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AIMS: To examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non-interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study. METHODS: Data on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV-specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time-dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all-cause mortality was examined. RESULTS: A total of 147 primary events were accrued during up to 54 months of follow-up. In all, 60 CV-specific deaths, 44 non-fatal MIs and 57 non-fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12-1.40; p

Aims To identify factors associated with glucose control, as measured by HbA1c over 4 years, in people with type 2 diabetes starting insulin therapy. Methods CREDIT, an observational cohort study, collected data semi-annually over 4 years, on people with type 2 diabetes starting any insulin, in 311 centres in 12 countries; 2803 people had data on HbA1c during follow-up. Multivariable backward regression analysis selected characteristics associated with glycaemic control from a limited number of candidate variables. Results Before starting insulin therapy, HbA1c was 9.3% (78 mmol/mol) and decreased to 7.6% (60 mmol/mol) after 1 year, and changed little after that. Insulin dose increased from 0.21 U/kg to 0.36 U/kg at 1 year, and then by 0.10 U/kg over the next 3 years. Body weight increased by 2.0 kg in the first year and increased little thereafter. Poorer glycaemic control over the 4 years was mainly determined by the HbA1c before starting therapy, after accounting for the other statistically significant associated variables in multivariable analysis: higher BMI, younger age, longer diabetes duration, more glucose-lowering drugs, using basal insulin alone, higher insulin dose and female sex. At 4 years, a higher current insulin dose was the characteristic most strongly associated with a higher concurrent HbA1c. Conclusions HbA1c at the start of insulin therapy was the characteristic most predictive of later HbA1c, after accounting for other variables associated with HbA1c. This may provide some justification for earlier insulin introduction to improve glucose control to target.

Aim To identify factors associated with documented symptomatic and severe hypoglycaemia over 4 years in people with type 2 diabetes starting insulin therapy. Materials and methods CREDIT, a prospective international observational study, collected data over 4 years on people starting any insulin in 314 centres; 2729 and 2271 people had hypoglycaemia data during the last 6 months of years 1 and 4, respectively. Multivariable logistic regression was used to select the characteristics associated with documented symptomatic hypoglycaemia, and the model was tested against severe hypoglycaemia. Results The proportions of participants reporting ≥1 non‐severe event were 18.5% and 16.6% in years 1 and 4; the corresponding proportions of those achieving a glycated haemoglobin (HbA1c) concentration

Background and aims: TEENs is an international, cross-sectional observational study, conducted in 20 countries in order to assess T1D management and psychosocial parameters in 8-25-year-olds (y/o). Data on diet management, lifestyle factors and education needs by target HbA1c attainment from the Italian cohort are reported. Materials and methods: Data were collected at 23 centres by participant interview, medical record review and participant/parent survey from 1,009 Italian youth (46% female) in three age groups: 8-12 y/o (n=330), 13-18 y/o (n=490), and 19-25 y/o (n=189). HbA1c was measured uniformly using A1cNow™ with target HbA1c defined as 18 y/o (ADA). Results: Overall, 40% of participants met HbA1c targets. Measuring food intake based on experience was the most common method used by all age groups, followed by carbohydrate counting (Table). Of the participants who used carbohydrate counting, a higher percentage met target HbA1c than did not in all age groups, with a significant effect on target attainment due to carbohydrate counting compared with other methods observed in 13-18 y/o (p=0.035). Avoiding sugars was the least common method used in all age groups. Across all age groups, participants who did not undertake any exercise were numerically less likely to reach HbA1c target; on the contrary, participants who exercised 1-2 days/week were numerically more likely to reach HbA1c target. Performing exercise had a significant effect on target HbA1c attainment in 8-12 y/o (p=0.012). The majority of participants were in the underweight/normal body mass index (BMI) category in all age groups, with no clear pattern between BMI class and the proportion of patients reaching HbA1c target. Participants of all ages commonly requested education on diet, carbohydrate counting, how to manage T1D during illness, and how to manage blood glucose levels with exercise. Conclusion: Carbohydrate counting and exercising at least twice per week help to attain HbA1c target across all age groups. Assessment of lifestyle factors suggests that efforts targeting carbohydrate counting and exercise could promote successful health outcomes and help more patients with T1D to reach the recommended HbA1c target. Supported by: Sanofi

Thirty small reflectometers not requiring mains electricity (23 Glucosemeter and 7 individual appliances of various makes) were tested under standardised laboratory conditions as to their relative and absolute accuracy in the measurement of blood glucose. The hexokinase method delivered the reference values. The investigation demonstrated systematic deviations of 1 to 97%, coincidental deviations of 8 to 24% and total deviations of between 25 and 153%. If one accepts a value of up to 50% for the total deviation only 13 out of 30 reflectometers are acceptable. The results show that each individual meter must be assessed by the doctor before it can be given to the patient for glucose monitoring at home.

HLA antigens A, B, C, DR and BF were determined in 14 sibling pairs with type I diabetes and in 61 patients without familial risks. Significantly positive associations of the disease with HLA DR3 and DR4 and a negative association with DR2 were found. Positive and negative associations with the various HLA A, B and C antigens (A1, A2, B8, B15, B18, Cw3) are of a secondary nature due to strong genetic coupling with primarily associated DR alleles. Localisation of diabetes-associated genes in the HLA DR region could be demonstrated in two families with HLA recombinations. In both cases the hypothetic disease gene segregated with the HLA DR segment. Joint evaluation of these data in an international series involving 1200 type I diabetics showed furthermore that around 90% of all patients are DR3 and/or DR4 positive, that the highest morbidity risk exists in DR3/4 heterozygosity and that DR4 positive persons usually fall ill before their 20th year of life and frequently in the last 3 months of the year. Allotment of clinical, epidemiological, virological and immunological criteria of type I diabetes to only one of the both risk factors indicates heterogeneous immunopathogenesis of the disease. HLA DR3 predisposes particularly to endocrine autoimmune disease and DR4 to increased virus susceptibility.

Randomized serial tests of their metabolic state over four weeks, without self-testing and during daily urinary glucose-profile testing (4 tests) with the Diabur-Test or blood-glucose levels with the Haemo-Gluco-test 20-800 (5 tests daily) on two days weekly were undertaken on 27 unselected insulin-treated outpatient diabetes. HbA1, blood glucose, serum cholesterol, triglycerides and VLDL, LDL and HDL cholesterol were the target values. The following metabolic values were significantly reduced (P less than 0.05) during blood-glucose self-testing, compared with the results during the non-testing phase: HbA1 on average by 11%, blood-glucose (starving) by 20%, serum cholesterol by 9%, serum triglycerides by 13%. Self-testing of urinary glucose (compared with the test-free phase) brought little improvement in the metabolic state. The results of self-testing were the more impressive the worse the metabolic state during the phase without self-testing. Except for VLDL and HDL cholesterol, changes in HbA1 correlated well during all phases with changes in the other metabolic values (P less than 0.05).

A 26-year-old female with severe complications from type I diabetes mellitus of 17 years' duration (proliferative retinopathy, nephropathy with renal failure and nephrotic syndrome) developed rapid deterioration of vision in the right eye to 6/60 over a period of several weeks. There were no other neurological signs. Ophthalmological examination showed no worsening of the diabetic retinopathy, but the presence of bilateral optic atrophy, confirmed by visual evoked potentials. CT scan did not reveal any retrobulbar process, and MR scans of both the optic nerves and the visual pathways were unremarkable. The clinical features and the investigations pointed towards ischaemic optic atrophy. Detailed platelet studies showed intravascular platelet activation and an ADP-inducible increase in aggregation, although thromboxane formation was almost absent because of cyclooxygenase inhibition by acetylsalicylic acid. These findings suggest that the ischaemia was due to microcirculatory disturbances secondary to diabetic microangiopathy and platelet hyperreactivity.

HISTORY AND CLINICAL FINDINGS A 71-year-old woman, a diabetic (type IIb) for 27 years, developed bilateral hemianopsia over a period of about 2 years. A few weeks before hospital admission the defect in her visual fields increased more rapidly and double vision occurred intermittently. The hemianopsia was demonstrated by finger perimetry. There was no evidence of heart failure or peripheral vascular disease. Muscle reflexes were normal, but there was a decrease in vibratory sensation in both feet. The cause of the visual disturbance was at first thought to be an ischaemic optic neuropathy. INVESTIGATIONS Biochemical tests showed an HbA1 of 12.8%, blood sugar levels were between 230 and 359 mg/dl, and there was increased intravascular platelet activation. Ophthalmological examination confirmed bitemporal hemianopsia and early retinopathy. Magnetic resonance imaging of the skull revealed an intra- and suprasellar cystic space-occupying lesion extending to the right optic chiasma. These findings, taken together, indicated an arachnoidal cyst. TREATMENT AND COURSE After the diabetic metabolic state had been normalized with insulin treatment (average of 30 IU of an intermediary insulin) and dietary measures, the cyst was evacuated stereotactically. The hemianopsia quickly improved markedly and the patient was discharged 4 days after the operation with her vision nearly fully restored.

The glucometer II system is a small measurement device with built-in batch-specific pressbutton calibration. The corresponding test strip "Glucostix" uses a two-color system. The blood glucose test strip can be evaluated both visually and by instrument. The precision determined in series was between 2.0% and 6.7% using control sera. The day-to-day precision was between 1.5% and 7.9%. Comparison of the methods on the basis of 781 and 109 capillary blood samples respectively revealed a good agreement between the hexokinase method or the glucose oxidase method (Beckman analyser) and the glucometer II values. The precision of measurement by the system was comparable in the two test strip batches employed. Visual reading of the test strips revealed a good agreement with the laboratory method in the hypoglycemic and normoglycemic range; at higher concentrations of blood glucose, a trend to underestimation of the measurement values was shown. The easy handling and small size of the instrument facilitates measurement of blood glucose by the patient under everyday conditions.

Reflocheck, a new microprocessor-regulated apparatus determining blood sugar levels was tested in six laboratories. In the range of 20-450 mg/dl the apparatus gave precise results (co-efficient of variance 0.8%-6.4%), in good agreement with results by the hexokinase method. Reflocheck is an accurate and reliable instrument for the measuring of blood glucose levels.

Long-term intermittent heparin-induced extracorporeal low-density lipoprotein (LDL)-cholesterol precipitation was performed in three men - aged 32, 52 and 56 years - with severe familial hypercholesterolaemia and angiographically demonstrated coronary heart disease. This significantly lowered by 65-70% their LDL-cholesterol concentration and by 48-54% their fibrinogen concentration. Fibrinogen elimination reduced plasma viscosity by 13-14% and clearly raised the transcutaneously measured partial pressure of oxygen by 33-50%. Clinically the improved microcirculation achieved a decrease in angina symptoms: the walking distance of the 52-year-old man increased from about 100 m to 4000 m, the daily need of glyceryl trinitrate falling from an average of 12 to 4 aerosol doses.

Periodic limb movements during sleep (PLMS) and obstructive sleep apnea syndrome (OSAS) are two common sleep disorders. The similarity in periodicity of periodic limb movements (PLMs) and obstructive sleep apneas (OSAs) led us to hypothesize the existence of a common central generator responsible for the periodicity of both OSAs and PLMs. In order to test this hypothesis, we compared apnea periodicity before continuous positive airway pressure (CPAP) treatment with PLMs periodicity during CPAP treatment in 26 OSA patients, consecutively recorded and treated in our sleep laboratory. The investigation on CPAP was performed twice, once during the initial evaluation and once during a follow-up evaluation after 3 months of home treatment with CPAP. Our results showed that, in this sample, 16 patients out of 26 had an association of OSAS and PLMS, defined as the occurrence of at least 5 PLMs per hour of sleep. The mean apnea interval - measured as the time between the beginning of two successive apneas - was 43.1 s (+/-15.2, SD) and the mean PLM interval - calculated in the same way - was 29.6 s (+/-15.2) during the baseline night, 28.5 s (+/-15.7) during the first CPAP night, and 29.8 s (+/-14.8) during the second CPAP night. Thus, the periodicity of the two phenomena (apneas and PLMs) was different, both before and after CPAP treatment (P< 0.05). When considering the interval between the end of an event (apnea or PLM) and the beginning of the next one the mean apnea interval was 19.5 s (+/-11. 6), and the mean PLM interval was 28.1 s (+/-15.3) during the untreated night, 26.6 s (+/-16) during the first CPAP night and 27.9 s (+/-15) during the second CPAP night. The shortening of apnea intervals with this method of measuring intervals reflects the longer duration of apneas as compared to PLMs. Again the intervals between PLMs were not different between each other but the intervals between apneas were different from the intervals between PLMs (P< 0. 05) These results show that the periodicity of PLMs is different from that of OSAs, suggesting that sleep apneas and PLMs are not generated by a common central generator.

Correctness and accuracy of Reflolux, a new microprocessor-controlled minireflectometer for measuring blood-glucose concentrations, were tested in ten instruments. There was good agreement between the Reflolux values and those obtained in the laboratory with the hexokinase method, over the entire range of 40-350 mg/dl with a relatively small margin of error. Thus the Reflolux provides even in the hypoglycaemic range values accurate enough for everyday use by a diabetic. An important advantage of this test system lies in the use of Haemo-Glukotest 20-800 test strips which, in conjunction with the Reflolux, provide a visual color comparison for blood-glucose levels in the range of 20-800 mg/dl.

Guidelines on the out-patient management of diabetic peripheral neuropathy have been developed from an international consensus meeting attended by diabetologists, neurologists, primary care physicians, podiatrists and diabetes specialist nurses. A copy of the full document follows this summary (Appendix 1). The document arose out of suggestions from Neurodiab, a subgroup of the European Association for the Study of Diabetes, that there was a need for guidelines developed by consensus, for the outpatient management of patients with diabetic neuropathy. An international consensus group was created, chaired by two of the authors. A pilot working party met in 1995, followed by a full working party of 39 experts, neurologists and diabetes physicians (Appendix 2). This compiled a draft guideline document which was circulated to a number of international bodies. After consultation with its members, the final guidelines were approved by Neurodiab (chairman F.A. Gries) towards the end of 1997. © 1998 John Wiley & Sons, Ltd.

Diabetic cardiovascular autonomic neuropathy (CAN) has been directly characterized by reduced or absent myocardial [123I]metaiodobenzylguanidine (MIBG) uptake, but there is no information available on the relationship between the myocardial adrenergic innervation defects and long-term glycaemic control. In a prospective study over a mean of 4 years we examined myocardial sympathetic innervation in 12 Type 1 (insulin-dependent) diabetic patients using MIBG scintigraphy (absolute and relative global MIBG uptake at 2 h p. i.) in conjunction with cardiovascular autonomic function tests, QTc interval, and QT dispersion. Six healthy non-diabetic subjects served as controls for the MIBG scintigraphy at baseline. HbA1c was measured twice a year. One patient, in whom MIBG accumulation was reduced maximally, died during follow up. Among the remaining patients 5 had good or borderline glycaemic control (mean HbA1c < 7.6 %; Group 1), whereas 6 patients were poorly controlled (mean HbA1c L 7.6 %; Group 2). Absolute global MIBG uptake increased from baseline to follow-up by 260 (−190–540) [median (range) ] cpm/g in Group 1 and decreased by −150 (−450–224) cpm/g in Group 2 (p < 0.05 vs Group 1). Relative global MIBG uptake decreased by −1.7 (−3.4–9.4) % in Group 1 and by −4.7 (−17.4–1.3) % in Group 2 (p < 0.05 vs Group 1). No differences between the groups were noted for the changes in the automatic function tests, QTc interval, and QT dispersion. In conclusion, long-term poor glycaemic control constitutes an essential determinant in the progression of left ventricular adrenergic dysinnervation which may be prevented by near-normoglycaemia. Evaluation of susceptibility to metabolic intervention may be superior when CAN is characterized directly by MIBG scintigraphy rather than by indirect autonomic function testing. [Diabetologia (1998) 41: 443–451]

OBJECTIVE To evaluate drug prescriptions and costs among diabetic patients in primary care practices in Germany. RESEARCH DESIGN AND METHODS Computerized data on prescriptions and costs (drug company sales prices) were analyzed in 30,604 diabetic and 17,723 (5% random sample) nondiabetic patients from 362 primary care practices during 1994. Relative use ratios for drug groups were obtained from logistic regression models (odds ratio [OR] for diabetes) controlling for age, sex, and other covariates. Relative costs (diabetic:nondiabetic) were estimated by direct age and sex standardization. RESULTS Diabetic patients had an increased prescription use for most drugs. A substantial increased use (OR ≥ 1.4) was found for cardiovascular drugs, fibrates, gout medication, laxatives, and wound care products. Diabetic subjects (7.9% of all patients) accounted for 21% of total annual prescription costs in the practices. Total costs (U.S. dollars) per patient-year were threefold higher (diabetic patients $384; control subjects $123). After excluding antidiabetic agents and age- and sex-standardization, relative costs were still 1.5 times higher (P < 0.05). Diabetes treatment accounted for 24% of total costs in diabetic patients (insulin 12%; oral antidiabetics 6%). The most important cost factor was cardiovascular drugs (CVDs) (39%). Three CVD groups accounted for about 50% of total CVD costs in diabetic patients (ACE inhibitors 25%; Ca-antagonists 16%; nitrates 10%). CONCLUSIONS Prescription use among diabetic patients in primary health care practices was predominantly increased for cardiovascular drugs and for treatment of diabetes-associated disorders. Diabetic patients accounted for over one-fifth of the total pharmacy costs in primary practices, indicating that diabetes is a major economic factor in drug use.

The authors performed a correlational study on nationwide spontaneous adverse drug reaction (ADR) reports related to the antioxidant thioctic acid (Thioctacid; ASTA Medica) in Germany from April 1992 to March 1995. Thioctacid was predominantly utilized by general practitioners and internists for treatment of diabetic neuropathy. The total number of treated patients was estimated using a nationwide drug prescription database (MediPlus, IMS: 362 general practitioners and internists) and pharmacy drug sales data. All Thioctacid prescriptions in MediPlus were assessed and the mean cumulative dosage/patient/year was calculated. Then, the total number of Thioctacid patients in Germany was estimated: N=nationwide pharmacy sales (kg)/mean cumulative dosage/patient (kg). From April 1992 to March 1995, 78 patients with 112 ADRs were notified on spontaneous reports. There was a decreasing number of ADR reports per year (32 to 21 patients/year). In parallel, the estimated total numbers of treated patients/year also decreased from 426,658 to 304,155 (p

Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant α-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of α-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was significantly lower in ALA 600 than in PLAC after 19 days (all P < 0.05). The total scale of the Hamburg Pain Adjective List (HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days (both P < 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate variability were randomly assigned to treatment with a daily oral dose of 800 mg α-lipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters of heart rate variability at rest were significantly improved in ALA compared with placebo. A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with α-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM.

Several biosensors have been developed for continuous monitoring of human blood glucose, which is desirable for insulin-dependent diabetic patients. Developments in the field of quantitative assays using infrared attenuated total reflection spectroscopy allow the determination of metabolites at low concentrations. The microdialysis technique can provide a continuous sampling of extracellular body fluids. As only compounds of low molecular weight are passed on, infrared spectrometric quantitation is eased considerably. Samples were obtained by microdialysis of human blood plasma and aqueous glucose solutions. Multivariate calibration by partial least-squares was evaluated for its analytical performance in ex-vivo blood glucose monitoring. Mean squared prediction errors obtained by cross validation were 5.4 mg/dL for dialysate samples from different patients and 1.3 mg/ dL for dialysates from glucose solutions. Further investigations were carried out to achieve miniaturization of the measuring and detection device.

Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Th1 cytokines gamma-interferon (IFN-gamma) (P = 0.028) and tumor necrosis factor alpha (TNF-alpha) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Th1 and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Th1 or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-alpha and IL-4 than normal subjects (P = 0.001-0.006). However, when the balance between Th1 and Th2 cytokine production was analyzed in individuals, the ratio between IFN-gamma or TNF-alpha and IL-4 or IL-10 was clearly biased toward Th1 reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Th1) in IDDM or humoral immunity (Th2) in Graves' disease.

Anti-oxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes mellitus, thus providing a rationale of potential therapeutic value for diabetic patients. The effects of the anti-oxidant alpha-lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (1200, 600, or 100 mg ALA) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and at each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the Hamburg Pain Adjective List, a multidimensional specific pain questionnaire, and the Neuropathy Symptom and Disability Scores were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score in the feet decreased from baseline to day 19 by -4.5 +/- 3.7 (-58.6%) points (mean +/- SD) in ALA 1200, -5.0 +/- 4.1 (-63.5%) points in ALA 600, -3.3 +/- 2.8 (-43.2%) points in ALA 100, and -2.6 +/- 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The response rates after 19 days, defined as an improvement in the total symptom score of at least 30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p = 0.002). The total scale of the Pain Adjective List was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p < 0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate that intravenous treatment with alpha-lipoic acid using a dose of 600 mg/day over 3 weeks is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions.

We studied the effect of severe reduction of beta-cell mass by 90% pancreatectomy on the immune tolerance to the endocrine pancreas. Four months after subtotal pancreatectomy all LEW.Han rats had developed mononuclear infiltration of islets and 9 of 14 rats were positive for islet-cell antibodies. Electron microscopy revealed lymphocytic invasion of endocrine tissue, lysis of beta cells and phagocytotic macrophages. None of these changes were seen 2 weeks after 90% pancreatectomy or 4 months after 10% pancreatectomy. Weekly substitution of islet antigens in the form of a homogenate of 100 islets into 90% pancreatectomized LEW.Han rats almost completely prevented the development of insulitis and autoantibodies. The dependence of insulitis on T cells was shown when 90% pancreatectomy in LEW.rnu rats (i.e., the congenic athymic nude strain), did not result in islet infiltration. The exocrine tissue remained normal in all experimental groups. During the observation period insulitis was not associated with overt diabetes but was accompanied by substantial enlargement of islets and of beta-cell mass, as shown by morphometry. Suppression of islet inflammation by injection of islet antigens abolished beta-cell regeneration, despite continuing metabolic stress in rats with 90% pancreatectomy. The findings indicate induction of islet autoimmunity in response to 90% but not to 10% pancreatectomy. We conclude that severe reduction of the islet-antigen mass allows the development of T-cell-dependent islet autoimmunity which indicates a loss of immune tolerance. In addition, the data suggest the existence of islet-antigen autoreactive immune cells in rats not genetically predisposed to autoimmune diabetes. Finally, we conclude that selective beta-cell regeneration occurs in association with insulitis.

An analytical multicomponent method for the blood substrates total protein, glucose, total cholesterol, triglycerides, and urea in human EDTA plasma by FT-IR spectroscopy is described. The spectra were obtained with the use of the attenuated total reflection technique. Partial least-squares was applied for multivariate calibration over optimized spectral ranges. The mean-square prediction errors for the population of 126 plasma samples of different patients calculated by cross-validation are in the range of clinical acceptance. Within an error variance analysis, the contributions of the reference method and the spectrometric measurement to the average (root mean square) prediction error have been estimated for each substrate, giving evidence of the limitations of the spectrometric method. The problem of the biocompatibility of the plasma has been investigated, and the protein adsorption onto the ATR crystal can be reduced to a constant and tolerable level by appropriate cleaning and rinsing. The potential for further improvement is discussed.

BACKGROUND We wished to investigate whether platelet activation is related to the clinical outcome during the 24 hours immediately after elective percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS In 102 patients with high-grade coronary stenosis admitted for elective PTCA, preprocedural platelet activation was characterized by flow cytometric measurement of the proteins CD62, CD63, and thrombospondin expressed on the platelet surface membrane. The prevalence of acute ischemic events during the 24 hours immediately after the procedure was then related to the pre-PTCA platelet activation status. Fifty-six patients were classified as "nonactivated," whereas 46 patients showed an increased percentage of activated platelets. Two patients developed acute occlusion (1.96%) and four patients high-grade restenosis (3.92%), as confirmed by second-look coronary angiography. All events occurred in patients classified as "activated" (six of 46, or 13%). None of these patients received beta-blocker medication, which was associated with lower expression of platelet membrane activation markers. In the nonactivated patient group, no clinical events were found (0 of 56, or 0%). This difference in prevalence is significant (p = 0.007). CONCLUSIONS We conclude that analysis of platelet membrane activation markers may help to predict an increased risk of acute ischemic events after angioplasty.

Near-infrared (NIR) spectra of the human inner lip were obtained by using a special optimized accessory for diffuse reflectance measurements. The partial-least squares (PLS) multivariate calibration algorithm was applied for linear regression of the spectral data between 9000 and 5500 cm−1 (Λ = 1.1–1.8 μm) against blood glucose concentrations determined by a standard clinical enzymatic method. Calibration experiments with a single person were carried out under varying conditions, as well as with a population of 133 different patients, with capillary and venous blood glucose concentration values provided. A genuine correlation between the blood glucose concentrations and the NIR-spectra can be proven. A time lag of about 10 min for the glucose concentration in the spectroscopically probed tissue volume vs. the capillary concentration can be estimated. Mean-square prediction errors obtained by cross-validation were in the range of 45 to 55 mg/dL. An analysis of different variance factors showed that the major contribution to the average prediction uncertainty was due to the reduced measurement reproducibility, i.e., variations in lip position and contact pressure. The results demonstrate the feasibility of using diffuse reflectance NIR-spectroscopy for the noninvasive measurement of blood glucose.

Vascular diseases and related complications still represent the main cause of death in diabetic patients. Neuropathy, nephropathy, retinopathy, and disturbed nutritive tissue perfusion may result from reduced capillary microcirculation. These disturbances are diabetes specific. Macroangiopathy does not differ structurally from atherosclerotic lesions of nondiabetic subjects, but leads to accelerated cerebral, coronary, and peripheral artery disease. Occurrence of life-terminating thrombotic events, which are superimposed on those vascular lesions, are increased. Thus, morbidity and mortality of diabetics depend mainly on vascular complications. Normal blood flow is a prerequisite of adequate organ perfusion and results from vasomotion, plasma components, corpuscular blood elements, vascular architecture, and the undisturbed interaction of these components at the endothelial interface. Functional thromboresistance of the endothelial layer is reduced in the diabetic state. Increased intravascular thrombin generation, reduced fibrinolytic potential, and hyperactive platelets lead to a prethrombotic state. This thrombotic diathesis increases the permanent danger of acute flow interruption. Activated platelets operate by three mechanisms: (1) Microembolization of the capillaries; (2) local progression of preexisting vascular lesions by secretion of constrictive, mitogenic, and oxidative substances; (3) trigger of the prognosis-limiting arterial thrombotic event. We were able to show that the increased functional properties of diabetic platelets result from the primary release of larger platelets with enhanced thromboxane formation capacity and increased numbers of functional glycoprotein receptors GPIb and GPIIb/IIIa, which are synthesized in the megakaryocytes. The megakaryocyte-platelet system is turned on in diabetes mellitus. It could be demonstrated with the Duesseldorf III method of flow cytometric activation marker testing (CD62, CD63, thrombospondin) that predominantly large platelets circulate in an activated state in diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether central nervous conduction deficits are related to the degree of peripheral neuropathy somatosensory evoked potentials (SEP) were measured after tibial nerve stimulation in 51 healthy subjects aged 39.3 (SE 2.0, (range 21-71) years and 100 insulin dependent diabetic patients aged 37.3 (1.5, 18-73) years. Five criteria were used for staging of peripheral neuropathy: nerve conduction; thermal discrimination threshold; vibration perception threshold; tendon reflexes; and neuropathic symptoms. Thirty seven patients had fewer than two abnormalities among the first four criteria and no symptoms (stage 0 = no neuropathy), 37 had 2 or more abnormalities but no symptoms (stage 1 = subclinical neuropathy); 26 had 2 or more abnormalities in conjunction with symptoms (stage 2 = symptomatic neuropathy). Multiple regression analysis was used to define the age and height dependent limits of normal of SEP at the 97.5th and 2.5th centiles. In five patients with stage 1, seven patients with stage 2, but no patient with stage 0 the individual SEP components were unrecordable. The relative frequencies of abnormally prolonged or non-evokable popliteal N8 latency as well as cortical N33 latency and N33/P40 amplitude increased significantly from stage 0 (3-30%) to stage 1 (22-62%) and stage 2 (46-84%) (p < 0.05 for each component and stage). The numbers and percentages of abnormal recordable spinal N22-30 and supraspinal N30-33 interpeak latencies were two (6.3%) and four (11.8%) in patients with stage 0, but these rates did not increase in subjects with stage 1 or 2. The components of SEP were significantly associated with the indices of peripheral and autonomic function tests. There were no major relations between the latencies of SEP and duration of diabetes or prevailing glycaemic control. These findings suggest that the degree of dysfunction along the somatosensory afferent pathways in insulin dependent diabetic patients depends on the stage of peripheral neuropathy; is not related to the degree of glycaemic control or duration of diabetes; and can be characterized mainly by an alteration of the cortical sensory complex and peripheral transmission delay, while spinal and supraspinal conduction deficits are detected infrequently.

Objectif Evaluer les caracteristiques, a l’instauration de l’insuline, associees a l’efficacite du controle glycemique des patients DT2 durant quatre annees. Patients et methodes Donnees recueillies dans 12 pays, 3 continents, pendant 4,0 ± 0,5 an. Controle glycemique defini par : (a) le taux moyen d’HbA1C sur quatre ans, (b) le taux d’HbA1C a quatre ans. Resultats La population etudiee (n = 2 803) etait composee de 49 % de femmes (taux initial d’HbA1C 9,5 ± 1,9 % (moyenne ± ET), âge 61 ± 10 ans, anciennete du diabete 11 ± 8 ans, IMC 29,4 ± 6,3 kg/m 2 ). Les facteurs predictifs univaries du taux moyen d’HbA1C sur quatre ans etaient l’âge, le sexe, l’IMC, l’HbA1C de base, les comorbidites, les antecedents CV familiaux, les hypoglycemiants oraux et le type d’insulinotherapie (tous p ≤ 0,01) ; l’anciennete du diabete, le tabagisme, la dose d’insuline, la pression arterielle, l’activite physique, et les maladies micro/macro-vasculaires n’etaient pas significativement correles. Le modele multivarie incluait quatre facteurs predictifs (p Conclusion Les caracteristiques cliniques sont le facteur predictif le plus puissant du controle glycemique sur quatre ans. Le taux d’HbA1C de base etait le facteur predictif le plus important, suggerant qu’il est plus approprie de debuter l’insuline avant que la deterioration du controle glycemique ne soit trop avancee. Les comorbidites sont egalement predictives, mais de maniere non independante des parametres cliniques.

To determine whether the degree of previous glycaemic control may modify cognitive responses to hypoglycaemia, the glycaemic thresholds for, and magnitude of cognitive dysfunction as assessed by P300 event-related potentials as well as subjective and hormonal responses during hypoglycaemia were evaluated. Hypoglycaemia was induced by intravenous insulin infusion in 18 Type 1 (insulin-dependent) diabetic patients, 7 of whom were strictly controlled (HbA1c: 6.3±0.3%; mean±SEM; Group 1) and 11 of whom were poorly controlled (HbA1c: 9.1±0.4%; Group 2). Within 60 min, mean blood glucose declined from 5.6 and 5.7 mmol/l (baseline) to a nadir of 1.6 and 1.8 mmol/l followed by an increase to 5.6 and 4.3 mmol/l after 120 min in Group 1 and 2, respectively. There was no significant difference between the groups in regard to P300 latency at baseline, but between 50 and 70 min a significant prolongation of this component was noted in Group 2 as compared with Group 1 at blood glucose levels between 1.6 and 2.3 mmol/l (p

Although neuropathy has long been recognized as a complication of diabetes, the impact of this condition has not been adequately established. The prevalence of diabetic neuropathy is virtually unknown because the published studies differ considerably with regard to definition, method of assessment, and patient selection. Furthermore, the determination of prevalence has been hampered by the fact that there is no generally accepted classification of the variety of manifestations of diabetic neuropathy. The introduction of new sensitive diagnostic methods aids in the detection of less severe stages of neuropathy, as compared with clinically based assessment, and renders the disease more prevalent. The prevalence of diabetic neuropathy in the few reported population-based studies was approximately 30%. We have evaluated the prevalence of cardiovascular autonomic neuropathy in a group of approximately 1000 diabetic patients randomly included from 21 hospitals in Germany, Austria, and Switzerland. The results of this study and those of a prospective study on the natural history of neural dysfunction during the first 5 years after diagnosis of type 1 diabetes will be presented.

The natural evolution of neural dysfunction was studied prospectively over 5 years following diagnosis of Type 1 (insulin-dependent) diabetes in 32 patients aged 12–36 years. Motor and sensory nerve conduction velocities, heart rate variation at rest and during deep breathing, and pupillary function were measured at diagnosis and after 3,12, 24,48, and 60 months. Thermal and vibration sensation thresholds were determined after 24, 48, and 60 months of diabetes. Mean HbA1 levels of months 3–60 within the normal range of

Macroangiopathy (or atherosclerosis) is a common and chronic complication in diabetic patients. Unlike other diabetic complications, atherosclerosis is not unique to diabetes, confounding analysis of its relationship with the diabetic condition. Evidence of an independent role for diabetes in the development of atherosclerosis remains equivocal. The main determinant of macrovascular disease may be an interaction between diabetes and the aging process. Similarly the question of a relationship between macrovascular disease and good metabolic control remains unanswered. Macroangiopathy in diabetic populations seems to be related to similar predictors and pathological mechanisms operating in the general population. However, after analysis of these common risk factors for macroangiopathy, a diabetes-specific risk remains. Low-density lipoprotein metabolism is markedly disturbed in poorly controlled diabetic patients. This is manifest as a concert of actions which increase formation of foam cells and fatty streaks. The next step in the atherosclerotic process, the formation of fibrous plaques, may be associated with the platelet hyperactivity seen in diabetes. This may promote overshooting of repair mechanisms at the vessel wall. Release of a specific diabetic serum growth factor from the platelets may be responsible for the later stages of fibrous plaque development and the increased atherosclerotic risk in diabetes.

A double blind placebo controlled trial was performed to evaluate the effects of the aldose reductase inhibitor, ponalrestat, on symptomatic diabetic neuropathy. After a 4-week placebo run-in phase, 60 patients were 2:1 randomized to receive either 600 mg ponalrestat or placebo once daily over 12 months. Forty-six patients, 30 of whom were treated with ponalrestat and 16 with placebo, completed the study. Motor and sensory nerve conduction, thermal and vibration sensation thresholds, heart rate variation at rest, E/I ratio, pupillary dilation velocity and pupillary reflex latency were determined at baseline and after 6 and 12 months. Neuropathic symptom scores were assessed every 3 months. Among the fifteen nerve function parameters studied, only trends in favour of ponalrestat were noted for heart rate variation and E/I ratio after 6 months (P = 0.06), but no significant differences between the groups could be demonstrated during the study. No adverse reactions were observed. It is concluded that one-year treatment with ponalrestat has no beneficial effects on symptoms or electrophysiological parameters in diabetic neuropathy.

We performed serial prospective ultrasound examinations of four flat and 17 soft carotid plaques during an average of 17 months in seven patients with heterozygous hypercholesterolemia during heparin-induced extracorporeal low density lipoprotein elimination on precipitation from plasma. By means of a specially designed quantitative three-dimensional ultrasound analysis, significant plaque volume reduction could be evaluated in all subjects, along with a marked reduction of total and low density lipoprotein cholesterol and fibrinogen serum levels.

Sodium lithium countertransport may be a genetic marker for arterial hypertension and for the risk of diabetic nephropathy in type 1 diabetic patients. Since various factors seem to influence the transport velocity including serum lipid alterations, erythrocytes of seven patients with severe hyperlipoproteinaemia who were chronically and intermittently treated with LDL apheresis were examined before and immediately after therapy. The LDL apheresis reduced sodium lithium countertransport significantly (0.383 vs 0.269, P less than 0.02). Therefore, we conclude that serum lipid composition must be considered when interpreting sodium lithium countertransport velocity.

The aim of the present study was to test whether proinsulin autoantibodies (IgG-PAA), insulin autoantibodies (IgG-IAA), and islet cell antibodies (ICA) may be used to identify subjects at risk for Type 1 diabetes. Pre-diabetic sera from 18 individuals who later developed diabetes were tested. Results were compared with 18 age-, sex-, and HLA-DR-matched non-diabetic control subjects from families with Type 1 diabetes. At a mean of 2.4 yr before the onset of diabetes, ICA were found in 13 patients (vs 0 control subjects, p less than 0.001), ELISA-determined IgG-IAA in 8 patients (vs 1 control subject, p less than 0.05) and ELISA-determined IgG-PAA in 4 patients (vs 2 control subjects, NS). ELISA-determined IgG-PAA do not appear to be useful predictors of the future development of Type 1 diabetes.