P = 0.01) in PIO (92, 160, and 204%) than in CON with acetylcholine (74, 130, and 144%) and with sodium nitroprusside (PIO = 164 and 253% vs. 116 and 230%; P = 0.04). The elevation in diameter was also greater in PIO (13 vs. 10%; P < 0.05). Vascular responses correlated with plasma free fatty acids, adiponectin, and low-density lipoprotein particle size but not with glycemic control.
Conclusion: These data indicate that pioglitazone improves vascular reactivity irrespective of glycemic control and suggest a close association with changes in fat cell metabolism.
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Introduction |
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, and IL-6, are commonly encountered abnormalities (6, 7, 8). These findings emphasize the pivotal role of abnormal vascular reactivity and inflammation in the development of accelerated atherosclerosis associated with insulin resistance and T2DM (4, 9).
The thiazolidinediones (TZDs) represent a unique class of drugs that improve insulin resistance, inhibit lipolysis, and reduce hyperglycemia by activating the nuclear transcription factor peroxisome proliferator-activated receptor 
(PPAR) in peripheral tissues (10). TZDs also have been shown to regulate the expression of various target genes in vascular smooth muscle cells (VSMCs), endothelial cells, and circulating monocytes (11, 12, 13), which play an important role in the development of the atherosclerotic plaque (14). TZDs have been shown to improve a number of cardiovascular risk factors (15), and most recently, pioglitazone has been demonstrated to be effective in secondary prevention of cardiovascular events in T2DM patients with evidence of macrovascular disease (16). The cardioprotective effect of pioglitazone cannot be explained by observed decreases in glycosylated hemoglobin (HbA1c), systolic blood pressure, and plasma triglycerides-to-high-density lipoprotein (HDL) cholesterol ratio (16). Previous studies have documented that pioglitazone ameliorates insulin resistance (17), improves endothelial dysfunction (18), reduces circulating cytokines and inflammatory biomarkers (19, 20), and elevates the plasma adiponectin concentration (21), all of which have antiatherogenic effects.
The relationship between metabolic control and vascular function is of considerable clinical significance, although it remains controversial. Earlier studies indicated that the improvement in endothelial dysfunction induced by TZDs is independent of glycemic control (20, 22). In the present study, our objectives were to extend these observations by examining the effects of pioglitazone on endothelial dysfunction and markers of inflammation in Mexican-Americans with T2DM and relate the changes in vascular reactivity to changes in glucose and lipid metabolism.
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Subjects and Methods |
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Thirty-one Mexican-American individuals with T2DM were recruited from the outpatient clinic at the Texas Diabetes Institute. Sixteen T2DM patients (nine female and seven male) randomly were assigned to receive pioglitazone and 15 T2DM (eight female and seven male) to receive placebo. Both groups were similar in age, body mass index (BMI), duration of diabetes, starting HbA1c, plasma lipids, endogenous glucose production (EGP), and insulin-stimulated total glucose disposal (TGD), as summarized in Table 1
. Mild hypertension treated with angiotensin converting enzyme inhibitors and diuretics was present in four patients in the pioglitazone group and in three patients in the placebo group, two patients in each group were receiving statin therapy, and there were two current smokers in each group. Body weight was stable (±3 pounds) in all subjects for at least 3 months before the enrollment in the study, and no subject participated in an excessively heavy physical activity program. At the time of randomization, all subjects were drug naive. No patients had any evidence of cardiovascular, renal, or major organ disease, as determined by routine history, physical examination, screening blood tests, urinalysis, or electrocardiogram. None of the patients had evidence of proliferative diabetic retinopathy or neuropathy. Patients who had ever received insulin therapy, metformin, or TZDs were excluded from the study. All subjects gave signed, informed consent before participation in the study. The protocol was approved by the Institutional Review Board of the University of Texas Health Science Center at San Antonio.
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The study design was randomized and double-blind. Before randomization, all subjects were instructed to consume a weight-maintaining diet containing 50% carbohydrate, 30% fat, and 20% protein. Patients were also instructed not to engage in any new physical activity during the study period. All studies were performed at the Clinical Research Center (CRC) at the Texas Diabetes Institute at 0800 h after a 10- to 12-h overnight fast. During the week before randomization, subjects reported to the CRC, and blood samples for the measurement of fasting plasma glucose (FPG), free fatty acids (FFA), lipid profile (particle size and number), adiponectin, high-sensitivity CRP (hsCRP), vascular cell adhesion molecule (VCAM), intracellular adhesion molecule (ICAM), TNF-, IL-6, and endothelin-1 (ET-1), and HbA1c were obtained. On the same day, all subjects received a euglycemic hyperinsulinemic clamp with insulin dose of 80 mU/m2·min simultaneously with tritiated glucose infusion to examine hepatic and peripheral tissue insulin sensitivity, as previously described (23). In brief, after an overnight fast, an iv catheter was inserted into an antecubital vein, and a primed (25 µCi x FPG/100), continuous (0.25 µCi/min) infusion of 3-[3H]glucose (NEN Life Science Products, Boston, MA) was started. A second catheter was inserted retrogradely into a vein in the dorsum of the hand, and the hand was placed in a hot box at 65 C. After a 150-min isotope equilibration period, baseline arterialized venous blood samples were collected at –30, –20, –10, –5, and 0 min for determination of plasma 3-[3H]glucose specific activity and insulin. At time zero, a primed continuous infusion of insulin at the rate of 80 mU/m2·min was started and continued for 180 min. Plasma glucose concentration declined to 100 mg/dl, at which level it was maintained by a variable infusion of 20% dextrose. Blood samples were collected every 10–15 min during the insulin clamp for the determination of plasma 3-[3H]glucose specific activity and insulin concentration.
Within 3–5 d after completion of the insulin clamp, subjects returned to the CRC, and vascular/endothelial function was assessed by 1) venous occlusion plethysmography (VOP) and 2) high-resolution ultrasonography (HRU), as described below. After completion of these baseline studies, patients were randomly assigned to receive either pioglitazone 15 mg/d or placebo. The dose of pioglitazone/placebo was increased to 30 mg/d and 45 mg/d at 4-wk intervals, as tolerated. If the home blood glucose measurements in the morning were above 150 mg/dl in three or more consecutive days, glipizide 5 mg once daily at breakfast was added to all patients, regardless of group treatment assignment, which was blinded to both physicians and the patients. Upon completion of the study data analyses, it became known that to achieve comparable glycemic control, glipizide was required in 10 subjects in the placebo group and in three subjects in the pioglitazone group.
Vascular studies
VOP. Changes in forearm blood flow (FBF) after 1) reactive hyperemia, 2) brachial arterial infusion of acetylcholine (ACh, endothelial-dependent), and 3) sodium nitroprusside (SNP, endothelial-independent) were used to evaluate the arterial vasodilatory response (24). On the morning of the study, a 20-gauge catheter was inserted into the brachial artery under local anesthesia (1% xylocaine; AstraZeneca LP, Wilmington, DE), and a rest period of 60 min was allowed. Five consecutive baseline measurements of FBF then were performed using a mercury strain gauge plethysmography (Hokanson Plethysmograph, model EC6; Hokanson, Bellevue, WA). Reactive hyperemia was induced by inflating an arm cuff above the elbow to 250 mm Hg for 5 min, and three consecutive FBF determinations were made between 10 and 30 sec after the cuff was deflated. Next, the intrabrachial artery infusion studies were performed. After patients rested for an additional 60 min, intrabrachial artery infusions of ACh (Miochol-E 1:100; Novartis, Duluth, GA) at the rates of 7.5, 15, and 30 µg/min were given for 12 min each with a 30-min interval between each infusion rate. The arterial line was then cleared with saline for 60 min, and intraarterial infusions of SNP (Nitropress, 25 mg/ml; Hospira Inc., Lake Forest, IL) at the rates of 3 and 10 µg/min were given for 12 min each with a 30-min interval between each infusion rate. Five consecutive measurements of FBF were obtained during each intrabrachial artery infusion. At the end of the experiment, the arterial line was removed, and compression to the area was applied for 10 min. All subjects were contacted within 24 h and again 3 d after the procedure to ascertain that there were no complications.
HRU. On a separate day, subjects returned to the CRC at 0800 h after an overnight fast, and vascular endothelial function was assessed with ultrasonography of the brachial artery during reactive hyperemia, using a technique modified from the method of Celermajer et al. (25) and following recently published guidelines (26). After a 30-min rest period, images were acquired and stored in a B-mode ultrasound using a 10.0-MHz linear array transducer (LOGIQ 7 scan system; GE Medical Systems, Milwaukee, WI). The brachial artery was scanned longitudinally, 5–10 cm above the elbow, and the velocity flow was measured with a pulsed-Doppler signal at a 60° angle to the vessel. The brachial artery diameter (BAD) was estimated with ultrasonic calipers at a fixed distance from an anatomical marker, when the lumen-intima interface was visualized on the near (anterior) and far (posterior) walls. After five consecutive determinations in the baseline period, the site was demarcated and the probe was secured around the arm. Next, the brachial artery blood flow was occluded with an arm cuff inflated at 250 mm Hg above the elbow for 5 min. After deflation of the cuff, continuous (cine) scan was obtained for a total of 5 min to record changes in flow velocity and BAD during the entire postischemic period.
Analytical procedures
Plasma glucose concentration was measured using the glucose oxidation method (Glucose Analyzer 2; Beckman Instruments, Fullerton, CA), and tritiated glucose specific activity was determined in barium/zinc deproteinized plasma samples. Plasma insulin (Diagnostic Products, Los Angeles, CA) was measured by RIA, HbA1c by affinity chromatography (Biochemical Methodology, Drower 4350; Isolab, Akron, OH), and plasma FFA concentration by enzymatic colorimetric quantification (Wako Chemicals, Neuss, Germany). Plasma adiponectin was measured by RIA, and plasma CRP, VCAM, ICAM, TNF-, IL-6, and ET-1 were measured by ELISA (Linco Research, St. Charles, MO). Lipid profile and particle size were determined by nuclear magnetic resonance spectroscopy (Liposcience, Inc., Raleigh, NC).
Calculations and presentation
Under steady-state postabsorptive conditions, the rate of glucose appearance (Ra) was calculated as the 3-[3H]glucose infusion rate (disintegrations per minute per minute) divided by the steady-state plasma 3-[3H]glucose specific activity (disintegrations per minute per milligram). During the insulin clamp, Ra was calculated from Steele’s equation (27), using a distribution volume of 250 ml/kg. EGP was calculated as: EGP = Ra– exogenous glucose infusion rate, and TGD equals the sum of residual EGP plus the exogenous glucose infusion rate. The hepatic insulin resistance (HIR) index was calculated as the product of EGP and plasma insulin in the baseline.
Determination of FBF using VOP was based on the changes in forearm circumference, as estimated by a computerized program during the arm cuff deflation, before and after 6 min of ACh and SNP infusion. Baseline values are expressed as milliliters per 100 g tissue per minute and represent the average of five measurements. Changes in FBF after ischemia and after intrabrachial artery infusions of ACh and SNP are expressed as percent increase from baseline.
Two independent investigators, who were blinded to the treatment assignment, analyzed the ultrasonography images offline. Baseline results represent the average of five measures before the inflation of the cuff, and postischemic changes are expressed as the mean percentage increase in BAD recorded in the cine scan between 50–60 sec after the release of the arm occlusion (26).
Statistical analysis
Statistical calculations were performed with StatView for Windows, version 5.0 (SAS Institute, Cary, NC). Values obtained before and after treatment within each group (intragroup) were analyzed using paired Student’s t test. Comparison between groups (intergroup) at baseline and after treatment was performed using ANOVA using Bonferroni post hoc testing. Pearson correlations between continuous variables were performed as measures of degree of association between metabolic and vascular parameters. Data are presented as mean ± SEM. A P value < 0.05 was considered statistically significant.
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Results |
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. After 24 wk of treatment, mean HbA1c (8.1–6.9% in the pioglitazone group and 7.9–7.0% in the placebo group) and fasting plasma glucose (181–135 mg/dl in the pioglitazone group and 176–139 mg/dl in the placebo group) decreased approximately equally in both groups, despite a significant increase in body weight (5 kg) and BMI (2 kg/m2) with pioglitazone therapy. Basal EGP declined slightly but not significantly in both groups, whereas the HIR decreased significantly with pioglitazone and remained unchanged in the placebo group. Although the residual EGP during the steady-state euglycemic hyperinsulinemia was similar in both groups, insulin-stimulated TGD increased by 40% in the pioglitazone group vs. 25% in the placebo group (P < 0.04). Plasma FFA concentration decreased by 30% in the pioglitazone-treated group vs. 10% in the placebo group (P < 0.03). Total and low-density lipoprotein (LDL)-cholesterol did not change in either group, whereas plasma triglycerides decreased equally by approximately 25% in both groups. Plasma high-density lipoprotein (HDL)-cholesterol concentration increased by 15% (P < 0.05) and did not change in the placebo group. Both LDL and HDL particle size increased significantly in the pioglitazone group and remained unchanged in the placebo group (P < 0.01).
Mean basal FBF, measured with VOP (Fig. 1A), was comparable in both groups at approximately 3.0 ml/100 g tissue per minute and increased slightly during reactive hyperemia by 119% (3.6 ± 0.4) and 133% (4.0 ± 0.3), respectively, before the start of pioglitazone and placebo therapy. After 24 wk of treatment, the percent increase in FBF during reactive hyperemia was greater in the pioglitazone vs. placebo group (153% = 4.6 ± 0.4 ml/100 g tissue per minute vs. 137% = 4.1 ± 0.4 ml/100 g tissue per minute; P = 0.003). ACh-stimulated vasodilation (Fig. 1B) was comparable in both groups at baseline, but the percent increase in FBF after 24 wk of therapy was significantly greater in the pioglitazone (92% = 5.8 ± 0.5, 160% = 7.8 ± 0.8, and 204% = 9.1 ± 0.8 ml/100 g tissue per minute) than in the placebo group (74% = 5.2 ± 0.5, 130% = 6.9 ± 0.7, and 144% = 7.3 ± 0.6 ml/100 g tissue per minute), respectively, at all three ACh infusion rates (7.5, 15, and 30 µg/min) (all P < 0.01). Similarly, SNP-stimulated vasodilation (Fig. 1C) was comparable in both groups at baseline, but the percent increase in FBF after 24 wk of therapy was significantly greater in the pioglitazone (164% = 4.9 ± 0.4 and 253% = 10.6 ± 0.9 ml/100 g tissue per minute) than in the placebo group (116% = 3.5 ± 0.4 and 230% = 9.9 ± 0.8 ml/100 g tissue per minute), respectively, at both SNP infusion rates (3.0 and 10 µg/min) (P < 0.04). Flow-mediated vasodilation (FMD), expressed as percent change in BAD, documented by HRU at 50–60 sec after ischemia (Fig. 1D), was comparable in both groups at baseline between 9 and 11% (0.32 ± 0.02 and 0.33 ± 0.01 cm). After 24 wk of pioglitazone therapy, FMD increased significantly (P = 0.03) to 13% (0.37 ± 0.02 cm), whereas it did not change in the placebo-treated group (10% = 0.33 ± 0.02 cm).
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). Plasma hsCRP decreased by 50% in the pioglitazone group (P < 0.01 vs. baseline) and declined slightly but not significantly in the placebo group (P = 0.04 pioglitazone vs. placebo). Changes in all other cytokines and biomarkers were comparable in both groups, although the declines in IL-6 (P < 0.05 vs. baseline in both groups), TNF- (P < 0.05 vs. baseline in the pioglitazone group), and VCAM (P < 0.05 vs. baseline in the pioglitazone group) tended to be greater in the pioglitazone-treated vs. placebo-treated subjects (Table 2).
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). Significant positive correlations were observed between the plasma adiponectin concentration and FMD (r = 0.37; P = 0.04) and ACh-stimulated vasodilation (r = 0.40; P = 0.03) (Fig. 2). In addition, positive correlations (not shown in graph) were documented between HDL-cholesterol concentration and ACh-stimulated vasodilation (r = 0.37; P = 0.05), between LDL-cholesterol particle size and reactive hyperemia as measured with VOP (r = 0.46; P = 0.01), and between TGD rates and FMD (r = 0.42; P = 0.02). In contrast, correlations between HbA1c and FMD, reactive hyperemia, and acetylcholine- and SNP-stimulated vasodilation were not statistically significant.
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Discussion |
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agonist exerted beneficial effects above and beyond those explained by glycemic control, whereas the effect of pioglitazone on other cytokines and inflammatory biomarkers was more related to improved glycemic control, which were equally affected in both groups. Consistent with these observations, there were significant correlations between the beneficial effects of pioglitazone to enhance endothelial-dependent and endothelial-independent vasodilation vs. plasma lipid (FFA, HDL-cholesterol, and LDL particle size) and adiponectin levels, whereas glycemic control did not correlate with improved vascular reactivity. These findings indicate that the pioglitazone-induced improvement in vascular function in patients with T2DM is more closely related to improvement in plasma lipid and adiponectin levels and less dependent upon glycemic control. It is important to emphasize, nonetheless, that our results do not entirely rule out an effect of glucose lowering to improve vascular function.
In agreement with previous results (17, 21), pioglitazone 45 mg/d reduced mean FPG and HbA1c in association with improved hepatic and peripheral insulin sensitivity. The metabolic improvements attained with pioglitazone were accompanied by an average increase in body weight of 5 kg, whereas in the placebo group the body weight did not change significantly. In pioglitazone-treated individuals the increase in body weight was strongly correlated with the reduction in HbA1c and improved insulin sensitivity, whereas no such correlations were observed in the placebo group, 70% of whom required glipizide to achieve the same degree of glycemic control. Although the improvement in insulin sensitivity in the present study was slightly superior in the pioglitazone vs. the placebo group (30 vs. 20%, P < 0.04), the most striking differences between these two anti-hyperglycemic treatment strategies related to the degree of suppression of lipolysis (30% decline in fasting plasma FFA concentration) and to the doubling of plasma adiponectin concentration, both of which occurred with pioglitazone therapy but not with the sulfonylurea-based treatment. Consistent with previous reports (16, 30), pioglitazone therapy caused an approximately 15% increase in plasma HDL-cholesterol concentration and modest but significant increases in both HDL- and LDL-cholesterol particles size. These findings further extend the beneficial metabolic effects of pioglitazone beyond those that can be explained by improved glycemic control.
The effects of pioglitazone on the vasodilatory capacity of the brachial artery in response to ischemia and to intrabrachial infusions of ACh and SNP were examined using two distinct techniques, VOP and HRU, with a strong positive correlation when used in diabetic subjects. The brachial arterial response to reactive hyperemia (both VOP and HRU) and to intrabrachial infusion of ACh primarily reflect endothelial-mediated vasodilation, whereas the response to intrabrachial infusion of SNP reflects the integrity of the VSMC relaxation process (25, 26). Both endothelial-dependent and -independent vasodilation improved significantly in the group treated with pioglitazone. Postischemic vasodilation, measured with both VOP and HRU methods, improved significantly by approximately 25%, and the increments in FBF during intrabrachial ACh infusion (7.5, 15, and 30 µg/min) increased by 20, 30, and 60%, respectively. Endothelial-independent arterial vasodilation, estimated by the percent increase in FBF after intrabrachial infusion of two doses of SNP also was approximately 50% higher in pioglitazone-treated compared with placebo patients. These observations are consistent with in vitro studies that have demonstrated a beneficial effect of the TZDs on the vasculature (11, 12). Pioglitazone also has been shown to enhance the increase in ACh-stimulated vasodilation observed with insulin infusion (18). TZDs are known to promote VSMC relaxation by stimulating the release of nitric oxide from vascular endothelial cells via inhibition of L-type calcium channels in the VSMC (31), and by their potent inhibition of VSMC proliferation and migration (11). A reduction in the formation of reactive oxygen species, a major pathway for the consumption of nitric oxide within the VSMC (24, 32), also has been shown after incubation of polymorphic nuclear leukocytes and mononuclear cells with troglitazone (13). Another potential mechanism that could explain the pioglitazone-induced endothelial-independent vasodilation relates to the reduction in local levels of vasoconstrictor prostaglandins (33).
Our results indicate that the improvement in vascular reactivity (both endothelial- and non-endothelial-dependent vasodilation) induced by pioglitazone in patients with T2DM is independent of glycemic control and is more closely associated with changes in plasmas lipid and adiponectin levels. Significant correlations were observed between plasma FFA, adiponectin concentrations, and LDL particle size and parameters of vascular reactivity. In contrast, the correlations between parameters of glycemic control and vascular reactivity were nonexistent. In a multivariate analysis, after adjusting for all the independent variables, a strong and significant correlation between plasma FFA (P = 0.02) and adiponectin (P = 0.04) concentrations and parameters of vascular reactivity is preserved (data not shown). These observations support the concept that pioglitazone improves endothelial dysfunction primarily by reducing plasma FFA and increasing adiponectin (34). Of note, our results suggest that improved glycemic control and reduction in plasma triglycerides are not sufficient to induce detectable improvements in vascular reactivity. On the other hand, the observation that a number of circulating cytokines and biomarkers of vascular damage and inflammation were equally decreased in diabetic patients, irrespective of the assigned treatment, reinforces the theory that improved glycemic control is important in achieving a reduction in the inflammatory component of the vascular disease process in T2DM (35).
Inhibition of lipolysis and decline in plasma FFA concentration have been a consistent finding in TZD-treated diabetic patients (17, 19, 20, 21) and the decrease in plasma FFA is closely correlated with improved insulin action in the liver and skeletal muscle (17, 19, 21). The present study extends these observations by demonstrating that the reduction in plasma FFA concentration is closely related to improved vascular smooth muscle function (Fig. 1C). These are in agreement with the results of Steinberg et al. (34), who demonstrated that the elevation of the plasma FFA concentration with lipid infusion in healthy lean subjects attenuated the endothelial-mediated increase in femoral artery blood flow. Additional evidence for a putative role of FFA on vascular function comes from the observation that oleic acid reduces nitric oxide synthase activity in cultured endothelial cells (36). Our findings also suggest that plasma levels of adiponectin, an adipocyte-derived peptide that increases with pioglitazone treatment, play a role in the improved vascular reactivity. This may be due to an effect of adiponectin to increase the availability of nitric oxide, to reduce oxidative stress, and/or to directly enhance VSMC relaxation as well as to the adipocytokine’s antiinflammatory action (37). Adiponectin also has been shown to inhibit lipolysis and stimulate intramyocellular fatty acid oxidation (38, 39), which would be expected to improve endothelial function.
In summary, our results demonstrate that pioglitazone treatment of Mexican-American type 2 diabetic individuals improves vascular reactivity and diabetic dyslipidemia, independent of enhanced glycemic control. The improvement in endothelial-dependent and -independent arterial vasodilation observed with pioglitazone is closely associated with reduced plasma FFA levels and increased plasma adiponectin concentration. In contrast, a reduction in plasma inflammatory cytokines/biomarkers is more closely linked to the improved glycemic control, being demonstrated in both pioglitazone- and glipizide-treated diabetic patients. These findings suggest that the beneficial vascular effects of pioglitazone in patients with T2DM are related to the effect of TZD on fat cell metabolism, with resultant changes in plasma FFA and adiponectin concentrations.
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Footnotes |
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Disclosure Statement: E.W., A.S., and N.M. have nothing to declare. R.A.D. is a member of the Speaker Bureau of Novartis, Eli Lilly, and Takeda North America and Advisory Board of Amylin/Eli Lilly Alliance, Bristol-Myers Squibb, and Takeda North America. E.C. is a member of the Speaker Bureau of Pfizer and Sanofi-Aventis and Advisory Board of Amylin/Eli Lilly Alliance and Takeda North America.
First Published Online January 23, 2007
Abbreviations: ACh, Acetylcholine; BAD, brachial artery diameter; BMI, body mass index; CRP, C-reactive protein; EGP, endogenous glucose production; ET-1, endothelin-1; FBF, forearm blood flow; FFA, free fatty acids; FMD, flow-mediated vasodilation; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; HIR, hepatic insulin resistance; HRU, high-resolution ultrasonography; hsCRP, high-sensitivity CRP; ICAM, intracellular adhesion molecule; LDL, low-density lipoprotein; PPAR, peroxisome proliferator-activated receptor ; SNP, sodium nitroprusside; T2DM, type 2 diabetes mellitus; TGD, total glucose disposal; TZD, thiazolidinedione; VCAM, vascular cell adhesion molecule; VOP, venous occlusion plethysmography; VSMC, vascular smooth muscle cell.
Received August 30, 2006.
Accepted January 11, 2007.
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agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82–86[CrossRef][Medline] target genes related to lipid storage in vivo. Diabetes Care 27:1660–1667This article has been cited by other articles:
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  M. Fernandez, C. Triplitt, E. Wajcberg, A. A. Sriwijilkamol, N. Musi, K. Cusi, R. DeFronzo, and E. Cersosimo Addition of Pioglitazone and Ramipril to Intensive Insulin Therapy in Type 2 Diabetic Patients Improves Vascular Dysfunction by Different Mechanisms Diabetes Care, January 1, 2008; 31(1): 121 - 127. [Abstract] [Full Text] [PDF]
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) or placebo (
) in T2DM Mexican-American subjects. A, FMD vs. plasma FFA concentration; B, SNP-stimulated vasodilation at the rate of 10 µg/min (SNP10) vs. plasma FFA concentration; C, ACh-stimulated vasodilation at the rate of 15 µg/min (Ach15) vs. plasma FFA concentration; D, FMD vs. plasma adiponectin concentration; E, ACh-stimulated vasodilation at the rate of 30 µg/min (Ach30) vs. plasma adiponectin concentration; F, Reactive hyperemia (RH) vs. plasma LDL particle size.