[Possibilities of influencing cardiovascular risk in type 2 diabetes mellitus by antidiabetic treatment Lowering of cardiovascular risk in treatment with liraglutide - Results of the LEADER]. / Moznosti ovlivnení kardiovaskulárního rizika u diabetes mellitus 2. typu antidiabetickou lécbouSnízení kardiovaskulárního rizika pri lécbe liraglutidem - výsledky studie LEADER.

UNLABELLED: The article summarizes current knowledge about the possibilities for influencing the cardiovascular risk in treatment of type 2 diabetes, especially focusing on the results of a prospective morbidity-mortality LEADER trial, which demonstrated the superiority of liraglutide in patients with very high cardiovascular risk. KEY WORDS: cardiovascular risk - LEADER - liraglutid - type 2 diabetes mellitus.

[Diabetic neuropathy]. / Diabetická neuropatie.

The paper deals with one of microvascular complications of diabetes - diabetic polyneuropathy. It is discussed comprehensively from its causes, incidence, its classification and diagnostic possibilities to the risks it entails for patients and therapeutic possibilities.Key words: autonomic neuropathy - diabetes mellitus - diabetic neuropathy - motor neuropathy - sensitive neuropathy - diabetic foot syndrome.

[Treatment of GLP1 receptor agonists and body mass control]. / Lécba agonisty receptoru pro GLP1 a kontrola hmotnosti.

The prevalence of obesity continues to be increasing in all age groups in most countries of the European Union (EU). Many obese people have a history of several successful weight losses, but very few are able to maintain the weight loss over a longer period of time. Initiation of the GLP1 RA administration during weight loss maintenance would inhibit weight loss-induced increases in soluble leptin receptor plasma concentrations resulting in higher level of free leptin thereby preventing weight regain. In contrast initiation of insulin treatment in type 2 diabetes patients is frequently accompanied with weight gain. The GLP1 administration results in HbA1c decrease accompanied with weight loss, presents attractive alternative to basal insulin. The question remains to be answered in the future, if the GLP1 RA administration is generally more frequently started in antiobese than antidiabetes implication.

Genetic variability in enzymes of metabolic pathways conferring protection against non-enzymatic glycation versus diabetes-related morbidity and mortality.

BACKGROUND: We hypothesized that genetic variability in genes encoding enzymes metabolizing glycolytic intermediates produced in excess under hyperglycemic conditions [i.e., transketolase (TKT), transaldolase, TKT-like protein 1, fructosamine 3-kinase (FN3K), glyoxalase 1 and glucose-6-phosphate dehydrogenase] could influence progression of diabetic nephropathy (DN) and diabetes-related morbidity and mortality. METHODS: A total of 19 single nucleotide polymorphisms (SNPs) in six candidate genes were studied in 314 type 2 diabetic subjects with variable stage of kidney disease (normo- and microalbuminuria, proteinuria, end-stage renal disease). SNP selection criteria were based on known functional effect and gene coverage. SNPs were detected using polymerase chain reaction based methods. Subjects were followed up for median of 38 months. Time-to-event analysis considered three end-points: 1) DN progression by at least one stage; 2) major cardiovascular event; and 3) all-cause mortality. RESULTS: We found combined effect of TKT SNP rs11130362 and FN3K SNP rs1056534 on DN progression (p<0.01). Additionally, TKT rs3736156 alone and also in combination with the previous two SNPs exhibited significant effect on incidence of major cardiovascular events (p<0.01 and p=0.01, respectively). CONCLUSIONS: Genetic variability in rate-limiting enzymes of pathways proposed to confer hypothetical protection against hyperglycemia might act as an important determinant of hyperglycemia toxicity in long-standing diabetes.

[Hypoglycemia as a limitation to the treatment of diabetes mellitus]. / Hypoglykemie jako limitace lécby diabetes mellitus.

In his paper, the author deals with hypoglycemia-related problems as the most frequent complication of the therapy for diabetes mellitus (DM). He points to threats that patients with hypoglycemia are exposed to, but also gives attention to risk groups of patients with regard to hypoglycemia development as well as different levels of the risk related to different antidiabetics.Key words: antidiabetics - diabetes mellitus - hypoglycemia.

ADMA, SDMA and L-arginine/ADMA ratio but not DDAH genetic polymorphisms are reliable predictors of diabetic nephropathy progression as identified by competing risk analysis.

BACKGROUND/AIMS: Complex interplay of genetic and (patho)physiological factors influence availability of nitric oxide during the development and progression of diabetic complications. We assessed predictive value of commonly studied methylated asymmetric and symmetric dimethylarginines (ADMA and SDMA) and selected single nucleotide polymorphisms (SNPs) in dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes for the progression of diabetic nephropathy (DN). METHODS: A total of 341 type 1 and type 2 diabetes patients with variable degree of kidney disease were included at baseline. Plasma levels of ADMA, SDMA and L-arginine were measured and six tagging SNPs in DDAH1 and 2 were determined. Progression of DN was defined as a transition from any given stage to a more advanced stage of albuminuria. Competing risk analysis was applied. RESULTS: Plasma levels of ADMA and SDMA significantly correlated with GFR. No significant genotype-phenotype relationship was ascertained for ADMA and DDAH variants, but SNP rs805304 exhibited marginally significant association with DN. ADMA, SDMA and L-arginine/ADMA ratio standardised to GFR were identified as significant predictors of DN progression but not GFR decline using multivariate competing risk analysis. CONCLUSIONS: In our study we confirmed potentially significant role of ADMA and SDMA for the assessment of risk of DN progression in European diabetic population.

Risk factors for depression and anxiety in painful and painless diabetic polyneuropathy: A multicentre observational cross-sectional study.

BACKGROUND: Despite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited. METHODS: This observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State-Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain-free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes-, neuropathy- and pain-related), the socio-economic and the cognitive factors (catastrophizing). RESULTS: The study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p < 0.001). Multiple regression analysis demonstrated the severity of pain and neuropathy, catastrophic thinking, type 2 DM, lower age and female sex as independent contributors to depression and anxiety. CONCLUSIONS: In addition to the severity of neuropathic pain and its cognitive processing, the severity of diabetic polyneuropathy and demographic factors are key independent contributors to emotional distress in diabetic individuals. SIGNIFICANCE: In large cohorts of well-defined painless and painful diabetic polyneuropathy patients and diabetic subjects without polyneuropathy, we found a high prevalence of the symptoms of depression and anxiety, mainly in painful individuals. We have confirmed neuropathic pain, its severity and cognitive processing (pain catastrophizing) as dominant risk factors for depression and anxiety. Furthermore, some demographic factors (lower age, female sex), type 2 diabetes mellitus and severity of diabetic polyneuropathy were newly identified as important contributors to emotional distress independent of pain.

Role of thiamine status and genetic variability in transketolase and other pentose phosphate cycle enzymes in the progression of diabetic nephropathy.

BACKGROUND: Pentose phosphate pathway (PPP) represents a potentially 'protective' mechanism in hyperglycaemia due to shunting of glycolytic intermediates into PPP reactions. We hypothesized that thiamine status (plasma and erythrocyte levels of thiamine and its esters) together with genetic variability in key PPP enzymes-transketolase (TKT), transaldolase and TKT-like-might contribute to the progression of diabetic nephropathy (DN) and mortality of diabetics. METHODS: A total of 240 diabetic subjects with variable degree of kidney disease were included at baseline and were followed up for a median of 26 (IQR 21-50) months. Concentrations of thiamine in plasma and whole blood and TKT-catalysed reaction were determined by HPLC. Single-nucleotide polymorphisms (SNPs) (n = 14) were genotyped by means of PCR using TaqMan chemistry (Applied Biosystems, Foster City, CA, USA). RESULTS: Significant differences in pTh, pThDP, eryThDP and eryTKT between DN-stage groups were ascertained (P < 0.05) with advancing stage of DN being accompanied with increasing values of pTh, pThDP and eryTKT but not eryThDP. A highly significant negative correlation (r = - 0.41, P < 0.001) was found between pThDP and eryThDP, and the tertiles of the ratio of eryThDP/pThDP were significantly associated with all-cause mortality rates (P = 0.0072). We also identified significant differences in the rate of DN progression between different pTDP tertile groups (P = 0.0017). No significant genetic effects were found. CONCLUSIONS: The results support the role of 'functional' thiamine deficiency in the development of hyperglycaemia-related pathology. Limited intracellular availability of active TKT co-factor seems to be a dominant abnormality.

Soluble RAGE, diabetic nephropathy and genetic variability in the AGER gene.

Diabetes mellitus, especially when complicated with decline of renal function due to diabetic nephropathy (DN), is associated with accumulation of advanced glycation end products (AGEs) exerting their adverse effects via receptor of AGE (RAGE). Soluble RAGE (sRAGE) is a truncated form of RAGE functioning as an inhibitor of AGE-mediated signalling. We studied relationships between sRAGE, renal function and genetic variability in the AGER gene in diabetic subjects. Study comprised a total of 265 diabetics (type 1 or 2 or LADA) with normoalbuminuria (n = 94) or DN (n = 171). sRAGE (assessed by ELISA) was significantly higher in DN than normoalbuminuria subjects (P = 0.007) and positively correlated with age, S-urea, S-creatinine and albuminuria and AGEs (determined spectrofluorimetrically), negatively with GFR (all P < 0.05); however, multivariate regression revealed that GFR was the only independent variable associated with sRAGE (P = 0.047). sRAGE did not correspond with carrier state of risk-haplotype copies (RAGE2) (P > 0.05). In conclusion, GFR is a principal determinant of sRAGE concentration and gradual sRAGE increase in subjects with advancing impairment of renal function is paralleled by AGEs.

Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study.

Different sensory profiles in diabetic distal symmetrical sensory-motor polyneuropathy (DSPN) may be associated with pain and the responsiveness to analgesia. We aimed to characterize sensory phenotypes of patients with painful and painless diabetic neuropathy and to assess demographic, clinical, metabolic, and electrophysiological parameters related to the presence of neuropathic pain in a large cohort of well-defined DSPN subjects. This observational cross-sectional multi-center cohort study (performed as part of the ncRNAPain EU consortium) of 232 subjects with nonpainful (n = 74) and painful (n = 158) DSPN associated with diabetes mellitus of type 1 and 2 (median age 63 years, range 21-87 years; 92 women) comprised detailed history taking, laboratory tests, neurological examination, quantitative sensory testing, nerve conduction studies, and neuropathy severity scores. All parameters were analyzed with regard to the presence and severity of neuropathic pain. Neuropathic pain was positively correlated with the severity of neuropathy and thermal hyposensitivity (P < 0.001). A minority of patients with painful DSPN (14.6%) had a sensory profile, indicating thermal hypersensitivity that was associated with less severe neuropathy. Neuropathic pain was further linked to female sex and higher cognitive appraisal of pain as assessed by the pain catastrophizing scale (P < 0.001), while parameters related to diabetes showed no influence on neuropathic pain with the exception of laboratory signs of nephropathy. This study confirms the value of comprehensive DSPN phenotyping and underlines the importance of the severity of neuropathy for the presence of pain. Different sensory phenotypes might be useful for stratification of patients with painful DSPN for analgesic treatment and drug trials.

Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus.

AIMS: The aims of the study were (i) to ascertain prognostic value of serum uric acid (SUA) for diabetic kidney disease (DKD) progression and major adverse cardiovascular event (MACE) in a cohort of T2DM patients, (ii) to ascertain eventual protective effect of allopurinol treatment, (iii) to determine the effect of genetic variability in UA transporters on DKD progression, and (iv) to define optimal cut-off values for SUA in patients with DKD. METHODS: Study comprised 422 subjects with diabetes duration at least 15years followed-up for a median of 43 [IQR 22-77] months. Participants were categorized into stable or progressors according to their change in albuminuria or chronic kidney disease (CKD) stage. At baseline, 68% patients had hyperuricemia (SUA≥420µmol/l for men and ≥360µmol/l for women and/or allopurinol treatment). Five SNPs in the SLC2A9 and ABCG2 genes were determined by PCR. RESULTS: Time-to-event analysis with subgroups defined by the presence/absence of initial hyperuricemia revealed significant differences in all three end-points (P<0.0001 for DKD progression, P=0.0022 for MACE and P=0.0002 for death, log-rank test). Subjects with normal SUA not requiring allopurinol had median time to DKD progression 49months compared with remaining subjects (32months, P=0.0002, log-rank test). Multivariate Cox regression model revealed hyperuricemia (i.e. high SUA and/or allopurinol treatment) significant predictor of DKD progression independent of baseline CKD stage. Optimal cut-off values identified by ROC analysis for T2DM subjects were ≤377.5µmol/l for men and ≤309.0µmol/l for women. We found no differences in allele or genotype frequencies in selected SNPs between patients with and without hyperuricemia (all P>0.05). CONCLUSIONS: Our study demonstrated that initial hyperuricemia or need for allopurinol is an independent risk factor for DKD progression and that SUA levels in diabetic subjects conferring protection against DKD progression might be lower than current cut-offs for general population.

Resting Heart Rate Does Not Predict Cardiovascular and Renal Outcomes in Type 2 Diabetic Patients.

Elevated resting heart rate (RHR) has been associated with increased risk of mortality and cardiovascular events. Limited data are available so far in type 2 diabetic (T2DM) subjects with no study focusing on progressive renal decline specifically. Aims of our study were to verify RHR as a simple and reliable predictor of adverse disease outcomes in T2DM patients. A total of 421 T2DM patients with variable baseline stage of diabetic kidney disease (DKD) were prospectively followed. A history of the cardiovascular disease was present in 81 (19.2%) patients at baseline, and DKD (glomerular filtration rate < 60 mL/min or proteinuria) was present in 328 (77.9%) at baseline. Progressive renal decline was defined as a continuous rate of glomerular filtration rate loss ≥ 3.3% per year. Resting heart rate was not significantly higher in subjects with cardiovascular disease or DKD at baseline compared to those without. Using time-to-event analyses, significant differences in the cumulative incidence of the studied outcomes, that is, progression of DKD (and specifically progressive renal decline), major advanced cardiovascular event, and all-cause mortality, between RHR

Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial.

Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensin-converting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine < or =150 micromol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 +/- 0.18 at T0 to 3.98 +/- 0.11 at T4 (P < 0.05), which was maintained till T8 (4.11 +/- 0.13; P < 0.05 versus T0). Moreover, the sulodexide-induced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P = 0.03; 49% [30 to 63%], P = 0.0001; and 74% [64 to 81%], P = 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P = 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro- or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect.