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- insulin resistance (2)
- intact proinsulin (2)
- pioglitazone (2)
- thiazolidinediones (2)
- type 2 diabetes mellitus (2)
- Adipogenic effect (1)
- CYP2C8 variants (1)
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Background: Type 2 diabetes mellitus is associated with increased cardiovascular risk. One laboratory marker for cardiovascular risk assessment is high-sensitivity C-reactive protein (hsCRP).
Methods: This cross-sectional study attempted to analyze the association of hsCRP levels with insulin resistance, β-cell dysfunction and macrovascular disease in 4270 non-insulin-treated patients with type 2 diabetes [2146 male, 2124 female; mean age ±SD, 63.9±11.1years; body mass index (BMI) 30.1±5.5kg/m2; disease duration 5.4±5.6years; hemoglobin A1c (HbA1c) 6.8±1.3%]. It consisted of a single morning visit with collection of a fasting blood sample. Observational parameters included several clinical scores and laboratory biomarkers.
Results: Stratification into cardiovascular risk groups according to hsCRP levels revealed that 934 patients had low risk (hsCRP <1mg/L), 1369 patients had intermediate risk (hsCRP 1–3mg/L), 1352 patients had high risk (hsCRP >3–10mg/L), and 610 patients had unspecific hsCRP elevation (>10mg/L). Increased hsCRP levels were associated with other indicators of diabetes-related cardiovascular risk (homeostatic model assessment, intact proinsulin, insulin, BMI, β-cell dysfunction, all p<0.001), but showed no correlation with disease duration or glucose control. The majority of the patients were treated with diet (34.1%; hsCRP levels 2.85±2.39mg/L) or metformin monotherapy (21.1%; 2.95±2.50mg/L hsCRP). The highest hsCRP levels were observed in patients treated with sulfonylurea (17.0%; 3.00±2.43mg/L).
Conclusions: Our results indicate that hsCRP may be used as a cardiovascular risk marker in patients with type 2 diabetes mellitus and should be evaluated in further prospective studies.
Background and Objectives: In advanced β-cell dysfunction, proinsulin is increasingly replacing insulin as major component of the secretion product. It has been speculated that proinsulin has at least the same adipogenic potency than insulin, leading to an increased tendency of lipid tissue formation in patients with late stage β-cell dysfunction. Methods and Results: Mesenchymal stem cells obtained from liposuction material were grown in differentiation media containing insulin (0.01 μmol), proinsulin (0.01 μmol) or insulin+proinsulin (each 0.005 μmol). Cell culture supernatants were taken from these experiments and an untreated control at weeks 1, 2, and 3, and were stored at -80°C until analysis. Cell differentiation was microscopically supervised and adiponectin concentrations were measured as marker for differentiation into mature lipid cells. This experiment was repeated three times. No growth of lipid cells and no change in adiponectin values was observed in the negative control group (after 7/14/12 days: 3.2±0.5/3.3±0.1/4.4±0.5 ng/ml/12 h). A continuous differentiation into mature adipocytes (also confirmed by Red-Oil-staining) and a corresponding increase in adiponectin values was observed in the experiments with insulin (3.6±1.9/5.1±1.4/13.3±1.5 ng/ml/12 h; p<0.05 week 1 vs. week 3) and proinsulin (3.3±1.2/3.5±0.3/12.2±1.2 ng/ml/12 h; p<0.05). Comparable effects were seen with the insulin/proinsulin combination. Conclusions: Proinsulin has the same adipogenic potential than insulin in vitro. Proinsulin has only 10∼20% of the glucose-lowering effect of insulin. It can be speculated that the adipogenic potential of proinsulin may be a large contributor to the increased body weight problems in patients with type 2 diabetes and advanced β-cell dysfunction.
Background:Anecdotal reports from pediatric sites have indicated that some blood glucose meters may display wrong and misleading numbers rather than error indications, when operated in deviation from the instructions for use (IFU), eg by manipulating the strip during the count-down phase.Methods:This study was performed with 60 patients with diabetes (32 female, 28 male, 21 type 1, 39 type 2, age (mean±SD): 56±11 years) who measured their blood glucose levels twice with five different blood glucose meters (Precision? Xceed? [Abbott Medisense], Freestyle Mini? [Abbott Medisense], Accu-Chek? Comfort [Roche Diagnostics], Accu-Chek? Aviva [Roche Diagnostics], and Ascensia Contour? [Bayer Vital]). The first measurement was performed in accordance with the IFU, and the second by manipulating the test strip using a standardised inflexion/release procedure during the count-down phase. A standard glucose oxidase method (SuperGL) served as laboratory reference.Results:All meters worked in full compliance with current accuracy standards when operated according to the IFU. When manipulating the test strip, the results varied considerably: While changes in reliability were acceptable for two devices (Precision? Xceed?, Freestyle Mini?), the other devices produced an unacceptable number of errors and a series of entirely wrong values without error indication.Conclusions:The use of all devices is recommended when used according to the IFU. The use under the artificially induced impaired testing conditions is a major concern. This study underlines the importance of appropriate patient training regarding adherence to the IFU of glucose meters.
Aim:Pioglitazone is an established peroxisome proliferator-activated receptor ? agonist for the treatment of insulin resistance in patients with type 2 diabetes mellitus. This analysis of the observational IRIS III study was performed to evaluate the effects of pioglitazone treatment in relation to the degree of physical exercise activities in a large patient population under daily life conditions.Methods:A total of 1298 patients out of 2092 enrolled into the IRIS III study who had provided information about their exercise level could be included in the final analysis (622 female, 676 male; age: 63.1 ± 10.4 years, diabetes duration: 6.6 ± 5.0 years, mean ± SD). All patients were glitazone naïve prior to study entry. They received pioglitazone in addition to their previous oral antidiabetic treatment. The patients were stratified according to their physical activity level (never, sometimes, and regularly). Data were evaluated at baseline and after 20 ± 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. Hemoglobin A1c (HbA1c) was determined in a central laboratory, and insulin sensitivity was assessed by the IRIS II score.Results:Glycemic control, blood pressure, and the lipid profile improved independently from the degree of physical activity (e.g., no exercise vs frequent exercise: ?HbA1c: ?0.89 ± 1.2% vs ?0.72 ± 1.1%, not significant). A positive impact of exercise on insulin resistance could be observed at baseline, which, however, was further decreased by pioglitazone treatment [IRIS II score (baseline/end point): no exercise vs frequent exercise: 74.0 ± 15.9/62.5 ± 20.2 vs 66.7 ± 19.0/58.0 ± 21.8, p < 0.001/not significant].Conclusions:These observational results, obtained from a nonselected patient population under daily routine conditions, confirm that the benefits of pioglitazone treatment on glycemic control, lipid metabolism, and blood pressure are independent from physical activity. Exercise has a positive influence on insulin sensitivity, but pioglitazone shows additional favorable effects and is, therefore, recommended for use independently from the activity level of the patients.
Background:The aim of our study was to examine the efficacy of short-term intravenous insulin intervention followed by oral pioglitazone/metformin therapy to prevent patients from continuous insulin application.Methods:This prospective, open-label, 4-month pilot study comprised of 14 diabetes patients (5 female, 9 male; age 60 ± 2 years; body mass index 29 ± 3.2 kg/m2; hemoglobin A1c [HbAlc] 7.6 ± 1.1%) with (1) insufficient glycemic control under a dose of metformin >1700 mg/day and/or metformin plus additional oral antidiabetes drugs (OADs) and (2) appropriate residual ?-cell function. Initially, an inpatient 34 h continuous intravenous insulin infusion was performed, and metformin was given (2? 850 mg/day). Insulin was stopped, and pioglitazone 30 mg/day was added at the second inpatient day. Patients were followed for four months. Efficacy parameters [change of HbA1c, fasting blood glucose [FBG], intact proinsulin, adiponectin, and high-sensitivity C-reactive protein (hsCRP)] were assessed after initial normalization of blood glucose values by intravenous insulin and at the study end point.Results:During the acute insulin intervention, FBG levels were stabilized in all study subjects. In the following OAD treatment period, five patients showed an improvement of HbA1c > 0.5% [35.7%; seven patients remained stable (50.0%), two patients were nonresponders (14.3%)].Fasting glucose values dropped after insulin infusion (?17.7%; p < .001). This effect was maintained during the consecutive OAD treatment period (glucose +0.3%, not significant (NS); HbA1c ?6.0%; p < .05). The initial decrease in fasting intact proinsulin levels was also maintained during the study (end value ?41%, p < .05).Improvements in hsCRP values (postinsulin value, ?15%, NS; end value ?37%; p < .05) and adiponectin values (postinsulin value +15%, NS; end value +128%; p < .001) were demonstrated at end point only after continued glitazone intake.Conclusions:Our pilot study demonstrated that a beneficial effect of a short-term intravenous insulin application on glycemic control was effectively maintained by pioglitazone/metformin treatment for at least 4 months. In addition, the oral therapy significantly improved cardiovascular risk parameters.
BACKGROUND
There is increasing evidence that insulin resistance (IR) has an important implication in the pathogenesis of polycystic ovary syndrome (PCOS), a common endocrinopathy in women. This study was performed to investigate the impact of different treatments for IR on five currently discussed markers for insulin resistance: intact proinsulin, adiponectin, retinol-binding protein 4 (RBP4), resistin, and visfatin in patients with PCOS.
METHODS
Thirty-five women with clinically confirmed PCOS diagnosis were included in the study [age (mean+/-SD): 24.7+/-4.8 years; body mass index: 27.4+/-6.0 kg/m(2)]. They were randomized to receive either metformin (850 mg twice a day) or rosiglitazone (4 mg once a day). Blood samples for measurement of the HOMA(IR) score, visfatin, RBP4, intact proinsulin, resisitin, and adiponectin were taken at baseline and after 6 months of treatment.
RESULTS
Both drugs improved ovulation, and an increase in insulin sensitivity was observed, especially in the rosiglitazone arm. Adiponectin levels increased in both treatment arms (metformin: 8.6+/-3.3 to 16.7+/-7.2 mg/liter, p < 0.001; rosiglitazone: 8.2+/-3.5 to 26.2+/-9.5 mg/liter, p < 0.001), but the increase was more pronounced with rosiglitazone (p < 0.001). While no changes of visfatin concentrations were observed during rosiglitazone therapy (15.4+/-6.9 ng/ml vs 17.4+/-4.8 ng/ml, n.s.), there was an increase in the metformin treatment arm (11.9+/-4.0 to 21.8+/-8.3 ng/ml, p < 0.001). Significant increases demonstrated for RBP4 in both treatment arms were more pronounced in the metformin group (metformin: +66%, rosiglitazone: +33%). All patients were in stage I or II of ss-cell dysfunction and none of them showed increased intact proinsulin levels or changes in resisitin at baseline or end point.
CONCLUSIONS
Both drugs slightly improved ovulation in our PCOS patient population during 6 months of therapy, which was accompanied by improved insulin sensitivity and an increase in adiponectin levels. Metformin increased visfatin concentrations. Despite improved insulin resistance, an increase in RBP4 concentration was seen for both drugs. Rosiglitazone seems to be the more favorable drug under these circumstances. However, our results regarding visfatin and RBP4 contradict other reports and further research is required to clarify their value as diagnostic markers for the metabolic syndrome. In this study, adiponectin appeared to be the most promising indicator of both metabolic status and therapeutic success.
BACKGROUND
Type 2 diabetes mellitus (T2DM) is characterized by a proinflammatory and procoagulant condition. This study investigates the impact of a pioglitazone plus metformin therapy on biomarkers of inflammation and platelet activation in comparison to a treatment with glimepiride plus metformin.
METHODS
The study was designed as a multicenter, randomized, double-blinded two-arm trial. Patients with T2DM and dyslipidemia under metformin monotherapy with hemoglobin A1c value between 6.5% and 9.0% were eligible for trial participation. Blood was drawn at baseline and after 24 weeks of treatment from patients of five centers. Markers of inflammation and thrombocyte function (soluble CD40 ligand, thromboxane, vWillebrand factor, adhesion molecules, clotting reaction) were evaluated subsequently in a central laboratory.
RESULTS
A total of 46 patients were included in the final analyses. Mean (± standard deviation) age was 58.5 ± 9.0 years (13 women, 33 men; disease duration 6.3 ± 5.0 years; body mass index 32.0 ± 4.8 kg/m(2)). A total of 25 patients were treated with pioglitazone plus metformin, and 21 patients were in the glimepiride arm. There was a significant decline of E-selectin (-3.7 ± 4.8 ng/ml, p < .001 versus baseline), vWillebrand factor (-19.5 ± 32.0%, p < .05), and high-sensitivity C-reactive protein concentrations (-1.08 ± 0.91 mg/liter, p < .05) in the metformin + pioglitazone arm only (metformin + glimepiride, -0.5 ± 3.4 ng/ml, +1.4 ± 33.2%, + 0.08 ± 0.72 mg/liter, respectively, all not significant). Also, all other surrogate markers for platelet function and inflammation showed slight improvements in the metformin + pioglitazone arm but not in the metformin + glimepiride arm.
CONCLUSIONS
The fixed metformin + pioglitazone combination treatment showed an overall improvement of laboratory surrogate markers, indicating improvement of platelet function and of chronic systemic inflammation, which was not seen with metformin + glimepiride.
OBJECTIVE
Dyslipidemia in patients with type 2 diabetes is characterized by elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a predominance of small dense low-density lipoprotein (LDL) particles. Also, patients suffer from β-cell dysfunction, chronic systemic inflammation, increased hormonal visceral adipose tissue activity, and an increased risk of cardiovascular events. The aim of our study was to investigate the effect of a fixed pioglitazone + metformin (PM) combination (vs. glimepiride + metformin [GM]) on diabetic dyslipidemia.
RESEARCH DESIGN AND METHODS
A total of 288 type 2 diabetes patients completed this double-blind parallel study (187 men, 101 women; age [mean ± SD], 59 ± 10 years; body mass index, 32.6 ± 5.1 kg/m(2); hemoglobin A1c [HbA1c], 7.3 ± 0.8%). They were randomized to PM or GM for 6 months. Observation parameters at baseline and end point included HDL, LDL, triglycerides, fasting insulin, fasting glucose, total adiponectin, intact proinsulin, and high-sensitivity C-reactive peptide (hsCRP).
RESULTS
HDL increased in the PM group by 0.08 ± 0.25 mmol/L (GM, -0.01 ± 0.2.8 mmol/L; P < 0.001 vs. PM), whereas LDL increased in both groups (GM, 0.25 ± 0.90 mmol/L; PM, 0.29 ± 0.66 mmol/L; difference not significant between groups). Improvements were seen for triglycerides (PM, -0.47 ± 1.30; GM, -0.19 ± 1.39 mmol/L), HbA1c (PM, -0.8 ± 0.9%; GM, -1.0 ± 0.9%), and glucose (PM, -1.2 ± 2.1; GM, -1.2 ± 2.2 mmol/L). Decreases in fasting insulin (PM, -5.2 ± 11.9; GM, -0.1 ± 9.8 μU/mL; P < 0.001 between groups), hsCRP (PM, -0.9 ± 1.9; GM, 0.0 ± 1.8 mg/L; P < 0.001), and fasting intact proinsulin (PM, -5.5 ± 11.1; GM, -0.1 ± 10.0 pmol/L; P < 0.001) and an increase in adiponectin (PM, +6.8 ± 6.4 mg/L; GM, +0.7 ± 2.7 mg/L; P < 0.001) were seen in the PM arm, only.
CONCLUSIONS
With comparable glycemic control, the fixed PM combination was more efficacious on HDL cholesterol improvement than the GM combination. Additional positive effects were observed for biomarkers of lipid metabolism, β-cell function, activity of the visceral adipose tissue, and chronic systemic inflammation.
Addition of rosiglitazone to sulfonylurea has been shown to improve glycemic control in patients with type 2 diabetes previously treated with sulfonylurea monotherapy alone. This investigation was performed to assess the specific impact of rosiglitazone on insulin resistance, beta-cell function, cardiovascular risk markers, and adiponectin secretion in this treatment concept. One hundred two patients from a double-blind, 3-arm comparator trial (group 0, glimepiride + placebo, n = 30; group 4, glimepiride + 4 mg rosiglitazone, n = 31; group 8, glimepiride + 8 mg rosiglitazone, n = 41; 48 women, 54 men; age [mean +/- SD], 62.8 +/- 9.1 years; body mass index, 28.7 +/- 4.5 kg/m2; diabetes duration, 6.4 +/- 4.8 years; HbA1c, 8.1% +/- 1.5%) were analyzed after 0 and 16 weeks of treatment. Observation parameters were HbA1c, glucose, homeostasis model assessment for insulin resistance score, insulin, intact proinsulin, and adiponectin. Insulin resistance was defined by elevated intact proinsulin values or homeostasis model assessment for insulin resistance score of more than 2. All parameters were comparable in the 3 groups at baseline. Substantial and significant dose-dependent improvements were observed after addition of rosiglitazone for fasting glucose (group 0, -9 +/- 48 mg/dL; group 4, -38 +/- 47 mg/dL; group 8, -46 +/- 53 mg/dL), HbA1c (-0.1% +/- 0.7%, -1.1% +/- 1.2%, -1.3% +/- 1.2%), insulin (1.4 +/- 6.2, -1.2 +/- 5.3, -3.7 +/- 9.9 microU/mL), intact proinsulin (1.6 +/- 7.1, -2.0 +/- 4.6, -3.1 +/- 6.1 pmol/L), and high-sensitivity C-reactive protein (0.2 +/- 2.6, -1.7 +/- 3.5, -2.1 +/- 3.5 mg/L). After adjustment for changes in body weight, significant increases in adiponectin were detected with rosiglitazone, whereas glimepiride alone did not induce a comparable effect (-0.5 +/- 5.8, 8.8 +/- 22.9, 14.3 +/- 19.9 mg/L). The number of insulin-resistant patients decreased in both rosiglitazone treatment groups, whereas no change was seen with glimepiride alone. Next to the reported effects on glucose control, rosiglitazone provided an additional beneficial effect on insulin resistance, beta-cell function, and cardiovascular risk markers. In conclusion, our short-term investigation of rosiglitazone action provides further experimental support for the rationale of combining rosiglitazone with sulfonylurea drugs in patients with type 2 diabetes.
High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus
(2006)
C-reactive protein (CRP) is a liver-derived pattern recognition molecule that is increased in inflammatory states. It rapidly increases within hours after tissue injury, and it is suggested that it is part of the innate immune system and contributes to host defense. Since cardiovascular disease is at least in part an inflammatory process, CRP has been investigated in the context of arteriosclerosis and subsequent vascular disorders. Based on multiple epidemiological and intervention studies, minor CRP elevation [high-sensitivity CRP (hsCRP)] has been shown to be associated with future major cardiovascular risk (hsCRP: <1 mg/L = low risk; 1–3 mg/L = intermediate risk; 3–10 mg/L = high risk; >10 mg/L = unspecific elevation). It is recommended by the American Heart Association that patients at intermediate or high risk of coronary heart disease may benefit from measurement of hsCRP with regard to their individual risk prediction. Elevation of hsCRP is associated with increased risk of type 2 diabetes development in patients with all levels of metabolic syndrome. In type 1 and type 2 diabetes mellitus, hemoglobin A1c significantly correlates with hsCRP levels and future cardiovascular risk. Also, hsCRP levels increase with the stage of ?-cell dysfunction and insulin resistance. Non-diabetes drugs that have been shown to reduce hsCRP concentrations include aspirin, statins, cyclooxygenase-2 inhibitors, and fibrates. Recent intervention studies have also demonstrated the distinct efficacy of different anti-diabetes treatments on a variety of cardiovascular risk markers. Intensive insulin therapy may reduce inflammation, but this effect may be influenced by the degree of weight gain. Treatment with peroxisome proliferator-activated receptor ? has lead to substantial reduction of hsCRP and other cardiovascular risk markers in several comparator studies. Since this effect was shown to be independent of the degree of glycemic improvement, it can be regarded as a classspecific effect. Whether these findings translate into a reduction of overall cardiovascular mortality will soon be shown by the currently running thiazolidinedione outcome studies. Positive results in these trials will further strengthen the value and acceptance of hsCRP, which is recommended as a predictive laboratory marker for cardiovascular disease risk also in patients with diabetes mellitus.
BACKGROUND: The cross-sectional IRIS-II study tried to assess the prevalence of insulin resistance and macrovascular disease in orally treated patients with Type 2 diabetes. METHODS: In total, 4,270 patients were enrolled into the study (2,146 male, 2,124 female; mean +/- SD age 63.9 +/- 11.1 years; body mass index 30.1 +/- 5.5 kg/m2; duration of disease 5.4 +/- 5.6 years; hemoglobin A1c 6.8 +/- 1.3%). The study consisted of a single morning visit with completion of a standardized questionnaire and collection of a fasting blood sample. RESULTS: The mean intact proinsulin value was 11.4 +/- 12.4 pmol/L (normal range < 10 pmol/L). Homeostasis model assessment resulted in 1,147 insulin-sensitive patients (26.9%) and 3,123 patients (73.1%) with insulin resistance. Of the latter patients 1,465 (34.3% of all patients) had also elevated intact proinsulin values, while 1,658 (38.8%) had no proinsulin elevation. In contrast, 1,042 (24.4%) of the insulin-sensitive patients had normal intact proinsulin, and only 105 (2.4%) had elevated intact proinsulin concentrations (chi2 test P < 0.0001). A specificity of 93.2% (sensitivity 46.9%) was calculated for elevated intact proinsulin as an indirect marker for insulin resistance. Of the 1,451 patients treated with sulfonylurea 52% had elevated intact proinsulin values and increased prevalence of cardiovascular complications (odds ratio 1.45). CONCLUSION: Type 2 patients with elevated fasting intact proinsulin values can be regarded as being insulin resistant. The results confirm that fasting intact proinsulin is a suitable measure for beta-cell dysfunction and insulin resistance in type 2 diabetes and may be used to support therapeutic decisions.
Pioglitazone is an antidiabetic drug known to decrease peripheral, hepatic and vascular insulin resistance by the stimulation of PPARγ. In clinical trials, pioglitazone as monotherapy or in combination with other oral antidiabetic drugs or insulin has demonstrated to effectively improve blood glucose levels, long-term glucose control and the lipid profile. The vascular effects of pioglitazone include improvement of endothelial function and microcirculation, reduction of blood pressure and inflammatory surrogate markers of atherosclerosis, and a reduction of a composite measure of macrovascular events (death, stroke and myocardial infarctions). The drug is well tolerated and has an acceptable side effect profile. Because of its additional microvascular and macrovascular effects, pioglitazone is an attractive and effective treatment option for the management of Type 2 diabetes mellitus.
Fixed-dose combination of pioglitazone and glimepiride in the treatment of Type 2 diabetes mellitus
(2007)
Type 2 diabetes is characterized by impaired insulin sensitivity and disturbances in β-cell function. While glimepiride stimulates β-cell secretion and leads to a reduction of blood glucose levels, pioglitazone activates peroxisome proliferator-activated receptor-γ and improves insulin resistance. Combining these two modes of action has been shown to improve glucose and lipid metabolism, and to improve the overall cardiovascular risk in patients with Type 2 diabetes. The combination of glimepiride and pioglitazone is generally well tolerated and a fixed combination may lead to an improved compliance in patients. The purpose of this review is to evaluate the clinical data that has been published on this combination, appearing to represent a convenient way to obtain therapeutic targets in patients with Type 2 diabetes mellitus.
