Michal Krcma

Influence of cardiovascular autonomic neuropathy on atherogenesis and heart function in patients with Type 1 diabetes

AIM Cardiovascular autonomic neuropathy (CAN) increases mortality of patients with type 1 diabetes (Type 1 DM). We set out to find out whether the presence of CAN in asymptomatic, normotensive Type 1 DM affects endothelial function (marker of atherogenesis) and left ventricle function (marker of cardiomyopathy). METHODS Twenty-one Type 1 DM with CAN (Group A) and 35 Type 1 DM without CAN (Group B) were enrolled in the study. None of them suffered from any cardiovascular disease nor advanced chronic complications of diabetes. Both groups were comparable in age, glycemic control, BMI, and blood pressure. Markers of endothelial dysfunction and chronic inflammation were used as indicators of incipient atherogenesis. Left ventricle function was evaluated using echocardiography. RESULTS Both groups did not differ in any parameter of atherogenesis. However we found a statistically significant difference in values characterizing systolic and diastolic left ventricle functions between the groups. CONCLUSIONS CAN is not associated with elevation of markers of endothelial dysfunction and chronic inflammation in normotensive asymptomatic Type 1 DM. However CAN is associated with the impairment of systolic and diastolic left ventricle function and can thus be regarded as one of the risk factors of diabetic cardiomyopathy.

Analysis of continuous patient data from the Czech National Register of patients with type 1 and type 2 diabetes using insulin pump therapy

AIM Patient data from the Czech National Register of patients treated with Continuous Subcutaneous Insulin Infusion (CSII) were evaluated to compare treatment indication, efficacy and safety with specific regard to the type of diabetes (T1 vs. T2). METHODS Evaluation was done on complete data sets of at least 3 years from patients with either T1 diabetes (n=730, 93.1%) or T2 diabetes (n=54, 6.9%) between 1995 and 2006. RESULTS HbA(1c) decreased from 9.65 (+/-0.07) and 9.66 (+/-0.05) for T1 and T2 respectively to 8.24 (+/-0.07) for T1 and 8.52 (+/-0.27) for T2 after 1 year of treatment, 8.34 (+/-0.07) and 8.54 (+/-0.26) after 2 years and 8.44 (+/-0.07) and 8.71 (+/-0.25) after 3 years (adjusted mean values, +/-SEM). This reduction is significant for both diabetes types. Results gathered from the safety analysis revealed almost comparable results for both patient groups (rates of adverse events of 42.5 and 34.8 for T1 and T2, per 100 patients and year). CONCLUSION Both patient groups achieved substantial reduction of HbA(1c). Safety evaluation showed that fewer patients with T2 diabetes were affected by adverse events. According to that CSII treatment for patients with T2 diabetes is similarly effective with a slightly better safety profile.

Clostridium difficile infection in hospitalized patients at a Czech tertiary center: analysis of epidemiology, clinical features, and risk factors of fulminant course

Objective Clostridium difficile infection (CDI) has been increasing in incidence, with significant morbidity and mortality, and is subject to geographical and institutional variability. We aimed to characterize epidemiology and clinical manifestations of CDI in a Czech tertiary care center and to identify risk factors of fulminant course. Methods All adult patients hospitalized with primary CDI in a 3-year period were retrospectively identified. Epidemiological and clinically descriptive data were extracted from medical records. Multivariate analysis was used to identify the risk factors of fulminant course. The relationship between incidence of CDI and antibiotic consumption was evaluated. Results Overall, 183 CDI patients, median age 67 years, were enrolled. Hospital-acquired CDI was present in 85% of cases. The incidence of CDI was 1/10 000 patient-days. Hospital-acquired CDI hospital mortality was 22.4%. Severe CDI (SCDI) was identified in 15.8% of patients, with 62% mortality. SCDI patients had longer onset of symptoms to diagnosis interval compared with mild CDI (P=0.05). Multivariate analysis showed that SCDI patients were older (P=0.018), and more frequently had abnormal abdominal physical findings (P=0.001), higher inflammatory markers (P<0.001), higher creatinine (P=0.002), and lower albumin (P<0.001) than patients with mild CDI. Analysis of antibiotic consumption at departments with the highest incidence of CDI showed a trend toward higher incidence of CDI associated with penicillin use (P=0.08) and a negative correlation of CDI incidence with nitroimidazoles consumption (P=0.03). Conclusion CDI is less frequent in the conditions studied compared with literary data; however, the fulminant form has a very high mortality. Delayed recognition and treatment is a crucial determinant of the severity of CDI. The association between CDI and antibiotic consumption is less clear.

Influence of Physical Activity on Metabolic State Within a 3-h Interruption of Continuous Subcutaneous Insulin Infusion in Patients with Type 1 Diabetes

BACKGROUND The aim of this study was to evaluate the influence of physical activity on blood glucose, insulinemia, and ketone bodies level during interruption of insulin delivery. METHODS We enrolled 12 patients with type 1 diabetes (men with an average age of 33.4±8.66 years, body mass index of 25.7±3.75 mg/m(2), and glycated hemoglobin of 8.4±0.95%). The test was performed after overnight fasting at the usual insulin dosage. The delivery of insulin by the pump was stopped for 3 h, and blood samples were obtained in 30-min intervals for determination of blood glucose, insulinemia, β-hydroxybutyrate, non-esterified fatty acids, and acid-base balance parameters. A test with (EXE) or without (CON) physical exercise (moderate aerobic exercise) was performed in each patient at random in the course of 2 weeks. Results are presented as median (first quartile; third quartile). RESULTS Groups CON and EXE did not differ in blood levels of insulin during the test. Regarding time course of glycemia, we found differences only in min 270 for CON versus EXE of 15.2 (13.6; 16.7) and 13.9 (9.1;16.5) mmol/L, respectively (P=0.038). Concerning blood levels of β-hydroxybutyrate, we found significant differences in min 180-300 of the test: CON of 419 (354; 541), 485 (344; 580), and 107 (63; 156) μmol/L versus EXE of 690 (631; 723), 703 (562; 871), and 241 (113; 507) μmol/L (P<0.01). Comparable results were found in values of total ketone bodies and free fatty acids. CONCLUSIONS The influence of physical activity during a 3-h interruption of insulin pump treatment is evident, especially in the increase in plasma levels of non-esterified fatty acids and ketone bodies. Correction bolus leads to a rapid increase in insulinemia; however, normalization of blood glucose and ketone bodies is achieved within another 90 min.

The influence of insulin pump treatment on metabolic syndrome parameters in type 2 diabetes mellitus.

ZusammenfassungEINLEITUNG: Ziel unserer Studie war es, den Einfluss einer Langzeitbehandlung mit Insulinpumpen (CSII) auf Parameter des metabolischen Syndroms bei insulinresistenten schlecht eingestellten Typ 2 Diabetikern zu untersuchen. PATIENTEN UND METHODEN: Es wurden 13 adipöse (BMI >30 kg/m2) Patienten (8 Frauen, 5 Männer; mittleres Alter 58,8 ± 9,06 Jahre), die mindestens 12 Monate mit hohen Insulindosen (>0,8IU/kg/24 h) behandelt worden waren, in die Studie aufgenommen. Bevor die CSII Behandlung begonnen wurde, wurden alle Patienten nochmals bezüglich der Behandlung des Diabetes mellitus und des metabolischen Syndroms geschult. Parameter der Blutzuckerkontrolle wurden erfasst. Zur Evaluierung der Insulinresistenz wurden hyperinsulinämische euglykämische Clamp-Untersuchungen durchgeführt. Die Untersuchungen wurden nach 6 Monaten der Therapie mit CSII wiederholt. Der Wilcoxon-Vorzeichen-Rang-Test sowie Spearmans Rangkorrelationskoeffizient wurden zur statistischen Berechnung verwendet. Die Ergebnisse werden als Mediane (1. und 3. Quartile) angegeben. ERGEBNISSE: Bezüglich der Langzeitkontrolle der Glykämie traten keine Änderung nach der Behandlung mit CSII auf: Das HbA1c lag vor der CSII bei 9,6% (8,95; 10,60), nach 6 Monaten bei 9,80 (9,50; 10,20) %, der BMI änderte sich von 33,0 (32,1; 34,2) auf 32,9 (32,0; 34,5) kg/m2 und die tägliche Gesamt-Insulindosis war ebenfalls praktisch gleich (69,0 (65,0; 94,0) vs. 68,0 (58,9; 92,4) IU/24 h). Allerdings wurde eine statistisch signifikante Besserung der Insulinresistenz: M Wert CSII: 2,55 (1,92; 3,15) vs. 3,32 (2,23; 4,49) mg/kg/min (p < 0,01) nach CSII, sowie folgender Risikofaktoren der Atherosklerose (Koagulation, endotheliale Dysfunktion) gefunden: Fibrinogen 3,44 (3,13; 3,86) vs. 3,24 (2,77; 3,38) g/l, Faktor VII 115 (101; 128) vs. 109 (93; 119) %, Faktor VIII 230 (148; 260) vs. 188 (126; 225) %, vWF:RiCo 162 (141; 193) vs. 128 (100; 132) %, PAI-1 39 (30; 44) vs. 30 (25; 36) AU/ml, Thrombomodulin Ag 4,1 (3,7; 4,4) vs. 3,7 (3,45; 4.05) ng/ml (p < 0.01) festgestellt. SCHLUSSFOLGERUNGEN: Eine 6-monatige Insulinpumpentherapie führte bei übergewichtigen Typ 2 Diabetikern unabhängig von der Blutzuckereinstellung zu einem Abfall der Insulin-resistenz, und zu einer Besserung von Parametern des Fettstoffwechsels, der Koagulation des Bluts und der endothelialen Funktion.SummaryINTRODUCTION: The aim of our study was to evaluate the influence of long-term insulin pump treatment (CSII) on the parameters of metabolic syndrome in insulin-resistant patients with poorly controlled type 2 diabetes mellitus. PATIENTS AND METHODS: Thirteen obese (BMI >30) patients (8 women, 5 men), average age 58.8 ± 9.06 years, treated with an intensified insulin regimen with high doses of insulin (>0.8 IU/kg per 24 h) for at least 12 months were enrolled in the study. Prior to CSII treatment, all patients were reeducated regarding diabetes treatment and metabolic syndrome, and glycemic control parameters were assessed. Insulin resistance was evaluated with the hyperinsulinemic euglycemic clamp test. All tests were repeated after six months of CSII treatment. The Wilcoxon matched-pairs signed-rank test and Spearmans rank correlation coefficient were used for statistical evaluation. Results are presented as median (1st quartile; 3rd quartile). RESULTS: There were no changes in long-term glycemic control during the course of CSII treatment: HbA1c prior to CSII 9.60 (8.95; 10.60) vs. after 6 months 9.80 (9.50; 10.20) %, BMI 33.0 (32.1; 34.2) vs. 32.9 (32.0; 34.5), total daily insulin dose 69.0 (65.0; 94.0) vs. 68.0 (58.9; 92.4) IU/24 h in observed patients. There was a statistically significant improvement in insulin resistance: M value 2.55 (1.92; 3.15) vs. 3.32 (2.23; 4.49) mg/kg per min (P < 0.01), and improvement in atherosclerosis risk factors (blood coagulation and endothelial dysfunction): fibrinogen 3.44 (3.13; 3.86) vs. 3.24 (2.77; 3.38) g/l, factor VII 115 (101; 128) vs. 109 (93; 119) %, factor VIII 230 (148; 260) vs. 188 (126; 225) %, vWF:RiCo 162 (141; 193) vs. 128 (100; 132) %, PAI-1 39 (30; 44) vs. 30 (25; 36) AU/ml, thrombomodulin Ag 4.1 (3.7; 4.4) vs. 3.7 (3.45; 4.05) ng/ml (P < 0.01). CONCLUSIONS: Six months of CSII treatment led to decrease in insulin resistance and improvement in parameters of lipid metabolism, blood coagulation and endothelial dysfunction independently of glycemic control and weight.

On-line Blood Glucose Level Calculation

Diabetes is a silent disease. It is the 8th most common cause of death that does not hurt until it is too late and the disease has developed. Technology plays a vital role in managing diabetes and educating patients about importance of the treatment. The patient must be able to manage his blood glucose level. However, blood glucose level is measured sporadically as it causes important discomfort to the patient. Measuring glucose level in subcutaneous tissue is minimally invasive technique and thus considerably comfortable, but this level may be different from blood glucose level. We implemented a recently proposed method of blood glucose level calculation from the continuously measured subcutaneous tissue glucose level. Then, we developed a web portal that makes this method accessible to any doctors office and any diabetic patient. To the best of our knowledge, we are the very first web portal that does this. In this paper, we describe the portal.

Could we predict asymptomatic cardiovascular autonomic neuropathy in type 1 diabetic patients attending out-patients clinics?

ZusammenfassungHINTERGRUND UND ZIELE: Die kardiovaskuläre autonome Neuropathie (KAN) ist bei Patienten mit Typ 1 Diabetes mellitus (DM1) mit einer erhöhten Morbidität und Mortalität verbunden. Diese Komplikation kann über lange Zeit ohne Symptome einhergehen. Ziel dieser Studie war es die Prävalenz, den Schweregrad und mögliche Vorhersageparameter der asymptomatischen KAN zu erfassen. PATIENTEN UND METHODEN: 107 Patienten mit DM1 (52 Männer, 55 Frauen, Alter 39,8 ± 12,4 Jahre [18–72]; Dauer des DM1: 16,6 ± 9,5 Jahre [0,5–43], Alter bei Manifestation 23,5 ± 12,8 Jahre [1–54], BMI 25,1 ± 3,2 [1,9–33,91]) wurden untersucht. Das Vorliegen einer KAN wurde mit Hilfe von Standard-Reflex-Testen (Ewing Batterie) erhoben und die Patienten wurden entsprechend den Ergebnissen in drei Gruppen eingeteilt: Gruppe 0 ohne KAN, Gruppe I mit erstgradiger KAN und Gruppe 2 mit zweitgradiger KAN. Wir erhoben außerdem die mit KAN am häufigsten einhergehenden chronischen Komplikationen des DM1, Episoden schwerer Hypoglykämie, zeitliche Parameter des DM1 (Patientenalter, Dauer des DM1, Alter bei Manifestation) und außerdem DM1-spezifische Parameter wie glykosyliertes Hb, BMI, kardiovaskuläre Erkrankungen und Blutdruck. Die Vorhersagbarkeit einer KAN wurde entsprechend den erhobenen Korrelationen beurteilt. ERGEBNISSE: Nur 50 der 107 der Patienten (46%) zeigten keine KAN. Bei 38 Patienten (36%) fanden wir eine erstgradige , bei 19 (18%) eine zweitgradige KAN. KAN korrelierte mehr mit der Dauer des DM1 (p < 0,001), als mit dem Alter der Patienten (p < 0,05). Es bestand eine grenzwertig signifikante Korrelation (p = 0,053) mit dem glykosylierten Hb. Weiters haben wir eine signifikant positive Korrelation zwischen KAN und dem Auftreten von chronischen Komplikationen (periphere Neuropathie: p < 0,001), Retinopathie: p < 0,001, Nephropathie: erhöhtes Kreatinin: p < 0,03, Albuminurie: p < 0,01) gefunden. Obwohl der Blutdruck bei allen Patienten im Normalbreich (124,2/74,5 ± 11,5/7,8 mmHg) lag, wurde eine positive Korrelation mit der KAN (p < 0,05) bestätigt. Zu den akuten Komplikationen des DM1 bestand keine Korrelation. SCHLUSSFOLGERUNGEN: Unsere Studie zeigt, dass die asymptomatische KAN bei Patienten mit DM1 sehr häufig ist. Mit Hilfe von multifaktorieller logistischer Regression konnten wir zeigen, dass bei gleichzeitigem Vorliegen von Albuminurie, peripherer Neuopathie und erhöhtem systolischem Blutdruck eine hohe Wahrscheinlichkeit für das zusätzliche Vorhandensein einer KAN besteht.SummaryBACKGROUND AND AIMS: Diabetic cardiovascular autonomic neuropathy (CAN) is associated with increased morbidity and mortality. This complication may be asymptomatic for a long time. The aim of this study was to assess the prevalence, severity and predictors of asymptomatic CAN in patients with type 1 diabetes mellitus (DM1). PATIENTS AND METHODS: 107 patients with DM1 were enrolled: 52 men and 55 women aged 39.8 ± 12.4 years (18–72), duration of DM 16.6 ± 9.5 years (0.5–43), age at DM manifestation 23.5 ± 12.8 years (1–54) and BMI 25.1 ± 3.2 (18.9–33.91). CAN was assessed using standard cardiovascular reflex tests (Ewing battery) and the patients were divided into three groups according to the results: Group 0, without CAN; Group I, 1st degree CAN; Group II, 2nd degree CAN. We assessed the most frequent relationships between CAN and chronic complications, episodes of severe hypoglycemia, time-related parameters (age of patients, duration of diabetes, age at manifestation), glycosylated hemoglobin (HbA1c), BMI, cardiovascular diseases and blood pressure, and determined the predictability of CAN on the basis of these relationships. RESULTS: Only 50 of the 107 patients (46%) showed no CAN. We found 1st degree CAN in 38 patients (36%) and 2nd degree CAN in 19 (18%). CAN correlated more significantly with the duration of diabetes (p < 0.001) than with age (p < 0.05). The relationship between CAN and HbA1c was on the borderline of statistical significance (p = 0.053). We found a positive correlation between CAN and the presence of chronic complications [peripheral neuropathy (p < 0.001), retinopathy (p < 0.001), and some markers of nephropathy: creatinine (p < 0.03), albuminuria (p < 0.01)]. Although blood pressure was within the physiological range (124.2/74.5 ± 11.5/7.8 mmHg) in all patients, a positive correlation with CAN was confirmed (p < 0.05). No relationship with occurrence of severe hypoglycemia was found. CONCLUSIONS: According to our results, asymptomatic CAN is very frequent in patients with DM1. By using multifactorial logistic regression (step-wise) analysis we demonstrated that if albuminuria, peripheral neuropathy and elevated systolic BP are present simultaneously, there is a high probability that the patient also has CAN (84.9% of initial group correctly predicted, p < 0.001).

The insulin analog glargine during an unplanned pregnancy.

Sir, We have read with interest the papers by Leipold and coworkers on diabetic fetopathy and the editorial on ‘designer’ insulins [1–3]. The use of the insulin analog glargine during pregnancy is not recommended. What we do with this treatment during unplanned pregnancy? We present the cases of seven women with type 1 diabetes treated with the insulin analog glargine during pregnancy. The unplanned pregnancies were diagnosed at 5–10 weeks’ gestation. The patients were treated with long-acting glargine and multiple daily injections of shortacting analogs (lispro, aspart). Glycosylated hemoglobin levels before and during pregnancy are shown in Table 1. Patient E never become reconciled to her disease and did not cooperate, even during pregnancy. Slight progression of diabetic retinopathy occurred during pregnancy in patients B and F; both women had diabetes of 15–16 years duration with unsatisfactory glycemic control over a long period, and hyperglycemia went down too fast during pregnancy. Patient C (with treated autoimmune thyroiditis) was diagnosed with Addison’s disease at the end of pregnancy; severe hypoglycemias occurred repeatedly at very low insulin dose. The pregnancy of patient D was complicated by hypothyroidism at 14 weeks’ gestation. All the women delivered at 37–38 weeks: two vaginally and five by caesarean section. Seven children with mean weight 3370 g (2900–3700 g) were born without congenital malformations. The newborns of patients E, F and G had symptoms of considerable diabetic fetopathy, with dyspnea (two children, Apgar score 7-8-9) and hypoglycemia (one child). The other four newborns were without neonatal complications. Our patients were informed about the lack of experience in using glargine during pregnancy; they decided not to change the treatment and signed an informed consent. Rapid-acting analog insulins are more potent than regular insulin in reducing postprandial hyperglycemia in diabetic pregnant women [4]. The advantage of using the analog insulin glargine in pregnancy lies in reducing the number of nocturnal hypoglycemias, which may hinder the achievement of tight glycemic control [4]. Animal studies did not confirm a negative effect of insulin analogs (lispro, aspart and glargine) on embryo-fetal development [4, 5], and any evidence of side effects on the fetus (newborn) was not shown in studies on the use of lispro in more than 800 diabetic pregnant women [5]. The use of lispro during pregnancy has been approved. Results of a randomized trial with aspart (322 type 1 diabetic patients) were presented at the meeting of the American Diabetes Association in June 2006. Treatment with aspart was at least as safe as human insulin regarding perinatal outcome [6]. Only case reports on the use of glargine during pregnancy were found in the literature: a total of six diabetic type 1 patients were treated with glargine during the whole pregnancy [7, 8]; in five other patients it was used during [9] and in four patients after the first trimester [7, 10–11]. All the women delivered newborns without malformations. Two studies with glargine in type 1 diabetic women were presented at the ADA meeting: in a multi-center control trial with 47 patients, treatment with glargine during pregnancy appeared to be as safe and efficient as with Protaphan insulin [12]; in the other study of 115 women on glargine, no evidence of increased congenital malformations or adverse maternal or fetal outcomes was demonstrated [13]. In conclusion: the use of aspart during pregnancy has been approved in Europe from July 2006, but treatment with glargine during pregnancy is still not recommended. Further randomized trials are needed. Note: This work was supported by grant MSM 21620814 from the Ministry of Education to the Faculty of Medicine, Charles University, Prague.

An Evolutionary Approach for Estimating the Blood Glucose by Exploiting Interstitial Glucose Measurements

The diabetes is correlated to a malfunction of the pancreas that produces very little or no insulin. A way to improve the quality of life of people with diabetes is to implement an artificial pancreas able to inject an insulin bolus when necessary. The aim of this paper is to devise a possibly step in constructing the fundamental element of such an artificial pancreas estimation of the blood glucose (BG) through interstitial glucose (IG) measurements. In particular, a new methodology is presented to derive a mathematical relationship between BG and IG by exploiting the ability of the evolutionary techniques in solving this regression task. An automatic procedure is used to estimate the missing BG values within this database. To validate the discovered model a comparison with other models is carried out during the experimental phase.

National Register of patients with insulin pump treatment in the Czech Republic

Aims: The national register of patients treated with continuous subcutaneous insulin infusion (CSII) exists in the Czech Republic since 1998. The aim of this report is to present data on current situation and treatment results of CSII on wide unselected population. Methods: At present, we gather data from 52 departments of diabetology in the Czech Republic from patients with diabetes of all types treated with CSII. The data are collected continuously utilizing a special database program or by means of questionnaires. Results: We register data of 2060 patients treated with CSII to the end of 2005. Patients with type 1 diabetes represent 88.5%, type 2 8.5%, other 3%, men 47.7%, women 52.3%. The average age is 39.74±3.98 years, the duration of the CSII treatment is 4.56 ± 3.34 years. The insulin pump treatment leads to statistically significant improvement of glycemic control – HbA1c before CSII 9.60 ± 2.083% vs. after first and second year of treatment 8.47 ± 1.840 and 8.38 ± 1.611% (p < 0.001) respectively. The same trend is observed in the total insulin dose. Conclusions: The Register is a unique national project that maximally objectively, long-lastingly and continually monitors patients treated with insulin pumps. Our results show an enduring character of the improvement of monitored parameters.