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Background: The prognostic importance of several hematological parameters has been scarcely investigated in type 2 diabetes. So, we aimed to evaluate their prognostic importance for development of complications in a cohort of type 2 diabetes., Methods: In a prospective study, 689 individuals with type 2 diabetes had blood red cell, platelet and leukocyte parameters obtained at baseline. Multivariate Cox analyses examined the associations between several hematological parameters (including neutrophyl-to-lymphocyte, lymphocyte-to-monocyte, platelet-to-lymphocyte, and monocyte-to-HDL ratios) and the occurrence of microvascular (retina, renal and peripheral neuropathy) and cardiovascular complications (total cardiovascular events [CVEs], and major adverse CVEs [MACEs]), and all-cause and cardiovascular mortality. Improvements in risk discrimination were assessed by C-statistics and Integrated Discrimination Improvement (IDI) index., Results: During a median follow-up of 10.5 years, 212 patients had a CVE (174 MACEs), 264 patients died (131 cardiovascular deaths); 206 had a renal, 161 a retinopathy and 179 patients had a neuropathy outcome. In multivariate-adjusted analyses, the lymphocytes count and lymphocyte-to-monocyte ratio were protective (hazard ratios [HRs]: 0.77 and 0.72, respectively), whereas the neutrophyl-to-lymphocyte and platelet-to-lymphocyte ratios were associated with increased risks (HRs: 1.19 and 1.17) for all-cause mortality. For cardiovascular mortality, the monocytes count, the neutrophyl-to-lymphocyte and monocyte-to-HDL ratios were associated with increased risks and the lymphocyte-to-monocyte ratio was protective. Higher lymphocyte-to-monocyte ratio was protective for renal failure outcome. However, none of them improved risk discrimination., Conclusions: Low lymphocytes count and leukocyte ratios that mainly included lymphocytes were predictors of macrovascular complications and mortality in individuals with type 2 diabetes. However, they did not improve risk prediction over traditional risk factors.

Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.

The impairment of cardiovascular autonomic control among the underdiagnosed complication of diabetes mellitus (DM) with a high prevalence rate of up to 60% in type 2 DM (T2DM). Cardiac autonomic neuropathy (CAN) is an independent risk factor for cardiovascular mortality, arrhythmia, silent ischemia, any major cardiovascular event, and heart failure. We aimed to evaluate cardiovascular autonomic activity by different physiological maneuvers, study risk factors for diabetic CAN including age, gender, duration of diabetes, body mass index (BMI), and glycemic control, and correlate CAN stage with risk factors. One hundred and forty-two T2DM patients consisted of 62 males and 80 females and 100 volunteers as a control sample. Cardiac autonomic functions were assessed by Ewing's tests. Glycated hemoglobin (HbA1c), body weight, height, body mass index (BMI), and waist-hip ratio (WHR) were also measured. Cardiovascular autonomic functions and Ewing scores were significantly different in people with diabetes when compared with control healthy subjects. Ewings test values and Ewing scores were significantly different between diabetics with and without CAN and within patients with different CAN staging. People with diabetes with CAN have a significantly longer duration of disease when compared to those without CAN. A strong association has been found between CAN severity and patient age, duration of disease, HbA1c severity, and the WHR (P < 0.001) but not with BMI. The duration of disease and HbA1c level appear to be associated with the development of CAN (P = 0.001 and P = 0.008, respectively). The poorer glycemic control and the longer the duration of the disease, the higher the prevalence of CAN in T2DM. Age, duration of disease, WHR, and HbA1c are well correlated with the severity of CAN. Parasympathetic impairment is more sensitive to the detection of autonomic dysfunctions than do sympathetic impairment.

Purpose: Type 2 diabetes-related polyneuropathy (DPN) is associated with increased vascular events and mortality, but determinants and outcomes of pain in DPN are poorly understood. We sought to examine the effect of neuropathic pain on vascular events and mortality in patients without DPN, DPN with pain (DPN + P), and DPN without pain (DPN-P)., Methods: A retrospective cohort study was conducted within a large health system of adult patients with type 2 diabetes from January 1, 2009 through December 31, 2016. Using an electronic algorithm, patients were classified as no DPN, DPN + P, or DPN-P. Primary outcomes included number of vascular events and time to mortality. Independent associations with DPN + P were evaluated using multivariable negative binomial and Cox proportional hazards regression models, adjusting for demographics, socioeconomic characteristics, and comorbidities., Results: Of 43 945 patients with type 2 diabetes (age 64.6 ± 14.0 years; 52.1% female), 13 910 (31.7%) had DPN: 9104 DPN + P (65.4%) vs 4806 DPN-P (34.6%). Vascular events occurred in 4538 (15.1%) of no DPN patients, 2401 (26.4%) DPN + P, and 1006 (20.9%) DPN-P. After adjustment, DPN + P remained a significant predictor of number of vascular events (incidence rate ratio [IRR] = 1.55, 95% CI, 1.29-1.85), whereas no DPN was protective (IRR = 0.70, 95% CI, 0.60-0.82), as compared to DPN-P. Compared to DPN-P, DPN + P was also a significant predictor of mortality (hazard ratio = 1.42, 95% CI, 1.25-1.61)., Conclusions: Our study found a significant association between pain in DPN and an increased risk of vascular events and mortality. This observation warrants longitudinal study of the risk factors and natural history of pain in DPN., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study aimed to compare cause-specific mortality rates in patients with type 2 diabetes with and without various vascular complications., Methods: In Japanese hospitals, we followed up 30 834 patients with a mean age of 64.4 (standard deviation [SD]: 11.1) years. Patients were followed up from 2003 to 2007 for a median of 7.5 (interquartile range: 6.1-9.7) years. We calculated cause-specific mortality rates (number of deaths/1000 person-years) and confounder-adjusted hazard ratios in patients with macrovascular disease and in those with diabetic nephropathy, neuropathy and retinopathy, allowing for overlap of complications., Results: All-cause mortality rate was highest (51.4) in the nephropathy group, followed by the macrovascular disease group (45.2), the neuropathy group (39.5), the retinopathy group (38.7) and the nonvascular complication group (18.1). In the nephropathy group, morality rates of ischaemic heart, cerebrovascular, and infectious diseases and cancer were also highest among the groups. However, the cancer mortality rate was similar among the vascular complication groups. Relative to the nonvascular complication group, covariate-adjusted hazard ratios for ischaemic heart and cerebrovascular disease mortality were triple to quadruple in the macro- and microvascular complication groups. All-cause mortality rates rose exponentially according to age., Conclusion: Highest risks of all-cause, cancer, and ischaemic heart, infectious, and cerebrovascular disease mortality were determined in Japanese patients with diabetic nephropathy. Although cancer is the primary cause of death in Japanese patients with diabetes, cancer mortality rates are similar among those with and without vascular complications., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Objective: To compare cognitive function, mood and sleep status in patients with and without diabetic neuropathic pain (DNP) and their relationship with pain intensity, diabetes complications, and quality of life. To determine whether these relationships differ depending on the sensorial phenotype., Methods: Cross-sectional study performed on patients with type-2 diabetes-mellitus and neuropathy. Presence of DNP, pain intensity and phenotype, mood status, sleep characteristics and quality of life were measured., Results: A total of 130 patients (65 with DNP) were included. DNP was related to poor sleep quality (OR = 1.03;CI95%:1.02-1.05), pain treatment (OR = 3.00,CI95%:1.24-7.29) or previous anxiety (OR = 2.70,CI95%:1.05-6.99). Patients with specific phenotypes or depression (=0.82,CI95%:-0.02-1.67) referred more severe pain. More complications were related to older age (OR = 1.40,CI95%:1.12-1.66), higher pain intensity (OR = 1.51,CI95%:1.00-2.28), lower cognitive performance (OR = 1.25,CI95%:1.09-1.43), previous anxiety (OR = 10.48,CI95%:1.46-75.24) and insulin treatment (OR = 124.50,CI95%:6.64-2335.06). Decrease in mental quality of life was associated with sleep disorders (β = -0.33,CI95%:-0.48,-0.23), physical comorbidities (β = -9.73,CI95%:-18.15, -1.31) and previous anxiety (β = -7.91,CI95%:-13.04, -2.77). Lower scores in physical quality of life were related to sleep disorders (β = -0.12,CI95%:-0.21, -0.18), obesity (β = -8.35,CI95%:-13.16, -3.55), longer time since diagnosis (β = -0.72,CI95%:-1.44;0.01) and disability (β = -14.58,CI95%:-24.69; -4.48)., Conclusions: The results support the idea that mental comorbidity and sleep disorders are factors associated with DNP and greater pain intensity, more diabetes complications and lower quality of life. Moreover, they highlight the relationship between sensorial phenotypes and pain intensity, and lower cognitive performance and diabetes complications., Competing Interests: Declaration of Competing Interest This work was supported by Andalusian Society of Family and Community Medicine – SAMFyC (Spain) and by the collaboration between the University of Cádiz and the Grünenthal Foundation. The Grünenthal Foundation is a private non-profit making organization that promotes the dissemination of scientific knowledge and supports research. The authors declare that there is no duality of interest associated with this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The prognostic importance of an increased visit-to-visit blood pressure variability (BP-VVV) for the future development of micro- and macrovascular complications in type 2 diabetes has been scarcely investigated and is largely unsettled. We aimed to evaluate it in a prospective long-term follow-up study with 632 individuals with type 2 diabetes., Methods: BP-VVV parameters (systolic and diastolic standard deviations [SD] and variation coefficients) were measured during the first 24-months. Multivariate Cox analysis, adjusted for risk factors and mean BP levels, examined the associations between BP-VVV and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications (total cardiovascular events [CVEs], major adverse CVEs [MACE] and cardiovascular and all-cause mortality). Improvement in risk discrimination was assessed by the C-statistic and integrated discrimination improvement (IDI) index., Results: Over a median follow-up of 11.3 years, 162 patients had a CVE (132 MACE), and 212 patients died (95 from cardiovascular diseases); 153 newly-developed or worsened diabetic retinopathy, 193 achieved the renal composite outcome (121 newly-developed microalbuminuria and 95 deteriorated renal function), and 171 newly-developed or worsened peripheral neuropathy. Systolic BP-VVV was an independent predictor of MACE (hazard ratio: 1.25, 95% CI 1.03-1.51 for a 1-SD increase in 24-month SD), but not of total CVEs, cardiovascular and all-cause mortality, and of any microvascular outcome. However, no BP-VVV parameter significantly improved cardiovascular risk discrimination (increase in C-statistic 0.001, relative IDI 0.9%)., Conclusions: Systolic BP-VVV was an independent predictor of MACE, but it did not improve cardiovascular risk stratification. The goal of anti-hypertensive treatment in patients with type 2 diabetes shall remain in controlling mean BP levels, not on decreasing their visit-to-visit variability.

Background: Microvascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes., Methods: We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis., Results: Out of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59-7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65-15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42-94.57], p < 0.0001). After adjustments, HRs were: 1 MC 2.05 (95% CI 0.88-4.76), 2 MC 1.98 (95% CI 0.75-5.21), 3 MC 7.02 (95% CI 2.44-20.20, p = 0.002). Forty-nine subjects (6.7%) had at least one cardiovascular event, and cumulative incidence went from no-MC 2.2% (Ref) to 1 MC 5.0%; (HR 2.27 [95% CI 0.96-5.38]), 2 MC 26.8% (HR 12.88 [95% CI 5.82-28.50]) and 3 MC 40.9% (HR 29.34 [95% CI 11.59-74.25], p < 0.0001). Upon adjustments, HRs were: 1 MC 1.59 (95% CI 0.65-3.88), 2 MC 4.33 (95% CI 1.75-10.74), 3 MC 9.31 (95% CI 3.18-27.25, p < 0.0001). Thirty-five individuals (4.8%) had at least one coronary event, which cumulative incidence increased with MC burden (p < 0.0001)., Conclusions: In type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

Aims: To ascertain the effects of improvements in diabetic foot services over 18 years on incidence of diabetic foot ulceration. We also compared survival time from first ulcer development with presence of neuropathy, peripheral vascular disease, age and healing., Methods: Persons with new ulceration and those at high risk of ulcer development were referred to community podiatry from 1998. Their details were recorded, with verbal consent, on a central database. The effects of neuropathy, peripheral vascular disease, healing and age on survival were analysed by Cox proportional hazards ratios., Results: The incidence of first ulcer presentation decreased from 11.1 to 6.1 per 1000 persons between 2003 to 2017 (P <0.0001). Recurrent ulceration incidence remained stable. Prevalence of chronic and new foot ulceration combined increased from 20.7 to 33.1 per 1000 persons (P <0.0001). Ten-year survival was 85% for persons presenting with first ulcer and aged < 65 years, 50% for those aged 65-74 years and 25% for those aged 75-81 years (P < 0.0001). In those with peripheral vascular disease 5-year survival was 35% (P <0.001)., Conclusions: Integrated care for the diabetic foot in one National Health Service (NHS) health service area over 18 years was associated with a reduction in first presentations of diabetic foot ulceration, but failed to reduce recurrent ulceration. Cumulative prevalence of all ulcers continues to increase. Monitoring ulceration incidence can inform audit and planning of diabetic foot care services. Survival is better than reported previously in persons < 65 years and in the absence of peripheral vascular disease., (© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims/hypothesis: The role of burden and duration of multiple microvascular complications on mortality rate has not been explored in detail in type 1 diabetes. Taking complication burden and time-updated duration into account we aimed to quantify mortality rate in individuals with and without microvascular complications., Methods: This observational clinical cohort included 3828 individuals with type 1 diabetes attending the Steno Diabetes Center Copenhagen in 2001-2013. We used information on mortality and detailed clinical measures of microvascular complications from electronic patient records. Poisson models were used to model mortality rates according to complication burden., Results: During 26,665 person-years of follow-up, 503 deaths occurred. Compared with individuals without microvascular complications, the mortality rate ratio was 2.20 (95% CI 1.79, 2.69) for individuals with diabetic kidney disease, 1.72 (95% CI 1.39, 2.12) for individuals with neuropathy and 1.02 (95% CI 0.77, 1.37) for individuals with retinopathy, all adjusted for calendar time (year/month/day), age, duration of diabetes, sex, HbA 1c , LDL-cholesterol, BMI, smoking status, systolic blood pressure, use of antihypertensive and lipid-lowering medication, and cardiovascular disease status. In individuals with two complications or more, the risk of mortality did not exceed the combined risk from each individual complication. Mortality rate ratios increased immediately after diagnosis of neuropathy and diabetic kidney disease. Mortality rate ratios were independent of the duration of neuropathy and retinopathy, while the mortality rate associated with diabetic kidney disease reached a stable level after approximately 3 years., Conclusions/interpretation: Neuropathy and diabetic kidney disease are strong and independent risk markers of mortality in type 1 diabetes, whereas no evidence of higher mortality rate was found for retinopathy. We found no indication that the mortality risk with multiple complications exceeds the risk conferred by each complication separately. The duration spent with microvascular complications had only a marginal effect on mortality.

Diabetes is one of the most common chronic pathologies around the world, involving treatment with general clinicians, endocrinologists, cardiologists, ophthalmologists, nephrologists and a multidisciplinary team. Patients with type 2 Diabetes Mellitus (T2DM) can be affected by cardiac autonomic neuropathy, leading to increased mortality and morbidity. In this review, we will present current concepts, clinical features, diagnosis, prognosis, and possible treatment. New drugs recently developed to reduce glycemic level presented a pleiotropic effect of reducing sudden death, suggesting a potential use in patients at risk.

Aims: Charcot foot is a rare but disabling complication to diabetic neuropathy, and can cause permanent, limb-threatening deformities. The aim of this study was to investigate a population of patients a Charcot foot on a case-by-case basis, in order to assess the consequences of an acute Charcot foot and its complications., Methods: The study was conducted a retrospective study of patients admitted to the Copenhagen Wound Healing Center between 1996 and 2015 with the diagnosis of Charcot foot (DM14.6) and diabetes mellitus type 1 or 2 (DE10.X and DE11.X). Physical and electronic records were used, and compared to data from the Danish Diabetes Registry., Results: In total 392 patients were identified of which 173 were included. There were 26% with type 1 diabetes (initial HbA1c 81.7 ± 21.4 mmol/mol) and 74% with type 2 diabetes (initial HbA1c 66.5 ± 20.3 mmol/mol). Primary off-loading was with a removable walker in 95% of the cases (average off-loading time 8.3 months). The 5-year mortality was 14% with a mean survival time of 12.7 years. There was an association between lack of compliance and occurrence of foot complications, as well as between having a Charcot foot and leaving the workforce., Conclusion: More patients had type 1 diabetes compared to the background population, and they had a higher HbA1c than the general population of diabetes patients. A total of 67% developed complications such as ulcers, while patients non-compliant to treatment did significantly worse than those being compliant. The 5-year mortality was low, 14%, and comparable to diabetes patients without Charcot foot., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Identify in patients with type 2 diabetes what changes in the feet would be associated with demographic, clinical, biochemical and treatment characteristics and which would increase the risk of mortality., Methods: Retrospective longitudinal study evaluating the alterations in feet of outpatients attended at a nursing visit. Data from the clinical history and foot exam were collected from 918 medical records of a convenience sample., Results: At 10 years, the cumulative mortality attributable to peripheral polyneuropathy was 44.7%, to peripheral artery disease was 71.7%, to both conditions were 62.4%, and to amputation was 67.6%. After multivariate analysis, duration of nursing follow-up remained as the only protective factor against death (p < 0.001)., Conclusions: The risk of death in these patients decreased when they had consultations with a nurse educator. Ischemic feet, amputation, and coronary artery disease remained independent risk factors.

Background/aims: Ultrafiltration rate (UFR) appears to be associated with mortality in prevalent hemodialysis (HD) patients. However, the association of UFR with mortality in incident HD patients remains unknown., Methods: We examined a US cohort of 110,880 patients who initiated HD from 2007 to 2011. Baseline UFR was divided into 5 groups (<4, 4 to <6, 6 to <8, 8 to <10, and ≥10 mL/h/kg body weight [BW]). We examined predictors of higher baseline UFR using logistic regression and the association of baseline UFR and all-cause and cardiovascular (CV) mortality using Cox proportional hazard models with adjustments for demographics, comorbidities, and markers of malnutrition-inflammation-cachexia syndrome., Results: Patients were 63 ± 15 years, with 43% women, 32% African Americans, and had a mean baseline UFR of 7.5 ± 3.1 mL/h/kg BW. In the fully adjusted logistic regression models, factors associated with higher UFR (≥7.5 mL/h/kg BW) included Hispanic ethnicity, diabetes, and higher dietary protein intake. There was a linear association between UFR and all-cause and CV mortality, where UFR ≥10 mL/h/kg BW (reference UFR 6-<8 mL/h/kg BW) conferred the highest risk in both unadjusted (HR 1.15 [95% CI 1.10-1.19]) and adjusted models (HR 1.23 [95% CI 1.16-1.31]). The linear association with all-cause mortality remained consistent across strata of age, urine volume, and treatment time., Conclusions: Higher UFR is independently associated with higher all-cause and CV mortality in incident HD patients. Clinical trials are warranted to examine the effects of lowering UFR on outcomes., (© 2018 S. Karger AG, Basel.)

Purpose of Review: This article reviewed very recent papers (2016) discussing or bringing clinical evidences of the possible common pathways leading to diabetic foot syndrome (DFS) and increased mortality rates., Recent Findings: Diabetic patients with diabetic foot syndrome have a mortality rate greater than twofold when compared with non-ulcerated diabetics. In addition, the 5-year mortality rate following amputation is estimated at 39-68%, a life expectancy comparable to aggressive types of cancer or advanced congestive heart failure. The majority of patients with diabetic foot ulcer also present insulin resistance, central obesity, dyslipidemia, and hypertension that characterize the metabolic syndrome that, in turn, is associated with an elevated risk of major cardiovascular events. Sensory neuropathy is the primary cause of more the 60% of diabetic foot ulcer. Diabetic peripheral neuropathy is a microvascular complication of diabetes mellitus and in type 2 diabetes, not only hyperglycemia but also other metabolic alterations and persistent inflammatory status due to adiposity play a major role in axon injury. Elevated triglycerides have been showed to be an independent risk factor for lower extremity amputation in diabetic patients. Also, toxic adiposity, oxidative stress, mitochondrial dysfunction, activation of the polyol pathway, accumulation of advanced glycation end products (AGEs), and elevation of inflammatory markers are also implicated in diabetic vascular disease and neuropathy. The hypotheses that the association between DFS and increased rates of mortality reflects the progression of micro- and macrovascular complications are reinforced by the additional association of DFU to renal failure and retinopathy.

We investigated the associations between diabetes (type 1, type 2 or no diabetes) and intracerebral haemorrhage (ICH) incidence as well as case fatality after ICH, in a retrospective cohort study of people aged 40 to 89 years in Scotland during the period 2004 to 2013, using linkage of population-based records of diagnosed diabetes, hospital discharges and deaths. We calculated ICH incidence and 30-day case fatality after hospital admission for ICH, along with their relative risks (RR) and 95% confidence intervals (CIs), among people with type 1 or type 2 diabetes compared to people without diabetes, adjusting for age, sex and socio-economic status (SES). There were 77, 1275 and 9778 incident ICH events and the case-fatality rate was 44% (95% CI 33, 57), 38% (95% CI 35, 41) and 36% (95% CI 35, 37) in people with type 1, type 2 and without diabetes, respectively. In comparison with absence of diabetes, type 1 diabetes was associated with a higher incidence of ICH (1.74, 95% CI 1.38-2.21) and higher case fatality after ICH (1.35, 95% CI 1.01-1.70), after adjustment for age, sex and SES. The small increases in ICH incidence (1.06, 95% CI 0.99-1.12) and case-fatality (1.04, 95% CI 0.96-1.13) in people with type 2 diabetes compared with people without diabetes were not statistically significant., (© 2017 John Wiley & Sons Ltd.)

Aim: To determine the association of neuropathy and other complications with emotional distress and depression among patients with longstanding type 1 diabetes (T1DM)., Methods: Canadians with ≥50years of T1DM completed a questionnaire including assessment of distress and depression by the Problem Areas in Diabetes Scale (PAID) and Geriatric Depression Scale (GDS), respectively. Complications were determined using the Michigan Neuropathy Screening Instrument (Questionnaire Component), fundoscopy reports, renal function tests, and self-reported peripheral-(PVD) and cardiovascular (CVD) disease. Associations were analyzed by Poisson regression., Results: Among 323 participants, 137 (42.4%) had neuropathy, 113 (36.5%) nephropathy, 207 (69.5%) retinopathy, 95 (29.4%) CVD, and 31 (9.8%) PVD. The neuropathy subgroup had higher prevalence of distress (13 (9.5%) vs. 6 (3.3%), p=0.029) and depression (34 (24.9%) vs. 12 (6.5%), p<0.001). Adjusting for diabetes complications, neuropathy was associated with higher PAID (adjusted RR 1.44 (95% CI 1.14-1.82), p=0.003) and GDS scores (adjusted RR1.57 (1.18-2.11), p=0.002). Independent of potential confounders, neuropathy remained associated with higher PAID (adjusted RR 1.39 (1.10-1.76), p=0.006) and GDS scores (adjusted RR 1.37 (1.03-1.83), p=0.032). Associations with neuropathy were not fully explained by neuropathic pain., Conclusion: Compared to other complications, neuropathy had the greatest association with distress and depression in longstanding T1DM, independent of pain. Strategies beyond pain management are needed to improve quality of life in diabetic neuropathy., (Copyright © 2017. Published by Elsevier Inc.)

Our previous studies showed that direct injury to the sciatic nerve (chronic constriction injury or axotomy) is associated with a numerical increase in synaptic number in the rat spinal dorsal horn. The aim of this study was to determine whether painful diabetic neuropathy (PDN) was also associated with numerical changes in the synaptic or neuronal numbers in the spinal dorsal horn. Overall, 17 adult SD rats were allocated randomly into the control group (n=5) and the streptozotocin (STZ) group (n=12). STZ was injected intraperitoneally to induce diabetes. In the STZ group, seven rats (STZ-H) showed hyperglycemia (fasting blood glucose >11.1 mM) and the rest of the five rats (STZ-N) did not. Rats were fed and observed for 28 days after hyperglycemia. Two of the seven STZ-H rats died of infection during the observation period. Body weight and paw withdraw threshold (PWT) decreased in the rest of the five STZ-H rats. Twenty-eight days after hyperglycemia, the L5 segment of the spinal cord was removed; paraffin-embedded sections were prepared and stained with Nissl's method and synaptophysin immunohistochemistry, respectively. The optical dissector (a stereological technique) was used to estimate the numbers of neurons and synapses in the spinal dorsal horn. Compared with the control group, the synaptic number and ratio between the numbers of synapses and neurons in the L5 segment of the spinal dorsal horn were increased significantly in the STZ-H rats (P<0.05), whereas the neuronal number did not change significantly (P>0.05). Parameters of STZ-N rats showed no significant changes. In conclusion, PDN, a form of neuropathic pain, is also associated with a synaptic plasticity (numerical increase) in the spinal dorsal horn. This numerical change might be the reason for central sensitization resulting in reduced pain threshold, enhanced responsiveness, and expanded receptive fields associated with PDN. Therefore, our studies indicate that neuropathic pain conditions with different etiologies might show the same synaptic numerical plasticity changes.

Aims: The purpose of this study was to portray the impact of comorbidities on inpatient cost and utilization in Charcot neuroarthropathy (CN) patients., Methods: Two cohorts, CN and diabetic peripheral neuropathy (DPN), were identified by ICD-9 codes in the California Office for Statewide Health Planning and Development 2009-2012 public patient discharge files. DPN and CN costs and length of stay (LOS) were compared adjusting for the number of chronic conditions. The impact of the Elixhauser comorbidity measures and other comorbidities on costs and LOS in CN subjects was evaluated., Results: CN was associated with 17.2% higher costs and 1.4 days longer LOS compared to DPN alone. Adjusting for 0.71 additional chronic conditions in CN patients accounted for 79.8% of variance and estimated a 13.9% cost difference between cohorts. Subjects averaged 4.5 Elixhauser comorbidities with higher scores corresponding to increased cost, LOS, and inpatient mortality. Other diabetic foot risk factors demonstrated that foot ulcers, foot infections, and osteomyelitis had significantly higher costs. Patients with foot ulcers, osteomyelitis, and depression had significantly increased LOS., Conclusions: Systemic and local comorbidities significantly impact the cost, utilization, and inpatient mortality in inpatient management of Charcot foot., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Cardiovascular autonomic neuropathy in diabetics is a common but often underestimated and underdiagnosed complication of diabetes mellitus. One of the most clinical apparent forms of cardiovascular autonomic neuropathy is orthostatic hypotension., Objectives: To retrospectively assess the association of the orthostatic hypotension (OH) with macrovascular and microvascular complications of diabetes mellitus and to determine its effect on mortality., Design and Methods: We retrospectively analyzed 187 patients with diabetes mellitus (60 patients with diabetes type 1 and 127 patients with diabetes type 2). Patients were divided into groups according to presence or absence of OH and type of diabetes. Association of OH with macrovascular and microvascular complications was evaluated and the effect of OH on 10-year all-cause mortality was also assessed., Results: OH was present in 31.7% of patients with diabetes type 1 (DM1) and in 32.3% of patients with diabetes type 2 (DM2). OH was positively associated with the prevalence of myocardial infarction in DM1 (OR=10.67) and with prevalence of stroke in DM2 (OR=3.33). There was also a strong association of OH and the prevalence of peripheral artery disease in both DM1 (OR=14.18) and DM2 (OR=3.26). Patients with both types of diabetes and OH had significantly higher prevalence of nephropathy (DM1 OR=8.68, DM2 OR=3.24), retinopathy (DM1 OR=8.09, DM2 OR=4.08) and peripheral neuropathy (DM1 OR=17.14, DM2 OR=7.51) Overall 10year mortality rate was higher in diabetic patients with OH., Conclusions: Presence of OH in diabetics is associated with higher prevalence of macrovascular and microvascular complications of diabetes mellitus and also with higher 10-year mortality., (Copyright © 2016 Elsevier Inc. All rights reserved.)

As of March 2016, we continue to advocate the diagnosis of diabetic neuropathy using a simple foot examination or monofilament, which identifies only those with severe neuropathy and hence risk of foot ulceration. Given the fact that the 5-year mortality rate of diabetic patients with foot ulceration is worse than that of most common cancers, surely we should be identifying patients at an earlier stage of neuropathy to prevent its progression to a stage with such a high mortality? Of course, we lament that there is no licensed treatment for diabetic neuropathy. Who is to blame? As researchers and carers, we have a duty of care to our patients with diabetic neuropathy. So, we have to look forward not backwards, and move away from our firmly entrenched views on the design and conduct of clinical trials for diabetic neuropathy. Relevant organizations such as Neurodiab, the American Diabetes Association and the Peripheral Nerve Society have to acknowledge that they cannot continue to endorse a bankrupt strategy. The FDA needs an open and self-critical dialogue with these organizations, to give pharmaceutical companies at least a fighting chance to deliver effective new therapies for diabetic neuropathy., (© 2016 Elsevier Inc. All rights reserved.)

Objective: To quantify polyneuropathy impairments and comorbidities utilizing the Rochester Epidemiology Project (2010 census = 148,201)., Methods: ICD-9-CM coding identified polyneuropathy cases (2006-2010) and their 5:1 age- and sex-matched controls. Mortality and impairments were evaluated while identifying and adjusting for Charlson Index comorbidities., Results: Overall prevalence of polyneuropathy was 1.66%, and markedly rose to 6.6% in persons older than 60 years. Cases (n = 2,892) had more comorbidities than controls (n = 14,435) with higher median Charlson Index (6 vs 3, p < 0.001). Diabetes with end-organ disease represented the largest increased comorbidity in cases compared with controls (46.8% vs 6.5%). Diabetic polyneuropathy was the most common specific subtype (38.2%). Miscoded idiopathic cases and false-negative controls also commonly had diabetic polyneuropathy. Median modified Rankin Scale score was considerably higher for cases than controls (4 vs 1, p < 0.001). Multiple comorbidities were found associated with polyneuropathy after adjusting for diabetes co-occurrence, including pulmonary disease, dementia, and others. Polyneuropathy was an independent contributor to multiple functional impairments including difficulty walking (odds ratio [OR] = 1.9), climbing stairs (OR = 2.0), using an assistive device (OR = 2.0), fall tendency (OR = 2.4), work disability (OR = 4.2), lower limb amputations (OR = 3.9), and opioid use (OR = 2.7). Prevalent cases had a younger median age at death than controls (80 vs 86 years, p < 0.001), and incident cases had a 6-month shorter survival., Conclusions: Polyneuropathies have notable neurologic impairments beyond their identified multiple comorbidities. Life expectancy is shortened. Diabetic polyneuropathy is underidentified. The quantified extent of the disease burden and refined comorbidity associations emphasize that greater research efforts and health care initiatives are needed., (© 2015 American Academy of Neurology.)

Increasingly, we recognise that type 2 diabetes in youth is a disease with an aggressive time course and a significant complication risk. On the other hand, outcomes for youth with type 1 diabetes appear generally to be improving. With increasing numbers of both types of diabetes in youth, it is timely that a comparative perspective is offered to help clinicians prognosticate more appropriately. Contemporary comparative studies add a new perspective to a consistent story, that for youth-onset type 2 diabetes, the development and progression of cardio-renal complications are increased and the survival prognosis is significantly worse than for type 1 diabetes. Here, we review this mounting evidence, highlight the importance of metabolic syndrome factors in the excess risk and underscore that there remains a significant mortality gap for youth with either type of diabetes, to be addressed as a matter of urgency.

The data of the literature and own data on the frequency and mechanisms of gastrointestinal symptoms in patients with diabetes mellitus type 2 are discussed. Changes in the gastrointestinal tract with diabetes mellitus type 2 are detected over its entire length and occur more frequently than in the general population. Among the reasons of it the presence of autonomic neuropathy, factor of hyperglycemia, increased anxiety and depression in patients are discussed.

Aims: Identifying individuals with diabetes at high risk of cardiovascular disease (CVD) remains challenging. We aimed to establish whether peripheral neuropathy (PN) is associated with incident CVD events and to what extent information on PN may improve risk prediction among individuals with type 2 diabetes., Methods: We obtained data for individuals with type 2 diabetes, and free of CVD, from a large primary care patient cohort. Incident CVD events were recorded during a 30-month follow-up period. Eligible individuals had complete ascertainment of cardiovascular risk factors and PN status at baseline. The association between PN and incident CVD events (non-fatal myocardial infarction, coronary revascularisation, congestive cardiac failure, transient ischaemic attack and stroke) was evaluated using Cox regression, adjusted for standard CVD risk factors. We assessed the predictive accuracy of models including conventional CVD risk factors with and without information on PN., Results: Among 13 043 eligible individuals, we recorded 407 deaths from any cause and 399 non-fatal CVD events. After adjustment for age, sex, ethnicity, systolic blood pressure, cholesterol, body mass index, HbA1c, smoking status and use of statin or antihypertensive medication, PN was associated with incident CVD events (HR 1.33; 95% CI 1.02 to 1.75, p=0.04). The addition of information on PN to a model based on standard CVD risk factors resulted in modest improvements in discrimination for CVD risk prediction and reclassified 6.9% of individuals into different risk categories., Conclusions: PN is associated with increased risk for a first cardiovascular event among individuals with diabetes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Diabetes mellitus is the commonest cause of an autonomic neuropathy in the developed world. Diabetic autonomic neuropathy causes a constellation of symptoms and signs affecting cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory, and sudomotor systems. Several discrete syndromes associated with diabetes cause autonomic dysfunction. The most prevalent of these are: generalized diabetic autonomic neuropathy, autonomic neuropathy associated with the prediabetic state, treatment-induced painful and autonomic neuropathy, and transient hypoglycemia-associated autonomic neuropathy. These autonomic manifestations of diabetes are responsible for the most troublesome and disabling features of diabetic peripheral neuropathy and result in a significant proportion of the mortality and morbidity associated with the disease.

Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality and resulting in a huge economic burden for diabetes care. The clinical assessment of diabetic peripheral neuropathy and its treatment options are multifactorial. Patients with DN should be screened for autonomic neuropathy, as there is a high degree of coexistence of the two complications. A review of the clinical assessment and treatment algorithms for diabetic neuropathy, painful neuropathy, and autonomic dysfunction is provided., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To compare clinical profile of long-term survivors and nonsurvivors with type 2 diabetes (T2DM)., Research Design and Methods: After conducting a retrospective survey of >200,000 case records, we identified T2DM survivors (>40 years of duration) and age at diagnosis and sex-matched T2DM nonsurvivors. Prevalence of complications and causes of death were analyzed. Retinopathy was diagnosed by retinal photography. Microalbuminuria and macroalbuminuria, peripheral vascular disease based on ankle-brachial index <0.9, coronary artery disease based on history of myocardial infarction or coronary revascularization, and neuropathy based on vibration perception threshold >20 V were compared in both groups., Results: The mean duration of diabetes of survivors (n = 238) was 43.7 ± 3.9 years, and that of the nonsurvivors (n = 307), at time of death, was 22.4 ± 11.0 years (P < 0.001). Nonsurvivors had significantly higher systolic and diastolic blood pressures, plasma glucose, HbA1c, serum cholesterol, LDL cholesterol, and triglycerides and lower HDL cholesterol compared with long-term survivors (P < 0.001 for all parameters except systolic blood pressure, which was P = 0.027). Myocardial infarction (46.4%) and renal failure (16.6%) were the most common causes of death. Prevalence of most complications was higher among survivors because of longer duration and older age, as follows, for survivors versus nonsurvivors: retinopathy, 76 vs. 62%; microalbuminuria, 39.1 vs. 27.3%; macroalbuminuria, 8.4 vs. 23.7%; neuropathy, 86.5 vs. 63.5%; peripheral vascular disease, 23.1 vs. 11.4%; and coronary artery disease, 44.5 vs. 40.7%., Conclusions: Long-term survivors with T2DM had better glycemic and blood pressure control and more favorable lipid profiles.

Diabetes can exacerbate seizures and worsen seizure-related brain damage. In the present study, we aimed to determine whether the standard antiepileptic drug pregabalin (PGB) protects against pilocarpine-induced seizures and excitotoxicity in diabetes. Adult male Sprague-Dawley rats were divided into either a streptozotocin (STZ)-induced diabetes group or a normal saline (NS) group. Both groups were further divided into subgroups that were treated intravenously with either PGB (15 mg/kg) or a vehicle; all groups were treated with subcutaneous pilocarpine (60 mg/kg) to induce seizures. To evaluate spontaneous recurrent seizures (SRS), PGB-pretreated rats were fed rat chow containing oral PGB (450 mg) for 28 consecutive days; vehicle-pretreated rats were fed regular chow. SRS frequency was monitored for 2 weeks from post-status epilepticus day 15. We evaluated both acute neuronal loss and chronic mossy fiber sprouting in the CA3 area. In addition, we performed patch clamp recordings to study evoked excitatory postsynaptic currents (eEPSCs) in hippocampal CA1 neurons for both vehicle-treated rats with SRS. Finally, we used an RNA interference knockdown method for Kir6.2 in a hippocampal cell line to evaluate PGB's effects in the presence of high-dose ATP. We found that compared to vehicle-treated rats, PGB-treated rats showed less severe acute seizure activity, reduced acute neuronal loss, and chronic mossy fiber sprouting. In the vehicle-treated STZ rats, eEPSC amplitude was significantly lower after PGB administration, but glibenclamide reversed this effect. The RNA interference study confirmed that PGB could counteract the ATP-sensitive potassium channel (KATP)-closing effect of high-dose ATP. By opening KATP, PGB protects against neuronal excitotoxicity, and is therefore a potential antiepileptogenic in diabetes. These findings might help develop a clinical algorithm for treating patients with epilepsy and comorbid metabolic disorders.

Background and Purpose: To investigate the relationships of diabetic neuropathy to all-cause and diabetes-related mortality in patients with type 2 diabetes after controlling for significant correlates., Methods: We examined 326 patients diagnosed as diabetic polyneuropathy by nerve conduction study in Keelung city, Taiwan, in 2002 and followed them up to ascertain the cause and date of death until the end of 2006. The cause and date of death were recorded for the deceased patients. Information on significant correlates in association with diabetic polyneuropathy and all-cause and diabetes-related mortality was also collected., Results: With median follow-up time of 62.28 months, 44 patients with type 2 diabetes died. The cause of death related to diabetes accounted for 59% (n = 26) of the deceased. Univariate analysis shows that the presence of diabetic neuropathy confers higher risk for all-cause mortality (hazard ratio [HR] = 4.88) and mortality from diabetes (HR = 6.58). The significant finding still persisted after adjustment for age, gender, blood pressure, smoking, history of cardiovascular/cerebrovascular disease, duration of diabetes, waist circumference, fasting plasma glucose, total cholesterol, hemoglobin, and creatinine (adjusted HR = 4.44 for all-cause death and adjusted HR = 11.82 for diabetes-related mortality, respectively)., Conclusions: Diabetic polyneuropathy was an independent predictor for all-cause and diabetes-related mortality. The presence of neuropathy together with other significant prognostic factors is informative to predict all-cause death and death from diabetes-related disease for patients diagnosed as type 2 diabetes., (© 2012 The Author(s). European Journal of Neurology © 2012 EFNS.)

Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.

Aim: To compare the long-term predictive power of heart rate variability (HRV) based on 24 h ECG recordings with a battery of simple autonomic function tests with regard to all-cause mortality in diabetic individuals., Methods: 240 diabetic persons were randomly selected from the diabetic population. A 24-h ECG was obtained and analysed on the Pathfinder 700. In the RR Tools Program time domain and frequency domain parameters were computed. Five function tests were conducted: Valsalva ratio, heart rate response to standing (30:15 ratio), expiration/inspiration ratio (E/I ratio), orthostatic blood pressure response (Ortho BP), and increase in diastolic blood pressure during sustained handgrip., Results: 178 patients agreed to participate and 136 patients who completed all 5 function tests and had an acceptable ECG recording were included in the analyses. 64 individuals (47%) died during the 15½ year follow-up. Using Cox proportional hazard analyses correcting for age and gender we found that among the HRV parameters only the power in the low frequency band (LF) had an independent predictive value on all-cause mortality (p=0.0002). Multivariate analysis of the five function tests showed that Valsalva (p=0.002), 30:15 ratio (p=0.037), and handgrip (p=0.037) were independent predictors of death. When finally the independent predictors among the function tests and the HRV parameters were assessed in the same model, no significant value could be shown for LF power (p=0.44)., Conclusion: The study indicates that simple autonomic function tests are superior to HRV based on 24-h ECG recordings in predicting all-cause mortality in the diabetic population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Gastroparesis is a well-recognized, long-term complication of diabetes. Prokinetic drugs are often not effective, prompting the development of alternative therapies. We report our experience of using one such alternative, endoscopic botulinum toxin injection, to ameliorate diabetic gastropathy in association with pancreas and islet-cell transplant patients., Materials and Methods: Three male diabetic patients aged 42 to 55 years had been treated with botulinum toxin in our center. Two patients were both after-simultaneous pancreas-kidney transplant and 1 was awaiting islet-cell transplant after pancreatectomy. Mechanical gastric outlet obstruction was first excluded by radiological and endoscopic studies. Between 100 and 200 IU of toxin were then injected in the prepyloric region using an endoscopic technique. A subjective scoring scale was used to assess symptoms before and after botulinum therapy., Results: Improvement in subjective symptom severity scoring was seen in all patients, with a posttreatment improvement from 55% to 91%. Such improvement was temporary in 2 patients and long-lasting in 1 patient., Conclusions: The time for improvement of gastric autonomic function after pancreas or islet-cell transplantation remains unclear. Some patients may continue to be symptomatic, leading to increasing morbidity. However, endoscopic botulinum injections may provide short-term relief while waiting for improvement and spare patients the morbidity associated with more-invasive therapies.

Diabetic foot syndrome is a major complication for patients with diabetes mellitus. About 25% of the 6 million patients with diabetes in Germany will suffer from diabetic foot syndrome at some point during the course of disease. Diabetic neuropathy and peripheral vascular disease are the main causative factors in the pathogenesis of diabetic foot ulcers. The mortality rate of these patients is more than twice as high as that of the average population. 25% of costs incurred by patients with diabetes are spent on diabetic foot ulcers, and 50% of hospital days are attributed to the treatment of the diabetic foot syndrome. This syndrome is also the most common cause of non-traumatic amputations. Both the risk of amputation and mortality are much increased in case of peripheral vascular disease. Hence, the aim is to lower the still high number of amputations in Germany by appropriate preventive measures as well as by multidisciplinary diagnostics and therapy.

In order to evaluate the relationship between cardiovascular autonomic neuropathy and corrected QT interval (QTc) with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus, we followed up for 5 years 67 patients attending the outpatient Endocrinology Service. 82% completed follow-up and cardiovascular events occurred in 16 patients. We found that long QTc interval was the only variable significantly associated with cardiovascular morbidity and mortality in the multiple logistic regression analysis (RR: 13.56, 95% CI: 2.01-91.36) (p = 0.0074).

Background: Cardiovascular autonomic neuropathy is a major complication in patients with diabetes mellitus (DM), and baroreflex sensitivity (BRS) reportedly can predict cardiovascular prognosis in type 2 DM patients. The hypothesis that cardiovascular events are associated with gender differences in BRS was tested in the present study., Methods and Results: From 1998, we have evaluated BRS by phenylephrine methods in 185 consecutive type 2 DM patients. The long-term prognostic value of BRS was compared between 91 female (5812 years) and 94 male patients (5811 years). There was no significant difference in age or severity and duration of DM between the 2 groups. When compared to male, the BRS value in female patients was significantly lower (9.266.0 vs. 5.975.0 ms/mmHg, P < 0.0001). During a mean of 62.7 months of follow-up, 16 female patients developed cardiovascular events (17.6%) including stroke, acute myocardial infarction, angina pectoris requiring percutaneous coronary intervention or coronary artery bypass grafting and congestive heart failure requiring admission, while only 4 male patients developed events (4.3%, P < 0.005). In females, the Kaplan-Meier curves revealed that those with depressed BRS (< 6 ms/mmHg) had a higher incidence of cardiovascular events than those with preserved BRS (P < 0.05), but this relationship was not observed in male patients., Conclusions: Although the reason why females had a more depressed BRS remains unclear, our findings demonstrated that a depressed BRS value can accurately predict cardiovascular events, especially in female patients with type 2 DM.

Objective: Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants., Research Design and Methods: CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates., Results: During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55-2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P < 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (P(interaction) > 0.7)., Conclusions: Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

Objective: To compare the mortality of patients with an acute Charcot foot with a matched population with uninfected neuropathic foot ulcers (NFUs)., Research Design and Methods: Data were extracted from a specialist departmental database, supplemented by hospital records. The findings were compared with the results of earlier populations with Charcot foot and uninfected NFUs managed from 1980. Finally, the results of all patients with acute Charcot foot and all control subjects managed between 1980 and 2007 were compared with normative mortality data for the U.K. population., Results: A total of 70 patients presented with an acute Charcot foot (mean age 57.4 +/- 12.0 years; 48 male [68.6%]) between 2001 and 2007; there were 66 matched control subjects. By 1 October 2008, 13 (eight male; 18.6%) patients with a Charcot foot had died, after a median of 2.1 years (interquartile range 1.1-3.3). Twenty-two (20 male; 33.3%) control subjects had also died after a median of 1.3 years (0.6-2.5). There was no difference in survival between the two groups (log-rank P > 0.05). Median survival of all 117 patients with acute Charcot foot managed between 1980 and 2007 was 7.88 years (4.0-15.4) and was not significantly different from the control NFU patients (8.43 years [3.4-15.8]). When compared with normative U.K. population data, life expectancy in the two groups was reduced by 14.4 and 13.9 years, respectively., Conclusions: These data confirm that the mortality in patients presenting to our unit with either an acute Charcot foot and an uninfected neuropathic ulcer was unexpectedly high.

Introduction: Overweight men with diabetes often report erectile dysfunction (ED), but few studies have examined effects of weight loss on this problem., Aim: This study examined 1-year changes in erectile function (EF) in overweight/obese men with type 2 diabetes participating in the Look AHEAD (Action for Health in Diabetes) trial., Methods: Participants in Look AHEAD were randomly assigned to a control condition involving diabetes support and education (DSE) or to intensive lifestyle intervention (ILI) involving group and individual sessions to reduce weight and increase physical activity. Men from five of the clinical sites in Look AHEAD completed the International Index of Erectile Function (IIEF) at baseline (N = 372) and at 1 year (N = 306) (82%)., Main Outcome Measures: Changes in EF as reported on the EF subscale of the IIEF., Results: At 1 year, the ILI group lost a greater percent of initial body weight (9.9% vs. 0.6 %) and had greater improvements in fitness (22.7% vs. 4.6%) than DSE. EF improved more in ILI (17.3 +/- 7.6 at baseline; 18.6 +/- 8.1 at 1 year) than in DSE (18.3 +/- 7.6 at baseline; 18.4 +/- 8.0 at 1 year); P = 0.04 and P = 0.06 after adjusting for baseline differences. Using established norms for none (i.e., normal EF), and three grades (i.e., mild, moderate, and severe) ED, 8% of men in ILI reported a worsening of EF from baseline to 1 year, 70% stayed in the same category, and 22% reported improvements. In contrast, 20% of DSE reported worsening, 57% stayed in the same category, and 23% improved (P = 0.006)., Conclusion: In this sample of older overweight/obese diabetic men, weight loss intervention was mildly helpful in maintaining EF.

Aims/hypothesis: Type 1 diabetes is a chronic disease leading to complications such as peripheral neuropathies, nephropathy and cardiovascular disease. Pancreatic islet transplantation is being extensively investigated for blood glucose control in animals and in human type 1 diabetic patients, but the question of whether it can reverse long-term diabetic complications has not been fully explored. We investigated the effects of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes., Methods: Three groups of rats were used: healthy controls, diabetic and diabetic rats transplanted with microencapsulated islets at 2 months after diabetes induction, when neuropathy was detectable by a decrease in tail nerve conduction velocity (NCV) and impaired nociceptive thresholds. Blood glucose levels and body weight were measured weekly. The variables considered were: thermal (hot plate test) and mechanical sensitivity (Randal-Selitto paw withdrawal test), NCV and Na+, K+-ATPase activity in the sciatic nerve. At the end of the experiments hearts were removed for morphometric determination and myocyte number, and kidneys removed for histological examination., Results: Islet transplantation in diabetic rats induced normoglycaemia in a few days, accompanied by a rapid rise in body weight and amelioration of impaired nociceptive thresholds, as well as normalisation of NCV and Na(+), K(+)-ATPase, which were both about 25% below normal in diabetic rats. Myocyte loss was reduced (-34%) by islet transplantation and the observed mild kidney damage of diabetic rats was prevented., Conclusions/interpretation: Besides controlling glycaemia, transplantation of microencapsulated pancreatic islets induced almost complete regression of neuropathy and prevented cardiovascular alterations.

Type II diabetes mellitus accounts for 90% of all cases of diabetes, and its inclusion in health evaluation has shown that its complications have a considerable impact on the population's quality of life. The current article presents the results of the Global Burden of Disease Study in Brazil for the year 1998, with an emphasis on diabetes mellitus and its complications. The indicator used was disability-adjusted life years (DALY), using a discount rate of 3%. In Brazil, ischemic heart disease, stroke, and diabetes accounted for 14.7% of total lost DALYs. Brazil showed a higher proportion of years lived with disability (YLDs) among total DALYs for diabetes as compared to other countries. Retinopathy and neuropathy were the complications that contributed most to YLDs. According to forecasts, diabetes mellitus will have an increasing impact on years of life lost due to premature death and disability in the world, shifting from the 11th to 7th cause of death by 2030. It is thus urgent to implement effective measures for prevention, early diagnosis, counseling, and adequate follow-up of patients with diabetes mellitus.

Aims/hypothesis: We sought to identify factors related to short-term outcome of foot ulcers in patients with diabetes treated in a multidisciplinary system until healing was achieved., Methods: Consecutively presenting patients with diabetes and worst foot ulcer (Wagner grade 1-5, below ankle) (n = 2,511) were prospectively followed and treated according to a standardised protocol until healing was achieved or until death. The number of patients lost to dropout was 31. The characteristics of the remaining 2,480 patients were: 1,465 men, age 68 +/- 15 years (range 18-96), type 1 diabetes 18%, type 2 diabetes 82% and insulin-treated 62%., Results: The healing rate without major amputation in surviving patients was 90.6% (n = 1,867). Sixty-five per cent (n = 1,617) were healed primarily, 9% (n = 250) after minor amputation and 8% after major amputation; 17% (n = 420) died unhealed. Out of 2,060 surviving patients, 1,007 were neuroischaemic (48.8%). In a multiple regression analysis, primary healing was related to co-morbidity, duration of diabetes, extent of peripheral vascular disease and type of ulcer. In neuropathic ulcers, deep foot infection, site of ulcer and co-morbidity were related to amputation. Amputation in neuroischaemic ulcers was related to co-morbidity, peripheral vascular disease and type of ulcer. Age, sex, duration of diabetes, neuropathy, deformity and duration of ulcer or site of ulcer did not have an evident influence on probability of amputation., Conclusions/interpretation: Patients with diabetic foot ulcer suffer from multi-organ disease. Factors related to outcome are correspondingly complex.

The aim of this study was to examine any association between the presence of diabetes in patients with gas gangrene of the legs and mortality following major lower limb amputation. In a retrospective study, patients submitted to amputation of lower limbs for anaerobic infections were evaluated in the period from January 2005 to January 2007 in the University Hospital de Base in Sao Jose do Rio Preto. All the patients were hospitalized for the treatment of ulcerated lesions of the leg. The study sample consisted of 30 men and 10 women aged between 46 and 87 years (mean 69 years) suffering from anaerobic infections. During treatment, the presence of crepitation in the skin was observed as was gas by radiological examination. Amputation was performed within 2 to 6 hours after diagnosis. Diabetes was identified in 33 patients and death occurred within the perioperative period in 12 cases. Diabetes is associated with the necessity of amputation for gas gangrene resulting in a high mortality rate.

Cardiovascular autonomic diabetic neuropathy (CADN) is one of the most common diabetes-associated complications. Disturbed heart rate variability (HRV) is very often the earliest symptom, even in clinically asymptomatic patients. The following article offers a topical overview for those working or interested in the fields of diabetology and cardiology.

Cardiovascular autonomic neuropathy (CAN) is one of the most clinically significant complications of diabetes mellitus (DM), but one of the least frequently diagnosed. In this review, we discuss the major risk factors for the development and progression of CAN in patients with DM, the natural history of autonomic neuropathy and its impact on cardiovascular disease in DM, as well as the tests for the early diagnosis and staging of CAN in the clinical practice. The bibliographic research was based on two databases: Medline and Tripdatabase, with the following descriptors: diabetic cardiovascular autonomic neuropathy and cardiovascular autonomic neuropathy and diabetes. We selected English and German articles, written between 1998 and 2007. In its initial stages (early and intermediate), CAN may be diagnosed and reversed. However, in advanced cases (severe stage), the only treatment that remains is a symptomatic one. CAN is associated with higher cardiovascular morbidity and mortality rates and poor quality of life in diabetic individuals.

Pancreas and kidney transplants have specific indications, benefits and risks. The procedure has become more common and more often as long-term success has improved and risks have decreased. Compared with a patient being on dialysis, simultaneous pancreas-kidney transplant offers a distinct advantage when it comes to mortality, quality of life and diabetic complications. Since there can be a living-donor kidney transplant,, a possibly similar patient and graft survival by 10 years follow-up, this procedure should be considered. Pancreas after kidney transplants, when successful, can improve microvascular complications compared with kidney transplant alone, but immediate mortality may be higher. Solitary pancreas transplantation can improve the quality of life in selected patients, but it may also increase the immediate risk of mortality due to the complexity of the surgery and the risks of immunosupression. The results of Islet transplantation differ from the higher metabolic performance achieved by whole pancreas allotransplantation and its applicability is limited to selected adult diabetic patients.

Objective and Design: Pain and peripheral neuropathy are frequent complications of end-stage renal disease (ESRD). Because drug treatment is associated with numerous side effects and is largely ineffective in many maintenance hemodialysis (MHD) patients, nonpharmacologic strategies such as electrotherapy are a potential recourse. Among various forms of electrostimulation, high-tone external muscle stimulation (HTEMS) is a promising alternative treatment for symptomatic diabetic peripheral polyneuropathy (PPN), as demonstrated in a short-term study. Based on these novel findings, we performed a prospective, nonrandomized, pilot trial in MHD patients to determine (1) whether HTEMS is also effective in treating diabetic PPN in the uremic state, and (2) whether uremic PPN is similarly modulated., Patients and Interventions: In total, 40 MHD patients diagnosed with symptomatic PPN (25 with diabetic and 15 with uremic PPN) were enrolled. Both lower extremities were treated intradialytically with HTEMS for 1 hour, three times a week. Initially, a subgroup of 12 patients was followed for 4 weeks, and a further 28 patients for 12 weeks. The patients' degree of neuropathy was graded at baseline before HTEMS and after 1 and 3 months, respectively. Five neuropathic symptoms (tingling, burning, pain, numbness, and numbness in painful areas) as well as sleep disturbances were measured, using the 10-point Neuropathic Pain Scale of Galer and Jensen (Neurology 48:332-338, 1997). A positive response was defined as the improvement of one symptom or more, by at least 3 points. Other parameters included blood pressure, heart rate, dry body weight, and a routine laboratory investigation., Results: The HTEMS led to a significant improvement in all five neuropathic symptoms, and to a significant reduction in sleep disturbances for both diabetic and uremic PPN. The response was independent of the patient's age, with a responder rate of 73%. The improvement of neuropathy was time-dependent, with the best results achieved after 3 months of treatment. The HTEMS was well-tolerated by nearly all patients., Conclusions: This pilot study shows for the first time that HTEMS can ameliorate the discomfort and pain associated with both diabetic and uremic PPN in MHD patients, and could be a valuable supplement in the treatment of pain and neuropathic discomfort in patients who do not respond to, or are unable to participate in, exercise programs during hemodialysis treatment.

A shared and additive genetic variance component-long-term survivor (LTS) model for familial aggregation studies of complex diseases with variable age-at-onset phenotype and non-susceptible subjects in the study cohort is proposed. LTS has been used from the early 1970s, especially in epidemiological studies of cancer. The LTS model utilizes information on the age at onset (survival) distribution to make inference on partially latent susceptibility. Bayesian modeling with uninformative priors is used and estimates of the posterior distribution of age at onset and susceptibility parameters of interest have been obtained using Bayesian Markov chain Monte Carlo (MCMC) methods with OpenBugs program. A simulation study confirms that we obtain posterior estimates of the model parameters on shared and genetic variance components of age at onset and susceptibility with good coverage rates. Further, we analyze familial aggregation of diabetic nephropathy (DN) in large Finnish cohort of 528 sibships with type 1 diabetes (T1D). According to the variance components estimated a substantial familial variation in the susceptibility to DN exist among families, while time to DN is less influenced by shared familial factors.