The IRIS III study: pioglitazone improves metabolic control and blood pressure in patients with type 2 diabetes without increasing body weight.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
A Pfützner
Publications and source records attributed to A Pfützner.
Comment on: Haider DG, Schaller G, Kapiotis S, Maier C, Luger A, Wolzt M (2006) the release of the adipocytokine visfatin is regulated by glucose and insulin. Diabetologia 49:1909-1914.
Explore the source record for details and available documents.
Adipocytes↗
[Current laboratory parameters in the differential diagnosis of type 2 diabetes mellitus. Proinsulin, adiponectin and others].
During the recent years increasing knowledge has been obtained in the understanding of the coincidence of type 2 diabetes and cardiovascular disease. Insulin resistance and beta cell failure were shown to have a direct impact in the pathogenesis of arteriosclerosis which goes far beyond the effects of elevated glucose levels. The use of additional laboratory parameters for the characterisation of patients with type 2 diabetes on a pathophysiological basis might improve treatment strategies and might help to reduce the cardiovascular risk in patients with type 2 diabetes. Intact proinsulin is secreted from the beta cell and increasing levels of intact proinsulin serve as an indicator of beta cell failure. In addition, increased levels of intact proinsulin were shown to predict insulin resistance with a specificity of 100 % and a sensitivity of about 50 %. On the other side, adiponectin, derived from the visceral adipose tissue, serves as a marker closely correlated to insulin sensitivity. Plasma adiponectin is a very sensitive marker of insulin resistance and might be used for the judgement of therapeutical interventions aimed to improve insulin sensitivity. In addition, both markers are predictive for the estimation of cardiovascular risk in patients with type 2 diabetes. Measurement of inflammation, by high sensitive CRP might add further information about the cardiovascular risk of a patient with type 2 diabetes.
Adiponectin↗
Impact of environmental temperature on skin thickness and microvascular blood flow in subjects with and without diabetes.
BACKGROUND: Glucose measurement from different skin areas might be influenced by changes in skin texture due to several environmental confounders. Our study was performed to investigate the effect of changes in ambient temperature on skin thickness and microvascular skin blood flow in subjects with and without diabetes at the lower forearm. METHODS: Thirteen subjects with diabetes and seven without diabetes participated in the study. The investigations were performed in a temperature- and humidity-controlled climatic chamber (EMPA, St. Gallen, Switzerland). Starting at 25 degrees C, the environmental temperature was changed in 4 degrees C steps every 40 min. Skin thickness was measured by an ultrasonic reflection technique, and microcirculation was measured by laser Doppler fluxmetry at the lower forearm. Study participants underwent the entire procedure on up to four separate study trials. RESULTS: Our study revealed a significantly reduced skin thickness (P<0.05) and microvascular blood flow (P<0.05) in patients with diabetes mellitus compared with controls without diabetes during the entire investigation. During declining ambient temperature a significant reduction in skin thickness (with diabetes, -0.09+/-0.13 mm; without diabetes, -0.06+/-0.11 mm; P<0.05) and microvascular blood flow (with diabetes, -41+/-49 arbitrary units; without diabetes, -46+/-51 arbitrary units; P<0.05) could be observed in both groups without significant differences between the two. CONCLUSIONS: Although skin thickness and microvascular skin blood flow at the lower forearm were found to be reduced in patients with diabetes compared with controls without diabetes, both groups revealed comparable dynamics in skin thickness and microvascular blood flow during changes in environmental temperature.
Adult↗
Performance of the continuous glucose monitoring system (CGMS) during development of ketosis in patients on insulin pump therapy.
AIMS: Ketoacidosis is one of the most severe complications of Type 1 diabetes. Development of ketosis leads to substantial shifts in electrolyte and ion concentrations in the different fluid compartments of the body. This study was performed to investigate the performance of the continuous glucose monitoring device (CGMS) during ketoacidosis. METHODS: Twelve patients with Type 1 diabetes using continuous subcutaneous insulin infusion (CSII) participated in this trial [10 women, two men; age (mean +/- sd) 34 +/- 9 years; disease duration 17 +/- 10 years; HbA(1c) 7.1 +/- 1.0%]. In the morning, patients ate breakfast and the insulin pump was stopped at 11.00 h and restarted after 8 h. Observation parameters during this experiment were: blood glucose (laboratory reference and CGMS), 3-hydroxy-butyrate (3-OHB), pH, Na, pCO(2), pO(2), free fatty acids, osmolarity, standard bicarbonate, and lactate. RESULTS: Blood glucose increased and reached a plateau within 2 h after pump stop (from 6.2 +/- 2.56 to 16.7 +/- 4.44 mmol/l, P < 0.001). A constant increase in 3-OHB (from 0.0 to 0.8 +/- 0.5 mmol/l, P < 0.001) and decrease in pH (from 7.43 +/- 0.02 to 7.40 +/- 0.03, P < 0.05) indicated ketosis development. Na decreased from 141 +/- 1.4 to 138 +/- 2.8 mmol/l, P < 0.001). Free fatty acids increased from 0.577 +/- 0.330 to 1.330 +/- 0.462 mmol/l (P < 0.001). The CGMS values showed excellent agreement with the capillary blood laboratory method during the entire experiment, and a modified error grid analysis revealed that 99.5% of the values were in the clinically acceptable zones A and B. CONCLUSION: The CGMS device was confirmed to be reliable and accurate during the development of hyperglycaemia and ketotic conditions.
Adult↗
Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month, open-label, observational, primary care study.
BACKGROUND: Insulin resistance and declining beta-cell function are the core defects in type 2 diabetes mellitus. It has been suggested that deteriorating glycemic control is related to baseline hemoglobin A(1c) (HbA(1c)) values and remaining beta-cell function. PATIENTS AND METHODS: We report glycemic data from a 3.5-year, open-label, observational, primary care study comparing 30 mg/day pioglitazone with 3.5 mg/day glibenclamide add-on to stable metformin monotherapy in 500 patients with type 2 diabetes. Insulin commencement was considered for patients with HbA(1c) > or = 8.0% or when vascular complications occurred. The change in HbA(1c) compared with baseline and the difference in time to failure to maintain glycemic control were calculated. RESULTS: At endpoint, HbA(1c) had decreased by 1.0% in the pioglitazone group (p < 0.005) and by 0.6% in the glibenclamide group (p < 0.05). Annual progression rates to insulin treatment were 6.6% (pioglitazone) and 16.4% (glibenclamide; p < 0.001 between-group difference). Mean weight increases of 3.5 +/- 0.42 kg in the pioglitazone group and 3.3 +/- 0.38 kg in the glibenclamide group were noted. Overall, both treatments were well tolerated. CONCLUSIONS: Pioglitazone add-on to metformin revealed significant benefits in long-term glycemic control compared with glibenclamide. This difference may be explained by a large between-group difference in HOMA-S, which was shown to correlate significantly to the change in HbA(1c). This suggests that a strategy to reduce insulin resistance to lower the burden of the beta-cell is superior to treatment with glibenclamide.
Aged↗
A fast and reliable single-run method for genotyping of the human cytochrome P450 2C8 gene for different ethnic groups.
Patients vary widely in their response to drug therapy according to their genetic background of drug metabolizing enzymes. The cytochrome P450 enzyme CYP2C8 is one of the major metabolizing enzymes involved in drug metabolism and thus a candidate for routine pharmacogenetic screening. The aim of this work was establishing a fast and reliable method to detect the three CYP2C8 genotypes CYP2C8*2, CYP2C8*3, CYP2C8*4, and the wildtype allele. An established real-time polymerase chain reaction (PCR) to detect two CYP2C8 genotypes was extended by introduction of a third hybridization probe. After optimization of running conditions, the new triplex method was evaluated using 200 DNAs of African origin as templates. Standard methods were performed as controls. The new triplex real-time PCR was fast, reliable and reproducible. The obtained results showed no deviation from the results of the established technique. The polymorphism of the CYP2C8 gene among an African population showed the expected distribution (68% wildtype gene, 32% at least one CYP2C8*2 allele). Pharmacogenetics gain increasing interest in routine medical care to prevent severe adverse effects or the application of ineffective drugs. We here provide a fast, reliable and reproducible method in one single assay run to detect three relevant CYP2C8 alleles independent of the patient's ethnic origin.
Aryl Hydrocarbon Hydroxylases↗
Transiliac bone biopsy in osteoporosis: frequency, indications, consequences and complications. An evaluation of 99 consecutive cases over a period of 14 years.
Bone biopsy is a diagnostic procedure restricted to untypical, unclear and complicated cases in evidence-based guidelines on diagnosis and treatment of osteoporosis. Its relevance has been a topic of recent controversial discussion. This study was performed to evaluate its role and relevance in routine use. A total of 99 horizontal transiliac bone biopsies performed over a time period of 14 years because of an osteological indication in one single centre were analysed, which reflects that bone biopsy followed about 0.003% of patients' consultations. Bone biopsies were indicated for osteoporotic males (n = 63) and premenopausal osteoporotic females (n = 18) without endocrine abnormality and normal immunofixation (serum and urine), suspected systemic/malignant disease such as mastocytosis, osteogenesis imperfecta, non-secreting plasmocytoma, metastatic infiltration (n = 16) and decreasing bone mineral density under anti-osteoporotic treatment (n = 2). The most frequent diagnoses besides osteoporosis were normal histology, borderline finding towards mild osteoporosis, and osteoporomalacia with relevant osteoidosis. In some cases, pathological findings in bone marrow were detected. In most cases (82/99), bone biopsy led to consequences in medical treatment. Following histopathological diagnosis, 16 patients did not receive any anti-osteoporotic treatment. In six patients, further diagnostic procedures were initiated because of bone histology. Bone biopsy was well tolerated and complications were rare and mild. In conclusion, despite all progress in non-invasive diagnostic procedures for metabolic bone diseases such as osteoporosis, there remains a small but significant subset of patients who may benefit from inclusion of bone biopsy into the diagnostic procedure.
Adult↗
Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study.
BACKGROUND: Patients with type 2 diabetes mellitus are at high risk of cardiovascular disease. Carotid intima-media thickness (IMT) is a strong predictor of myocardial infarction and stroke. METHODS AND RESULTS: We compared the effects of pioglitazone-based therapy (45 mg/d) and glimepiride-based treatment (2.7+/-1.6 mg/d) for 12 and 24 weeks on metabolic control (HbA1c), insulin resistance (homeostasis model assessment), and carotid IMT (B-mode ultrasonography) in a randomized controlled study in 173 orally treated patients with type 2 diabetes (66 women, 107 men; mean+/-SD age, 62.6+/-7.9 years; body mass index, 31.8+/-4.6 kg/m2; HbA1c, 7.5+/-0.9%). Treatment was generally well tolerated in both groups. Despite similar improvements in metabolic control (HbA1c) after 24 weeks (-0.8+/-0.9% [pioglitazone] versus -0.6+/-0.8% [glimepiride]; P=NS), carotid IMT was reduced only in the pioglitazone group after 12 weeks (-0.033+/-0.052 versus -0.002+/-0.047 mm [glimepiride]; P<0.01 between groups) and 24 weeks (-0.054+/-0.059 versus -0.011+/-0.058 mm [glimepiride]; P<0.005 between groups). Insulin resistance was also improved only in the pioglitazone group (homeostasis model assessment, -2.2+/-3.4 versus -0.3+/-3.3; P<0.0001 between groups). Reduction of IMT correlated with improvement in insulin resistance (r=0.29, P<0.0005) and was independent of improvement in glycemic control (r=0.03, P=0.68). CONCLUSIONS: We found a substantial regression of carotid IMT, independent of improved glycemic control, after 12 and 24 weeks of pioglitazone treatment. This finding may have important prognostic implications for patients with type 2 diabetes mellitus.
Aged↗
[Pitfalls in the diagnosis and treatment optimization of type 2 diabetes].
The diagnosis of diabetes mellitus would appear a simple matter. However, potential pitfalls in clinical practice need to be avoided, and this requires knowledge and attention. An initially pathological oral glucose tolerance test should be repeated before establishing a final diagnosis, since such necessary preconditions as a 10 to 16 hours fast, or alcohol abstinence, are difficult to monitor in the clinical setting. Accurate glucose testing requires appropriate sample preparation and handling. Further pitfalls may be encountered during treatment: HbA1c assessment is associated with certain limitations and does not permit the estimation of glucose variations. To establish a differential diagnoses between type 1 (LADA) and type 2 diabetes in older patients GAD must be measured. New biochemical markers such as adiponectin and intact proinsulin may facilitate treatment decisions and monitoring in patients with type 2 diabetes.
Adiponectin↗
Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control.
New scores and biochemical markers have recently been published for diagnosis of insulin resistance and beta-cell dysfunction (such as intact proinsulin, adiponectin, IRISII-score). One goal of this 6-month prospective controlled study was to evaluate the impact of pioglitazone (45 mg) vs. glimepiride (1-6 mg, in the intend to optimize therapy) on these markers. Observation parameters were: IRIS-II score, HOMA-score, ATP III score, HbA (1c), fasting glucose, lipids, intact proinsulin, adiponectin, and adverse events. The study was completed by 173 patients (66 female, 107 male, age +/- STD: 63 +/- 8 years, disease duration: 7.2 +/- 7.2 years, HbA (1c): 7.53 +/- 0.85 %, pioglitazone arm: 89 patients). The groups were not different for any of the observation parameters at baseline, and a similar reduction in HbA (1c) was seen in both groups (p < 0.001). In the pioglitazone group, reductions were observed for the IRIS-II and HOMA scores (p < 0.001 vs. glimepiride at endpoint) fasting glucose (p < 0.001), insulin (p < 0.001), LDL/HDL ratio (p < 0.001), hsCRP (p < 0.05), intact proinsulin (p < 0.001), and an increase was seen in HDL (p < 0.001), adiponectin (p < 0.001) and BMI (p < 0.001). In conclusion, treatment with pioglitazone resulted in an improvement of markers for insulin resistance and beta-cell dysfunction, independent from blood glucose control. Adiponectin, intact proinsulin, and the IRIS-II score may be suitable parameters for monitoring of these additional beneficial therapeutic effects.
Biomarkers↗
Pharmacological PPARgamma stimulation in contrast to beta cell stimulation results in an improvement in adiponectin and proinsulin intact levels and reduces intima media thickness in patients with type 2 diabetes.
The role of intact proinsulin and adiponectin in endothelial dysfunction and insulin resistance has been receiving increasing attention. This study investigates the effect of PPARgamma stimulation or beta-cell stimulation on metabolic and vascular parameters in patients with type 2 diabetes. In our study, 173 type 2 diabetic patients were recruited and randomly assigned to pioglitazone 45 mg or glimepiride 1 - 6 mg treatment. Intima media thickness of the carotid artery, glycemic control, insulin resistance, adiponectin and intact proinsulin levels were assessed at baseline and after six months of treatment. Despite similar improvements in metabolic control (HbA (1c) after 24 weeks: - 0.8 +/- 0.9% [pioglitazone] vs. - 0.6 +/- 0.8% [glimepiride]; mean +/- SD; p < 0.0001, respectively), improvements in intima media thickness (- 0.033 +/- 0.052 mm; p < 0.0001), proinsulin intact (- 5.92 +/- 10.04 pmol/l; p < 0.0001), adiponectin (10.9 +/- 6.3 microg/ml; p < 0.0001) and HOMA score (- 2.21 +/- 3.40; p < 0.0001) were observed by pioglitazone but not glimepiride treatment. Reduction in intima media thickness was correlated with improved insulin sensitivity (r = 0.29; p = 0.0003), and proinsulin intact levels (r = 0.22; p = 0.006), while an inverse correlation was found with adiponectin levels (r = - 0.37; p < 0.0001). Measurement of adiponectin and intact proinsulin enables characterization of the metabolic situation and an estimation of atherosclerotic risk in patients with type 2 diabetes.
Aged↗
Clinical and laboratory evaluation of a new specific ELISA for intact proinsulin.
Intact proinsulin is a marker for pancreatic beta-islet cell secretion status, and elevated levels indicate insulin resistance of type 2 diabetic patients with a high diagnostic specificity. Determination of intact proinsulin in fasting morning plasma samples can be used to establish and/or identify the optimal anti-diabetic treatment as well as to monitor a potential protective treatment effect on beta-islet cell dysfunction. For widespread use as a routine marker, simple and reliable assays must become available for measurement in clinical laboratories. This study was performed to evaluate a new ELISA method specific for intact proinsulin determination compared with a commercial chemiluminescence test. Intra-assay imprecision was determined to be 2.4 - 5.5% (inter-assay: 3.2 - 4.3%). A sample cohort derived from non-diabetic healthy subjects (66 female, 29 male, age (median, range): 37 (19-77) years) was used to calculate a reference range for non-diabetic individuals of 1.8 - 11.0 pmol/l. The comparison of samples obtained from 7 diabetic patients (2 female, 5 male, age: 66 (44-72) years) from oral glucose tolerance tests resulted in an excellent correlation between the ELISA and the chemiluminescence assay (r = 0.989; p<0.001). A sample stability investigation with different sample specimens revealed that intact proinsulin is stable for two days at room temperature in EDTA whole blood and heparin whole blood tubes without centrifugation, while serum samples should be centrifuged immediately and frozen to retain intact proinsulin concentrations. As EDTA whole blood is the routine sample specimen for determination of HbA1c, a marker frequently measured in diabetic patients, this finding underlines the practicability of analyzing intact proinsulin from the same blood specimen. In conclusion our study revealed that the new ELISA shows excellent agreement with the commonly used chemiluminescence immunoassay. The ELISA can easily be introduced into routine laboratories and does not require any further specific instrumentation. Our additional finding that intact proinsulin is stable in EDTA whole blood samples, which can be obtained from the routine.sample for HbA1c measurement, is increasing the probability of the acceptance of this marker for routine assessment of beta-cell dysfunction and insulin resistance in type 2 diabetes.
Adult↗
[Practical diagnosis in insulin resistance and beta-cell dysfunction and resulting therapeutic consequences].
Explore the source record for details and available documents.
Blood Glucose↗
[The diagnosis of an autonomic dysfunction of the lower limb as a major aspect of the neurological investigation and risk assessment of a diabetic foot syndrome].
Sensomotoric diabetic polyneuropathy is often associated with damage to autonomic nerve fibers. In the case of the lower extremity, this manifests in the form of a sudomotoric and/or vasomotoric disorder. This in turn is believed to be closely related to the development of neurotrophic ulcerations of the foot. The sudomotoric disorder leads to anhidrosis of the skin of the foot, leading to the formation of rhagades and fissures. Neurovascular problems with disordering of microvascular perfusion and trophic disturbances then become risk factors for foot ulcers, in particular when skin traumata occur in addition. Various methods for identifying an autonomic function disturbance in the lower limb are based either on the measurement of sweat secretion or on the investigation of peripheral microvascular function. A purposeful assessment of risk and prevention of neurotrophic damage in the lower limb is possible only on the basis of a rigorous differential diagnostic work-up of the diabetic polyneuropathy.
Autonomic Nervous System Diseases↗
IRIS II study: the IRIS II score--assessment of a new clinical algorithm for the classification of insulin resistance in patients with Type 2 diabetes.
AIMS: With the increasing availability of new drugs for the treatment of insulin resistance in patients with Type 2 diabetes, simple methods for their identification is an important challenge. The aim of our study was to compute a new algorithm for estimating insulin resistance in a routine clinical setting. METHODS: Clinical data and blood samples were collected from 4265 Type 2 diabetic patients from 149 clinical sites. A clinical algorithm to estimate insulin resistance was developed by stepwise multiple regression analysis. The new generated score was compared with the HOMAIR-score, calculated from fasting insulin and glucose levels measured in a central laboratory. In a subgroup of 48 patients, the score was verified against a frequently sampled intravenous glucose tolerance test with subsequent modified minimal model analysis according to Bergman. RESULTS: Multiple regression analysis revealed fasting blood glucose, BMI, triglycerides and HDL as the most powerful predictors of insulin resistance which were used for further computation of the IRIS II score. A significant overall correlation was found between the HOMAIR-score and the new clinical IRIS II score (r = 0.42; P < 0.0001). Compared with HOMAIR, the new score revealed a specificity of 0.95, a sensitivity of 0.34 and a positive predictive value of 0.95. This was in good agreement with the subset analysis of the intravenous glucose tolerance test, where a sensitivity of 0.37 and a specificity of 0.85 of the IRIS II score was calculated. Patients with insulin resistance according to the IRIS II score revealed an increased odds ratio for overall vascular complications (1.28; 1.11-1.46; P < 0.001). CONCLUSIONS: The new IRIS II score can identify insulin resistance in Type 2 diabetic patients with high predictive value and high specificity.
Algorithms↗
Development and evaluation of a rapid and reliable method for cytochrome P450 2C8 genotyping.
The analysis of gene polymorphisms has started to become an interesting field of new services to be provided by clinical laboratories for both, clinical research and routine determinations. To expand the use of these methods and to increase the benefit for patients and the society, cheap and reliable methods for genotyping also allowing for high-turnover analysis need to be established in clinical laboratories. The presented investigation was performed to develop and evaluate a fast real-time PCR method for the detection of three different allele mutations of Cytochrome P450 isoenzyme 2C8 (CYP2C8*2, *3, and *4), which have been demonstrated to influence drug metabolism (and thus the efficacy) of a variety of drugs. The DNA of 122 Caucasian subjects (56 male, 66 female, age (mean +/- STD): 50 +/- 16 years) was analyzed for these mutations by means of classical RFLP-PCR and a new protocol developed for the LightCycler real-time PCR method. The polymorphisms within the CYP2C8 gene were detected by use of two primer pairs and three different pairs of hybridization probes. The results of both methods were perfectly concordant and comparable to results published in the literature (allele frequencies: CYP2C8*2: 0.016, *3: 0.140, *4: 0.074). A subsequent analysis of the related costs revealed comparable resource requirements but substantially longer time needs for RFLP-PCR, resulting in higher overall analysis costs for the older method. In conclusion, the elaborated protocol for real-time PCR analysis of gene mutations CYP2C8*2, *3, and *4 is reliable and cost effective, and thus, suitable for routine laboratory use.
Aryl Hydrocarbon Hydroxylases↗
Impact of low frequency transcutaneous electrical nerve stimulation on symptomatic diabetic neuropathy using the new Salutaris device.
In a double blind, randomised study, 19 patients suffering from mild-to-moderate symptomatic diabetic neuropathy (Total Symptom Score, NTSS 4-16) received either treatment with the new transcutaneous electrical nerve stimulation (TENS) device "Salutaris" (verum group) or a placebo treatment with an identical but electrically inactive device (placebo group). Stimulation pads were placed at the anatomical localisation of the peroneal nerve and stimulation was performed using a low frequency mode. At baseline (V1), after 6 (V2), and 12 (V3) wk of treatment, the patients' symptoms were registered using the new total symptom score (NTSS-6) and a visual analogue scale (VAS). In addition, sensory nerve thresholds (temperature, vibration, pain) and microvascular function were measured at the lower limb at baseline and after 12 wk of treatment. Active TENS-treatment resulted in a significant improvement in NTSS-6 score after 6 wk (-42%) and after 12 wk (-32%) of treatment (baseline: 10.0+/-3.3, 6 wk: 5.8+/-5.0, p<0.05; 12 wk: 6.8+/-3.9, p=0.05; placebo group: baseline: 7.6+/-3.1; 6 wk: 8.1+/-5.1, n.s.; 12 wk: 6.5+/-6.1, n.s.). Subanalysis of the different qualities of the NTSS-score revealed an improvement in numbness (2.2+/-1.0 to 1.6+/-1.3; p<0.03); lancinating pain (1.6+/-1.1 to 0.6+/-0.9; p<0.02) and allodynia (1.4+/-1.6 to 0.5+/-1.0; p<0.05). Also, a significant improvement in the VAS rating was found after 6 wk of TENS therapy (19.8+/-5.0 to 14.4+/-9.6; p<0.05), while no change was observed in the placebo arm. In conclusion, our study indicates that the new TENS device "Salutaris" is a convenient, non-pharmacological option for primary or adjuvant treatment of painful diabetic neuropathy.
Aged↗