Reduced myocardial 123I-metaiodobenzylguanidine uptake in newly diagnosed IDDM patients.

123I-labeled metaiodobenzylguanidine (123I-MIBG) scintigraphy is a novel technique for the assessment of cardiac sympathetic dysinnervation. To evaluate defects of the cardiac autonomic nervous system at the onset of IDDM, this technique together with conventional electrocardiogram (ECG)-based cardiac reflex tests and measurement of the QT interval was applied to 22 newly diagnosed metabolically stabilized IDDM patients without myocardial perfusion abnormalities (99mTc-labeled methoxyisobutylisonitrile scintigraphy) and 9 matched control subjects. Seventeen diabetic patients (77%), but none of the control subjects, were observed to have a reduced global myocardial uptake of 123I-MIBG. In contrast, only two diabetic patients (9%) demonstrated an ECG-based cardiac autonomic neuropathy (two or more of five age-related cardiac reflex tests abnormal) (P < 0.001). In newly diagnosed IDDM patients, the uptake of 123I-MIBG was reduced more in the posterior myocardial region compared with the lateral and apical region (P < 0.01, P = 0.03). The septal myocardial region exhibited a smaller uptake than the lateral myocardial region (P = 0.02). The maximum/minimum 30:15 ratio correlated with the global, anterior, lateral, and septal myocardial uptake of 123I-MIBG (P < 0.05, P < 0.05, P < 0.01, P < 0.05). A correlation between global and regional myocardial 123I-MIBG uptake and HbA1c or QT interval was not observed. Newly diagnosed metabolically stabilized IDDM patients without myocardial perfusion defects show evidence of cardiac sympathetic dysinnervation, as indicated by a reduction of 123I-MIBG uptake, at a significant higher proportion than ECG-based cardiac autonomic neuropathy. Furthermore, they present with regional differences of myocardial 123I-MIBG uptake.

The AGE/RAGE/NF-(kappa)B pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT).

Binding of ligands to the receptor for advanced glycation end products (RAGE) results in activation of the transcription factor nuclear factor kappa B (NF-(kappa)B) and subsequent expression of NF-(kappa)B-regulated cytokines. This has been shown to be a relevant pathomechanism in diabetic polyneuropathies (PNP). To determine whether this pathway may contribute to the pathogenesis of PNP due to impaired glucose tolerance (IGT) we performed a pilot study to demonstrate the presence of the RAGE ligand N (epsilon)-(Carboxymethyl)lysine (CML), the receptor itself and N-(kappa)B in sural nerve biopsies of 4 patients with IGT-related PNP. Biopsies of either 4 patients with diabetic PNP and with Charcot-Marie-Tooth disease (CMT) I and II served as positive and negative controls, respectively. In IGT-related PNP and diabetic PNP, CML, RAGE, and NF-(kappa)B was found in the perineurium, epineurial vessels and in part in endoneurial vessels. CMT patients showed, if any, only weak staining for one or the other antigen. These data suggest that activation of the RAGE pathway may be one of the first steps in the pathogenesis of PNP even before chronic hyperglycemia occurs.

Glycaemic control in type II diabetic tube-fed patients with a new enteral formula low in carbohydrates and high in monounsaturated fatty acids: a randomised controlled trial.

OBJECTIVES: To investigate the effects of long-term treatment with a new enteral formula low in carbohydrates and high in monounsaturated fatty acids (MUFAs), in comparison with a standard formula, on glycaemic control in tube-fed type II diabetic patients. DESIGN: Randomised, double-blind, controlled, multi-centre trial. SETTING: Early rehabilitation centres, primary care and nursing facilities. SUBJECTS: A total of 78 patients with insulin-treated type II diabetes with HbA(1C) > or =7.0% and/or fasting blood glucose >6.66 mmol/l, who required enteral tube feeding due to neurological dysphagia. INTERVENTIONS: Patients received 113 kJ (27 kcal)/kg of body weight of either test feed or an isoenergetic, isonitrogenous enteral formula (control) for 12 weeks. Glycaemic control (total daily insulin dosage (IU), fasting blood glucose, and HbA(1C)) and gastrointestinal tolerance were monitored daily. RESULTS: After 12 weeks, median values for changes from baseline were as follows (test group vs control group, 'data as available' analysis): total daily IUs -6.0 vs 0.0 (P=0.0024), fasting blood glucose (mmol/l) -1.59 vs -0.08 (P=0.0068); HbA(1C) (%) -0.8 vs 0.0 (P=0.0016). Both formulas were tolerated comparably. CONCLUSIONS: This study indicates that in tube-fed insulin-treated type II diabetic patients, the new low-carbohydrate, high MUFA formula results in a more effective glycaemic control than the standard diet, while being comparable in safety.

Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy.

OBJECTIVE: To evaluate the association of autoantibodies to complement-fixing sympathetic ganglia (CF-SG), and tyrosine phosphatase (IA-2) with electrocardiogram (ECG)-based cardiac autonomic neuropathy (CAN) in long-term IDDM. RESEARCH DESIGN AND METHODS: We examined the prevalence of autoantibodies to CF-SG (by complement-fixing indirect immunoflourescence), GAD, and IA-2 (by radioligand assay) and islet cells (by indirect immunofluorescence) in 96 long-term IDDM patients (41 with ECG-based CAN, > or = 2 of 5 cardiac reflex tests abnormal; 55 without ECG-based CAN). As a control group, 89 healthy nondiabetic subjects were investigated. RESULTS: CF-SG autoantibodies were observed more frequently in long-term IDDM patients than in the control group (25 vs. 4%, P = 0.0001). Of the IDDM patients, 14 (34%) with CAN and 10 (18%) without CAN presented with CF-SG autoantibodies (P = 0.06). GAD or IA-2 autoantibodies were detected in 14 (34%) and 17 (41%) IDDM patients with CAN, compared with 24 (44%) and 29 (53%) IDDM patients without CAN (P = 0.2, P = 0.2). Islet cell antibodies were observed in 6 (15%) IDDM patients with and in 9 (16%) IDDM patients without CAN (P = 0.5). CONCLUSIONS: In long-term IDDM, the role of CF-SG autoantibodies, which tend to be more frequent in patients with ECG-based CAN, requires further investigations. The persistence of GAD and IA-2 autoantibodies is not related to ECG-based CAN.

Clinical utility of nonenzymatically glycosylated blood proteins as an index of glucose control.

This study compares the utility of nonenzymatically glycosylated serum proteins (lys-GSP) to glycosylated hemoglobins (HbA1a-c) as control indices of glucose homeostasis in patients with IDDM. The diagnostic value of lys-GSP was also examined in patients with non-insulin-dependent diabetes mellitus, in subjects with impaired glucose tolerance, and in two patients with insulinoma. The intraindividual fluctuation of lys-GSP in normoglycemic subjects is very small, resulting in an interindividual range of 3.0 +/- 0.3 lysine-bound glucose/mg protein (means +/- SD, N = 52). HbA1a-c with a normal range of 6.4 +/- 0.9% (N = 52) shows greater variability. In IDDM there is no overlap of lys-GSP levels between the normal and the diabetic range at the 95% confidence level. In patients treated with an open-loop insulin delivery system failure of normalization of the glucose balance was clearly discernible by an elevation of GSP. In contrast, in about 40% of the patients with incomplete glycemic control the HbA1a-c levels fell within the normal range. The utility of lys-GSP for diagnosis of diabetes is compared with the results of 60 oral glucose tolerance tests. Two patients suffering from insulinoma displayed decreased lys-GSP values. From these results it appears that determination of lys-GSP represents a more sensitive parameter for long-term control than HbA1a-c and is suitable for monitoring even small fluctuations of blood glucose.

Mapping of 41 chemotaxis, flagellar and motility genes to a single region of the Sinorhizobium meliloti chromosome.

Three previously identified gene clusters that contain chemotaxis (che), flagellar (fla) and motility (mot) genes of Sinorhizobium meliloti (formerly Rhizobium meliloti) were mapped to a contiguous 45-kb region of the S. meliloti RU11/001 genome by pulsed-field gel electrophoresis (PFGE) in combination with Southern hybridization. The entire region was cloned and sequenced. The map combines 32 che, fla (flg, flh, fli) and mot genes and nine new open reading frames that probably encode taxis-related functions as well. It is concluded that between 80 and 90% of the genes responsible for chemotaxis and motility are located in a single region of the S. meliloti chromosome near the his-39 marker.

Intensive insulin therapy with insulin lispro in patients with type 1 diabetes reduces the frequency of hypoglycemic episodes.

In a randomized, open-label, controlled cross-over trial, 107 patients with type 1 diabetes were treated with either regular human insulin or insulin lispro, a rapid-acting insulin analogue. After a lead-in period of 2 to 4 weeks, the patients were randomized to receive intensified insulin treatment with one of the insulins. NPH-human insulin was used for basal substitution in both groups. The crossover took place after 3 months of treatment. Efficacy and safety of the drugs were established by the assessment of hemoglobin A1c, pretest blood glucose, 1 and 2-hour postprandial glucose excursions, number of hypoglycemic episodes, daily insulin doses, body weight, insulin antibodies, and the number and severity of adverse events. A questionnaire comprised of four primary domains was used to measure some quality of life aspects of the patients. Both treatment regimens were well tolerated. While no differences were seen in the hemoglobin A1c values, there was a trend for a decrease in the pretest blood glucose levels and significant decreases of the 1 and 2-hour postprandial glucose excursions in the patients treated with insulin lispro. The number of hypoglycemic episodes was also significantly lower in the insulin lispro treatment period. The evaluation of the quality of life questionnaire revealed an improvement in the patients treatment satisfaction for the insulin lispro group. During treatment with insulin lispro, the basal insulin doses increased slightly. However, the total daily insulin doses decreased to a greater extent with insulin lispro as compared to regular human insulin. Human insulin-specific antibody binding values at endpoint were not different for the two treatments. In conclusion, intensive insulin treatment with insulin lispro therapy results in improved postprandial glycemic control and HbA1c levels at least equal to the treatment with regular human insulin but with less hypoglycemia and more treatment satisfaction for the patient.

Three-year follow-up on scintigraphically assessed cardiac sympathetic denervation in patients with long-term insulin-dependent (type I) diabetes mellitus.

Scintigraphy using I-123-metaiodobenzylguanidine (I-123-MIBG) and Tc-99m-methoxyisobutylisonitrile (Tc-99m-MIBI) allows assessment of the cardiac sympathetic innervation and the myocardial perfusion. To investigate the natural history of cardiac sympathetic denervation in long-term diabetic patients without myocardial perfusion defects, global and regional I-123-MIBG and Tc-99m-MIBI uptake was determined (score 1-6; 1 = normal uptake, 6 = no uptake) in 22 patients with insulin-dependent (type I) diabetes mellitus (IDDM) at 3-year follow-up. All patients were treated with intensive insulin therapy and HbA1c was 8.0% +/- 1.0% at entry compared with 7.9% +/- 1.1% at follow-up. Cardiac sympathetic denervation (I-123-MIBG uptake score > 2), initially observed in 18 patients, was detectable in 21 patients at follow-up. The global myocardial I-123-MIBG uptake score deteriorated in eight patients, remained unchanged in 11 and improved in three patients. The changes in mean global I-123-MIBG uptake score (3.5 +/- 1.0 versus 3.8 +/- 0.8) were not significant. Reduction of the anterior, lateral, posterior, septal, and apical I-123-MIBG uptake did not progress significantly during follow-up. The mean uptake score of the posterior myocardial region (4.7 +/- 0.8) was smaller than the uptake score of the anterior (3.0 +/- 1.1, p = 0.001), lateral (3.2 +/- 0.9, p < 0.001) and septal (4.1 +/- 1.1, p < 0.05) myocardial regions. At follow-up, moderate myocardial perfusion defects (global Tc-99m-MIBI uptake score = 3) were detectable in four patients. Our study demonstrates that scintigraphically assessed cardiac sympathetic denervation does neither significantly regress nor progress on the average in a group of long-term IDDM patients during a 3-year follow-up. Thus, it is concluded that cardiac sympathetic abnormalities are a persistent, yet frequent phenomenon in long-term IDDM patients.

Transcutaneous and intra-arterial blood gas monitoring--a comparison during apnoea testing for the determination of brain death.

Intra-arterial (i.a.) and transcutaneous (t.c.) blood gas monitoring were compared with in vitro blood gas analysis (abg) during apnoea testing for the determination of brain death in a prospective observational study. All three methods were used simultaneously in 19 patients in whom brain death was suspected. Brain death was confirmed in each case adhering to the recommendations of the Scientific Advisory Board of the German Federal Chamber of Physicians which demand a PCO2 of at least 60 mmHg. In vitro parameters ranged from 23.2 to 80.4 mmHg (PCO2), 52.7 to 509.9 mmHg (PO2), and 7.072 to 7.591 (pH). The intra-individual correlations between both monitoring methods (rPCO2=0.958, rPO2=0.859) and between each of them and abg (r>0.960) were high. Absolute deviations from abg for the corrected as well as uncorrected measurements were similar for both methods, except with regard to group bias where an advantage for the i.a. values emerged. Since many of the i.a. measurements failed and the disposable i.a. probes cost much more than the t.c. electrodes, the i.a. technique at present holds no advantage over t.c. measurements in testing for apnoea in suspected brain death except where simultaneous monitoring of pH and temperature are desired.

[Studies on orocecal transit in diabetes mellitus]. / Untersuchungen zum orozäkalen Transit bei Diabetes mellitus.

The present study investigated changes of gastrointestinal transit in diabetes mellitus by a variant of the hydrogen exhalation method, which produces reliable estimates of oro-cecal transit times of a lactulose test meal. Relation to metabolic state and small fibre neuropathy was also evaluated. The latter was indexed by Airaksinen's variability score for resting pulse frequency, Ewing's index of respiratory sinus arrhythmia, and warm and cold thresholds at the foot. 15 inpatients with verified type I diabetes (nine female, six male) and eleven healthy controls (nine female, two male) were under investigation. Ages ranged from 19 to 47 and 27 to 49 years, respectively. No clearcut signs of angiopathy or neuropathy were present in patients. HbA1c values were moderately high (means +/- s = 8.2 +/- 1.6). Diabetes patients showed prolonged transit compared to controls (means +/- s = 102.7 +/- 28.2 min, and 79.6 +/- 15.4, resp.; p = 0.02, U-test). Two patients had extremely long transit times, none showed acceleration. However, neither indices of small fibre neuropathy nor metabolic parameters were significantly correlated with transit measures. Prolonged oro-cecal transit, therefore, seems to be due to a specific visceral-autonomic or primary enteric neuropathy, which is still limited to the gastrointestinal system in this stage, and/or metabolic effects.

[The periodontal findings and microflora in insulin-dependent (type 1) diabetics]. / Parodontalbefund und Mikroflora bei insulin-abhängigen (Typ-I-)Diabetikern.

In 42 insulin-dependent type-I diabetics (age: 25.1 +/- 6 years; history of diabetes: 6.7 +/- 6.6 years) and in 118 control patients (age: 26.1 +/- 5.7 years) the oral health status including a periodontal examination was assessed. In addition, diabetic patients served to study the microflora in gingival pockets and on the mucosa of the cheek. The dental examination comprised the assessment of oral hygiene (Approximal Plaque Index, API), gingival inflammation (Sulcus Bleeding Index, SBI, and Gingival Index, GI) and of loss of attachment. Special medical history forms were used to gather information about the quality of metabolic equilibration and about laboratory values pertinent to diabetes. A significant positive correlation was found between poor metabolic adjustment (high glykosylized HbA1) and loss of attachment (r = 0.527). A significant relation was also detected between the administered insulin dose and gingival conditions (r = 0.404). The plasma leukocyte level was positively correlated to the SBI value (r = 0.546) as well as to the GI value (r = 0.496). Bacteriological investigation of subgingival samples revealed an increased amount of gram-positive, anaerobic rods (27.5%), especially corynebacteria (7.4%). Their numbers showed a narrow correlation to SBI (mean value: 48.1%) and GI (mean value: 1.9).

[New options in the treatment of various forms of diabetic neuropathy]. / Sensomotorische und autonome Neuropathie. Neue Therapieoptionen, die Sie kennen sollten.

The classification and incidence of diabetic neuropathy, and the therapeutic options available, are presented in the evidence-based guidelines of the German Diabetes Association for sensorimotor and autonomic neuropathy (www. AWMF.de). Treatment decisions relating basic measures (e.g. optimization of management, multifactorial medication), neuropathic pain and diabetic-neuropathic foot syndrome can be taken on the basis of a simple care pathway. More recent therapeutic options in the treatment of pain are gabapentin, pregabalin, duloxetine and other drugs. For the treatment of erectile dysfunction, the new PDE5 inhibitors vardenafil and tadalafil are now available in addition to sildenafil. A new candidate for a pathogenetically valid treatment is the PKC inhibitor ruboxistaurin.

[Significance of pedography in the diagnosis and treatment of the diabetic foot syndrome]. / Diagnostik und Therapie des diabetischen Fusssyndroms. Was leistet die Pedographie?

Pedographic systems are now in use in many research centers and hospitals throughout the world. The platform system permits rapid and accurate static and dynamic measurement of the local pressure loading on the plantar surface of the foot, and also permits a functional assessment of the roll-over process in the bare foot. The in-shoe system employing an insole measures the pressure distribution within an orthopedic shoe and enables an accurate comparison of the loading situation before and after fitting. As an additional diagnostic tool, pedography improves preventive measures and the quality of the orthopedic treatment of the diabetic foot.