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Aims/hypothesis: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN., Methods: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up., Results: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA 1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA 1c , diabetes duration and sex (p=0.03)., Conclusions/interpretation: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN., (© 2023. The Author(s).)

Introduction: The prevalence of neuropathic lesions in young patients with type 1 diabetes mellitus (T1DM) at the time of transition from pediatric care to adult-oriented diabetes care is poorly studied. A comparative study with healthy volunteers to assess the possible neuropathic condition of this special population and to identify the potential early screening needs has not been performed yet. The results may provide important feedback to pediatric diabetes care and a remarkable baseline reference point for further follow up in adult diabetes care., Patients and Methods: Twenty-nine young patients with T1DM [age: 22.4 ± 2.9 years; HbA1c: 8.5 ± 2.1%, diabetes duration: 12.2 ± 5.8 years; (mean ± SD)] and 30 healthy volunteers (age: 21.5 ± 1.6 years; HbA1c: 5.3 ± 0.3%) were involved in the study. Autonomic function was assessed by standard cardiovascular reflex tests. Complex peripheral neuropathic testing was performed by Neurometer ® , Neuropad ® -test, Tiptherm ® , Monofilament ® , and Rydel-Seiffer tuning fork tests., Results: T1DM patients had significantly higher diastolic blood pressure than controls (80 ± 9 vs. 74 ± 8 mmHg, p < 0.01), but there was no significant difference in systolic blood pressure (127 ± 26 vs. 121 ± 13 mmHg). Cardiovascular reflex tests had not revealed any significant differences between the T1DM patients and controls. No significant differences with Neurometer ® , Neuropad ® -test, and Monofilament ® were detected between the two groups. The vibrational sensing on the radius on both sides was significantly impaired in the T1DM group compared to the controls with Rydel-Seiffer tuning fork test (right: 7.5 ± 1.0 vs. 7.9 ± 0.3; left: 7.5 ± 0.9 vs. 7.9 ± 0.3, p < 0.05). The Tiptherm ® -test also identified a significant impairment in T1DM patients (11 sensing failures vs. 1, p < 0.001). In addition, the neuropathic complaints were significantly more frequently present in the T1DM patient group than in the controls (9 vs. 0, p < 0.01)., Conclusion: In this young T1DM population, cardiovascular autonomic neuropathy and cardiac morphological alterations could not be found. However, Rydel-Seiffer tuning fork and Tiptherm ® -tests revealed peripheral sensory neurological impairments in young T1DM patients at the time of their transition to adult diabetes care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vágvölgyi, Maróti, Szűcs, Póczik, Urbán-Pap, Baczkó, Nemes, Csajbók, Sepp, Kempler, Orosz, Várkonyi and Lengyel.)

Background: People with diabetic cardiovascular autonomic neuropathy (CAN) have increased cardiovascular mortality. However, the association between distal symmetric polyneuropathy (DSPN) or CAN with all-cause mortality is much less investigated. Thus, we set out to examine the effect of CAN and DSPN on all-cause mortality in a well-phenotyped cohort., Methods: All diabetes cases ( n = 1,347) from the catchment area of a secondary diabetes care centre who had medical examination including neuropathy assessment between 1997 and 2016 were followed up for all-cause mortality in the NHS Hungary reimbursement database until 2018. We investigated the association of CAN (Ewing tests) and DSPN (Neurometer) with all-cause mortality using Cox models stratified by diabetes type., Results: Altogether, n = 131/1,011 persons with type 1/type 2 diabetes were included. Of the participants, 53%/43% were male, mean age was 46 ± 12/64 ± 10 years, diabetes duration was 13 ± 10/7 ± 8 years, 42%/29% had CAN, and 39%/37% had DSPN. During the 9 ± 5/8 ± 5-year follow-up, n = 28/494 participants died. In fully adjusted models, participants with type 1 diabetes patients with versus without DSPN had an increased mortality (HR 2.99, 95% CI 1.4-8.63), while no association with CAN was observed. In type 2 diabetes, both DSPN and CAN independently increased mortality (HR 1.32, 95% CI: 1.07-1.64, and HR 1.44, 95% CI: 1.17-1.76)., Conclusions: Our results are compatible with an increased risk of mortality in people with type 1 diabetes and DSPN. Furthermore, we report a similarly strong association between DSPN and CAN and all-cause mortality in type 2 diabetes mellitus., Competing Interests: The authors declare that that they have no competing interests., (Copyright © 2021 Orsolya E. Vági et al.)

Background: There are few papers comparing complications of type 1 diabetes with those of a similarly young age with type 2 diabetes. The aim of our nationwide study was to compare the risks of mortality and morbidities between the two types of diabetes (age ≤ 40)., Methods: We identified all young adult patients with type 1 diabetes who were recorded in the database of the Hungarian National Health Insurance Fund between 2001 and 2014 (n = 11 863) and compared them with a population of similar age with young adult type 2 diabetes (n = 47 931). The incidence of all-cause mortality, myocardial infarction, stroke, any type of cancer, diabetic ketoacidosis, and hypoglycemia was followed from the onset of diabetes to the date of death or end of study period., Results: The risks of all-cause mortality were significantly higher in patients with type 1 compared with patients with type 2 diabetes (hazard ratio, 95%CI; 2.17, 1.95-2.41; P < .0001). The risks of myocardial infarction (0.90, 0.71-1.13; P = 0.36) and stroke (1.06, 0.87-1.29; P = .582) were not significantly different in type 1 compared with type 2. In contrast, the risk of cancer (1.35, 1.15-1.59; P = .0003), dialysis (2.20, 1.76-2.75; P < .0001), hypoglycemia (7.70, 6.45-9.18; P < .0001), and ketoacidosis (22.12, 19.60-25.00; P < .0001) was higher among patients with type 1 compared with those with type 2 diabetes., Conclusions: A comparatively higher incidence of diabetic ketoacidosis and hypoglycemia and higher risk of cancer and dialysis in patients with type 1 diabetes than in those with type 2 may play a role in the higher risk of mortality., (© 2019 The Authors Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.)

Cardiac autonomic neuropathy (CAN) is a common complication in type 1 and 2 diabetes and is defined as the impairment of autonomic control of the cardiovascular system. CAN is strongly associated with increased mortality, and in some studies with morbidity of vascular complications, such as stroke, coronary artery disease and myocardial infarction. At the early stages, CAN can be subclinical and it becomes clinically evident as the disease progresses. Subclinically, the disease is defined by cardiovascular reflex testing, which may have prognostic implications. Clinically, the impairment in autonomic function is associated with resting tachycardia, exercise intolerance, orthostatic hypotension, syncope, intraoperative cardiovascular instability, silent myocardial infarction and ischemia, and increased mortality. Although very common and serious, CAN is a frequently overlooked complication of diabetes. Because the progression of cardiovascular denervation is partly reversible or can be slowed down in the early stages of the disease, recent guidelines strongly recommend screening for CAN in patients with diabetes. In this review we summarize the diagnostic tools suggested in the screening for diabetic CAN. Orv Hetil. 2019; 160(35): 1366-1375.

Objective: Historically, a set of 5 Cardiovascular Autonomic Reflex Tests (CARTs) were considered to be the gold standard in the assessment of Cardiovascular Autonomic Neuropathy (CAN). However, measuring diastolic Blood Pressure (BP) response to sustained handgrip is omitted in recent guidelines. We aimed to assess the association between the handgrip and the other 4 tests as well as to identify determinants of the handgrip test results in diabetic patients., Patients and Methods: 353 patients with diabetes (DM) were recruited (age: 60.2±7.4 years; female: 57.2%; BMI: 29.3±2.1 kg/m2; DM duration: 15.6±9.9 years; HbA1c: 7.8±1.4% (66 mmol/mol); with type 1 DM: 18.1%). CAN was assessed by 5 CARTs: the deep breathing test, Valsalva ratio, 30/15 ratio, handgrip and orthostatic hypotension test., Results: Sensitivity and specificity of the handgrip test in the diagnosis of definite CAN were 24.6% (95%CI 17.7-33.1%) and 79.4% (95%CI 73.3-84.4%), respectively. Results of the handgrip test did not show any association with those of the deep-breathing test (y=0.004, p=0.563), 30/15 ratio (y=0.282, p=0.357), Valsalva ratio (y=-0.058, p=0.436) and orthostatic hypotension (y=-0.026, p=0.833). Handgrip test abnormality showed an independent association with higher initial diastolic BP (OR 1.05, p=0.0009) and an independent inverse association with the presence of hypertension (OR=0.42, p=0.006)., Conclusion: Our data confirm that the handgrip test should no longer be part of the cardiovascular autonomic testing being highly dependent on hypertensive status and baseline diastolic BP. Exaggerated exercise pressor response is proposed as putative mechanism for the inverse association between abnormal results of the handgrip test and hypertension. Adequate CARTs are important to allow their use in clinical trials and for the prevention of DM-associated complications by initiating early treatment.

Aim: To investigate the genetic background of human defensin expression in type 1 and 2 diabetes., Methods: Associations between DEFA1/DEFA3 gene copy number polymorphism and diabetes as well as between the promoter polymorphisms of DEFB1 and diabetes were studied. The copy number variation of the DEFA1/DEFA3 genes was determined in 257 diabetic patients (117 patients with type 1 and 140 with type 2 diabetes). The control group consisted of 221 age- and gender-matched healthy blood donors. The cumulative copy numbers of the DEFA1/DEFA3 genes were detected by using quantitative PCR analysis. To evaluate the HNP 1-3 (human neutrophil peptide 1-3 or α-defensin) levels in the circulation, plasma HNP 1-3 concentrations were measured by ELISA. The expression of DEFA1/A3 in peripheral leukocytes of the diabetic patients was measured by quantitative RT PCR analysis. Three SNPs of the human DEFB1 (human defensin β-1) gene: DEFB1 G-20A (rs11362), DEFB1 C-44G (rs1800972) and DEFB1 G-52A (rs1799946) were genotyped by Custom TaqMan(®) Real Time PCR assay., Results: Significant differences were observed in HNP1-3 levels between the healthy subjects and both groups of diabetic patients. The mean ± SE was 28.78 ± 4.2 ng/mL in type 1 diabetes, and 29.82 ± 5.36 ng/mL in type 2 diabetes, vs 11.94 ± 2.96 ng/mL in controls; P < 0.01 respectively. There was no significant difference between patients with type 1 and type 2 diabetes in the high plasma concentrations of HNP1-3. The highest concentrations of α-defensin were found in diabetic patients with nephropathy (49.4 ± 4.8 ng/mL), neuropathy (38.7 ± 4.8 ng/mL) or cardiovascular complications (45.6 ± 1.45 ng/L). There was no significant difference in the cumulative copy numbers of DEFA1/DEFA3 genes between controls and patients, or between patients with the two types of diabetes. Comparisons of HNP 1-3 plasma level and DEFA1/A3 copy number of the same patient did not reveal significant relationship between defensin-α levels and the gene copy numbers (r (2) = 0.01). Similarly, no positive correlation was observed between the copy numbers and the mRNA expression levels of DEFA1/A3. Regarding the C-44G polymorphism of DEFB1, the GG "protective" genotype was much less frequent (1%-2%) among both groups of patients than among controls (9%)., Conclusion: Elevated HNP1-3 levels in diabetes are independent of DEFA1/DEFA3 copy numbers, but GG genotype of C-44G SNP in DEFB1 gene may result in decreased defensin β-1 production.

Aims/hypothesis: Cardiac autonomic neuropathy (CAN) is associated with increased morbidity and mortality in type 1 diabetes. Apart from glycaemic control, risk factors for CAN have not been extensively studied., Methods: As part of the EURODIAB Prospective Complications Study, CAN--defined as either a loss of heart rate variability or postural hypotension on standing--was assessed at baseline and follow-up (7.3+/-0.6 years from baseline) in patients with type 1 diabetes., Results: Follow-up measurements were available for 956 participants without CAN at baseline (age at baseline 31.3+/-8.9 years, duration of diabetes 13.5+/-8.3 years). During follow-up, 163 (17%) subjects developed CAN, yielding an incidence of 23.4 per 1,000 person-years. Blood pressure, weight, the presence of cardiovascular disease, albuminuria, distal symmetrical polyneuropathy (DSP) and retinopathy at baseline were associated with the incidence of CAN after adjustment for sex, duration of diabetes and HbA(1)c. In a multivariate regression model, baseline factors associated with an increased risk of developing CAN were age [odds ratio (OR)=1.3 per decade, 95% CI 1.1-1.7], HbA(1)c (OR=1.2 per percentage point, 95% CI 1.1-1.4), systolic blood pressure (OR=1.1 per 10 mmHg, 95% CI 1.0-1.3), feeling faint on standing (OR=2.0, 95% CI 1.2-3.2), DSP (OR=1.9, 95% CI 1.2-3.0) and retinopathy (OR=1.7, 95% CI 1.1-2.6)., Conclusion/interpretation: This study confirms the importance of exposure to hyperglycaemia as a risk factor for CAN. A small set of variables, including HbA(1)c, hypertension, DSP and retinopathy, predict the risk of CAN. Clinical trials are needed to address the impact of intensive antihypertensive treatment on CAN in type 1 diabetes.

Aims: To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study., Methods: The study involved the examination of randomly selected Type I (insulin-dependent) diabetic patients from 31 centres in 16 European countries. Neuropathic symptoms and two tests of autonomic function (changes in heart rate and blood pressure from lying to standing) were assessed and data from 3007 patients were available for the present analysis. Autonomic neuropathy was defined as an abnormality of at least one of the tests., Results: The prevalence of autonomic neuropathy was 36% with no sex differences. The frequency of one and two abnormal reflex tests was 30% and 6%, respectively. The R-R ratio was abnormal in 24% of patients while 18% had orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on standing. Significant correlations were observed between autonomic neuropathy and age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been identified from the study: the strong relationship of autonomic neuropathy to cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05) and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was related to the presence of cardiovascular disease (P < 0.0001). All analyses were adjusted for age, duration of diabetes and HbA1c. However, data have been only partly confirmed by logistic regression analyses. Frequency of dizziness on standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had problems with bladder control., Conclusion: Cardiovascular reflex tests, even in the form of the two tests applied, rather than a questionnaire, seem to be appropriate for the diagnosis of autonomic neuropathy. The study has identified previously known and new potential risk factors for the development of autonomic neuropathy, which may be important for the development of risk reduction strategies. Our results may support the role of vascular factors in the pathogenesis of autonomic neuropathy.

Aim: To examine the prevalence of hypertension and the rates of hypertension awareness by investigating treatment and control among respondents to the EURODIAB IDDM Complications Study, and to explore the variation in hypertension management by age, sex and end-organ damage., Methods: A cross-sectional study, examining 3250 randomly selected Type 1 diabetic patients from 31 diabetes clinics in 16 European countries between 1989 and 1990. Mean age was 32.7 years (SD= 10.0) and mean duration of diabetes mellitus (DM) was 14.7 years (SD=9.3). Subjects were asked about a history of high blood pressure (BP) and current prescribed medications were recorded by the subject's physician. Hypertension was defined as having a systolic BP > or = 140 mmHg or diastolic BP > or = 90 mmHg or current use of antihypertensives. Control was defined as a BP < 130/85 mmHg., Results: Twenty-four per cent of subjects had hypertension, among whom fewer than one-half (48.5%) were aware of a previous diagnosis and a similar proportion (42.2%) were on treatment. Only 11.3% of those with hypertension were both treated and controlled. The majority (81%) of those receiving drug therapy for hypertension were on a single drug, most commonly an angiotensin-converting enzyme inhibitor (47%)., Conclusion: These data show the extent of undermanagement of hypertension in Type 1 DM across Europe prior to the publication of the St. Vincent Declaration and provide a useful baseline against which future improvements in the management of hypertension can be monitored.

The aim of the present study was to investigate peripheral sensory nerve function in diabetic children and adolescents without neurological symptoms. Ninety-two children and adolescents with Type 1 (insulin-dependent) diabetes mellitus (mean +/- SD age: 14.2 +/- 2.1 years, diabetes duration: 5.8 +/- 3.0 years) and 80 healthy control subjects (age: 13.8 +/- 2.2 years) matched for age, sex, body mass index, and height standard deviation score were involved in the study. Using a sine-wave transcutaneous stimulator, current perception threshold (CPT) testing at 2000, 250 and 5 Hz was performed on the left median and peroneal nerves. Diabetic children had increased CPT at 2000 Hz on both nerves as compared to the control group (median (interquartile range), median nerve: 2.43 (2.20-3.43) vs 1.80 (1.51-2.60) mA, p = 0.02; peroneal nerve: 3.51 (2.81-4.82) vs 2.70 (2.04-3.70) mA, p = 0.01). Twenty-one (23%) of patients had CPT values higher than that of any healthy individual. Of these, elevated CPT was observed in 9 (9.8%) patients on the median nerve, in 8 (8.7%) patients on the peroneal nerve, and in 4 (4.3%) patients on both median and peroneal nerves. Using multiple logistic regression analysis, worse long-term metabolic control and advanced puberty were independently predictive of peripheral sensory nerve dysfunction as the dependent variable (adjusted OR (95% CI): 3.4 (1.2-6.2), p = 0.01, and 2.8 (1.1-5.6), p = 0.03, respectively). In conclusion, evidence of peripheral sensory nerve dysfunction is not rare in children and adolescents with diabetes and can be demonstrated by CPT testing in asymptomatic patients. Poor metabolic control is a risk factor for such subclinical neuropathy, and pubertal development may be involved in the pathogenesis of diabetic peripheral neuropathy.

The hypothesis that diabetic patients with autonomic neuropathy are at increased risk of severe hypoglycaemia was examined in an epidemiological study of over 3000 IDDM patients in Europe (EURODIAB IDDM Complications Study). Autonomic function was assessed by two standard cardiovascular tests: change in heart rate and systolic blood pressure on standing. Severe hypoglycaemia was defined as an attack serious enough to require the help of another person. Compared to patients (68%) reporting no attacks in the last year, those reporting one or more attacks were older (34.0 +/- 10.7 vs 32.1 +/- 9.9 years, mean +/- SD, p < 0.0001), had had diabetes for a longer period (16.6 +/- 9.5 vs 13.8 +/- 9.1 years, p < 0.0001), had better glycaemic control (HbA1c 6.4 +/- 1.8 vs 6.9 +/- 1.9%, p < 0.0001) and were more likely (p = 0.002) to have abnormal responses to both autonomic tests (13.0 vs 7.7%). A single abnormal autonomic response was not associated with an increased risk of severe hypoglycaemia. The odds ratio for severe hypoglycaemia in people with abnormal responses to both autonomic tests, compared to those with normal responses, was 1.7 (95% confidence interval 1.3, 2.2) after controlling for age, duration of diabetes, glycaemic control and study centre. In conclusion, a combined autonomic deficit in heart rate and blood pressure responses to standing is associated with only a modest increase in the risk of severe spontaneous hypoglycaemia. Although the increase in risk is not large, severe hypoglycaemia was a frequently reported event in this study. IDDM patients with deficient autonomic responses who strive for tight glycaemic control may therefore be at particular risk of severe hypoglycaemia.