Differential type 2 diabetes therapy based on pathophysiological aspects

Type 2 Diabetes is characterized by a deficit in early insulin secretion and increased insulin resistance. Based on the measurement of fasting and 2 h postprandial blood glucose a simple typing of hyperglycemia is possible in isolated fasting hyperglycemia (IFH), isolated postprandial hyperglycemia (IPH) and combined hyperglycemia (CH). IFH is predominantly associated with insulin resistance whereas in IPH a more pronounced insulin deficit is found. This and other simple parameters such as BMI, comorbidities and age are the basis of differential therapy with OAD if best efforts with life style modification fail to reach the target values of the lipid triad. Patients with IFH profit particularly from metformin and long acting sulfonylureas (glimepiride, glibenclamide). Patients with IPH are candidates for prandial antidiabetics (AGI, nateglinide, repaglinide). Antihyperglycemic agents such as metformin and AGI bear no risk of hyperglycemia and reduce body weight. Prandial insulin secretagogues have lower risk of weight gain and hypoglycemia than long acting sulfonylureas. They are therefore beneficial in obese patients and the elderly. The same principles are valid for combination treatment. With exception of insulin secretagogues all OAD can be combined if monotherapy fails to reach the target levels of the gluco-triad. Instead of a stepwise treatment algorithm an individualized therapy based on pathophysiology and comorbidities taking into account the global risk seems to be beneficial.     

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol

Aims/hypothesis Studies suggest that in addition to blood glucose concentrations, thiazolidinediones such as rosiglitazone improve some cardiovascular (CV) risk factors and surrogate markers, that are abnormal in type 2 diabetes. However, fluid retention might lead to cardiac failure in a minority of people. The aim of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study is to evaluate the long-term impact of these effects on CV outcomes, as well as on long-term glycaemic control, in people with type 2 diabetes.Materials and methods RECORD is a 6-year, randomised, open-label study in type 2 diabetic patients with inadequate blood glucose control (HbA₁c 7.1–9.0%) on metformin or sulphonylurea alone. The study is being performed in 327 centres in Europe and Australasia. After a 4-week run-in, participants were randomised by current treatment stratum to add-on rosiglitazone, metformin or sulphonylurea, with dose titration to a target HbA₁c of 7.0%. If confirmed HbA₁c rises to 8.5%, either a third glucose-lowering drug is added (rosiglitazone-treated group) or insulin is started (non-rosiglitazone group). The same criterion for failure of triple oral drug therapy in the rosiglitazone-treated group is used for starting insulin in this group. The primary endpoint is the time to first CV hospitalisation or death, blindly adjudicated by a central endpoints committee. The study aim is to evaluate non-inferiority of the rosiglitazone group vs the non-rosiglitazone group with respect to CV outcomes. Safety, tolerability and study conduct are monitored by an independent board. All CV endpoint and safety data are held and analysed by a clinical trials organisation, and are not available to the study investigators while data collection is open.Results Over a 2-year period a total of 7,428 people were screened in 25 countries. Of these, 4,458 were randomised; 2,228 on background metformin, 2,230 on background sulphonylurea. Approximately half of the participants are male (52%) and almost all are Caucasian (99%).Conclusions/interpretation The RECORD study should provide robust data on the extent to which rosiglitazone, in combination with metformin or sulphonylurea therapy, affects CV outcomes and progression of diabetes in the long term.     

Geschichte und Definition(en) des metabolischen Syndroms

Metabolic syndrome--a cluster of metabolic diseases and hypertension--is not a new disease. It has been present in the upper classes of all highly developed cultures suffering from over-nutrition and limited physical activity. In the medical literature, it can be found in Renaissance and Baroque times. We are presently experiencing a global tsunami of this syndrome as over-nutrition and lack of movement are typical for large groups of the population. The current definition of metabolic syndrome of the American Heart Association/National Heart, Lung and Blood Institute and the International Diabetes Federation incorporates the quartet central obesity, hypertension, increased blood sugar and dyslipidemia (hypertriglyceridemia, low HDL cholesterol). Thus, simple, collective diagnostics and therapy for this finely meshed group of diseases together with its risk factors is possible.     

Relationship between diurnal blood pressure variation and diurnal blood glucose levels in type 2 diabetic patients

BACKGROUND: Hypertension and hyperglycemia are established risk factors for progression of microangiopathies and macroangiopathies in type 2 diabetes mellitus. Cardiovascular risk is even more increased in diabetic patients with nocturnal nondipping or postprandial hyperglycemia. We therefore investigated the relationship between diurnal hyperglycemia and diurnal blood pressure (BP) variation in patients. METHODS: One hundred seven hypertensive type 2 diabetic patients received a 24-h ambulatory BP recording. In addition, a diurnal blood glucose profile was assessed under standardized conditions on the same day: before breakfast, 2 h after breakfast, before lunch, 2 h after lunch, before dinner, 2 h after dinner, at 10:00 pm, at midnight, and 3:00 am of the following day. Degrees of fasting and postprandial hyperglycemia were calculated as area under the curve. RESULTS: Nocturnal nondipping occurred in 73% of our patients. Nondippers showed higher postprandial blood glucose excursions than dippers (59.5 +/- 29 v 40.7 +/- 33 mmol h/L), whereas fasting hyperglycemia or glycosylated hemoglobin (HbA(1c)) were not significantly different (56.6 +/- 49 v 54.1 +/- 44 mmol h/L and 8.8% +/- 1.9% v 8.2% +/- 1.8% for nondippers and dippers, respectively). Nocturnal nondipping was associated with a higher urinary protein excretion and lower day/night heart rate ratio. Multivariate analysis revealed postprandial hyperglycemia as an independent predictor for nondipping. CONCLUSIONS: Postprandial rather than fasting hyperglycemia was associated with abnormal diurnal BP variation. These observations might favor treatment regimes targeted on postprandial hyperglycemia, which could restore dipping pattern.     

Common infectious agents in multiple sclerosis: a case-control study in children

Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein-Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS.     

Acarbose: oral anti-diabetes drug with additional cardiovascular benefits

Acarbose is an alpha-glucosidase inhibitor acting specifically at the level of postprandial glucose excursion. This compound lowers HbA(1c) by 0.5-1% in patients with Type 2 diabetes, either drug naive or in combination with other antidiabetic drugs. In those with impaired glucose tolerance (IGT), it reduces the incidence of newly diagnosed diabetes by 36.4%. Furthermore, it has beneficial effects on overweight, reduces blood pressure and triglycerides, and downregulates biomarkers of low-grade inflammation. In the Study To Prevent Non-Insulin-Dependent-Diabetes-Mellitus (STOP-NIDDM) trial, acarbose significantly reduced the progression of intima media thickness, incidence of cardiovascular events and of newly diagnosed hypertension. In a meta-analysis of patients with Type 2 diabetes (MERIA), acarbose intake was associated with a reduction of cardiovascular events by 35%. Acarbose is a very safe drug but in approximately 30% of patients, it can cause gastrointestinal complaints due to its mode of action, which in the majority disappear after 1-2 months. Acarbose is approved for treatment of IGT in 25 countries. It can be given alone or in combination with other oral antidiabetics and insulin. Acarbose is particularly effective in those with IGT and early diabetes and patients with comorbidities of the metabolic syndrome.     

How to evaluate PCR assays for the detection of low‐level DNA

High sensitivity of PCR‐based detection of very low copy number DNA targets is crucial. Much focus has been on design of PCR primers and optimization of the amplification conditions. Very important are also the criteria used for determining the outcome of a PCR assay, e.g. how many replicates are needed and how many of these should be positive or what amount of template should be used? We developed a mathematical model to obtain a simple tool for quick PCR assay evaluation before laboratory optimization and validation procedures . The model was based on the Poisson distribution and the Binomial distribution describing parameters for singleplex real‐time PCR‐based detection of low‐level DNA. The model was tested against experimental data of diluted cell‐free foetal DNA. Also, the model was compared with a simplified formula to enable easy predictions. The model predicted outcomes that were not significantly different from experimental data generated by testing of cell‐free foetal DNA. Also, the simplified formula was applicable for fast and accurate assay evaluation. In conclusion, the model can be applied for evaluation of sensitivity of real‐time PCR‐based detection of low‐level DNA, and may also assist in design of new assays before standard laboratory optimization and validation is initiated.     

Instrumented measurements of laxity in patients who have a Gore-Tex anterior cruciate-ligament substitute

Twenty patients who had substitution of the anterior cruciate ligament with a Gore-Tex synthetic ligament were evaluated preoperatively and postoperatively with the University of California at Los Angeles instrumented clinical-testing apparatus, which records anterior-posterior force versus displacement-response curves of the tibia with respect to the femur at 20 degrees of flexion of the knee. The mean age of the patients was thirty-three years (range, nineteen to fifty-four years). The duration of follow-up ranged from twenty-four to forty-four months (mean, thirty-one months). The mean preoperative difference in anterior laxity between the injured knee and the normal knee (4.5 millimeters with neutral rotation of the foot) was unchanged two years after the operation; at that time, all patients had an anterior laxity of the injured knee of more than eight millimeters, and 90 per cent had a difference in anterior laxity of more than two millimeters between sides. The mean values for anterior stiffness at fifty and 100 newtons of anterior force were unchanged after the operation, remaining at 40 to 50 per cent of normal levels. At 200 newtons, or 20.4 kilograms (forty-five pounds) of anterior force, the mean stiffness of the involved knee was 11 to 17 per cent greater than that of the normal knee. Clinically, there were improvements in both subjective and objective knee-rating scores. All but four patients had a reduction of at least one grade in the pivot-shift score; in thirteen, the pivot-shift sign was eliminated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study

BACKGROUND: This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes (HbA1c > or = 7.5% to < or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. RESULTS: There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. CONCLUSIONS: Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.