Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy.

AIMS: Type 1 diabetes can be complicated with neuropathy that involves immune-mediated and inflammatory pathways. Glucagon-like peptide-1 receptor agonists such as liraglutide, have shown anti-inflammatory properties, and thus we hypothesized that long-term treatment with liraglutide induced diminished inflammation and thus improved neuronal function. METHODS: The study was a randomized, double-blinded, placebo-controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2-1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing. RESULTS: Thirty-nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin-6 (-22.6%; 95% confidence interval [CI]: -38.1, -3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with -3.38 kg (95% CI: -5.29, -1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (-40.2%; 95% CI: -60.6, -9.5; P = .02). CONCLUSION: Hitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.

The degree of autonomic modulation is associated with the severity of microvascular complications in patients with type 1 diabetes.

OBJECTIVE: The objective of this study was to elucidate whether the degree of autonomic modulation is associated with the degree of microvascular complications in patients with type 1 diabetes. METHODS: A total of 290 type 1 individuals with diabetes were randomly recruited during normal visits to outpatient clinics at 4 Danish hospitals. The degree of autonomic modulations was quantified by measuring heart rate variability (HRV) during passive spectral analysis and active tests (valsalva ratio [VT], response to standing [RT], and deep breathing [E:I]). To describe possible associations between severity of microvascular complications and measures of autonomic modulation, multivariate analysis was performed. RESULTS: After adjusting for diabetes duration, sex, age, pulse pressure, heart rate, and smoking, autonomic dysfunction remained significantly correlated with severity of retinopathy, nephropathy, and peripheral neuropathy in individuals with type 1 diabetes patients. CONCLUSIONS: Autonomic dysfunction is present in early stages of retinopathy, nephropathy, and peripheral neuropathy in patients with type 1 diabetes.

Cardiovascular autonomic neuropathy is associated with macrovascular risk factors in type 2 diabetes: new technology used for routine large-scale screening adds new insight.

The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.

Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.

BACKGROUND: Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved ß-cell function in recent-onset type 1 diabetes. METHODS: We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. FINDINGS: Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. INTERPRETATION: Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. FUNDING: National Institutes of Health and Juvenile Diabetes Research Foundation.

Lifestyle diseases and cardiovascular risk factors are interrelated to deficiencies of major substrates in ATP synthesis.

Recent studies on diabetes and metabolic syndrome indicate a common disturbance of inorganic phosphate (Pi) metabolism. Pi is an important substrate in the formation of adenosine triphosphate (ATP), and many lifestyle diseases and cardiovascular risk factors similarly show deficiencies in either 1 or 2 major components of ATP synthesis. Age, male gender, hypertension, obesity, hypertriglyceridemia, metabolic syndrome, and diabetes mellitus are all associated with hypophosphatemia. In addition, tobacco smoking, hyperchylomicronemia, hypertension, and diabetes may involve defects in tissue oxygen delivery. Hypophosphatemia may lead to a critical decrease in intracellular Pi and to mitochondrial dysfunction, which might be counter-acted by the pharmacological use of fructose 1,6-diphosphate.

Disturbance of inorganic phosphate metabolism in diabetes mellitus: its impact on the development of diabetic late complications.

The pathogenesis of diabetic late complications (DLC) is multifactorial. Studies of mechanisms leading to early functional microvascular changes in retina and kidneys point towards a disturbance in the metabolism of inorganic phosphate (Pi) in diabetes. Since tissue hypoxia and reduced high energy phosphates may be important factors in the development of DLC, the influence of Pi concentration on the metabolism and function of the erythrocytes and renal tubular cells, as well as the relationship of the concentration of Pi to total oxygen consumption, have been reviewed. While extensive research data in non-diabetic conditions support the suggestion, that the Pi concentration is a determining factor in regulation of metabolism and rate of oxygen consumption, diabetes shows the opposite behavior. In diabetes, the highest oxygen consumption is associated with the lowest concentration of Pi. Many conventionally-treated juvenile diabetic patients respond as if their tissues were in a state of chronic hypoxia. A disturbance in phosphate handling occurs in the kidney tubules, where the excessive sodium-dependent glucose entry in diabetics depolarizes the electrochemical sodium gradient and consequently impairs inorganic phosphate reabsorption. Similar changes may occur in other cells and tissues in which glucose entry is not controlled by insulin, and particularly in poorly-regulated diabetic patients in whom long-term vascular complications are more likely.

Change from oral antidiabetic therapy to insulin and risk of urinary tract infections in Type 2 diabetic patients: a population-based prescription study.

BACKGROUND: Diabetes is a risk factor for urinary tract infections (UTI), but the impact of insulin treatment and glycaemic control on UTI risk is not clear. METHODS: We determined the risk of antibiotic-treated UTI episodes in a population-based cohort of 2737 Type 2 diabetic patients who switched from oral antidiabetic drug (OAD) to insulin therapy. Each patient was observed for 365 days before and after the switch date, excluding a 120-day time window around this date. Episodes of UTI were defined as filled prescriptions for a UTI-specific antibiotic. We used conditional logistic regression to estimate the relative risk (odds ratio) of having one or more UTIs in the insulin vs. OAD period overall and stratified by glycaemic change. RESULTS: After the switch to insulin, 53% of all patients experienced a decrease in individual mean hemoglobin A1c (median decrease=1.5%, interquartile range 0.9%-2.3%). Episodes of treated UTIs occurred in 446 (16.3%) Type 2 diabetic patients in the insulin period and 437 (16.0%) in the OAD period (relative risk 1.04, 95% CI 0.86-1.26). Stratified analyses showed no consistent association between levels of glycaemic improvement and decreased UTI risk during insulin treatment. CONCLUSIONS: Among patients with Type 2 diabetes, no evidence was found that switch to insulin therapy with or without tightened glycaemic control decreased their high annual risk of antibiotic-treated UTI episodes.

The North Jutland County Diabetic Retinopathy Study (NCDRS).

PURPOSE: This study set out to map the associations between retinal lesions, visual acuity (VA) and the presence of clinically significant macular oedema (CSMO) in diabetes subjects. METHODS: This cross-sectional study comprised 656 type 1 and 328 type 2 diabetes subjects undergoing retinopathy screening in the County of North Jutland, Denmark. Numbers of specific retinal lesions were quantified from retinal photographic recordings. Associations between CSMO, number of specific retinal lesions and VA were established. The percentages of eyes with CSMO ascribed to retinal lesions were calculated. RESULTS: The presence of CSMO, number of specific retinal lesions and VA were all significantly associated. The parameter with the highest statistical association with CSMO measured by Spearman's correlation coefficient was hard exudates (type 1: 0.524; type 2: 0.715), followed by microaneurysms (type 1: 0.298; type 2: 0.508), retinal haemorrhages (type 1: 0.227; type 2: 0.595), cottonwool spots (type 1: 0.207; type 2: 0.259) and VA (type 1: - 0.137; type 2: - 0,175). CONCLUSIONS: All retinal lesions are significantly associated with CSMO and together can predict for up to 42.3% (in type 1 diabetes) and 64.3% (in type 2 diabetes) of CSMO cases.

Disturbance of inorganic phosphate metabolism in diabetes mellitus: clinical manifestations of phosphorus-depletion syndrome during recovery from diabetic ketoacidosis.

The acute effects of intracellular phosphate depletion and hypophosphatemia on organs and tissues in and during recovery from diabetic ketoacidosis (DKA) have been reviewed. When insufficient phosphate and/or oxygen are available for high energy phosphate synthesis, cell homeostasis cannot be maintained and cell integrity may be impaired. The clinical consequences are recognized as occasional cause of morbidity and mortality. Although phosphate repletion has not been routinely recommended in the treatment of DKA, physicians should be aware of these clinical conditions and phosphate repletion in such situations should be considered.

Disturbance of inorganic phosphate metabolism in diabetes mellitus: temporary therapeutic intervention trials.

A paradoxical metabolic imbalance in inorganic phosphate occurs from the early onset of diabetes and may lead to a reduction of high energy phosphates and tissue hypoxia. These changes take place in the cells and tissues in which the entry of glucose is not controlled by insulin, and particularly in poorly regulated diabetes patients in whom long-term vascular complications are more likely to occur. Several therapeutic intervention trials have been carried out, including assessment of optimal glucose regulation, the effect of dietary inclusion of calcium diphosphate and pharmaceutical intake of etidronate disodium (EHDP), but none of these modalities wholly overcome the problem. The potential therapeutic application of fructose-1, 6-diphosphate, however, which also acts as human bioenergy, holds a great deal of promise as an efficacious and well-tolerated therapeutic regimen.

Diabetes, glycemic control, and risk of hospitalization with pneumonia: a population-based case-control study.

OBJECTIVE: To examine whether diabetes is a risk factor for hospitalization with pneumonia and to assess the impact of A1C level on such risk. RESEARCH DESIGN AND METHODS: In this population-based, case-control study we identified patients with a first-time pneumonia-related hospitalization between 1997 and 2005, using health care databases in northern Denmark. For each case, 10 sex- and age-matched population control subjects were selected from Denmark's Civil Registration System. We used conditional logistic regression to compute relative risk (RR) for pneumonia-related hospitalization among subjects with and without diabetes, controlling for potential confounding factors. RESULTS: The study included 34,239 patients with a pneumonia-related hospitalization and 342,390 population control subjects. The adjusted RR for pneumonia-related hospitalization among subjects with diabetes was 1.26 (95% CI 1.21-1.31) compared with nondiabetic individuals. The adjusted RR was 4.43 (3.40-5.77) for subjects with type 1 diabetes and 1.23 (1.19-1.28) for subjects with type 2 diabetes. Diabetes duration >or=10 years increased the risk of a pneumonia-related hospitalization (1.37 [1.28-1.47]). Compared with subjects without diabetes, the adjusted RR was 1.22 (1.14-1.30) for diabetic subjects whose A1C level was <7% and 1.60 (1.44-1.76) for diabetic subjects whose A1C level was >or=9%. CONCLUSIONS: Type 1 and type 2 diabetes are risk factors for a pneumonia-related hospitalization. Poor long-term glycemic control among patients with diabetes clearly increases the risk of hospitalization with pneumonia.

Type 2 diabetes and pneumonia outcomes: a population-based cohort study.

OBJECTIVE: We sought to examine whether type 2 diabetes increases risk of death and complications following pneumonia and to assess the prognostic value of admission hyperglycemia. RESEARCH DESIGN AND METHODS: This was a population-based cohort study of adults with a first-time hospitalization for pneumonia between 1997 and 2004 (n = 29,900) in northern Denmark. Information on diabetes, comorbidity, laboratory findings, pulmonary complications, and bacteremia was obtained from medical databases. We used regression to compute adjusted relative risks of pulmonary complications, bacteremia, and mortality rate ratios (MRRs) within 90 days following hospitalization among patients with and without type 2 diabetes. The prognostic impact of admission hyperglycemia was studied in a subcohort (n = 13,574). RESULTS: In total, 2,931 (9.8%) pneumonia patients had type 2 diabetes. Mortality among diabetic patients was greater than that among other patients: 19.9 vs. 15.1% after 30 days and 27.0 vs. 21.6% after 90 days, respectively, corresponding to adjusted 30- and 90-day MRRs of 1.16 (95% CI 1.07-1.27) and 1.10 (1.02-1.18). Presence of type 2 diabetes did not predict pulmonary complications or bacteremia. Adjustment for hyperglycemia attenuated the association between type 2 diabetes and mortality. High glucose level on admission was a predictor of death among patients with diabetes and more so among those without diagnosed diabetes: adjusted 30-day MRRs for glucose level >or=14 mmol/l were 1.46 (1.01-2.12) and 1.91 (1.40-2.61), respectively. CONCLUSIONS: Type 2 diabetes and admission hyperglycemia predict increased pneumonia-related mortality.

Statin use and mortality within 180 days after bacteremia: a population-based cohort study.

OBJECTIVE: To examine the association between preadmission statin use and mortality among patients with bacteremia in a population-based setting. DESIGN: Observational study based on prospective registration of bacteremia episodes and mortality over a 6-yr period. SETTING: North Jutland County, Denmark (population, 500,000). PATIENTS: A total of 5,353 adult patients hospitalized with bacteremia from 1997 to 2002. Individuals treated with statins (n = 176) were identified by record-linkage with the County Prescription Database. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared mortality rates 0-30 and 31-180 days after bacteremia in patients with and without preadmission statin use, adjusted for gender, age group, level of comorbidity, alcohol-related conditions, use of immunosuppressive drugs and systemic antibiotics, and focus on infection. The 30-day mortality in statin users vs. nonusers was similar (20.0% vs. 21.6%, adjusted mortality rate ratio 0.93, 95% confidence interval 0.66-1.30). Among survivors after 30 days, however, statin therapy was associated with a substantially decreased mortality up until 180 days after the bacteremia (8.4% vs. 17.5%, adjusted mortality rate ratio 0.44, 95% confidence interval 0.24-0.80). This tendency toward similar short-term and decreased longer term mortality associated with statin use was observed consistently in both community-acquired and nosocomial bacteremia episodes and when analyses were restricted to patients with previous cardiovascular discharge diagnoses or diabetes. CONCLUSIONS: This study provides evidence against the hypothesis that statin use has an effect on short-term mortality after bacteremia. Statin use was, however, associated with a substantially decreased mortality between 31 and 180 days after bacteremia.

Diabetes mellitus as a risk and prognostic factor for community-acquired bacteremia due to enterobacteria: a 10-year, population-based study among adults.

Diabetes was examined as a risk factor and a prognostic factor for community-acquired bacteremia caused by Escherichia coli and other enterobacteria in a series of 1317 adult case patients, with 10 population control subjects per case. Persons with diabetes had a substantially increased risk for enterobacterial bacteremia (adjusted odds ratio, 2.9; 95% confidence interval, 2.4-3.4). Among patients with bacteremia, diabetes was also associated with a poorer prognosis.

Risk of community-acquired pneumococcal bacteremia in patients with diabetes: a population-based case-control study.

OBJECTIVE: We conducted this population-based case-control study to examine whether diabetes is associated with an increased risk of community-acquired pneumococcal bacteremia. RESEARCH DESIGN AND METHODS: We included 598 cases in the North Jutland County Bacteremia Registry, Denmark, with residence in the county and a first hospitalization for community-acquired pneumococcal bacteremia from 1992 through 2001. Ten sex- and age-matched population control subjects per case were selected, using a unique personal identifier. Diabetes was determined by record linkage with the County Prescription Database (for prescriptions for antidiabetic drugs) and the Hospital Discharge Registry (for previous hospitalizations with diabetes or diabetic complications). We performed conditional logistic regression to estimate odds ratios (ORs) for pneumococcal bacteremia among diabetic and nondiabetic persons, with adjustment for a range of comorbid diseases considered to be risk factors for pneumococcal infection. RESULTS: The crude OR for pneumococcal bacteremia in persons with diabetes was 1.9 (95% CI 1.4-2.6). After adjustment for comorbidity, the OR decreased to 1.5 (95% CI 1.1-2.0). The impact of diabetes on the risk for pneumococcal bacteremia was most pronounced in adults aged 40 years and younger (adjusted OR 4.2, 95% CI 1.1-16.7) and in persons without any other coexisting morbidity (adjusted OR 2.3, 95% CI 1.3-3.9). Under the assumptions that the association was causal and that there is a 5% overall prevalence of diabetes in our study population, 24 of 1,000 admissions with incident pneumococcal bacteremia may be attributed to diabetes. CONCLUSIONS: Diabetes seems to be a risk factor for community-acquired pneumococcal bacteremia.

Diabetes and outcome of community-acquired pneumococcal bacteremia: a 10-year population-based cohort study.

OBJECTIVE: Patients with diabetes may carry a higher case fatality of invasive pneumococcal infection compared with nondiabetic patients due to decreased immunity, risk of metabolic derangement, or angiopathy. We conducted a population-based cohort study to assess the impact of diabetes on mortality within 90 days in patients with pneumococcal bacteremia. RESEARCH DESIGN AND METHODS: All patients with community-acquired pneumococcal bacteremia in North Jutland County, Denmark, from January 1992 to December 2001 were retrieved from the County Bacteremia Registry. Using civil registry numbers, patients with diabetes were identified by record linkage with the County Prescription Database (for antidiabetic drugs) and the County Hospital Discharge Registry. Mortality within 90 days was determined through the Central Population Registry. Mortality rates were compared for diabetic and nondiabetic patients and adjusted for sex, age, and comorbidity. RESULTS: Among 628 patients aged >15 years with community-acquired pneumococcal bacteremia, 63 (10.0%) had diabetes. The diabetic patients were slightly older (median age 71.7 years) than the nondiabetic patients (67.0 years), and the proportion of patients with comorbidity was higher in the diabetic group (59 vs. 46%). Mortality in diabetic patients compared with nondiabetic patients was 11.1 vs. 16.5% after 30 days and 16.0 vs. 19.5% after 90 days, respectively. After adjustment for sex, age, and comorbidity, the mortality rate ratio for diabetic patients was 0.6 (95% CI 0.3-1.2) compared with the nondiabetic patients. CONCLUSIONS: Diabetic patients with community-acquired pneumococcal bacteremia appear not to have a higher case fatality than nondiabetic patients.

[Photographic screening for diabetic retinopathy in the county of North Jutland. The first fully digitalized telemedicine-screening clinic]. / Fotoscreening for diabetisk retinopati i Nordjyllands Amt. Landets første fuldt digitaliserede telemedicinske screeningsklinik.

Screening for diabetic retinopathy was introduced in Denmark in 1988. At present, screening is carried out in four of the 14 counties, thus being available to a minority of diabetic subjects. According to the WHO but also the National Board of Health, all diabetic patients should undergo screening for diabetic retinopathy. Not only does screening pay off in terms of preservation of vision, it is also cost-effective, as confirmed in the present study. The first fully digitized clinic for retinopathic screening in diabetic patients was recently introduced in the County of North Jutland. Preliminary results from this clinic indicate that all procedures can be handled in this fully digitized system. We therefore predict that fully digitized clinics for retinopathic screening will be introduced throughout Denmark in the future.

Diabetes patients' ability to estimate dietary carbohydrate content for use in a decision support system.

The aim of the study was to assess Type 1 (insulin-dependent) diabetic patients' ability to give valid information of the dietary carbohydrate (CHO) intake and to use the log function of a blood glucose meter for easy transfer of data to a decision support system. 18 Type 1 diabetic patients were enrolled from the Diabetes Outpatient Clinic at the Department of Endocrinology, Aalborg Hospital, Denmark. The patients were divided in subgroups of 4 or 5 patients and was instructed by the dietitian how to estimate the CHO intake and by the doctor in the use of the Accutrend DM blood glucose meter. During a 3 days data collecting period the patients were asked to keep a written diary containing a description of the meals, the estimated CHO intake, the insulin-dosage and the time of the meals and insulin injections, and to make 8-point blood glucose profiles daily. They were furthermore asked to use the log function of the Accutrend DM blood glucose meter. At the second visit the data were discussed individually with the patients and if there where more than three data points missing using the log function the patients were asked to repeat the data collection. A deviation of 10 grams or more, between the patient's and the dietician's estimate, was seen in 7.3% of the meals following the first instruction, in 1.0% of the meals following the second instruction, and in 2.4% of the meals following the third and last instruction. In conclusion, this study showed that Danish Type 1 diabetic patients were able to estimate the dietary carbohydrate content with a high degree of correctness, and to use the log function of the blood glucose meter, after a maximum of 3 hours of training.