Open Access

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.

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.

BACKGROUND In recent randomized clinical trials, an unusual reporting pattern of glycemic data and hypoglycemic events potentially related to an internet enabled blood glucose meter (MyGlucoHealth, BGM) was observed. Therefore, this clinical study was conducted to evaluate the system accuracy of the BGM in accordance with the ISO15197:2015 guidelines with additional data collection. METHODS To investigate system accuracy, 10 of 3088 devices and 6 of 23 strip lots, used in the trials, were selected by a randomization procedure and a standard repeatability assessment. YSI 2300 STAT Plus was used as the standard reference method. The samples were distributed as per the ISO15197:2015 recommendations with 20 additional samples in the hypoglycemic range. Each sample was tested with 6 devices and 6 strip lots with double determinations. RESULTS Overall, 121 subjects with blood glucose values 26-423 mg/dL were analyzed, resulting in 1452 data points. In all, 186/1452 readings (12.8%) did not meet the ISO acceptance criteria. Data evaluated according to the FDA guidelines showed that 336/1452 (23.1%) readings did not meet the acceptance criteria. A clear bias toward elevated values was observed for BG <100 mg/dL (MARD: 11.0%). CONCLUSIONS The results show that the BGM, although approved according to standard regulatory guidelines, did not meet the level of analytical accuracy required for clinical treatment decisions according to ISO 15197:2015 and FDA requirements. In general, caution should be exercised before selection of BGMs for patients and in clinical trials.

BACKGROUND In recent clinical trials, use of the MyGlucoHealth blood glucose meter (BGM) and electronic diary was associated with an unusual reporting pattern of glycemic data and hypoglycemic events. Therefore, the performance of representative BGMs used by the patients was investigated to assess repeatability, linearity, and hematocrit interference in accordance with regulatory guidelines. METHOD Ten devices and 6 strip lots were selected using standard randomization and repeatability procedures. Venous heparinized blood was drawn from healthy subjects, immediately aliquoted and adjusted to 5 target blood glucose (BG) ranges for the repeatability and 11 BG concentrations for the linearity tests. For the hematocrit interference test, each sample within 5 target BG ranges was split into 5 aliquots and adjusted to hematocrit levels across the acceptance range. YSI 2300 STAT Plus was used as the laboratory reference method in all experiments. RESULTS Measurement repeatability or precision was acceptable across the target BG ranges for all devices and strip lots with coefficient of variation (CV) between 3.4-9.7% (mean: 5.7%). Linearity was shown by a correlation coefficient of .991; however, a positive bias was seen for BG <100 mg/dL (86% measurements did not meet ISO15197:2015 acceptance criteria). Significant hematocrit interference (up to 20%) was observed for BG >100 mg/dL (ISO15197:2015 acceptance criteria: ±10%), while the results were acceptable for BG <100 mg/dL. CONCLUSIONS The BGM met repeatability requirements but demonstrated a significant measurement bias in the low BG range. In addition, it failed the ISO15197:2015 criteria for hematocrit interference.

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 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.

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 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.